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Antonio LA MARCA

Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

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Pubblicazioni

2023 - "Functional Outcomes and Quality of Life After Laparoscopic Nerve-Sparing Radical Treatment of Parametrial Deep Infiltrating Endometriosis" [Articolo su rivista]
Alboni, Carlo; Sampogna, Veronica; Airoud, Mirvana; Malmusi, Stefania; Farulla, Antonino; Colucci, Giuseppe; Camacho Mattos, Ludovica; Pecchi5, Annarita; Gaia, Giorgia; LA MARCA, Antonio
abstract

2023 - De novo variants and recombination at 4q35: hints for preimplantation genetic testing in facioscapulohumeral muscular dystrophy [Articolo su rivista]
Pini, Sara; Napoli, Floriana Maria; Tagliafico, Enrico; Marca, Antonio La; Bertucci, Emma; Salsi, Valentina; Tupler, Rossella
abstract

2023 - How adenomyosis changes throughout pregnancy: A retrospective cohort study [Articolo su rivista]
Bertucci, Emma; Sileo, Filomena G; Diamanti, Marialaura; Alboni, Carlo; Facchinetti, Fabio; La Marca, Antonio
abstract

Objective To study how adenomyosis changes during pregnancy and to possibly correlate these changes to maternal and fetal outcomes. Methods Retrospective exploratory cohort study including 254 women with a pre-conceptional/first-trimester scan to document adenomyosis and known obstetric outcome. If visible, adenomyosis signs were documented in each trimester and postpartum. Mann-Whitney U tests or chi(2) tests were used for continuous and categorical variables, respectively. Results A globular uterus was reported in 79% (n = 52) of women with adenomyosis in the first trimester, in 38% (n = 20) and 2% (n = 1) of women in the second and third trimesters, respectively, and postpartum in 77% (n = 34) of women. Asymmetrical thickening (n = 20, 30%) and cysts (n = 15, 23%) were only visible in 1st trimester. Adenomyosis was associated with miscarriage (odds ratio [OR] 5.9, 95% confidence interval [CI] 2.4-14.9, P < 0.001) also in normal conception only (OR 5.1, 95% CI 1.8-14.2, P = 0.002) or adjusting for maternal age (adjusted OR 5.9, 95% CI 2.3-15.2, P < 0.001). Gestational age at delivery was lower in adenomyosis (P = 0.004); the cesarean section rate was higher than in controls (OR 2.5, 95% CI 1.3-4.8, P = 0.007) also adjusting for age (adjusted OR 2.07, 95% CI 1.06-4.08, P = 0.035). Conclusions Signs of adenomyosis were visible but progressively disappeared in pregnancy; adenomyosis was associated with an increased risk of early miscarriage. Prospective studies are needed to confirm our results.

2023 - Treatment algorithms for high responders: What we can learn from randomized controlled trials, real-world data and models [Articolo su rivista]
Drakopoulos, Panagiotis; Khalaf, Yakoub; Esteves, Sandro C; Polyzos, Nikolaos P; Sunkara, Sesh K; Shapiro, Daniel; Rizk, Botros; Ye, Hong; Costello, Michael; Koloda, Yulia; Salle, Bruno; Lispi, Monica; D'Hooghe, Thomas; La Marca, Antonio
abstract

A high ovarian response to conventional ovarian stimulation (OS) is characterized by an increased number of follicles and/or oocytes compared with a normal response (10-15 oocytes retrieved). Ac-cording to current definitions, a high response can be diagnosed before oocyte pick-up when >18-20 follicles >= 11-12 mm are observed on the day of ovulation triggering; high response can be diagnosed after oocyte pick-up when >18-20 oocytes have been retrieved. Women with a high response are also at high risk of early ovarian hyper-stimulation syndrome (OHSS)/or late OHSS after fresh embryo transfers. Women at risk of high response can be diagnosed before stimulation based on several indices, including ovarian reserve markers (anti-Mullerian hormone [AMH] and antral follicle count [AFC], with cutoff values indicative of a high response in patients with PCOS of >3.4 ng/mL for AMH and >24 for AFC). Owing to the high proportion of high responders who are at the risk of developing OHSS (up to 30%), this educational article provides a framework for the identification and management of patients who fall into this category. The risk of high response can be greatly reduced through appropriate management, such as individualized choice of the gonadotropin starting dose, dose adjustment based on hormonal and ultrasound monitoring during OS, the choice of down-regulation protocol and ovulation trigger, and the choice between fresh or elective frozen embryo transfer. Appropriate management strategies still need to be defined for women who are predicted to have a high response and those who have an unex-pected high response after starting treatment.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).

2022 - Chronic endometritis in recurrent implantation failure: Use of prednisone and IVF outcome [Articolo su rivista]
Giulini, S.; Grisendi, V.; Sighinolfi, G.; Di Vinci, P.; Tagliasacchi, D.; Botticelli, L.; La Marca, A.; Facchinetti, F.
abstract

In recurrent implantation failure patients (RIF), the main criteria for diagnosis of chronic endometritis, is the presence of plasma cells CD138+ in endometrial biopsy. The aim of the present study was to evaluate if treatment with prednisone, in patients with RIF and chronic endometritis, improve IVF outcome. A retrospective study was performed between 2019 and 2020. A total of 27 patients with RIF and an endometrial biopsy positive for CD56+ cells were enrolled. The treatment with prednisone 10 mg per day is began together with controlled ovarian stimulation (COS). Among endometrial biopsies, 13 (48.14%) were positive also for CD138 cells, and an antibiotic treatment was added. In all patients, after therapy, in the subsequent IVF cycle, the clinical pregnancy rate was 25.9% and the live birth rate was 22.2%. Analysing pregnancies according to the percentage of CD 56 cells on endometrial biopsy, the live birth rate in the subgroup of patients with marked endometritis (defined by the presence of >10% CD56+cells) was 29.41%, while in the subgroup with mild endometritis (CD 56 >5% and <10%) was 10%. In the subgroup with mild endometritis with CD 138 positive the live birth was 25%, while in patients with CD 138 negative no live birth were observed. In patients with RIF the count of at least two cell types (CD 138 and CD 56 cells) on endometrial biopsies is advisable. Our study suggests a benefit of prednisone and antibiotic treatment on live birth rate in a subsequent IVF cycle.

2022 - Neither rationale nor scientific evidence exist to support that double stimulation is potentially unsafe [Articolo su rivista]
Casarini, Livio; Vaiarelli, Alberto; Cimadomo, Danilo; Santi, Daniele; Simoni, Manuela; Garcìa-Velasco, Juan Antonio; Alviggi, Carlo; La Marca, Antonio; Rienzi, Laura; Ubaldi, Filippo Maria
abstract

2022 - The negative impact of most relevant infections on fertility and Assisted Reproduction Technology [Articolo su rivista]
Carbone, Luigi; Conforti, Alessandro; LA Marca, Antonio; Cariati, Federica; Vallone, Roberta; Raffone, Antonio; Buonfantino, Cira; Palese, Michela; Mascia, Marika; DI Girolamo, Raffaella; Capuzzo, Martina; Esteves, Sandro C; Alviggi, Carlo
abstract

Infections may act with variable impact on the physiopathology of the reproductive organs, determining infertility or reducing the outcomes of assisted reproduction technology. The aim of this narrative review is to describe the existing evidence regarding the pathogens with a supposed or recognized role in reproductive medicine. Viral hepatitis, as HIV, can reduce sperm quality. Syphilis carries a risk of erectile dysfunction and increased endometrial thickness. Chlamydia is the main cause of pelvic inflammatory disease. In relation to Mycoplasma and Ureaplasma spp., only few species seem to show a correlation with infertility and poor in-vitro fertilization outcomes. There is evidence of a role for bacterial vaginosis in early pregnancy loss. HPV infection in males seems to determine infertility. Herpesviruses are more a risk for fetuses than for fertility itself. Zika virus is responsible for altered early embryo development and waiting to conceive is recommended in suspected or confirmed cases. The impact of SARS-CoV-2 is yet to be elucidated. Rubella and toxoplasmosis can provoke important congenital defects and therefore screening is mandatory before conception; a vaccine for Rubella is recommended. Further and well-designed studies are still needed to better elucidate the role of some infectious agents, to improve fertility and its treatments.

2022 - The putative roles of FSH and AMH in the regulation of oocyte developmental competence: From fertility prognosis to mechanisms underlying age-related subfertility [Articolo su rivista]
Buratini, J.; Dellaqua, T. T.; Dal Canto, M.; La Marca, A.; Carone, D.; Mignini Renzini, M.; Webb, R.
abstract

BACKGROUND: Fertility loss during female ageing is associated with increasing basal FSH and decreasing anti-Müllerian hormone (AMH) concentrations, together with compromised oocyte quality, presumably due to increased oxidative stress (OS) and DNA damage, as well as reduced metabolic and meiotic competences. Basal FSH and AMH circulatory concentrations have been broadly utilized as IVF success predictors, regardless of fluctuations in prognostic accuracy; basal FSH and AMH perform better in pre-advanced maternal age (AMA: >35 years) and AMA patients, respectively. The relationships between FSH and AMH intrafollicular levels and IVF outcomes suggest, nevertheless, that both hormones regulate oocyte competence, supporting the hypothesis that changes in FSH/AMH levels cause, at least in part, oocyte quality degradation during ageing. To understand the reasons behind the fluctuations in FSH and AMH prognostic accuracies and to clarify their participation in mechanisms determining oocyte competence and age-related subfertility, a deeper knowledge of the regulation of FSH and AMH intrafollicular signalling during the female reproductive lifespan, and of their effects on the cumulus-oocyte complex, is required. OBJECTIVE AND RATIONALE: An extensive body of information on the regulation of FSH and AMH intrafollicular availability and signalling, as well as on the control of folliculogenesis and oocyte metabolism, has been accumulated. However, these datasets have been explored within the relatively narrow boundaries of their specific subjects. Given the aforementioned gaps in knowledge and their clinical relevance, herein we integrate clinical and basic data, within a wide biological perspective, aiming to shed light on (i) the reasons for the variability in the accuracy of serum FSH and AMH as fertility markers, and on (ii) the potential roles of these hormones in mechanisms regulating oocyte quality, particularly those associated with ageing. SEARCH METHODS: The PubMed database encompassing the period between 1960 and 2021 was searched. Principal search terms were FSH, FSH receptor, AMH, oocyte, maternal age, cumulus, transzonal projections (TZPs), actin, OS, redox, reactive oxygen species, mitochondria, DNA damage, DNA repair, aneuploidy, spindle, meiosis, gene expression, transcription, translation, oocyte secreted factors (OSFs), cAMP, cyclic guanosine monophosphate, natriuretic peptide C, growth differentiation factor 9, bone morphogenetic protein 15 and fibroblast growth factor. OUTCOMES: Our analysis suggests that variations in the accuracy of fertility prognosis reflect a modest association between circulatory AMH levels and oocyte quality as well as increasing basal FSH inter-cycle variability with age. In addition, the basic and clinical data articulated herein support the hypothesis that increased intrafollicular FSH levels, as maternal age advances, may override the physiological protective influences of AMH and OSFs against excessive FSH signalling in cumulus cells. This would result in the disruption of oocyte homeostasis via reduced TZP-mediated transfer of cumulus-derived molecules essential for meiotic competence, gene expression, redox activity and DNA repair. WIDER IMPLICATIONS: In-depth data analysis, encompassing a wide biological perspective has revealed potential causative mechanisms of age-related subfertility triggered by alterations in FSH/AMH signalling during the female reproductive life. Insights from new mechanistic models arising from this analysis should contribute to advancing our comprehension of oocyte biology in humans and serve as a valuable reference for novel AMA subfertility treatments aimed at improving oocyte quality through the modulation of AMH/FSH action.

2021 - Developing a core outcome set for future infertility research: an international consensus development study [Articolo su rivista]
Duffy, J. M. N.; Alahwany, H.; Bhattacharya, S.; Collura, B.; Curtis, C.; Evers, J. L. H.; Farquharson, R. G.; Franik, S.; Giudice, L. C.; Khalaf, Y.; Knijnenburg, J. M. L.; Leeners, B.; Legro, R. S.; Lensen, S.; Vazquez-Niebla, J. C.; Mavrelos, D.; Mol, B. W. J.; Niederberger, C.; Ng, E. H. Y.; Otter, A. S.; Puscasiu, L.; Rautakallio-Hokkanen, S.; Repping, S.; Sarris, I.; Simpson, J. L.; Strandell, A.; Strawbridge, C.; Torrance, H. L.; Vail, A.; van Wely, M.; Vercoe, M. A.; Vuong, N. L.; Wang, A. Y.; Wang, R.; Wilkinson, J.; Youssef, M. A.; Farquhar, C. M.; Abou-Setta, A. M.; Aguilera, J. J.; Atanda, O. O. A.; Balkenende, E. M. E.; Barnhart, K. T.; Beebeejaun, Y.; Bhattacharya, S.; Black, M.; Bofill, M.; Chambers, G. M.; Chughtai, A. A.; Crosby, J. A.; Cuevas-Saiz, I.; D'Angelo, A.; Dubois, D. D.; Duckitt, K.; Encinas, C.; Fincham, A.; Gerval, M. -O.; Giang, N. H.; Gibreel, A.; Gingel, L. J.; Glanville, E. J.; Glujovsky, D.; Granne, I.; Griesinger, G.; Gupta, D.; Hamzehgardeshi, Z.; Hickey, M.; Hirsch, M.; Horton, M.; Hull, M. L.; Jain, S.; Jansa Perez, M.; Jones, C. A.; Jordan, V.; Kamath, M. S.; Kostova, E.; La Marca, A.; Khac Le, T.; Leader, A.; Li, J.; Loto, O. M.; Marks, K. L.; Mctavish, A. R.; Mills, D. J.; Nair, R. R.; Thi Phuong Nguyen, D.; Pacey, A. A.; Sadler, L. C.; Sagle, P.; Schwarze, J. -E.; Shapiro, H. M.; Showell, M.; Siristatidis, C. S.; Sood, A.; Tu Tran, C.; Votteler, E. L.; Wang, C. C.; Watson, A.; Yossry, M.
abstract

Study Question: Can a core outcome set to standardize outcome selection, collection, and reporting across future infertility research be developed? Summary Answer: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCT) and systematic reviews evaluating potential treatments for infertility. What is Known Already: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions, and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. Study Design, Size, Duration: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). Participants/Materials, Setting, Methods: Healthcare professionals, researchers, and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. Main Results and the Role of Chance: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin, and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth, and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. Limitations, Reasons for Caution: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition, and an arbitrary consensus threshold. Wider Implications of the Findings: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection, and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Ferility and Sterility, and Human Reproduction, have committed to implementing this core outcome set. Study Funding/Competing Interest(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund, and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. Hans Evers reports being the Editor Emeritus of Human Reproduction. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Annika Strandell reports consultancy fees from Guerbet. Ernest Ng reports research sponsorship from Merck. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. Trial Registration Number: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

2021 - Dose adjustment of follicle-stimulating hormone (FSH) during ovarian stimulation as part of medically-assisted reproduction in clinical studies: a systematic review covering 10 years (2007–2017) [Articolo su rivista]
Fatemi, H.; Bilger, W.; Denis, D.; Griesinger, G.; La Marca, A.; Longobardi, S.; Mahony, M.; Yin, X.; D'Hooghe, T.
abstract

Background: Individualization of the follicle-stimulating hormone (FSH) starting dose is considered standard clinical practice during controlled ovarian stimulation (COS) in patients undergoing assisted reproductive technology (ART) treatment. Furthermore, the gonadotropin dose is regularly adjusted during COS to avoid hyper- or hypo-ovarian response, but limited data are currently available to characterize such adjustments. This review describes the frequency and direction (increase/decrease) of recombinant-human FSH (r-hFSH) dose adjustment reported in clinical trials. Methods: We evaluated the proportion of patients undergoing ART treatment who received ≥ 1 r-hFSH dose adjustments. The inclusion criteria included studies (published Sept 2007 to Sept 2017) in women receiving ART treatment that allowed dose adjustment within the study protocol and that reported ≥ 1 dose adjustments of r-hFSH; studies not allowing/reporting dose adjustment were excluded. Data on study design, dose adjustment and patient characteristics were extracted. Point-incidence estimates were calculated per study and overall based on pooled number of cycles with dose adjustment across studies. The Clopper–Pearson method was used to calculate 95% confidence intervals (CI) for incidence where adjustment occurred in < 10% of patients; otherwise, a normal approximation method was used. Results: Initially, 1409 publications were identified, of which 318 were excluded during initial screening and 1073 were excluded after full text review for not meeting the inclusion criteria. Eighteen studies (6630 cycles) reported dose adjustment: 5/18 studies (1359 cycles) reported data for an unspecified dose adjustment (direction not defined), in 10/18 studies (3952 cycles) dose increases were reported, and in 11/18 studies (5123 cycles) dose decreases were reported. The studies were performed in women with poor, normal and high response, with one study reporting in oocyte donors and one in obese women. The median day that dose adjustment was permitted was Day 6 after the start of treatment. The point estimates for incidence (95% CI) for unspecified dose adjustment, dose increases, and dose decreases were 45.3% (42.7, 48.0), 19.2% (18.0, 20.5), and 9.5% (8.7, 10.3), respectively. Conclusions: This systematic review highlights that, in studies in which dose adjustment was allowed and reported, the estimated incidence of r-hFSH dose adjustments during ovarian stimulation was up to 45%.

2021 - Fertility preservation for genetic diseases leading to premature ovarian insufficiency (POI) [Articolo su rivista]
La Marca, A.; Mastellari, E.
abstract

Purpose: The current review aims to summarize the data available concerning the applicability of fertility preservation techniques to genetic conditions at risk of premature ovarian insufficiency (POI). Methods: A literature review through the PubMed Database was carried out. Results: About 10% of cases of POI is related to genetic diseases. The most frequent conditions associated with POI are Turner syndrome and fragile X pre-mutation; mutation of BRCA 1-2 genes and several other mutations and genetic syndromes have recently been highlighted, although they rarely occur. If a diagnosis is issued before POI onset, counseling on currently available fertility preservation techniques is advisable. In case of spontaneous menarche (this can occur variably depending on the mutation) established techniques like embryo or oocyte cryopreservation can be proposed, even if, in some cases, their effectiveness may be reduced by ovarian alterations connected to the mutation. Ovarian tissue cryopreservation has recently been defined as an established medical procedure for fertility preservation in young cancer patients and may be an option for prepubertal patients. However, it is still experimental in special populations with genetic diseases causing POI. New innovative experimental techniques, like in vitro maturation of immature oocytes (IVM) and vitro activation (IVA) of immature follicles on ovarian tissue, have shown limited but encouraging data and they will be probably available in the near future. For a correct risk-benefit evaluation, the following aspects should be considered: actual knowledge about the pathology-specific efficacy of the various techniques, the average age of onset of POI, the possible risks associated with the procedure in relation to the underlying pathology, the probability of spontaneous conception, as well as the health implications of a possible future pregnancy. Conclusions: Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI. Early diagnosis increases the chances to apply these techniques. No specific recommendations concerning fertility preservation for each genetic pathology are available, and clinicians should first counsel the patient and her relatives about known risks and benefits of the available techniques, both those established and those considered as experimental.

2021 - Greetings from the new Editor-in-Chief [Articolo su rivista]
La Marca, A
abstract

2021 - Letter to editor [Articolo su rivista]
Nelson, S. M.; La Marca, A.
abstract

2021 - Maternal age affects the relationship of basal FSH and anti-Müllerian hormone concentrations with post-ICSI/IVF live birth [Articolo su rivista]
Buratini, J.; Dal Canto, M.; De Ponti, E.; Brambillasca, F.; Brigante, C.; Gippone, S.; Mignini Renzini, M.; La Marca, A.
abstract

Research question: Does the association of basal FSH and anti-Müllerian hormone (AMH) concentrations with post-IVF/intracytoplasmic sperm injection (ICSI) live birth change with maternal age? Design: A total of 2003 IVF/ICSI patients were stratified according to basal FSH/AMH in concordant favourable (CF; AMH >1 ng/ml and FSH ≤10 IU/l), concordant unfavourable (CU; AMH ≤1 ng/ml and FSH >10 IU/l), discordant with favourable AMH (DFA) and discordant with favourable FSH (DFF) groups, as well as according to age in pre-advanced maternal age (pre-AMA; <35), AMA-1 (≥35, ≤37), AMA-2 (>37, ≤40) and AMA-3 (>40). IVF/ICSI outcomes were compared among CF, CU, DFA and DFF groups, and the association of basal FSH and AMH concentrations with live birth was tested by univariate and multivariate analysis in total, pre-AMA and AMA groups, separately. Results: Different outcome patterns were observed in discordant AMH/FSH groups from different age categories; favourable basal FSH concentrations were associated with higher delivery rates in pre-AMA patients, but with lower delivery rates in AMA groups. Within pre-AMA patients, DFF patients presented higher delivery rates but lower oocyte yield compared with DFA patients. In the univariate analysis, favourable AMH (P < 0.02) and oocyte yield (P < 0.002) were positively associated with live birth in all AMA groups. The multivariate analysis revealed that favourable basal FSH, but not AMH or oocyte yield, is associated with live birth in pre-AMA patients independently of other variables (P = 0.012). Conclusions: The relationship of basal FSH and AMH with IVF/ICSI success changes with maternal age; basal FSH better reflects clinical outcomes probably determined by oocyte quality in pre-AMA patients, while AMH better suits AMA patients.

2021 - No evidence for SARS-CoV-2 presence in ovarian tissue and peritoneal cavity from a COVID-19 positive woman undergoing urgent fertility preservation procedure [Articolo su rivista]
Seracchioli, Renato; Raimondo, Diego; Salucci, Paolo; LA Marca, Antonio; Vicenti, Rossella; Paradisi, Roberto; Lazzarotto, Tiziana
abstract

2021 - Perinatal and obstetric outcomes in singleton pregnancies following fresh versus cryopreserved blastocyst transfer: a meta-analysis [Articolo su rivista]
Conforti, A.; Picarelli, S.; Carbone, L.; La Marca, A.; Venturella, R.; Vaiarelli, A.; Cimadomo, D.; Zullo, F.; Rienzi, L.; Ubaldi, F. M.; Alviggi, C.
abstract

The transfer of cryopreserved blastocysts is increasing in IVF centres. However, little is known about the perinatal and obstetric outcomes of this procedure. In an attempt to further elucidate these issues, a systematic review and meta-analysis was conducted to compare cryopreserved transfer with fresh blastocyst embryo transfer. The results show that the risk of both preterm (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.80–0.99, P = 0.04) and low birthweight births (OR 0.82, 95% CI 0.68–0.99, P = 0.04) was significantly lower after cryopreserved blastocyst transfer than after fresh blastocyst transfer. The rate of large for gestational age births was significantly higher (OR 1.68, 95% CI 1.55–1.82, P < 0.00001) and the rate of small for gestational age births significantly lower (OR 0.59, 95% CI 0.54–0.65, P < 0.00001) after cryopreserved blastocyst transfer. The transfer of cryopreserved blastocysts was associated with a significantly lower risk of placental abruption (OR 0.58, 95% CI 0.40–0.83, P = 0.003) but a significantly higher risk of Caesarean section (OR 1.21, 95% CI 1.01–1.43, P = 0.03). In conclusion, the perinatal and obstetric outcomes associated with the transfer of cryopreserved blastocysts differ from those associated with fresh blastocyst transfer.

2021 - Pregnant woman infected by Coronavirus disease (COVID-19) and calcifications of the fetal bowel and gallbladder [Articolo su rivista]
Sileo, Fg; Tramontano, Al; Leone, C; Meacci, M; Gennari, W; Ternelli, G; La Marca, A; Lugli, L; Berardi, A; Facchinetti, F; Bertucci, E
abstract

COVID-19 was declared to be a pandemic due to the rapid increase of cases around the world, including the number of pregnant women. Data about vertical transmission of COVID-19 are still limited and controversial: in most cases, although a positive mother, the virus could not be isolated in amniotic fluid, cord blood, breast milk or neonatal throat swab in these patients. No data have been published about possible intrauterine sonographic signs of infection. A pregnant woman was diagnosed with SARS-CoV-2 at 35 t5 weeks of gestation and managed conservatively at home. At transabdominal ultrasound at 38+3 weeks, fetal bowel and gallbladder calcifications were noted. CMV and other infectious agents were ruled out an iterative caesarean section was performed at 38+5 weeks without complications. Placenta resulted negative for SARS-CoV-2; the umbilical cord blood sample was IgG positive and IgM negative as per maternal infection. The baby developed respiratory distress syndrome requiring endotracheal surfactant administration and nasal-CPAP for one day but nasopharyngeal swabs at birth and after 48 hours were SARS-CoV-2 negative. Neonatal abdominal ultrasound showed normal liver, acalculous gallbladder with mild parietal thickening. The baby was discharged in good conditions. Although gallbladder calcifications and echogenic bowel are highly suspicious of viral infection and were thought to be due to the vertical transmission of SARS-CoV-2, these findings were not corroborated by the results of our diagnostic tests; these sonographic findings might represent a false positive of fetal infection in mother affected by COVID-19 since vertical transmission appears to be rare.

2021 - Progestins for pituitary suppression during ovarian stimulation for ART: A comprehensive and systematic review including meta-analyses [Articolo su rivista]
Ata, B.; Capuzzo, M.; Turkgeldi, E.; Yildiz, S.; La Marca, A.
abstract

BACKGROUND: Progestins are capable of suppressing endogenous LH secretion from the pituitary. Progestins can be used orally and are less expensive than GnRH analogues. However, early endometrial exposure to progestin precludes a fresh embryo transfer (ET), but the advent of vitrification and increasing number of oocyte cryopreservation cycles allow more opportunities for using progestins for pituitary suppression. OBJECTIVE AND RATIONALE: This review summarizes: the mechanism of pituitary suppression by progestins; the effectiveness of progestins when compared with GnRH analogues and with each other; the effect of progestins on oocyte and embryo developmental potential and euploidy status; and the cost-effectiveness aspects of progestin primed stimulation. Future research priorities are also identified. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, the Web of Science and Scopus were screened with a combination of keywords related to ART, progesterone, GnRH analogue and ovarian stimulation, in various combinations. The search period was from the date of inception of each database until 1 April 2020. Only full text papers published in English were included. OUTCOMES: Overall, the duration of stimulation, gonadotrophin consumption and oocyte yield were similar with progestins and GnRH analogues. However, sensitivity analyses suggested that progestins were associated with significantly lower gonadotrophin consumption than the long GnRH agonist protocol (mean difference (MD) = -648, 95% CI = -746 to -550 IU) and significantly higher gonadotrophin consumption than the short GnRH agonist protocol (MD = 433, 95% CI = 311 to 555 IU). Overall, live birth, ongoing and clinical pregnancy rates per ET were similar with progestins and GnRH analogues. However, when progestins were compared with GnRH agonists, sensitivity analyses including women with polycystic ovary syndrome (risk ratio (RR) = 1.27, 95% CI = 1.06 to 1.53) and short GnRH agonist protocols (RR = 1.14, 95% CI = 1.02 to 1.28) showed significantly higher clinical pregnancy rates with progestins. However, the quality of evidence is low. Studies comparing medroxyprogesterone acetate, dydrogesterone and micronized progesterone suggested similar ovarian response and pregnancy outcomes. The euploidy status of embryos from progestin primed cycles was similar to that of embryos from conventional stimulation cycles. Available information is reassuring regarding obstetric and neonatal outcomes with the use of progestins. Despite the lower cost of progestins than GnRH analogues, the mandatory cryopreservation of all embryos followed by a deferred transfer may increase cost per live birth with progestins as compared to an ART cycle culminating in a fresh ET. WIDER IMPLICATIONS: Progestins can present an effective option for women who do not contemplate a fresh ET, e.g. fertility preservation, anticipated hyper responders, preimplantation genetic testing, oocyte donors, double stimulation cycles.

2021 - Sperm donation: an alternative to improve post-ICSI live birth rates in advanced maternal age patients [Articolo su rivista]
Mignini Renzini, M.; Dal Canto, M.; Guglielmo, M. C.; Garcia, D.; De Ponti, E.; La Marca, A.; Vassena, R.; Buratini, J.
abstract

STUDY QUESTION: Can sperm donation increase live birth rates following ICSI in advanced maternal age (AMA) patients? SUMMARY ANSWER: Sperm donation increases the live birth rate in AMA ICSI cycles. WHAT IS KNOWN ALREADY: In ICSI practice, sperm donation has been predominantly applied to overcome male infertility. The involvement of paternal age and lower sperm quality in the severe reduction in fertility observed in AMA patients remains to be clarified. STUDY DESIGN, SIZE, DURATION: Retrospective multicenter cohort study including data generated between 2015 and 2019 from 755 ICSI cycles achieving a fresh embryo transfer, of which 337 were first homologous cycles (normozoospermic partner sperm and homologous oocytes) and 418 were first sperm donation cycles (donor sperm and homologous oocytes). The association of sperm origin (partner vs donor) with live birth was assessed by multivariate analysis in non-AMA (<37 years, n = 278) and AMA (≥37 years, n = 477) patients, separately, including in the model all variables previously found to be associated with live birth in a univariate analysis (number of MII oocytes recovered, number of embryos transferred, and maternal age). ICSI outcomes were compared between sperm donation and homologous cycles in overall, non-AMA and AMA patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in three fertility clinics and included 755 Caucasian patients aged 24-42 years undergoing their first homologous or sperm donation ICSI cycle achieving a fresh embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: The multivariate analysis revealed that sperm donation was positively associated with the likelihood of a live birth independently of all other variables tested in AMA (P = 0.02), but not in non-AMA patients. Live birth, delivery, and miscarriage rates differed substantially between sperm donation and homologous AMA cycles; live birth and delivery rates were 70-75% higher (25.4% vs 14.5% and 22.5% vs 13.5%, respectively; P < 0.01), while miscarriage occurrence was less than half (18.0% vs 39.5%; P < 0.01) in sperm donation compared to homologous AMA cycles. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective nature, differences in patients profiles between sperm donation and homologous-control groups and varying proportion of donor cycles between fertility centers, although these variations have been controlled for in the statistical analysis. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that sperm donation increases live birth rates while reducing miscarriage occurrence in AMA patients, and thus may be a valid strategy to improve ICSI outcomes in this growing and challenging patient group.N/A.

2021 - Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study [Articolo su rivista]
Duffy, J. M. N.; Bhattacharya, S.; Bofill, M.; Collura, B.; Curtis, C.; Evers, J. L. H.; Giudice, L. C.; Farquharson, R. G.; Franik, S.; Hickey, M.; Hull, M. L.; Jordan, V.; Khalaf, Y.; Legro, R. S.; Lensen, S.; Mavrelos, D.; Mol, B. W.; Niederberger, C.; Ng, E. H. Y.; Puscasiu, L.; Repping, S.; Sarris, I.; Showell, M.; Strandell, A.; Vail, A.; van Wely, M.; Vercoe, M.; Vuong, N. L.; Wang, A. Y.; Wang, R.; Wilkinson, J.; Youssef, M. A.; Farquhar, C. M.; Abou-Setta, A. M.; Aguilera, J. J.; Alahwany, H.; Atanda, O. O. A.; Balkenende, E. M. E.; Barnhart, K. T.; Beebeejaun, Y.; Black, M.; Chambers, G. M.; Chughtai, A. A.; Crosby, J. A.; Cuevas-Saiz, I.; Curtis, C.; D'Angelo, A.; Dubois, D. D.; Duckitt, K.; Encinas, C.; Gerval, M. -O.; Giang, N. H.; Gibreel, A.; Gingel, L. J.; Glanville, E. J.; Glujovsky, D.; Granne, I.; Griesinger, G.; Gupta Repromed, D.; Hamzehgardeshi, Z.; Hirsch, M.; Horton, M.; Jain, S.; Jansa Perez, M.; Jones, C. A.; Kamath, M. S.; Knijnenburg, J.; Kostova, E.; La Marca, A.; Khac Le, T.; Leader, A.; Leeviers, B.; Li Chinese, J.; Loto, O. M.; Marks, K. L.; Martinez-Vazquez, R. M.; Mctavish, A. R.; Mills, D. J.; Nair, R. R.; Thi Phuong Nguyen, D.; Otter, A. -S.; Pacey, A. A.; Rautakallio-Hokkanen, S.; Sadler, L. C.; Sagle, P.; Schwarze, J. -E.; Shapiro, H. M.; Simpson, J. L.; Siristatidis, C. S.; Sood, A.; Strawbridge, C.; Torrance, H. L.; Tu Tran, C.; Votteler, E. L.; Wang, C. C.; Watson, A.; Yossry, M.
abstract

Study Question: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? Summary Answer: Consensus definitions for individual core outcomes, contextual statements, and a standardized reporting table have been developed. What is Known Already: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. Study Design, Size, Duration: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. Participants/Materials, Setting, Methods: Healthcare professionals, researchers, and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. Main Results and the Role of Chance: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines, and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. Limitations, Reasons for Caution: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. Wider Implications of the Findings: A minimum data set should assist researchers in populating protocols, case report forms, and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. Study Funding/Competing Interest(s): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund, and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Craig Niederberger reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. Ernest Ng reports research sponsorship from Merck. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their ‘traffic light’ system for infertility treatment ‘add-ons'. Lan Vuong reports consultancy and conference

2021 - T-shaped uterus: What has been done, what should be done [Articolo su rivista]
la Marca, A.; Imbrogno, M. G.; Gaia, G.; Alboni, C.
abstract

T-shaped uterus is a uterine malformation which has been suggested to be associated with poor reproductive performance. Over the years, different diagnostic methods have been used to determine the anatomical status of the female genital tract and to recognize any anomalies and the 3D-ultrasound is now considered the gold standard in diagnosing uterine anomalies. The importance of a correct diagnosis of the T-shaped uterus relates to the impact that such malformation has on female fertility. Although, to date, the prevalence does not seem to be so high, the fertility of the woman is reported to be somehow compromised by this uterine dysmorphism. Correcting the abnormal uterine morphology could be the main goal in order to optimize reproductive outcomes. To date, hysteroscopic correction of T-shaped uterus may be considered in patients with infertility, recurrent miscarriages or recurrent IVF failure. However, the absence of randomized controlled trials, multicentric data and the difficulty to state that metroplasty was the reason for improved outcome, make the data available inconclusive. More studies, led by an objective diagnosis, are urgently needed to understand the real impact of T-shaped uterus on the reproductive life of women and its effective prevalence in the population of infertile women.

2021 - The complex relationship between female age and embryo euploidy [Articolo su rivista]
LA Marca, Antonio; Capuzzo, Martina; Imbrogno, Maria G; Donno, Valeria; Spedicato, Giorgio A; Sacchi, Sandro; Minasi, Maria G; Spinella, Francesca; Greco, Pierfrancesco; Fiorentino, Francesco; Greco, Ermanno
abstract

BACKGROUND: Female age is the strongest predictor of embryo chromosomal abnormalities and has a nonlinear relationship with the blastocyst euploidy rate: with advancing age there is an acceleration in the reduction of blastocyst euploidy. Aneuploidy was found to significantly increase with maternal age from 30% in embryos from young women to 70% in women older than 40 years old. The association seems mainly due to chromosomal abnormalities occurring in the oocyte. We aimed to elaborate a model for the blastocyst euploid rate for patients undergoing in-vitro fertilization/intra cytoplasmic sperm injection (IVF/ICSI) cycles using advanced machine learning techniques.METHODS: This was a retrospective analysis of IVF/ICSI cycles performed from 2014 to 2016. In total, data of 3879 blastocysts were collected for the analysis. Patients underwent PGT-Aneuploidy analysis (PGT-A) at the Center for Reproductive Medicine of European Hospital (Rome, Italy) have been included in the analysis. The method involved wholegenome amplification followed by array comparative genome hybridization. To model the rate of euploid blastocysts. the data were split into a train set (used to fit and calibrate the models) and a test set (used to assess models' predictive performance). Three different models were calibrated: a classical linear regression; a gradient boosted tree (GBT) machine learning model; a model belonging to the generalized additive models (GAM).RESULTS: The present study confirms that female age, which is the strongest predictor of embryo chromosomal abnormalities, and blastocyst euploidy rate have a nonlinear relationship, well depicted by the GBT and the GAM models. According to this model, the rate of reduction in the percentage of euploid blastocysts increases with age: the yearly relative variation is -10% at the age of 37 and -30% at the age of 45. Other factors including male age, female and male Body Mass Index. fertilization rate and ovarian reserve may only marginally impact on embryo euploidy rateCONCLUSIONS: Female age is the strongest predictor of embryo chromosomal abnormalities and has a non-linear relationship with the blastocyst euploidy rate. Other factors related to both the male and female subjects may only minimally affect this outcome.

2021 - The interchangeability of two assays for the measurement of anti-Müllerian hormone when personalizing the dose of FSH in in-vitro fertilization cycles [Articolo su rivista]
La Marca, A.; Tolani, A. D.; Capuzzo, M.
abstract

Objective: Study the interchangeability of Roche Elecsys and Beckman Coulter Access anti-Müllerian Hormone (AMH) assays to select the gonadotropin starting dose in IVF cycles. Methods: Patients’ AMH was measured using both Elecsys and Access automated assays. AMH values were then used to calculate the FSH starting dose. The main outcome is the percentage of women that would have been stratified to a different dose of gonadotropin due to differences in AMH values from the two tests. Results: The Access assay systematically gives higher values compared with the Elecsys assay (slope = 0.88). For Follitropin Alfa, the difference in starting dose was > 15% in 2/113 patients, when Access AMH was used instead of Elecsys. For Follitropin Delta the difference in the starting dose was >15% in 21/113 patients when using Access AMH. When considering women with high ovarian reserve, only 4/51 would have received a Follitropin Delta dose that exceeded a 15% difference using Access AMH as a substitute for the Elecsys value. Conclusions: The use of the Roche Elecsys or Beckman Coulter Access leads to modest differences in AMH values, which seem to little affect the calibration of FSH dose used for ovarian stimulation.

2021 - Use of AMH in the Differential Diagnosis of Anovulatory Disorders Including PCOS [Articolo su rivista]
Capuzzo, M.; La Marca, A.
abstract

Since the historical use of gonadotrophin and estradiol levels to define the different anovulatory disorders has shown some limitations, the use of other markers such as anti-müllerian hormone (AMH) has been proposed. This review addresses the role of AMH in the differential diagnosis of anovulatory disorders, especially focusing on its value in the prognostic characterization of their severity. Current limitations and future clinical applications are discussed.

2020 - COVID-19 and assisted reproductive technology services: Repercussions for patients and proposal for individualized clinical management [Articolo su rivista]
Alviggi, C.; Esteves, S. C.; Orvieto, R.; Conforti, A.; La Marca, A.; Fischer, R.; Andersen, C. Y.; Buhler, K.; Sunkara, S. K.; Polyzos, N. P.; Strina, I.; Carbone, L.; Bento, F. C.; Galliano, D.; Yarali, H.; Vuong, L. N.; Grynberg, M.; Drakopoulos, P.; Xavier, P.; Llacer, J.; Neuspiller, F.; Horton, M.; Roque, M.; Papanikolaou, E.; Banker, M.; Dahan, M. H.; Foong, S.; Tournaye, H.; Blockeel, C.; Vaiarelli, A.; Humaidan, P.; Ubaldi, F. M.
abstract

The prolonged lockdown of health services providing high-complexity fertility treatments -as currently recommended by many reproductive medicine entities- is detrimental for society as a whole, and infertility patients in particular. Globally, approximately 0.3% of all infants born every year are conceived using assisted reproductive technology (ART) treatments. By contrast, the total number of COVID-19 deaths reported so far represents approximately 1.0% of the total deaths expected to occur worldwide over the first three months of the current year. It seems, therefore, that the number of infants expected to be conceived and born -but who will not be so due to the lockdown of infertility services- might be as significant as the total number of deaths attributed to the COVID-19 pandemic. We herein propose remedies that include a prognostic-stratification of more vulnerable infertility cases in order to plan a progressive restart of worldwide fertility treatments. At a time when preventing complications and limiting burdens for national health systems represent relevant issues, our viewpoint might help competent authorities and health care providers to identify patients who should be prioritized for the continuation of fertility care in a safe environment.

2020 - COVID-19: lessons from the Italian reproductive medical experience [Articolo su rivista]
La Marca, A.; Niederberger, C.; Pellicer, A.; Nelson, S. M.
abstract

2020 - Comparison of euploidy rates of blastocysts in women treated with progestins or GnRH antagonist to prevent the luteinizing hormone surge during ovarian stimulation [Articolo su rivista]
La Marca, A.; Capuzzo, M.; Sacchi, S.; Imbrogno, M. G.; Spinella, F.; Varricchio, M. T.; Minasi, M. G.; Greco, P.; Fiorentino, F.; Greco, E.
abstract

STUDY QUESTION: Does the prevalence of euploid blastocysts differ between patients treated with progestin primed ovarian stimulation (PPOS) and those treated with conventional ovarian stimulation? SUMMARY ANSWER: The numbers of blastocysts and euploid blastocysts per patient and the number of euploid embryos per injected oocyte are similar for patients undergoing progestin-primed ovarian stimulation and for those undergoing conventional ovarian stimulation with GnRH antagonist. WHAT IS KNOWN ALREADY: New approaches to ovarian stimulation have been developed based on the use of drugs administrable by mouth instead of via injections. Attention has been dedicated to progestins to block the LH surge. Previous data regarding the number of oocytes retrieved and the number of good-quality embryos generated in PPOS have demonstrated similar outcomes when compared to conventional ovarian stimulation, even if some concerns regarding the quality of embryos have been advanced. STUDY DESIGN, SIZE, DURATION: This is a prospective non-inferiority age-matched case-control study. In a period of 6 months, a total of 785 blastocysts from 1867 injected oocytes obtained from 192 patients were available for analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women undergoing IVF and preimplanation genetic testing (PGT) cycles were included. Forty-eight patients were treated with PPOS, and for each of them three age-matched historical controls (n = 144) treated with a GnRH antagonist protocol were selected. PGT was performed according to next-generation sequencing technology. MAIN RESULTS AND THE ROLE OF CHANCE: Basal characteristics were similar in the two groups; a substantial similarity of the main outcome measures in the two treatment groups has also been found. The rate of formation of euploid blastocysts per oocyte was 21% in both the two treatment groups. The percentage of patients with euploid embryos and the total number of euploid blastocysts per patient (median and interquartile range, IQR) in the PPOS group were 38.7 (25.5-52.9) and 2 (1.3-3.1), respectively. These figures were not significantly different in women treated with the GnRH antagonist protocol i.e. 42 (28-53.8) and 2.1 (1.3-2.9), respectively. LIMITATIONS, REASONS FOR CAUTION: This was a case-control study which may limit the reliability of the main findings. WIDER IMPLICATIONS OF THE FINDINGS: Our results encourage the use of PPOS, especially for oocyte donation, for fertility preservation and for patients in which total freezing of embryos is foreseen, for those expected to be high responders or candidates for preimplantation genetic testing. However, studies aiming to investigate the effect of PPOS on the live birth rate are warranted.None.

2020 - Correction to: SARS-CoV-2 testing in infertile patients: different recommendations in Europe and America (Journal of Assisted Reproduction and Genetics, (2020), 10.1007/s10815-020-01887-3) [Articolo su rivista]
La Marca, A.; Nelson, S. M.
abstract

Table 1 of the original version of this article unfortunately was incorrectly formatted in the pdf version, making it unclear for readers.

2020 - Developing a core outcome set for future infertility research: An international consensus development study [Articolo su rivista]
Duffy, J. M. N.; Alahwany, H.; Bhattacharya, S.; Collura, B.; Curtis, C.; Evers, J. L. H.; Farquharson, R. G.; Franik, S.; Giudice, L. C.; Khalaf, Y.; Knijnenburg, J. M. L.; Leeners, B.; Legro, R. S.; Lensen, S.; Vazquez-Niebla, J. C.; Mavrelos, D.; Mol, B. W. J.; Niederberger, C.; Ng, E. H. Y.; Otter, A. S.; Puscasiu, L.; Rautakallio-Hokkanen, S.; Repping, S.; Sarris, I.; Simpson, J. L.; Strandell, A.; Strawbridge, C.; Torrance, H. L.; Vail, A.; van Wely, M.; Vercoe, M. A.; Vuong, N. L.; Wang, A. Y.; Wang, R.; Wilkinson, J.; Youssef, M. A.; Farquhar, C. M.; Abou-Setta, A. M.; Aguilera, J. J.; Atanda, O. O. A.; Balkenende, E. M. E.; Barnhart, K. T.; Beebeejaun, Y.; Bhattacharya, S.; Mctavish, A. R.; Black, M.; Bofill, M.; Jordan, V.; Showell, M.; Chambers, G. M.; Chughtai, A. A.; Crosby, J. A.; Schwarze, J. -E.; Cuevas-Saiz, I.; D'Angelo, A.; Dubois, D. D.; Duckitt, K.; Encinas, C.; Fincham, A.; Gerval, M. -O.; Giang, N. H.; Le, T. K.; Nguyen, D. T. P.; Tran, C. T.; Gibreel, A.; Gingel, L. J.; Perez, M. J.; Mills, D. J.; Marks, K. L.; Glanville, E. J.; Glujovsky, D.; Granne, I.; Griesinger, G.; Gupta, D.; Hamzehgardeshi, Z.; Hickey, M.; Hirsch, M.; Horton, M.; Hull, M. L.; Jain, S.; Jones, C. A.; Shapiro, H. M.; Kamath, M. S.; Kostova, E.; La Marca, A.; Leader, A.; Li, J.; Loto, O. M.; Nair, R. R.; Pacey, A. A.; Sadler, L. C.; Sagle, P.; Siristatidis, C. S.; Sood, A.; Votteler, E. L.; Wang, C. C.; Watson, A.; Yossry, M.
abstract

STUDY QUESTION: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? SUMMARY ANSWER: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form.

2020 - ESHRE guideline: ovarian stimulation for IVF/ICSI† [Articolo su rivista]
Ovarian Stimulation, The Eshre Guideline Group On; Bosch, Ernesto; Broer, Simone; Griesinger, Georg; Grynberg, Michael; Humaidan, Peter; Kolibianakis, Estratios; Kunicki, Michal; La Marca, Antonio; Lainas, George; Le Clef, Nathalie; Massin, Nathalie; Mastenbroek, Sebastiaan; Polyzos, Nikolaos; Sunkara, Sesh Kamal; Timeva, Tanya; Töyli, Mira; Urbancsek, Janos; Vermeulen, Nathalie; Broekmans, Frank
abstract

What is the recommended management of ovarian stimulation, based on the best available evidence in the literature?

2020 - Elevated levels of nitrous dioxide are associated with lower AMH levels: A real-world analysis [Articolo su rivista]
La Marca, A.; Spaggiari, G.; Domenici, D.; Grassi, R.; Casonati, A.; Baraldi, E.; Trenti, T.; Simoni, M.; Santi, D.
abstract

STUDY QUESTION: Are there any associations between environmental pollutants and ovarian reserve, expressed by anti-Mullerian hormone (AMH) serum levels? SUMMARY ANSWER: In this first real-world approach to demonstrate the relationship between air pollutants and serum AMH levels, adverse associations were observed for nitrogen dioxide (NO2) but not with particulate matter. WHAT IS KNOWN ALREADY: In recent years, air pollution has emerged as a potential disrupter to the homeostasis of physiological hormones, possibly affecting human reproduction. Although the influence of age and smoking on AMH levels is largely accepted, the relationship between AMH and the environment has not currently been established. STUDY DESIGN, SIZE, DURATION: A longitudinal, observational, retrospective, real-world study was carried out, including all AMH measurements performed in a single laboratory from January 2007 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum AMH data were connected to patients' age and residential address, to include air pollution data after geo-localisation. The air pollution considered daily particulate matter (PM) and NO2 values. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1463 AMH measurements were collected (mean 1.94 ng/ml, median 0.90 ng/ml). AMH was inversely related to patients' age in women older than 25 years (adjusted R-squared 0.120, P < 0.001), but not in those younger than 25 years (adjusted R-squared 0.068, P = 0.055). AMH levels were inversely related to environmental pollutants, such as PM10 (Rho =-0.088, P = 0.001), PM2.5 (Rho =-0.062, P = 0.021) and NO2 (Rho =-0.111, P < 0.001). After subdividing the dataset into quartiles for PM10 and PM2.5, the influence of age on AMH serum levels was found to be a stronger influence than that exerted by PM (P = 0.833 and P = 0.370, respectively). On the contrary, considering NO2 quartiles, higher AMH levels were observed in third quartile compared to fourth quartile, even after adjustment for age (P = 0.028), indicating a stronger influence of NO2 exposure on AMH serum levels. Considering an AMH cut-off of 0.3 ng/ml, a significant higher frequency of women with severe ovarian reserve reduction in the fourth quartile was shown only for NO2 (P = 0.010). LIMITATIONS, REASONS FOR CAUTION: Several limitations should be underlined, such as the lack of information about work and life habits of each patient and the retrospective nature of the analysis performed on real-world data. WIDER IMPLICATIONS OF THE FINDINGS: Although the genetic component is highly predictive for defining the ovarian reserve at birth, potentially modifiable environmental factors could influence the rate of decline in AMH and ovarian reserve during adulthood. STUDY FUNDINGCOMPETING INTEREST(S): Authors have neither funding nor competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

2020 - Genetic conditions impairing female fertility [Articolo su rivista]
Mastellari, E.; La Marca, A.
abstract

Fertility represents a biological and psychological requirement for women. Some genetic diseases represent a rare cause of infertility, being responsible for 10% of cases of premature ovarian insufficiency. Among these, the most frequent and also those most studied by researchers are Turner Syndrome - due to a karyotype abnormality of the X chromosome pair - and the presence of fragile X premutation (FMR1). To exclude these conditions the diagnostic workup for non-iatrogenic premature ovarian insufficiency (POI) involves the performance of a karyotype analysis and the search for the FMR1 gene mutation, as well as the search for the presence of Y-chromosomal material. However, several other mutations and genetic syndromes associated with POI development have recently been highlighted, although they occur rarely, such as the GALT gene mutation in galactosemia or the FOXL2 gene mutation in BPES and many others, and further autosomal genetic testing are indicated if clinical suspicion is present. Mutations of BRCA 1 and 2 genes, make patients at genetically determined high risk of developing early ovarian or breast cancer and of getting POIs for the treatments they must undergo to prevent it (prophylactic bilateral oophorectomy) or treat it (chemotherapy). The management of impaired fertility is not less important than that of other syndromic manifestations for the quality of life of patients. Few data are available regarding the efficiency of cryopreservation of reproductive material (oocytes, embryos or ovarian tissue) in order to preserve fertility in this particular subgroup of patients, but certainly it represents a promising chance and a hope for the future.

2020 - Gonadotrophins modulate cell death-related genes expression in human endometrium [Articolo su rivista]
Sacchi, S.; Sena, P.; Addabbo, C.; Cuttone, E.; La Marca, A.
abstract

Gonadotrophins exert their functions by binding follicle-stimulating hormone receptor (FSHR) or luteinizing hormone and human chorionic gonadotropin receptor (LHCGR) present on endometrium. Within ovaries, FSH induces autophagy and apoptosis of granulosa cells leading to atresia of non-growing follicles, whereas hCG and LH have anti-apoptotic functions. Endometrial cells express functioning gonadotrophin receptors. The objective of this study was to analyze the effect of gonadotrophins on physiology and endometrial cells survival. Collected endometria were incubated for 48 or 72 h with 100 ng/mL of recombinant human FSH (rhFSH), recombinant human LH (rhLH) or highly purified hCG (HPhCG) alone or combined. Controls omitted gonadotrophins. The effect of gonadotrophins on cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1), hypoxia inducible factor 1α (HIF1A), and cell-death-related genes expression was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Immunohistochemistry for microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B) and apoptotic protease activating factor 1 (APAF-1) was performed. Gonadotrophins are able to modulate the endometrial cells survival. FSH induced autophagy and apoptosis by increasing the relative expression of MAP1LC3B and FAS receptor. In FSH-treated samples, expression of apoptosis marker APAF-1 was detected and co-localized on autophagic cells. hCG and LH does not modulate the expression of cell-death-related genes while the up-regulation of pro-proliferative epiregulin gene was observed. When combined with FSH, hCG and LH prevent autophagy and apoptosis FSH-induced. Different gonadotrophins specifically affect endometrial cells viability differently: FSH promotes autophagy and apoptosis while LH and hCG alone or combined with rhFSH does not.

2020 - Identification of research priorities in infertility and assisted reproduction: an international, multicentre study [Articolo su rivista]
Garcia, D.; Brazal, S.; Lindenberg, F.; Toft, E.; La Marca, A.; Borras, R.; Rodrigues Lorenzon, A.; Barbour Chehin, M.; Silva, L.; Leme Alves da Motta, E.; Ripero, M.; Madero, J. I.; Mello Marinho, R.; Araujo de Oliveira, C.; Junqueira Caetano, J. P.; Bolivar, A.; Rodriguez, A.; Vassena, R.
abstract

Research question: What are the main research interests among patients of assisted reproductive technologies (ART)? Design: Cross-sectional study consisting of an anonymous online survey sent to 2112 patients from eight centres in four countries in 2018. Patients were asked to identify research questions relevant to them in the field of infertility and ART. Answers were categorized into topics and ranked by frequency. A long list of the top 30 research topics was extracted from the aggregate results, from which a short list of the top 10 research topics was created. Ten research questions were finally formulated. Results: A total of 945 responses were analysed. Main interests were side-effects, success rates, infertility prevention and emotional support. The 10 research questions were: 1. What are the side-effects of drugs used in ART treatments? (51.6%). 2. What are the most effective methods to cope with infertility from the psychological point of view? (35.7%). 3. What effects could diet have on fertility? (25.9%). 4. What are ART success rates per clinical profile? (24.8%). 5. Are there some habits and lifestyle factors that could prevent infertility? (20.0%). 6. What are the long-term risks associated with ART in mother and child? (18.5%). 7. Are alternative therapies such as acupuncture, yoga and meditation effective to treat/prevent infertility? (18.5%). 8. What is the impact of exercise on fertility? (15.4%). 9. How does oocyte quantity and quality affect fertility? (9.5%). 10. What are the genetic patterns or hereditary conditions causing/related to infertility? (9.5%). Conclusions: Researchers and clinicians should keep in mind that, in addition to success rates and safety, patients greatly value research into causes, prevention and emotional aspects of infertility.

2020 - Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival [Articolo su rivista]
Casarini, L.; Lazzaretti, C.; Paradiso, E.; Limoncella, S.; Riccetti, L.; Sperduti, S.; Melli, B.; Marcozzi, S.; Anzivino, C.; Sayers, N. S.; Czapinski, J.; Brigante, G.; Poti, F.; La Marca, A.; De Pascali, F.; Reiter, E.; Falbo, A.; Daolio, J.; Villani, M. T.; Lispi, M.; Orlando, G.; Klinger, F. G.; Fanelli, F.; Rivero-Muller, A.; Hanyaloglu, A. C.; Simoni, M.
abstract

Molecular Biology; Female Reproductive Endocrinology; Endocrine Regulation

2020 - Polycystic ovary syndrome, amenorrhea and the diagnostic role of anti-Müllerian hormone [Articolo su rivista]
Capuzzo, M.; Donno, V.; LA MARCA, A.
abstract

The differential diagnosis of anovulatory disorders is actually based on serum gonadotrophin and estradiol levels. However, several other markers have been proposed. The purpose of this review was to underline the role of anti-Müllerian hormone (AMH) as a possible marker in differential diagnosis of the anovulatory diseases and its use as a predictive marker of prognosis. In this article we discuss clinical and experimental evidences actually existing in literature and we suggest new potential clinical application of AMH.

2020 - SARS-CoV-2 testing in infertile patients: different recommendations in Europe and America [Articolo su rivista]
La Marca, A; Nelson, Sm.
abstract

2020 - Standardizing definitions and reporting guidelines for the infertility core outcome set: An international consensus development study [Articolo su rivista]
Duffy, J. M. N.; Bhattacharya, S.; Bofill, M.; Collura, B.; Curtis, C.; Evers, J. L. H.; Giudice, L. C.; Farquharson, R. G.; Franik, S.; Hickey, M.; Hull, M. L.; Jordan, V.; Khalaf, Y.; Legro, R. S.; Lensen, S.; Mavrelos, D.; Mol, B. W.; Niederberger, C.; Ng, E. H. Y.; Puscasiu, L.; Repping, S.; Sarris, I.; Showell, M.; Strandell, A.; Vail, A.; van Wely, M.; Vercoe, M.; Vuong, N. L.; Wang, A. Y.; Wang, R.; Wilkinson, J.; Youssef, M. A.; Farquhar, C. M.; Abou-Setta, A. M.; Aguilera, J. J.; Alahwany, H.; Atanda, O. O. A.; Balkenende, E. M. E.; Barnhart, K. T.; Beebeejaun, Y.; Black, M.; Repromed, D. G.; Chambers, G. M.; Chughtai, A. A.; Crosby, J. A.; Schwarze, J. -E.; Cuevas-Saiz, I.; Curtis, C.; D'Angelo, A.; Dubois, D. D.; Duckitt, K.; Encinas, C.; Gerval, M.; Giang, N. H.; Le, T. K.; Nguyen, D. T. P.; Tran, C. T.; Gibreel, A.; Gingel, L. J.; Perez, M. J.; Marks, K. L.; Mills, D. J.; Glanville, E. J.; Glujovsky, D.; Granne, I.; Griesinger, G.; Hamzehgardeshi, Z.; Hirsch, M.; Horton, M.; Jain, S.; Jones, C. A.; Shapiro, H. M.; Kamath, M. S.; Knijnenburg, J.; Kostova, E.; La Marca, A.; Leader, A.; Leeviers, B.; Chinese, J. L.; Loto, O. M.; Martinez-Vazquez, R. M.; Mctavish, A. R.; Nair, R. R.; Otter, A. -S.; Pacey, A. A.; Rautakallio-Hokkanen, S.; Sadler, L. C.; Sagle, P.; Simpson, J. L.; Siristatidis, C. S.; Sood, A.; Strawbridge, C.; Torrance, H. L.; Votteler, E. L.; Wang, C. C.; Watson, A.; Yossry, M.
abstract

STUDY QUESTION: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? SUMMARY ANSWER: Consensus definitions for individual core outcomes, contextual statements and a standardized reporting table have been developed. WHAT IS KNOWN ALREADY: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. STUDY DESIGN, SIZE, DURATION: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. MAIN RESULTS AND THE ROLE OF CHANCE: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. WIDER IMPLICATIONS OF THE FINDINGS: A minimum data set should assist researchers in populating protocols, case report forms and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. E.H.Y.N. reports research sponsorship from Merck. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their ‘traffic light’ system for infertility treatment ‘add-ons’. N.L.V. reports consultancy and conference fees from Ferring,

2020 - Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis [Articolo su rivista]
La Marca, Antonio; Busani, Stefano; Donno, Valeria; Guaraldi, Giovanni; Ligabue, Guido; Girardis, Massimo
abstract

Can the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus induce testis damage and dysfunction?

2020 - Testing for SARS-CoV-2 (COVID-19): a systematic review and clinical guide to molecular and serological in-vitro diagnostic assays [Articolo su rivista]
La Marca, A.; Capuzzo, M.; Paglia, T.; Roli, L.; Trenti, T.; Nelson, S. M.
abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease 2019 (COVID-19) pandemic has demanded rapid upscaling of in-vitro diagnostic assays to enable mass screening and testing of high-risk groups, and simultaneous ascertainment of robust data on past SARS-CoV-2 exposure at an individual and a population level. To meet the exponential demand in testing, there has been an accelerated development of both molecular and serological assays across a plethora of platforms. The present review discusses the current literature on these modalities, including nucleic acid amplification tests, direct viral antigen tests and the rapidly expanding laboratory-based and point of care serological tests. This suite of complementary tests will inform crucial decisions by healthcare providers and policy makers, and understanding their strengths and limitations will be critical to their judicious application for the development of algorithmic approaches to treatment and public health strategies.

2020 - The performance of the Elecsys® anti-Müllerian hormone assay in predicting extremes of ovarian response to corifollitropin alfa [Articolo su rivista]
Neves, A. R.; Blockeel, C.; Griesinger, G.; Garcia-Velasco, J. A.; Marca, A. L.; Rodriguez, I.; Drakopoulos, P.; Alvarez, M.; Tournaye, H.; Polyzos, N. P.
abstract

Research question: What is the performance of anti-Müllerian hormone (AMH) as measured by the Elecsys® AMH assay in predicting ovarian response in women treated with 150 µg corifollitropin alfa (CFA)? Design: Multicentre, prospective study conducted between December 2015 and April 2018. Women were aged 18–43 years, had regular menstrual bleeding, a body mass index of 17–35 kg/m2 and weighed 60 kg or over. Exclusion criteria: previous oophorectomy, history of ovarian hyperstimulation syndrome, a previous IVF and intracytoplasmic sperm injection cycle producing over 30 follicles measuring 11 mm or wider, basal antral follicle count (AFC) over 20 or polycystic ovarian syndrome. All women were treated with 150 μg CFA followed by recombinant FSH (150–300 IU/day) in a fixed gonadotrophin releasing hormone antagonist protocol. Results: Of the 219 patients enrolled, 22.8% had low ovarian response (three or fewer oocytes), 66.2% had normal response and 11% had high ovarian response (15 or more oocytes). The AMH and AFC presented an area under the curve of 0.883 (95% CI 0.830 to 0.936) and 0.879 (95% CI 0.826 to 0.930), respectively, for low ovarian response; and an AUC of 0.865 (95% CI 0.793 to 0.935) and 0.822 (95% CI 0.734 to 0.909) for high ovarian response. An AMH cut-off of 1.0 ng/ml provided a sensitivity of 92.0% and a specificity of 66.9% in the prediction of low ovarian response; a cut-off of 2.25 ng/ml predicted high ovarian response with a sensitivity of 54.2% and a specificity of 91.8%. Conclusions: The automated Elecsys® AMH assay predicts ovarian response in a CFA antagonist protocol. The best predictors of ovarian response in CFA-treated patients were AMH and AFC.

2020 - The predicted probability of live birth in In Vitro Fertilization varies during important stages throughout the treatment: analysis of 114,882 first cycles [Articolo su rivista]
La Marca, A.; Capuzzo, M.; Donno, V.; Mignini Renzini, M.; Giovane, C. D.; D'Amico, R.; Sunkara, S. K.
abstract

Research Question: How much the variability in patients’ response during in vitro fertilization (IVF) may add to the initial predicted prognosis based only on patients’ basal characteristics? Design: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). Data involving 114,882 stimulated fresh IVF cycles were retrospectively analyzed. Logistic regression was used to develop the models. Results: Prediction of live birth was feasible with moderate accuracy in all of the three models; discrimination of the model based only on basal patients’ characteristics (AUROC 0.61) was markedly improved adding information of number of embryos (AUROC 0.65) and, mostly, number of oocytes (AUROC 0.66). Conclusions: The addition to prediction models of parameters such as the number of embryos obtained and especially the number of oocytes retrieved can statistically significantly improve the overall prediction of live birth probabilities when based on only basal patients’ characteristics. This seems to be particularly true for women after the first IVF cycle. Since ovarian response affects the probability of live birth in IVF, it is highly recommended to add markers of ovarian response to models based on basal characteristics to increase their predictive ability.

2019 - A novel transnational fresh oocyte donation (TOD) program based on transport of frozen sperm and embryos [Articolo su rivista]
La Marca, A.; Dal Canto, M.; Buccheri, M.; Jasonni, Valerio; Mignini Renzini, M.; Da Col Rodriguez, Giorgio Alberto; Vassena, R.
abstract

STUDY QUESTION: What is the clinical efficacy of an oocyte donation program based on the transportation of frozen semen and embryos between two countries? SUMMARY ANSWER: The transnational oocyte donation program is efficient and reliable and it could provide a first-line strategy to overcome the lack of donors in some countries. WHAT IS KNOWN ALREADY: While there is increasing need for donated oocytes, in many countries the availability of donors is still insufficient to cover the therapeutic demands, and patients are referred abroad for treatment. Since embryo cryopreservation is reliable and efficient, we propose a strategy based on frozen embryos instead of frozen oocytes to satisfy the increasing demand for cross border oocyte donation. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study including 630 patients treated from December 2015 to July 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women were treated with elective vitrified-thawed embryo shipping and embryo transfer (ET) between two IVF clinics, one in Spain and one in Italy. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 2617 embryos were created for the 630 patients and the survival rate after warming was 98.5%. After the first ET the live birth rate (LBR) was 30.6%. In 476 patients (75.5%), embryos were transferred at the cleavage stage (Day 2 or 3) and the LBR was 29.2%. Vitrified blastocysts were available for 154 patients (24.5%) and the LBR was 35%. Among patients who did not achieve a pregnancy after the first frozen ET (FET), 92.5% had at least one frozen embryo for successive procedures. 213 patients underwent a second FET. The LBR at the second FET was 30%. The cumulative LBR at the end of the observation period was 39.3%. LIMITATIONS, REASONS FOR CAUTION: The study design was retrospective. A direct comparison with vitrified oocyte donors cycle and subsequent fresh ET would have permitted to compare this strategy versus the current standard based on vitrified gametes. WIDER IMPLICATIONS OF THE FINDINGS: The LBR found in our study is more than acceptable and seems to be higher than what reported with vitrified oocytes. The transnational fresh oocyte donation program may have several advantages over the shipment of vitrified oocytes: similarly to the fresh oocyte donation program it allows for personalized care in oocyte recipient, which is provided by assigning a flexible number of oocytes, and at the same time it maintains the benefit of a frozen ART program permitting scheduling flexibility. The TOD program is efficient and may be proposed as a first-line strategy for distance and inter-countries oocyte donation programs.None.

2019 - Evaluation of the treatment with D-chiroinositol on levels of oxidative stress in PCOS patients [Articolo su rivista]
De Leo, V.; La Marca, A.; Cappelli, V.
abstract

Recent studies on the pathophysiology of infertility have shown that oxidative stress (OS) can be one of the causal factors. The OS is, by definition, an imbalance between the production of reactive oxygen species and antioxidant defense systems. It seems that oxidative stress plays an important role in almost all phases of human reproduction. In fact, reactive oxygen species are involved in the modulation of a large spectrum of reproductive functions such as oocyte maturation, ovarian steroidogenesis, corpus luteum functions and are involved in the processes of fertilization, embryo development and pregnancy, but also in some diseases that cause infertility. Polycystic ovary syndrome (PCOS) has recently been associated with increased oxidative stress, often put in relation to the syndrome's typical metabolic disorder. Inositol is an intracellular mediator of insulin, currently much used as a therapeutic agent in PCOS. While its main action takes place via insulin sensitization, little is known about the possible effects of other disorders, such as oxidative stress, associated with PCOS. Purpose of study was therefore to assess the effect of D-chiro-inositol on the state of oxidative stress in the follicular fluid of women with PCOS. Materials and methods. Follicular fluids were obtained from women who have turned to the Center for Diagnosis and Treatment of Sterility of Obstetrics and Gynecology of the University Hospital of Siena and Modena diagnosed with PCOS. The women were treated with D-chiro-inositol (500 mg × 2 per day) for 3 months before being subjected to cycles of in vitro fertilization. The state of oxidative stress was measured by marking of free thiol groups of proteins in the follicular fluid with 3-(N-maleimidopropionyl)-biocytin. Results. In our study we obtained a lesser presence of free thiol protein groups equal to 77.8% in the follicular fluid of women with PCOS not treated with D-chiro-inositol, compared to patients who instead have carried out such treatment. Conclusions. These results suggest that in PCOS women there is an increase of the oxidation of thiol groups of proteins follicular, correlated to a progressive increase of the oxidative stress and that the administration of D-chiro-inositol in patients with this disease seems to reduce the oxidation of thiol groups.

2019 - From a circle to a sphere: the ultrasound imaging of ovarian follicle with 2D and 3D technology [Articolo su rivista]
Re, Claudia; Mignini Renzini, Mario; Rodriguez, Amelia; Dal Canto, Mariabeatrice; Buccheri, Matteo; Sacchi, Sandro; Bartolucci, Silvia; Fadini, Rubens; La Marca, Antonio
abstract

Ultrasound follicular count (antral follicle count, AFC) is a necessary tool for measuring ovarian reserve, whereby the estimated number of follicles responsive to FSH can predict the number of oocytes retrieved in IVF cycles and may be the basis for individualized ovarian stimulation therapy. Advances in the ultrasound technology have recently lead to the improvement in resolution and quality of the image. Moreover the automatic measurements of follicular diameter by using some specific 3D software seems associated to several advantages when compared to the 2D technique. Examination time is reduced because the ultrasound scan data are stored and can be analyzed in detail at a later time. These data can be reconstructed in any plane, regardless of the original scan plane facilitating the detailed analysis. Another advantage is that this new technique reduces the operator's influence on scan interpretation and objectivity; therefore, interobserver variability is reduced. Using follicular volume obtained with sono AVC as the measure of follicular growth combined with volume-based criteria for the hCG triggering may in the future improve the treatment outcome compared to that achieved with conventional monitoring with follicular diameter. Better knowledge in this area could be helpful to optimize IVF outcome, by refining ovarian stimulation protocols and obtain high quality oocytes.

2019 - Future perspectives of PoseidOn stratification for clinical practice and research [Articolo su rivista]
Humaidan, P.; Marca, A. L.; Alviggi, C.; Esteves, S. C.; Haahr, T.
abstract

A total of 50% of patients undergoing IVF treatment has previously been estimated to fulfill the POSEIDON classification criteria; importantly, although the reproductive prognosis differs between patients, POSEIDON patients share the same characteristic of a low ovarian response to exogenous gonadotropin stimulation—independent of age. POSEIDON patients require focused attention as regards ovarian stimulation in order to increase the chances of having at least one euploid blastocyst for transfer—the success criterion for stimulation set forth by the POSEIDON Group. The key to success seems to be individualization in all steps of treatment. In this perspective article we discuss the future impact of the POSEIDON stratification for daily clinical practice as well as for research.

2019 - Gene expression profiles of human granulosa cells treated with bioequivalent doses of corifollitropin alfa (CFA) or recombinant human follicle-stimulating hormone (recFSH) [Articolo su rivista]
Sacchi, Sandro; Tenedini, Elena; Tondelli, Debora; Parenti, Sandra; Tagliasacchi, Daniela; Xella, Susanna; Marsella, Tiziana; Tagliafico, Enrico; La Marca, Antonio
abstract

Using recombinant DNA technologies, a chimeric gene containing the coding sequences of follicle stimulating hormone (FSH) β-subunit and C-terminal peptide of the human chorionic gonadotrophin (hCG) β-subunit have been designed to generate a new gonadotrophin named corifollitropin alfa (CFA). CFA has longer elimination half-life and slower rate of absorption compared with FSH, which makes CFA a long-acting hormone employed as a substitute of the recombinant FSH (recFSH) in the controlled ovarian stimulation (COS). The purpose of this study is to compare the gene expression profiles elicited by bioequivalent doses of CFA or recFSH in primary cultures of human granulosa cells (hGCs). Gonadotrophins exert their functions by binding FSH receptors (FSHRs), activating signaling pathways that increase the cyclic adenosine monophosphate (cAMP) intracellular content. Bioequivalence has been defined as the dose/duration of gonadotrophin treatment able to promote the same amount of intracellular cAMP. hGCs were treated with different doses of either gonadotrophin and the cAMP was measured after different incubation times to establish the bioequivalence. Results obtained by comparing the bioequivalent treatments, showed that CFA is more effective than recFSH in inducing aromatase gene expression after 6 and 24 h from the initial stimulation in agreement with its long-acting characteristic.

2019 - Ovarian antimüllerian hormone system: more complex than was thought [Articolo su rivista]
La Marca, A.
abstract

2019 - Ovarian reserve markers to identify poor responders in the context of poseidon classification [Articolo su rivista]
Grisendi, V.; Mastellari, E.; La Marca, A.
abstract

It is well-known that poor ovarian reserve is a cause of infertility, poor response to gonadotrophin stimulation and poor success rate after in vitro fertilization (IVF) cycles. Some years ago a consensus was elaborated on precise criteria which can lead to a correct identification of poor responders (the Bologna criteria). More recently, the POSEIDON group has proposed a new stratified classification of patients with low prognosis, also with the aim of providing clinical indications for the management of these patients. A literature search was carried out for studies that investigated the ability of ovarian reserve markers, in particular AMH and AFC, to predict poor ovarian response in IVF cycles; secondly, studies regarding the Bologna criteria and their prognostic value were analyzed and available literature on POSEIDON classification was reported. The most recent markers of ovarian reserve (serum AMH and ultrasound AFC) have shown to provide a direct and accurate measurement of ovarian follicle pool. These markers have generally shown comparable predictive power for ovarian response and a number of retrieved oocytes in IVF cycles. “Abnormal ovarian reserve test” is a very important parameter both in the Bologna criteria and in the POSEIDON classification. Several studies have already been published about the reproductive outcome of patients defined as poor responders according to the ESHRE Bologna criteria: all of them agree on the poor IVF outcome and low pregnancy rate of these patients. Instead, being the POSEIDON classification of very recent publication, the efficacy of the POSEIDON approach in improving management and outcomes of POR patients has yet to be tested and validated with future prospective clinical trials. Prediction of poor response may help clinicians choose the stimulation protocol with the aim of gaining patient compliance and cost reduction, and many efforts have been made by researchers in this sense, including the formulation of the Bologna criteria and of the POSEIDON classification, in which the ovarian reserve markers (AMH and AFC) play a fundamental role.

2019 - Reply: Is the transport of frozen embryos a good option to improve results in a transnational oocyte donation program? [Articolo su rivista]
La Marca, A.; Dal Canto, M. B.; Mignini Renzini, M.; Rodriguez, A.; Vassena, R.
abstract

2019 - Reply: The transnational fresh oocyte donation. Should it be the first choice when implementing an egg donation program in countries with low availability of donors? [Articolo su rivista]
La Marca, A.; Dal Canto, M.; Mignini Renzini, M.; Rodriguez, A.; Vassena, R.
abstract

2019 - Use of progestins to inhibit spontaneous ovulation during ovarian stimulation: the beginning of a new era? [Articolo su rivista]
La Marca, A.; Capuzzo, M.
abstract

Advances in oocyte and embryo cryopreservation for assisted reproduction prompted new approaches to ovarian stimulation. Attention has been paid to progesterone and its derivatives to block the LH surge, as oocyte vitrification removes possible harmful effects of progestins on endometrial receptivity. This review summarizes the current status of progestin use to inhibit ovulation during ovarian stimulation compared with conventional ovarian stimulation. Progestin-primed ovarian stimulation is shown to effectively inhibit spontaneous ovulation, without affecting the number of retrieved oocytes and embryo quality. Reproductive outcomes from ovarian stimulation with progestins appear similar to those from conventional ovarian stimulation, although large trials are needed to confirm this. Use of progestins allows better control of LH concentrations, lower costs and easier (oral) administration. Therefore, progestin-primed ovarian stimulation could be the first choice for ovarian stimulation in fertility preservation, oocyte donation and preimplantation genetic testing cycles. So-called ‘non-conventional’ ovarian stimulation protocols (luteal and random-start, double ovarian stimulation), which always require oocyte or embryo cryopreservation, may also use progestins to inhibit the endogenous LH surge. Since the ‘freeze-all’ strategy with delayed transfer is mandatory, high responders undergoing IVF could benefit more from this approach. Economic advantage remains to be demonstrated, as do pregnancy and neonatal outcomes.

2018 - Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency [Articolo su rivista]
Huhtaniemi, Ilpo; Hovatta, Outi; La Marca, Antonio; Livera, Gabriel; Monniaux, Danielle; Persani, Luca; Heddar, Abdelkader; Jarzabek, Katarzyna; Laisk-Podar, Triin; Salumets, Andres; Tapanainen, Juha S.; Veitia, Reiner A.; Visser, Jenny A.; Wieacker, Peter; Wolczynski, Slawomir; Misrahi, Micheline
abstract

Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.

2018 - Corrigendum to “Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV” [J Hepatol 68 (2018) 33–41](S0168827817322596)(10.1016/j.jhep.2017.08.019) [Articolo su rivista]
Karampatou, Aimilia; Han, Xue; Kondili, Loreta A.; Taliani, Gloria; Ciancio, Alessia; Morisco, Filomena; Critelli, Rosina Maria; Baraldi, Enrica; Bernabucci, Veronica; Troshina, Giulia; Guarino, Maria; Tagliavini, Simonetta; D'Ambrosio, Federica; Bristot, Laura; Turco, Laura; Rosato, Stefano; Vella, Stefano; Trenti, Tommaso; Neri, Isabella; La Marca, Antonio; Manthena, Shivaji; Goldstein, Andrea S.; Bruno, Savino; Bao, Yanjun; Gonzalez, Yuri Sanchez; Villa, Erica
abstract

It has come to our attention that the PITER framework investigator, Alessandro Federico, was incorrectly listed as F. Alessandro in the original manuscript. Please note that the correct name of this author is Alessandro Federico (2nd University of Naples). The correct list of PITER investigators is in the footnote below.

2018 - Erratum: Letter to the Editor: Individualized FSH dosing improves safety and reduces iatrogenic poor response while maintaining live-birth rates (Hum Reprod (2018) 33 (985-986) [Articolo su rivista]
La Marca, A.; Blockeel, C.; Bosch, E.; Fanchin, R.; Fatemi, H. M.; Fauser, B. C.; Garcia-Velasco, J. A.; Humaidan, P.; Tarlatzis, B. C.; Nelson, S. M.
abstract

The authors would like to apologise for the incorrect spelling of two of the authors' names. In the original article published online on the 27th March 2018, Peter Humaidan was listed as 'Peter Huamidan' and Christophe Blockeel was listed as 'Cristophe Blockeel'. The electronic version of this article has been updated at https:// doi.org/10.1093/humrep/dey061. The authors would like to assure readers that this does not affect any content of the letter.

2018 - Evidence for expression and functionality of FSH and LH/hCG receptors in human endometrium [Articolo su rivista]
Sacchi, Sandro; Sena, Paola; Degli Esposti, Chiara; Lui, Jessica; La Marca, Antonio
abstract

Purpose: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) mediate intracellular functions by binding their specific protein G-coupled gonadotrophin receptor, respectively FSH receptor (FSHR) and LH/choriogonadotrophin receptor (LHCGR). Whereas the expression of FSHR and LHCGR in mammals was considered gonad-specific and cell-specific, studies identified gonadotrophin receptors in human female extragonadal reproductive tissues. This study aims to demonstrate that gonadotrophin receptors are expressed in endometrium and mediates intracellular functions. Methods: Collected endometria (n = 12) from healthy patients (mean age of 36 ± 6) were primary cultured for 24 h. The presence of gonadotrophin receptors was evaluated by RT-PCR followed by the sequencing of the resulted amplicons and by immunohistochemistry in original samples. Endometrial primary cultures were treated with increasing concentration (range 0–100 ng/ml) of either recombinant human LH (rhLH) or recombinant human FSH (rhFSH). Endometria controls had gonadotrophin replaced by the same volume of the culture medium. In gonadotrophin-treated samples, it was evaluated the intracellular cyclic adenosine monophosphate (cAMP) content by enzymatic immunoassay and the expression of steroidogenic genes by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Results: The sequencing of the RT-PCR amplicons confirmed the presence of both gonadotrophin receptors and immunohistochemistry localized them on the membrane of endometrial glands cells throughout the glandular epithelium. The gonadotrophin-receptor complex was able to increase the intracellular cAMP in a dose-response and time-course manner and to induce steroidogenic genes expression. Conclusion: This study demonstrates that both gonadotrophin receptors are expressed along the glandular epithelium of endometria and they mediate the effects of gonadotrophins on intracellular functions.

2018 - Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI) [Articolo su rivista]
Lensen, Sarah F.; Wilkinson, Jack; Leijdekkers, Jori A.; La Marca, Antonio; Mol, Ben Willem J.; Marjoribanks, Jane; Torrance, Helen; Broekmans, Frank J.
abstract

Background: During a cycle of in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle-stimulating hormone (FSH) to induce multifollicular development in the ovaries. Generally, the dose of FSH is associated with the number of eggs retrieved. A normal response to stimulation is often considered desirable, for example the retrieval of 5 to 15 oocytes. Both poor and hyper-response are associated with increased chance of cycle cancellation. Hyper-response is also associated with increased risk of ovarian hyperstimulation syndrome (OHSS). Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response such as age. More recently, clinicians have begun using ovarian reserve tests (ORTs) to predict ovarian response based on the measurement of various biomarkers, including basal FSH (bFSH), antral follicle count (AFC), and anti-Müllerian hormone (AMH). It is unclear whether individualising FSH dose based on these markers improves clinical outcomes. Objectives: To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI. Search methods: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, LILACS, DARE, ISI Web of Knowledge, ClinicalTrials.gov, and the World Health Organisation International Trials Registry Platform search portal from inception to 27th July 2017. We checked the reference lists of relevant reviews and included studies. Selection criteria: We included trials that compared different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal or high responders based on AMH, AFC, and/or bFSH) and trials that compared an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm. Data collection and analysis: We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. Secondary outcomes included clinical pregnancy, moderate or severe OHSS, multiple pregnancy, oocyte yield, cycle cancellations, and total dose and duration of FSH administration. Main results: We included 20 trials (N = 6088); however, we treated those trials with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence quality ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding. Direct dose comparisons in women according to predicted response All evidence was low or very low quality. Due to differences in dose comparisons, caution is warranted in interpreting the findings of five small trials assessing predicted low responders. The effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy. Similarly, in predicted normal responders (nine studies, three comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units: OR 0.88, 95% CI 0.57 to 1.36; N = 522; 2 studies; I2= 0%) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the outcome of OHSS to enable any inferences. In predicted high responders, lower doses may or may not have an impact on rates of live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; N = 521; 1 study), OHSS, and clinical pregnancy. However, lower doses probably reduce the likelihood of moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; N = 521; 1 study). ORT-algorithm studies Four trials compared an ORT-based algorithm to a non-ORT control group.

2018 - Individualized FSH dosing improves safety and reduces iatrogenic poor response while maintaining live-birth rates [Articolo su rivista]
La Marca, Antonio; Blockeel, Christophe; Bosch, Ernesto; Fanchin, Renato; Fatemi, Human M.; Fauser, Bart C.; García-Velasco, Juan A.; Humaidan, Peter; Tarlatzis, Basil C.; Nelson, Scott M.
abstract

[No abstract available]

2018 - New strategies of ovarian stimulation based on the concept of ovarian follicular waves: From conventional to random and double stimulation [Articolo su rivista]
Sighinolfi, Giovanna; Sunkara, Sesh Kamal; La Marca, Antonio
abstract

The theory of a multicyclic development of follicles during the menstrual cycle prompted new approaches to ovarian stimulation, such as starting gonadotrophins for ovarian stimulation at any time during the menstrual cycle or using double stimulation during it, with stimulation in both the follicular and luteal phases. Because of the asynchrony between endometrial receptivity and embryo development with a ‘non-conventional start’ stimulation, all the oocytes/embryos are generally cryopreserved and transferred subsequently. This deferred transfer policy is currently possible given the advances in vitrification techniques, with success rates comparable to those following transfer with ‘fresh’ embryos. New stimulation approaches, together with advanced cryopreservation techniques, allow for a total ‘disarticulation’ between the time of the menstrual cycle, ovarian stimulation start and embryo transfer. This new approach to ovarian stimulation is particularly useful for women seeking fertility preservation, especially where a shortened time to starting cancer treatment is desirable. Also, poor responders could benefit from the new stimulation protocols by continuing ovarian stimulation after the first oocyte retrieval, thereby obtaining more oocytes or embryos compared with the conventional approach.

2018 - Perinatal outcomes following IVF with use of donor versus partner sperm [Articolo su rivista]
Kamath, Mohan Shashikant; Antonisamy, Belavendra; Selliah, Hepsy Y.; La Marca, Antonio; Sunkara, Sesh Kamal
abstract

It is a matter of interest whether pregnancies with the use of donor sperm are associated with a higher risk of adverse perinatal outcomes compared with partner sperm. Anonymized data were obtained from the Human Fertilization & Embryology Authority. Data from 1991 to 2011 involving a total of 95,787 singleton births (4523 with donor sperm and 91,264 with partner sperm) following fresh IVF/intracytoplasmic sperm injection (ICSI) were analysed to compare perinatal outcomes of preterm birth (PTB), low birthweight (LBW) and high birthweight (HBW). The risk of LBW was significantly lower (adjusted odds ratio [aOR] 0.88, 95% confidence interval [CI]: 0.79–0.99) following donor sperm versus partner sperm IVF/ICSI. There was no significant difference in the risk of PTB (aOR 0.93, 95% CI: 0.83–1.04), early PTB (aOR 0.86, 95% CI: 0.67–1.11), very LBW (aOR 0.95, 95% CI: 0.75–1.20), HBW (aOR 1.09, 95% CI: 0.98–1.21) and very HBW (aOR 1.15, 95% CI: 0.90–1.45) following donor sperm versus partner sperm IVF/ICSI. The current study did not demonstrate an increased risk of adverse perinatal outcomes following donor sperm compared with partner sperm IVF/ICSI treatment.

2018 - Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV [Articolo su rivista]
Karampatou, Aimilia; Han, Xue; Kondili, Loreta A; Taliani, Gloria; Ciancio, Alessia; Morisco, Filomena; Critelli, Rosina Maria; Baraldi, Enrica; Bernabucci, Veronica; Troshina, Giulia; Guarino, Maria; Tagliavini, Simonetta; D'Ambrosio, Federica; Bristot, Laura; Turco, Laura; Rosato, Stefano; Vella, Stefano; Trenti, Tommaso; Neri, Isabella; LA MARCA, Antonio; Manthena, Shivaji; Goldstein, Andrea S; Bruno, Savino; Bao, Yanjun; Gonzalez, Yuri Sanchez; Villa, Erica; Andreone, Pietro
abstract

Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+.

2017 - A randomized controlled trial investigating the use of a predictive nomogram for the selection of the FSH starting dose in IVF/ICSI cycles [Articolo su rivista]
Allegra, Adolfo; Marino, Angelo; Volpes, Aldo; Coffaro, Francesco; Scaglione, Piero; Gullo, Salvatore; La Marca, Antonio
abstract

The number of oocytes retrieved is a relevant intermediate outcome in women undergoing IVF/intracytoplasmic sperm injection (ICSI). This trial compared the efficiency of the selection of the FSH starting dose according to a nomogram based on multiple biomarkers (age, day 3 FSH, anti-Müllerian hormone) versus an age-based strategy. The primary outcome measure was the proportion of women with an optimal number of retrieved oocytes defined as 8-14. At their first IVF/ICSI cycle, 191 patients underwent a long gonadotrophin-releasing hormone agonist protocol and were randomized to receive a starting dose of recombinant (human) FSH, based on their age (150 IU if ≤35 years, 225 IU if >35 years) or based on the nomogram. Optimal response was observed in 58/92 patients (63%) in the nomogram group and in 42/99 (42%) in the control group (+21%, 95% CI = 0.07 to 0.35, P = 0.0037). No significant differences were found in the clinical pregnancy rate or the number of embryos cryopreserved per patient. The study showed that the FSH starting dose selected according to ovarian reserve is associated with an increase in the proportion of patients with an optimal response: large trials are recommended to investigate any possible effect on the live-birth rate.

2017 - Female age, serum antimüllerian hormone level, and number of oocytes affect the rate and number of euploid blastocysts in in vitro fertilization/intracytoplasmic sperm injection cycles [Articolo su rivista]
La Marca, A; Minasi, Mg; Sighinolfi, G; Greco, P; Argento, C; Grisendi, V; Fiorentino, F; Greco, E.
abstract

Abstract OBJECTIVE: To study the relative role of female age and ovarian reserve, measured through serum antimüllerian hormone (AMH) in determining the rate and number of euploid blastocysts in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. DESIGN: Retrospective analysis of cycles performed in 2014-2015. SETTING: Tertiary referral IVF center. PATIENT(S): A total of 578 infertile couples undergoing IVF/ICSI and preimplantation genetic screening (PGS) analysis. INTERVENTIONS(S): All embryos were cultured and biopsied at the blastocyst stage. The method involved whole-genome amplification followed by array comparative genome hybridization. Serum AMH was measured by means of the modified Beckman Coulter AMH Gen II assay. MAIN OUTCOME MEASURES: The rate and number of euploid blastocysts and their correlation with ovarian reserve and response to stimulation. RESULT(S): The mean (±SD) age of patients was 37.6 ± 4.1 years, and the mean number of blastocysts per patient was 3.1 ± 2. The total number of blastocysts available to the analysis was 1,814, and 36% of them were euploid after PGS. Age and serum AMH were significantly and independently related to the rate of euploid blastocysts available for patients. As an effect of the cohort size, the number of mature oocytes positively affected the total number of euploid blastocysts per patient. CONCLUSION(S): A strong positive age-independent relationship between AMH level and the rate of euploid blastocysts was found. This confirms that the measurement of ovarian reserve by means of AMH has high relevance when counseling infertile patients.

2017 - How much variation in oocyte yield after controlled ovarian stimulation can be explained? A multilevel modelling study [Articolo su rivista]
Rustamov, Oybek; Wilkinson, Jack; La Marca, Antonio; Fitzgerald, Cheryl; Roberts, Stephen A
abstract

How much variation in oocyte yield after controlled ovarian stimulation (COS) can be accounted for by known patient and treatment characteristics?

2017 - How to personalize ovarian stimulation in clinical practice [Articolo su rivista]
Sighinolfi, Giovanna; Grisendi, Valentina; La Marca, Antonio
abstract

Controlled ovarian stimulation (COS) in in vitro fertilization (IVF) cycles is the starting point from which couple's prognosis depends. Individualization in follicle-stimulating hormone (FSH) starting dose and protocol used is based on ovarian response prediction, which depends on ovarian reserve. Anti-Müllerian hormone levels and the antral follicle count are considered the most accurate and reliable markers of ovarian reserve. A literature search was performed for studies that addressed the ability of ovarian reserve markers to predict poor and high ovarian response in assisted reproductive technology cycles. According to the predicted response to ovarian stimulation (poor- normal- or high- response), it is possible to counsel couples before treatment about the prognosis, and also to individualize ovarian stimulation protocols, choosing among GnRH-agonists or antagonists for endogenous FSH suppression, and the FSH starting dose in order to decrease the risk of cycle cancellation and ovarian hyperstimulation syndrome. In this review we discuss how to choose the best COS therapy, based on ovarian reserve markers, in order to enhance chances in IVF.

2017 - Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing IVF/ICSI [Articolo su rivista]
Lensen, Sarah F.; Wilkinson, Jack; Mol, Ben Willem J.; La Marca, Antonio; Torrance, Helen; Broekmans, Frank J.
abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: This review has two objectives. These are: to assess the comparative effectiveness (pregnancy and live birth) and safety (ovarian hyperstimulation syndrome) in women undergoing in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI): of different doses of gonadotropin in women subgrouped by their expected response to stimulation, as defined by at least one ovarian reserve test (ORT) measure (do women with low, moderate or high anticipated response to ovarian stimulation, based on an ORT, benefit from a modified gonadotropin dose?); and of individualisation of gonadotropin dose using ORT, as compared to dose selection without ORT, or to an alternative individualised dosing algorithm using ORT (does using ORT to individualise gonadotropin dose improve IVF/ICSI outcomes, and is there evidence to suggest one algorithm is better than another?).

2017 - Individualization of controlled ovarian stimulation in vitro fertilization using ovarian reserve markers [Articolo su rivista]
Grisendi, Valentina; La Marca, Antonio
abstract

In assisted reproduction technologies (ART) the controlled ovarian stimulation (COS) therapy is the starting point from which a good oocytes retrieval depends. Treatment individualization is based on ovarian response prediction, which largely depends on a woman's ovarian reserve. Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are considered the most accurate and reliable markers of ovarian reserve.

2017 - Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial [Articolo su rivista]
Nyboe Andersen, Anders; Nelson, Scott M.; Fauser, Bart C. J. M.; García-Velasco, Juan Antonio; Klein, Bjarke M.; Arce, Joan-Carles; Tournaye, Herman; De Sutter, Petra; Decleer, Wim; Petracco, Alvaro; Borges, Edson; Barbosa, Caio Parente; Havelock, Jon; Claman, Paul; Yuzpe, Albert; Višnová, Hana; Ventruba, Pavel; Uher, Petr; Mrazek, Milan; Andersen, Anders Nyboe; Knudsen, Ulla Breth; Dewailly, Didier; Leveque, Anne Guivarc'h; La Marca, Antonio; Papaleo, Enrico; Kuczynski, Waldemar; Kozioł, Katarzyna; Anshina, Margarita; Zazerskaya, Irina; Gzgzyan, Alexander; Bulychova, Elena; Verdú, Victoria; Barri, Pedro; García-Velasco, Juan Antonio; Fernández-Sánchez, Manuel; Martin, Fernando Sánchez; Bosch, Ernesto; Serna, José; Castillon, Gemma; Bernabeu, Rafael; Ferrando, Marcos; Lavery, Stuart; Gaudoin, Marco; Fauser, Bart C. J. M.; Klein, Bjarke M.; Helmgaard, Lisbeth; Mannaerts, Bernadette; Arce, Joan-Carles
abstract

Objective To compare the efficacy and safety of follitropin delta, a new human recombinant FSH with individualized dosing based on serum antimüllerian hormone (AMH) and body weight, with conventional follitropin alfa dosing for ovarian stimulation in women undergoing IVF. Design Randomized, multicenter, assessor-blinded, noninferiority trial (ESTHER-1). Setting Reproductive medicine clinics. Patient(s) A total of 1,329 women (aged 18–40 years). Intervention(s) Follitropin delta (AMH <15 pmol/L: 12 μg/d; AMH ≥15 pmol/L: 0.10–0.19 μg/kg/d; maximum 12 μg/d), or follitropin alfa (150 IU/d for 5 days, potential subsequent dose adjustments; maximum 450 IU/d). Main Outcomes Measure(s) Ongoing pregnancy and ongoing implantation rates; noninferiority margins −8.0%. Result(s) Ongoing pregnancy (30.7% vs. 31.6%; difference −0.9% [95% confidence interval (CI) −5.9% to 4.1%]), ongoing implantation (35.2% vs. 35.8%; −0.6% [95% CI −6.1% to 4.8%]), and live birth (29.8% vs. 30.7%; −0.9% [95% CI −5.8% to 4.0%]) rates were similar for individualized follitropin delta and conventional follitropin alfa. Individualized follitropin delta resulted in more women with target response (8–14 oocytes) (43.3% vs. 38.4%), fewer poor responses (fewer than four oocytes in patients with AMH <15 pmol/L) (11.8% vs. 17.9%), fewer excessive responses (≥15 or ≥20 oocytes in patients with AMH ≥15 pmol/L) (27.9% vs. 35.1% and 10.1% vs. 15.6%, respectively), and fewer measures taken to prevent ovarian hyperstimulation syndrome (2.3% vs. 4.5%), despite similar oocyte yield (10.0 ± 5.6 vs. 10.4 ± 6.5) and similar blastocyst numbers (3.3 ± 2.8 vs. 3.5 ± 3.2), and less gonadotropin use (90.0 ± 25.3 vs. 103.7 ± 33.6 μg). Conclusion(s) Optimizing ovarian response in IVF by individualized dosing according to pretreatment patient characteristics results in similar efficacy and improved safety compared with conventional ovarian stimulation. Clinical Trial Registration Number NCT01956110.

2017 - Reply: Rapid changes in practice make analysis of historical databases irrelevant for contemporary counselling [Articolo su rivista]
Sunkara, S. K.; La Marca, A.; Polyzos, N. P.; Seed, P. T.; Khalaf, Y.
abstract

2017 - The anti-Müllerian hormone (AMH) induces forkhead box L2 (FOXL2) expression in primary culture of human granulosa cells in vitro [Articolo su rivista]
Sacchi, Sandro; Marinaro, Federica; Xella, Susanna; Marsella, Tiziana; Tagliasacchi, Daniela; La Marca, Antonio
abstract

Anti-Müllerian hormone (AMH) and forkhead box L2 (FOXL2) are two pivotal genes expressed in human granulosa cells (hGCs) where both genes share similar inhibitory functions on activation and follicular growth in order to preserve the ovarian follicle reserve. Furthermore, AMH and FOXL2 contribute to inhibit steroidogenesis, decreasing or preventing the activation of gonadotrophin-dependent aromatase CYP19A1 cytochrome P450 family 19 subfamily A member 1 (CYP19A1). The purpose of this study is to evaluate the role of AMH in regulating the expression of FOXL2.

2017 - Vitamin D and ovarian reserve: making clinical decisions [Articolo su rivista]
Drakopoulos, Panagiotis; La Marca, A; Polyzos, Nikolaos P
abstract

vit d may modify ovarian reserve

2016 - Clinical application of a nomogram based on age, serum FSH and AMH to select the FSH starting dose in IVF/ICSI cycles: a retrospective two-centres study [Articolo su rivista]
Papaleo, Enrico; Zaffagnini, Stefano; Munaretto, Maria; Vanni, Valeria Stella; Rebonato, Giorgia; Grisendi, Valentina; Di Paola, Rossana; La Marca, Antonio
abstract

Objective To externally validate a nomogram based on ovarian reserve markers as a tool to optimize the FSH starting dose in IVF/ICSI cycles. Study design A two-centres retrospective study including 398 infertile women undergoing their first IVF/ICSI cycle (June 2013–June 2014). IVF data were retrieved from two independent IVF centres in Italy (San Raffaele Hospital, Centre 1; Verona Hospital, Centre 2). A central lab for the routine measurement of AMH and FSH was used for both centres. All women were treated based on physical and hormonal characteristics according to locally adopted protocols. The nomogram was then retrospectively applied to the patients comparing the calculated starting dose to the one actually given. Results In Centre 1, 64/131 women (48.8%) had an ovarian response below the target. While 45 of these patients were treated with a maximal FSH starting dose (≥225 IU), n = 19/131 (14.5%) were treated with a submaximal dose. The vast majority of them (n = 17/19) would have received a higher FSH starting dose by using the nomogram. Seventeen patients (n = 17/131) had hyper response and about half of them would have been treated with a reduced FSH starting dose according to the nomogram. In Centre 2, 142/267 patients (53.2%) had an ovarian response below the target. While 136 of these were treated with a maximal FSH starting dose (≥225 IU), n = 6/267 were treated with a submaximal dose. The majority of them (n = 5/6) would have received a higher FSH starting dose. Thirty-two (n = 32/267) patients had hyper response and more than half of them would have been treated with a reduced FSH dose. Conclusion In both Centres, applying the nomogram would have resulted in more appropriate FSH starting doses compared to the the ones actually given based on clinicians choices. The use of an objective algorithm based on patient's age, serum FSH and AMH levels may thus be an effective advice on the selection of the tailored FSH starting dose. Hence, the use of this easily available nomogram could increase the proportion of patients achieving the optimal ovarian response.

2016 - Live birth and perinatal outcomes following stimulated and unstimulated IVF: Analysis of over two decades of a nationwide data [Articolo su rivista]
Sunkara, S. K.; La Marca, A.; Polyzos, N. P.; Seed, P. T.; Khalaf, Y.
abstract

STUDY QUESTION Does ovarian stimulation affect perinatal outcomes of preterm birth (PTB) and low birth weight (LBW) following IVF treatment. SUMMARY ANSWER Despite no significant differences in the risks of PTB and LBW between stimulated and unstimulated IVF in the present study, the study cannot exclude the effect of ovarian stimulation on the perinatal outcomes following IVF. WHAT IS ALREADY KNOWN Pregnancies resulting from assisted reproductive treatments (ART) are associated with a higher risk of pregnancy complications compared to spontaneously conceived pregnancies attributed to the underlying infertility and the in vitro fertilization techniques. It is of interest to determine the effect size of ovarian stimulation use in achieving a live birth and whether ovarian stimulation that is routinely used in IVF, affects perinatal outcomes of birth weight and gestational age at delivery compared to unstimulated IVF. STUDY DESIGN, SIZE, DURATION Anonymous data were obtained from the Human Fertilisation and Embryology Authority (HFEA), the statutory regulator of ART in the UK. The HFEA has collected data prospectively on all ART performed in the UK since 1991. Data from 1991 to 2011 comprising a total of 591 003 fresh IVF ± ICSI cycles involving 584 835 stimulated IVF cycles and 6168 unstimulated IVF cycles were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on all women undergoing either stimulated or unstimulated fresh IVF ± ICSI cycles during the period from 1991 to 2011 were analyzed to compare live birth rates, singleton live birth rates, perinatal outcomes of PTB, early PTB (<32 weeks), LBW and very LBW (<1500 grams) among singleton live births. Adjusted logistic regression was performed for each perinatal outcome for confounding factors: female age, period of treatment, cause of infertility, number of previous IVF cycles and previous live birth. MAIN RESULTS AND THE ROLE OF CHANCE Analysis of the large nationwide data demonstrated 3.5 times (95% confidence interval (CI): 3.1-3.9) as many unstimulated IVF cycles being required to achieve one live birth compared to stimulated IVF and 2.9 times (95% CI: 2.6-3.2) as many unstimulated IVF cycles being required to achieve one singleton live birth compared to stimulated IVF. There was no significant difference in the unadjusted odds for PTB (odds ratio (OR) 1.27, 95% CI: 0.80-2.00) and LBW (OR 1.48, 95% CI: 0.90-2.42) between stimulated and unstimulated IVF cycles. There was no significant difference in the risk of the adverse perinatal outcomes after adjusting for potential confounders; PTB (adjusted odds ratio (aOR) 1.43, 95% CI: 0.91-2.26) and LBW (aOR 1.58, 95% CI: 0.96-2.58). LIMITATIONS, REASONS FOR CAUTION Although the analysis was adjusted for a number of important confounders, the dataset had no information on smoking, body mass index (BMI) and the medical history of women during pregnancy to allow adjustment. Anonymized nature of the dataset did not make it permissible to analyse one cycle per woman. Given the smaller number of perinatal events with unstimulated IVF, a larger study is needed to investigate further. WIDER IMPLICATIONS OF THE FINDINGS Analysis of this large dataset demonstrates that ovarian stimulation has a vital role in maximizing efficacy of IVF. Although there were no significant differences for PTB and LBW following stimulated compared to unstimulated IVF, the CIs were wide enough to include possible clinically important effects. STUDY FUNDING/COMPETING INTEREST(S) No funding was obtained. There are no competing interests to declare.

2016 - Modulation of gonadotrophin induced steroidogenic enzymes in granulosa cells by d-chiroinositol [Articolo su rivista]
Sacchi, Sandro; Marinaro, Federica; Tondelli, Debora; Lui, Jessica; Xella, Susanna; Marsella, Tiziana; Tagliasacchi, Daniela; Argento, Cindy; Tirelli, Alessandra; Giulini, Simone; La Marca, Antonio
abstract

d-chiroinositol (DCI) is a inositolphosphoglycan (IPG) involved in several cellular functions that control the glucose metabolism. DCI functions as second messenger in the insulin signaling pathway and it is considered an insulin sensitizer since deficiency in tissue availability of DCI were shown to cause insulin resistance (IR). Polycystic ovary syndrome (PCOS) is a pathological condition that is often accompanied with insulin resistance. DCI can positively affects several aspect of PCOS etiology decreasing the total and free testosterone, lowering blood pressure, improving the glucose metabolism and increasing the ovulation frequency. The purpose of this study was to evaluate the effects of DCI and insulin combined with gonadotrophins namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on key steroidogenic enzymes genes regulation, cytochrome P450 family 19 subfamily A member 1 (CYP19A1) and cytochrome P450 side-chain cleavage (P450scc) in primary cultures of human granulosa cells (hGCs). We also investigated whether DCI, being an insulin-sensitizer would be able to counteract the expected stimulator activity of insulin on human granulosa cells (hGCs).

2016 - The anti-Müllerian hormone (AMH) acts as a gatekeeper of ovarian steroidogenesis inhibiting the granulosa cell response to both FSH and LH [Articolo su rivista]
Sacchi, Sandro; D'Ippolito, Giovanni; Sena, Paola; Marsella, Tiziana; Tagliasacchi, Daniela; Maggi, Elena; Argento, Cindy; Tirelli, Alessandra; Giulini, Simone; La Marca, Antonio
abstract

Anti Müllerian Hormone (AMH) has a negative and inhibitory role in many functions of human granulosa-lutein cells (hGCs) including notoriously the reduction of the aromatase CYP19A1 expression induced by follicle-stimulating hormone (FSH). No data have been provided on the possible role of AMH in modulating the response to luteinizing hormone (LH) (alone or combined with FSH) as well as its effect on other enzymes involved in steroidogenesis including aromatase P450scc. The aim of this study was to investigate the role of AMH as regulator of the basal and stimulated steroids production by hGCs.

2016 - The use of ovarian reserve markers in IVF clinical practice: a national consensus [Articolo su rivista]
La Marca, Antonio; Ferraretti, Anna Pia; Palermo, Roberto; Ubaldi, Filippo M
abstract

Ovarian reserve markers have been documented to perform very well in the clinical practice. While this is widely recognized, still now there is no consensus on how to use new biomarkers in the clinical practice. This study was conducted among Italian IVF centres using the Delphi technique, a validated consensus-building process. Briefly three consecutive questionnaires were developed for clinicians in charge of IVF centres. In the first rounds, participants were asked to rate the importance of a list of statements regarding the categorization of ovarian response and the diagnostic role of biomarkers. In round 3, participants were asked to rate their agreement and consensus on the list of statements derived from the first two rounds. There were 120 respondents. Consensus was achieved for many points: (a) poor ovarian response is predicted on the basis of the following: AMH < 1 ng/ml or AFC < 7, FSH ≥ 10 IU/l, age ≥ 40 yrs; (b) hyper-response is predicted on the basis of the following: AMH > 3 ng/ml or AFC > 14; (c) day 3 FSH measurement should always be associated to estradiol; (d) AMH can be measured on a random basis; (e) the measurement of the AFC with the 2D technology may be considered adequate and (f) the AFC should be measured in the early follicular phase and consists in the total number of 2-9 mm follicles in both the ovaries. The present study suggests that extensive consensus on the importance and use of new ovarian reserve markers to improve IVF safety and performance is already present among clinicians.

2015 - Increased risk of preterm birth and low birthweight with very high number of oocytes following IVF: an analysis of 65 868 singleton live birth outcomes [Articolo su rivista]
Sunkara, Sesh Kamal; La Marca, Antonio; Seed, Paul T; Khalaf, Yacoub
abstract

Is there a relation between the number of oocytes retrieved following ovarian stimulation and obstetric outcomes of preterm birth (PTB) and low birthweight (LBW) following IVF treatment?

2015 - Live birth rates in the different combinations of the Bologna criteria poor ovarian responders: a validation study [Articolo su rivista]
La Marca, Antonio; Grisendi, Valentina; Giulini, Simone; Sighinolfi, Giovanna; Tirelli, Alessandra; Argento, Cindy; Re, Claudia; Tagliasacchi, Daniela; Marsella, Tiziana; Sunkara, Sesh Kamal
abstract

to compare the baseline characteristics and chance of live birth in the different categories of poor responders identified by the combinations of the Bologna criteria and establish whether these groups comprise a homogenous population.

2015 - The menstrual cycle regularization following d-chiro-inositol treatment in PCOS women: a retrospective study [Articolo su rivista]
LA MARCA, Antonio; Grisendi, Valentina; Dondi, Giulia; Sighinolfi, Giovanna; Cianci, Antonio
abstract

Polycystic ovary syndrome is characterized by irregular cycles, hyperandrogenism, polycystic ovary at ultrasound and insulin resistance. The effectiveness of d-chiro-inositol (DCI) treatment in improving insulin resistance in PCOS patients has been confirmed in several reports. The objective of this study was to retrospectively analyze the effect of DCI on menstrual cycle regularity in PCOS women. This was a retrospective study of patients with irregular cycles who were treated with DCI. Of all PCOS women admitted to our centre, 47 were treated with DCI and had complete medical charts. The percentage of women reporting regular menstrual cycles significantly increased with increasing duration of DCI treatment (24% and 51.6% at a mean of 6 and 15 months of treatment, respectively). Serum AMH levels and indexes of insulin resistance significantly decreased during the treatment. Low AMH levels, high HOMA index, and the presence of oligomenorrhea at the first visit were the independent predictors of obtaining regular menstrual cycle with DCI. In conclusion, the use of DCI is associated to clinical benefits for many women affected by PCOS including the improvement in insulin resistance and menstrual cycle regularity. Responders to the treatment may be identified on the basis of menstrual irregularity and hormonal or metabolic markers.

2014 - Age-specific reference values for serum FSH and estradiol levels throughout the reproductive period [Articolo su rivista]
Grisendi, Valentina; Spada, Elena; Argento, Cindy; Plebani, Maddalena; Milani, Silvano; Seracchioli, Renato; Volpe, Annibale; LA MARCA, Antonio
abstract

High serum day 3 FSH levels are associated with poor ovarian reserve and reduced fertility, but the interpretation of FSH values according to age is still not univocal. The purpose of this study was to determine age-dependent reference values in women with regular menstrual cycles and FSH as a guide for specialists. The study was performed at the Department of Mother-Infant of a University-based tertiary care centre. One-hundred ninety-two healthy normal menstruating women were recruited for the study. All patients attended the department on menstrual cycle day 3 for a blood sample for FSH and estradiol determination. A linear relationship between FSH or estradiol serum levels and age was observed. The FSH level increased by 0.11 IU for every year of age (1 IU for every 9 years of age). The values of FSH and estradiol corresponding to the 5th, 25th, 50th, 75th, 95th centiles for any specific age have been calculated. Serum FSH levels need to be interpreted according to age-dependent reference values. Serum FSH levels on 95th centile for any age may represent a warning sign for reduced ovarian reserve.

2014 - Basal progesterone level as the main determinant of progesterone elevation on the day of hCG triggering in controlled ovarian stimulation cycles [Articolo su rivista]
Papaleo, Enrico; Corti, Laura; Vanni, Valeria Stella; Pagliardini, Luca; Ottolina, Jessica; De Michele, Francesca; LA MARCA, Antonio; Viganò, Paola; Candiani, Massimo
abstract

Modest increases of serum progesterone at human chorionic gonadotrophin (hCG) administration in controlled ovarian hyperstimulation (COH) cycles have been shown to have a negative impact on pregnancy outcomes. The aim of this study was to identify early predictors of progesterone elevation at hCG.

2014 - Corrigendum to The physiology and clinical utility of anti-Müllerian hormone in women [Hum Reprod Update, 20 (2014) 370-385] [Articolo su rivista]
Dewailly, Didier; Andersen, Claus Yding; Balen, Adam; Broekmans, Frank; Dilaver, Nafi; Fanchin, Renato; Griesinger, Georg; Kelsey, Tom W.; La Marca, Antonio; Lambalk, Cornelius; Mason, Helen; Nelson, Scott M.; Visser, Jenny A.; Hamish Wallace, W.; Anderson, Richard A.
abstract

N/A

2014 - Effects of the insulin sensitizer pioglitazone on menstrual irregularity, insulin resistance and hyperandrogenism in young women with polycystic ovary syndrome [Articolo su rivista]
Stabile, Gaspare; Borrielli, Irene; Artenisio, Alfredo Carducci; Bruno, Lucia Maria; Benvenga, Salvatore; Giunta, Loretta; LA MARCA, Antonio; Volpe, Annibale; Pizzo, Alfonsa
abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine cause of menstrual irregularities, hirsutism and acne. Women with PCOS present elevated plasma insulin levels, both fasting and after a glucose load, as an indirect evidence of insulin resistance. PCOS women may also present hypertension, low levels of HDL cholesterol, hypertriglyceridemia, visceral obesity and a higher level of CRP and fibrinogen that can predict an atherosclerotic risk.

2014 - FSHR polymorphism p.N680S mediates different responses to FSH in vitro [Articolo su rivista]
Casarini, Livio; Moriondo, Valeria; Marino, Marco; Adversi, Francesca; Capodanno, Francesco; Grisolia, Chiarina; LA MARCA, Antonio; LA SALA, Giovanni Battista; Simoni, Manuela
abstract

The single nucleotide polymorphism p.N680S of the follicle-stimulating hormone (FSH) receptor (FSHR) is a discrete marker of ovarian response but previous in vitro studies failed to demonstrate differences in the response to FSH between N and S carrier cells. Here we demonstrate that p.N680S mediates different kinetics of the response to FSH in vitro. Intracellular cAMP production is faster in p.N680S N than in S homozygous human granulosa cells (45 versus 90 min to achieve the plateau, respectively; Mann-Whitney's U-test; p < 0.005; n = 4). Reflecting the cAMP kinetics, phospho-ERK1/2 and -CREB activation, AREG and STARD1 gene expressions and progesterone production were qualitatively and quantitatively different in N versus S homozygous cells. Finally, the blockade of ERK pathway by U0126 abolishes the genotype-mediated different effects on gene expression and progesterone production (Mann-Whitney's U-test; p ≥ 0.005; n = 3).

2014 - Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice [Articolo su rivista]
LA MARCA, Antonio; Sunkara, Sesh Kamal
abstract

The main objective of individualization of treatment in IVF is to offer every single woman the best treatment tailored to her own unique characteristics, thus maximizing the chances of pregnancy and eliminating the iatrogenic and avoidable risks resulting from ovarian stimulation. Personalization of treatment in IVF should be based on the prediction of ovarian response for every individual. The starting point is to identify if a woman is likely to have a normal, poor or a hyper response and choose the ideal treatment protocol tailored to this prediction. The objective of this review is to summarize the predictive ability of ovarian reserve markers, such as antral follicle count (AFC) and anti-Mullerian hormone (AMH), and the therapeutic strategies that have been proposed in IVF after this prediction.

2014 - Ovarian response markers lead to appropriate and effective use of corifollitropin alpha in assisted reproduction [Articolo su rivista]
LA MARCA, Antonio; D'Ippolito, Giovanni
abstract

Corifollitropin alpha is a highly effective gonadotrophin, which maintains multifollicular growth for a week. The advantages of its administration include ease of use of the drug, making the treatment more patient friendly, resulting in a lower level of distress for the patient. At the same time, the pregnancy rate resulting from its use in IVF/intracytoplasmic sperm injection cycles is similar to that found when daily recombinant FSH is administered. The ovarian response to corifollitropin alpha is dependent on clinically established predictors such as baseline FSH, antral follicle count (AFC) and age. There is a general trend towards a higher ovarian response with an increasing AFC and the number of oocytes per attempt decreased with increasing baseline FSH and age. Even if the risk of ovarian hyperstimulation syndrome following corifollitropin alpha is very similar to the rate reported in literature for young women undergoing IVF, the risk of overstimulation may be reduced by avoiding maximal ovarian stimulation in women anticipated to be hyperresponders. High basal anti-Müllerian hormone and/or AFC can identify women with enhanced functional ovarian reserve at risk of overstimulation, and the risk is even higher if maximally stimulated with corifollitropin alpha or high dose of daily recombinant FSH. Corifollitropin alpha is a highly effective gonadotrophin which maintains multifollicular growth for a week. The ovarian response to corifollitropin was demonstrated to be dependent on clinically established predictors such as baseline FSH, antral follicle count (AFC) and age. There was a general trend toward a higher ovarian response with an increasing AFC and the mean number of oocytes per attempt decreased with increasing baseline FSH and age. Even if the risk of ovarian hyperstimulation syndrome (OHSS) following corifollitropin alpha is very similar to the rate of OHSS reported in literature for young women undergoing IVF, the risk of overstimulation may be reduced by avoiding maximal ovarian stimulation in women anticipated to be hyperresponders. Increasing evidence demonstrates that anti-Müllerian hormone and AFC exhibit a very good diagnostic performance in the prediction of hyperresponse. High basal anti-Müllerian hormone and/or AFC can identify women with enhanced functional ovarian reserve who are at risk of overstimulation if stimulated in IVF cycles and the risk is even higher if maximally stimulated with corifollitropin alpha or high dose of daily recombinant FSH.

2014 - Protein modification as oxidative stress marker in follicular fluid from women with polycystic ovary syndrome: the effect of inositol and metformin [Articolo su rivista]
Piomboni, P; Focarelli, R; Capaldo, A; Stendardi, A; Cappelli, V; Cianci, A; LA MARCA, Antonio; Luddi, A; De Leo, V.
abstract

The purpose of this study was to evaluate the oxidative stress status (OS) of follicular fluid (FF) and the oocyte quality in women with polycystic ovary syndrome (PCOS) undergoing different ovarian stimulation protocols.

2014 - Recombinant LH administration in subsequent cycle after "unexpected" poor response to recombinant FSH monotherapy [Articolo su rivista]
Papaleo, Enrico; Vanni, Valeria Stella; Viganò, Paola; LA MARCA, Antonio; Pagliardini, Luca; Vitrano, Rossella; Zanirato, Mara; Marsiglio, Elena; Privitera, Laura; Candiani, Massimo
abstract

Abstract Poor ovarian response (POR) is most frequently linked to the condition known as diminished ovarian reserve, but it can also occur in the absence of pathological ovarian reserve tests ("unexpected" POR). Because possible explanations include theca cells function deficiency, our aim was to evaluate the effect of r-LH administration in "unexpected" poor responders. A retrospective, single-centre, cohort study was conducted on 65 patients with AMH >0.5 ng/ml and/or AFC >5 with POR in their first cycle. Patients underwent a second IVF cycle with same protocol (long- or antagonist) and same starting dose of r-FSH used in the first cycle, plus daily addiction of 150 IU of r-LH from day 1. Compared to the first cycle, r-LH addition in the second cycle determined an increase in number of oocytes retrieved (p < 0.001), number of metaphase II oocytes (p < 0.05), E2 levels at hCG triggering (p < 0.001) and number of embryos transferred (p = 0.002). A 15% clinical pregnancy rate was also observed in the second cycle. Our results suggest that patients with non-pathological ovarian reserve tests and previous "unexpected" POR seem to benefit from r-LH addition in subsequent cycles without the need to increase the r-FSH starting dose, possibly due to an underlying occult theca cells deficiency.

2014 - Reference values in ovarian response to controlled ovarian stimulation throughout the reproductive period [Articolo su rivista]
LA MARCA, Antonio; Grisendi, Valentina; Spada, Elena; Argento, Cindy; Milani, Silvano; Plebani, Maddalena; Seracchioli, Renato; Volpe, Annibale
abstract

Abstract The age-related decline in ovarian response to gonadotropins has been well known since the beginning of ovarian stimulation in IVF cycles and has been considered secondary to the age-related decline in ovarian reserve. The objective of this study was to establish reference values and to construct nomograms of ovarian response for any specific age to gonadotropins in IVF/ICSI cycles. We analyzed our database containing information on IVF cycles. According to inclusion and exclusion criteria, a total of 703 patients were selected. Among inclusion criteria, there were regular menstrual cycle, treatment with a long GnRH agonist protocol and starting follicle-stimulating hormone (FSH) dose of at least 200 IU per day. To estimate the reference values of ovarian response, the CG-LMS method was used. A linear decline in the parameters of ovarian response with age was observed: the median number of oocytes decreases approximately by one every three years, and the median number of follicles &gt;16 mm by one every eight years. The number of oocytes and growing follicles corresponding to the 5th, 25th, 50th, 75th and 95th centiles has been calculated. This study confirmed the well known negative relationship between ovarian response to FSH and female ageing and permitted the construction of nomograms of ovarian response.

2014 - Reply: The two sides of the individualization of controlled ovarian stimulation [Articolo su rivista]
La Marca, Antonio; Sunkara, Sesk Kamal
abstract

The two sides of the individualization of controlled ovarian stimulation

2014 - The FSHR polymorphism p.N680S mediates different response kinetics to FSH in vitro [Abstract in Atti di Convegno]
Casarini, Livio; Moriondo, Valeria; Marino, Marco; Adversi, Francesca; Grisolia, Chiarina; LA MARCA, Antonio; LA SALA, Giovanni Battista; Simoni, Manuela
abstract

Introduction: FSH acts on its receptor (FSHR) resulting in signal transduction activation, gene expression and steroidogenesis. The FSHR common SNP p.N680S is a marker of gonadal response in vivo. However, in vitro dose–response experiments failed to demonstrate the molecular basis thereof so far. In this study, we systematically investigated whether p.N680S mediates different kinetics of FSH response in vitro. Design: We evaluated the activation kinetics of cAMP, phERK1/2, phCREB by ELISA and western blotting in FSHR homozygous, primary, human granulosa lutein cells (hGLC-680N, -680S) stimulated by 50 nM r-FSH for up to 2 h (short-term stimulation). Following short-term stimulation the expression of target genes was evaluated by real-time PCR after 12 h, and progesterone production kinetics over 24 h. Specific inhibitors/agonists (U0126, PMA) were used in the presence and in the absence of FSH. Results: Intracellular cAMP increased within 5–10 min in hGLC-680N, reaching the plateau in about 45 min. cAMP increase was delayed in hGLC-680S, reaching the plateau in 120 min, revealing different activation kinetics (Mann–Whitney U test; P<0.05; n=4). r-FSH-dependent cAMP stimulation kinetics resulted in different ERK1/2 and CREB phosphorylation, reaching maximal levels in 5–30 min in hGLC-680N, whereas, in hGLC-680S, these were weaker and steady over 2 h (Mann–Whitney U test; P<0.05; n=3). hGLC-680N stimulation resulted in higher expression levels of AREG and StAR (Mann–Whitney U test; P<0.05; n=4) and in subsequently different progesterone production kinetics, achieving overall higher levels in hGLC-680N vs -680S (Mann–Whitney U test; P<0.05; n=3). Interestingly, the different kinetics of progesterone production between hGLC-680N and -680S were interchanged by selective phospho-ERK1/2 blockade/activation through specific inhibitor/agonist, revealing a short-term cross-talk mediated by ERK1/2. Conclusions: This study demonstrates for the first time in vitro, how FSHR p.N680S mediates different response to FSH, resulting in different kinetics of cAMP, phERK1/2 and phCREB activation, and progesterone production.

2014 - The ovarian response to controlled stimulation in IVF cycles may be predictive of the age at menopause [Articolo su rivista]
LA MARCA, Antonio; Dondi, G; Sighinolfi, Giovanna; Giulini, Simone; Papaleo, E; Cagnacci, Angelo; Faddy, M. J.
abstract

Can the number of oocytes retrieved in IVF cycles be predictive of the age at menopause?

2014 - The physiology and clinical utility of anti-Mullerian hormone in women [Articolo su rivista]
Dewailly, Didier; Andersen, Claus Yding; Balen, Adam; Broekmans, Frank; Dilaver, Nafi; Fanchin, Renato; Griesinger, Georg; Kelsey, Tom W; LA MARCA, Antonio; Lambalk, Cornelius; Mason, Helen; Nelson, Scott M; Visser, Jenny A; Wallace, W. Hamish; Anderson, Richard A.
abstract

BACKGROUND The measurement of circulating anti-Müllerian hormone (AMH) has been applied to a wide array of clinical applications, mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries. AMH has been suggested to predict the ovarian response to hyperstimulation of the ovaries for IVF and the timing of menopause, and to indicate iatrogenic damage to the ovarian follicle reserve. It has also been proposed as a surrogate for antral follicle count (AFC) in the diagnosis of polycystic ovary syndrome (PCOS). METHODS This paper is a summary of presentations at a European Society of Human Reproduction and Embryology campus workshop on AMH, with literature cited until September 2013. Published peer-reviewed medical literature about AMH was searched through MEDLINE and was subjected to systematic review and critical assessment by the panel of authors. RESULTS Physiologically, recent data confirm that AMH is a follicular gatekeeper limiting follicle growth initiation, and subsequently estradiol production from small antral follicles prior to selection. AMH assays continue to evolve and technical issues remain; the absence of an international standard is a key issue. The dynamics of circulating AMH levels throughout life can be split into several distinct phases, with a peak in the early 20s before a decline to the menopause, with a strong and positive correlation with non-growing follicle recruitment. There is a more complex rise during childhood and adolescence, which is likely to be more reflective of different stages of follicle development. AMH shows limited short-term variability, but the influence of states such as prolonged oral contraceptive use need to be considered in clinical assessment. There are only very limited data on relationships between AMH and natural fertility at different stages of reproductive life, and while it has a relationship to age at menopause the marked variability in this needs further exploration. AMH may be useful in assessing the need for fertility preservation strategies and detecting post-chemotherapy or surgical damage to the ovarian reserve. Long-term follow-up of patients to ascertain fully the value of post-cancer serum AMH in predicting long-term ovarian function is required. There is a linear relationship between AMH and oocyte yield after ovarian stimulation, which is of value in predicting ovarian hyperstimulation. AMH can also identify 'poor responders', but it seems inappropriate at present to withhold IVF purely on this basis. Women with PCOS show markedly raised AMH levels, due to both the increased number of small antral follicles and intrinsic characteristics of those granulosa cells, and this may contribute to anovulation. The value of AMH in the diagnosis of PCOS remains controversial, but it may replace AFC in the future. CONCLUSIONS For the first time in female reproductive biology, it is possible to measure the submerged part of the iceberg of follicle growth, i.e. the intrinsic, so-called 'acyclic' ovarian activity. An international standard for AMH and improved assay validity are urgently needed to maximize the clinical utility of this very promising biomarker of ovarian function in a large array of clinical situations, both in childhood and adulthood.

2014 - The rate of high ovarian response in women identified at risk by a high serum AMH level is influenced by the type of gonadotropin [Articolo su rivista]
Arce, Joan Carles; Klein, Bjarke M; LA MARCA, Antonio
abstract

The aim was to compare ovarian response and clinical outcome of potential high-responders after stimulation with highly purified menotropin (HP-hMG) or recombinant follicle-stimulating hormone (rFSH) for in vitro fertilisation/intracytoplasmic sperm injection. Retrospective analysis was performed on data collected in two randomized controlled trials, one conducted following a long GnRH agonist protocol and the other with an antagonist protocol. Potential high-responders (n = 155 and n = 188 in the agonist and antagonist protocol, respectively) were defined as having an initial anti-Müllerian hormone (AMH) value >75th percentile (5.2 ng/ml). In both protocols, HP-hMG stimulation in women in the high AMH category was associated with a significantly lower occurrence of high response (≥15 oocytes retrieved) than rFSH stimulation; 33% versus 51% (p = 0.025) and 31% versus 49% (p = 0.015) in the long agonist and antagonist protocol, respectively. In the potential high-responder women, trends for improved live birth rate were observed with HP-hMG compared with rFSH (long agonist protocol: 33% versus 20%, p = 0.074; antagonist protocol: 34% versus 23%, p = 0.075; overall population: 34% versus 22%, p = 0.012). In conclusion, the type of gonadotropin used for ovarian stimulation influences high-response rates and potentially clinical outcome in women identified as potential high-responders.

2014 - The role of ovarian suspension in endometriosis surgery: a randomized controlled trial [Articolo su rivista]
Seracchioli, Renato; Di Donato, Nadine; Bertoldo, Valentina; LA MARCA, Antonio; Vicenzi, Claudia; Zannoni, Letizia; Villa, Gioia; Monti, Giorgia; Leonardi, Deborah; Giovanardi, Giulia; Venturoli, Stefano; Montanari, Giulia
abstract

A very high percentage of patients with severe pelvic endometriosis develop adhesions after laparoscopic surgery. The objective of this trial was to evaluate the role of ovarian suspension performed during surgery for severe endometriosis on ovarian adhesions and postoperative pelvic pain.

2013 - Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: An individual patient data approach [Articolo su rivista]
Broer, Simone L.; van Disseldorp, Jeroen; Broeze, Kimiko A.; Dolleman, Madeleine; Opmeer, Brent C.; Bossuyt, Patrick; Eijkemans, Marinus J. C.; Mol, Ben-Willem J.; Broekmans, Frank J. M.; Anderson, R. A.; Ashrafi, Mehrshad; Bancsi, L.; Caroppo, E.; Copperman, A.; Ebner, T.; Geva, M. Eldar; Erdem, M.; Greenblatt, E. M.; Jayaprakasan, K.; Fenning, Raine; Klinkert, E. R.; Kwee, J.; Lambalk, C. B.; La Marca, A.; Mcilveen, M.; Merce, L. T.; Muttukrishna, S.; Nelson, S. M.; Ng, H. Y.; Popovic-Todorovic, B.; Smeenk, J. M. J.; Tomás, C.; Van der Linden, P. J. Q.; van Rooij, I. A.; Vladimirov, I. K.
abstract

Background: Although ovarian reserve tests (ORTs) are frequently used prior to IVF treatment for outcome prediction, their added predictive value is unclear. We assessed the added value of ORTs to patient characteristics in the prediction of IVF outcome. Methods: An individual patient data (IPD) meta-analysis from published studies was performed. Studies on FSH, anti-Müllerian hormone (AMH) or antral follicle count (AFC) in women undergoing IVF were identified and authors were contacted. Using random intercept logistic regression models, we estimated the added predictive value of ORTs for poor response and ongoing pregnancy after IVF, relative to patient characteristics. Results: We were able to collect 28 study databases, comprising 5705 women undergoing IVF. The area under the receiver-operating characteristic curve (AUC) for female age in predicting poor response was 0.61. AFC and AMH each significantly improved the model fit (P-value &lt;0.001). Moreover, almost a similar accuracy was reached using AMH or AFC alone (AUC 0.78 and 0.76, respectively). Combining the two tests, however, did not improve prediction (AUC 0.80, P = 0.19) of poor response. In predicting ongoing pregnancy after IVF, age was the best single predictor (AUC 0.57), and none of the ORTs added any value. Conclusions: This IPD meta-analysis demonstrates that AFC and AMH clearly add to age in predicting poor response. As single tests, AFC and AMH both fully cover the prediction of poor ovarian response. In contrast, none of the ORTs add any information to the limited capacity of female age to predict ongoing pregnancy after IVF. The clinical usefulness of ORTs prior to IVF will be limited to the prediction of ovarian response. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

2013 - Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients [Articolo su rivista]
Arce, Joan Carles; LA MARCA, Antonio; Mirner Klein, Bjarke; Nyboe Andersen, Anders; Fleming, Richard
abstract

To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol.

2013 - External validation of anti-Müllerian hormone based prediction of live birth in assisted conception [Articolo su rivista]
Khader, Amani; Lloyd, Suzanne M; Mcconnachie, Alex; Fleming, Richard; Grisendi, Valentina; LA MARCA, Antonio; Nelson, Scott M.
abstract

External validation of anti-M??llerian hormone based prediction of live birth in assisted conception

2013 - Fresh blastocyst transfer as a clinical approach to overcome the detrimental effect of progesterone elevation at hCG triggering: a strategy in the context of the Italian law [Articolo su rivista]
Corti, Laura; Papaleo, Enrico; Pagliardini, Luca; Rabellotti, Elisa; Molgora, Michela; LA MARCA, Antonio; Vigano, Paola; Candiani, Massimo
abstract

To retrospectively evaluate whether fresh day-5 embryo transfer could overcomes the detrimental effect of subtle progesterone elevations at hCG administration on pregnancy outcomes in women undergoing ovarian hyperstimulation for IVF/ICSI cycles.

2013 - How Much Does AMH Really Vary in Normal Women? [Articolo su rivista]
LA MARCA, Antonio; Grisendi, Valentina; Griesinger, Georg
abstract

Anti-Mullerian Hormone (AMH) is an ovarian hormone expressed in growing follicles that have undergone recruitment from the primordial follicle pool but have not yet been selected for dominance. It is considered an accurate marker of ovarian reserve, able to reflect the size of the ovarian follicular pool of a woman of reproductive age. In comparison to other hormonal biomarkers such as serum FSH, low intra- and intermenstrual cycle variability have been proposed for AMH. This review summarizes the knowledge regarding within-subject variability, with particular attention on AMH intracycle variability. Moreover the impact of ethnicity, body mass index, and smoking behaviour on AMH interindividual variability will be reviewed. Finally changes in AMH serum levels in two conditions of ovarian quiescence, namely contraceptives use and pregnancy, will be discussed. The present review aims at guiding researchers and clinicians in interpreting AMH values and fluctuations in various research and clinical scenarios.

2013 - Individualization of the FSH starting dose in IVF/ICSI cycles using the antral follicle count [Articolo su rivista]
LA MARCA, Antonio; Grisendi, Valentina; Giulini, Simone; Argento, Cindy; Tirelli, Alessandra; Dondi, Giulia; Papaleo, Enrico; Volpe, Annibale
abstract

Individualization of the FSH starting dose in IVF/ICSI cycles using the antral follicle count

2013 - Oxidative stress status in follicular fluid and oocyte quality in women with polycystic ovary syndrome treated with inositol [Abstract in Atti di Convegno]
De Leo, V; Focarelli, R; Capaldo, A; Stendardi, A; Gambera, L; La Marca, A; Piomboni, P
abstract

N/A

2013 - Polymorphisms in gonadotropin and gonadotropin receptor genes as markers of ovarian reserve and response in in vitro fertilization [Articolo su rivista]
LA MARCA, Antonio; Sighinolfi, Giovanna; Argento, Cindy; Grisendi, Valentina; Casarini, Livio; Volpe, Annibale; Simoni, Manuela
abstract

Since gonadotropins are the fundamental hormones that control ovarian activity, genetic polymorphisms may alter gonadal responsiveness to glycoproteins; hence they are important regulators of hormone activity at the target level. The establishment of the pool of primordial follicles takes place during fetal life and is mainly under genetic control. Consequently, single nucleotide polymorphisms (SNPs) in gonadotropins and their receptors do not seem to be associated with any significant modification in the endowment of nongrowing follicles in the ovary. Indeed, the age at menopause, a biological characteristic strongly related to ovarian reserve, as well as markers of functional ovarian reserve such as anti-Müllerian hormone and antral follicle count, are not different in women with different genetic variants. Conversely, some polymorphisms in FSH receptor (FSHR) seem to be associated with modifications in ovarian activity. In particular, studies suggest that the Ser680 genotype for FSHR is a factor of relative resistance to FSH stimulation resulting in slightly higher FSH serum levels, thus leading to a prolonged duration of the menstrual cycle. Moreover, some FSHR gene polymorphisms show a positive association with ovarian response to exogenous gonadotropin administration, hence exhibiting some potential for a pharmacogenetic estimation of the FSH dosage in controlled ovarian stimulation. The study of SNPs of the FSHR gene is an interesting field of research that could provide us with new information about the way each woman responds to exogenous gonadotropin administration during ovulation induction.

2013 - Prediction of age at menopause from assessment of ovarian reserve may be improved by using body mass index and smoking status. [Articolo su rivista]
LA MARCA, Antonio; Sighinolfi, Giovanna; Papaleo, E; Cagnacci, Angelo; Volpe, Annibale; Faddy, M. J.
abstract

OBJECTIVE: Menopause is the consequence of exhaustion of the ovarian follicular pool. AMH, an indirect hormonal marker of ovarian reserve, has been recently proposed as a predictor for age at menopause. Since BMI and smoking status are relevant independent factors associated with age at menopause we evaluated whether a model including all three of these variables could improve AMH-based prediction of age at menopause. METHODS: In the present cohort study, participants were 375 eumenorrheic women aged 19-44 years and a sample of 2,635 Italian menopausal women. AMH values were obtained from the eumenorrheic women. RESULTS: Regression analysis of the AMH data showed that a quadratic function of age provided a good description of these data plotted on a logarithmic scale, with a distribution of residual deviates that was not normal but showed significant left-skewness. Under the hypothesis that menopause can be predicted by AMH dropping below a critical threshold, a model predicting menopausal age was constructed from the AMH regression model and applied to the data on menopause. With the AMH threshold dependent on the covariates BMI and smoking status, the effects of these covariates were shown to be highly significant. CONCLUSIONS: In the present study we confirmed the good level of conformity between the distributions of observed and AMH-predicted ages at menopause, and showed that using BMI and smoking status as additional variables improves AMH-based prediction of age at menopause.

2013 - Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: An individual patient data meta-analysis [Articolo su rivista]
Broer, Simone L.; Dólleman, Madeleine; Van Disseldorp, Jeroen; Broeze, Kimiko A.; Opmeer, Brent C.; Bossuyt, Patrick M. M.; Eijkemans, Martinus J. C.; Mol, Ben Willem; Broekmans, Frank J. M.; Aflatoonian, A.; Anderson, R. A.; Ashrafi, M.; Bancsi, L.; Caroppo, E.; Copperman, A. B.; Ebner, T.; Eldar-Geva, T.; Erdem, M.; Freour, T.; Gnoth, C.; Greenblatt, E. M.; Jayaprakasan, K.; Raine-Fenning, N.; Klinkert, E.; Kwee, J.; La Marca, A.; Lambalk, C. B.; McIlveen, M.; Mohiyiddeen, L.; Merce, L. T.; Muttukrishna, S.; Nardo, L. G.; Nelson, S. M.; Ng, H. Y.; Popovic-Todorovic, B.; Smeenk, J. M. J.; Tomás, C.; Van Der Linden, P. J. Q.; Van Rooij, I. A.; Vladimirov, I. K.
abstract

Objective: To evaluate whether ovarian reserve tests (ORTs) add prognostic value to patient characteristics, such as female age, in the prediction of excessive response to ovarian hyperstimulation in patients undergoing IVF, and whether their performance differs across clinical subgroups. Design: Authors of studies reporting on basal FSH, antimüllerian hormone (AMH), or antral follicle count (AFC) in relation to ovarian response to ovarian hyperstimulation were invited to share original data. Random intercept logistic regression models were used to estimate added value of ORTs on patient characteristics, while accounting for between-study heterogeneity. Receiver operating characteristic regression analyses were performed to study the effect of patient characteristics on ORT accuracy. Setting: In vitro fertilization clinics. Patient(s): A total of 4,786 women for the main analysis, with a subgroup of 1,023 women with information on all three ORTs. Intervention(s): None. Main Outcome Measure(s): Excessive response prediction. Result(s): We included 57 studies reporting on 32 databases. Female age had an area under the receiver operating characteristic curve of 0.61 for excessive response prediction. Antral follicle count and AMH significantly added prognostic value to this. A model with female age, AFC, and AMH had an area under the receiver operating characteristic curve of 0.85. The combination of AMH and AFC, without age, had similar accuracy. Subgroup analysis indicated that FSH performed significantly worse in predicting excessive response in higher age groups, AFC did significantly better, and AMH performed the same. Conclusion(s): We demonstrate that AFC and AMH add value to female age in the prediction of excessive response and that, for AFC and FSH, the discriminatory performance is affected by female age.

2013 - Reply of the authors [Articolo su rivista]
Arce, Joan Carles; LA MARCA, Antonio; Klein, Bjarke Mirner; Nyboe Andersen, Anders; Fleming, Richard
abstract

Reply of the authors

2013 - The combination of genetic variants of the FSHB and FSHR genes affects serum FSH in women of reproductive age [Articolo su rivista]
LA MARCA, Antonio; Papaleo, E; Alviggi, C; Ruvolo, G; De Placido, G; Candiani, M; Cittadini, E; De Michele, F; Moriondo, Valeria; Catellani, V; Volpe, Annibale; Simoni, Manuela
abstract

What is the effect of FSHB-211G>T together with the FSHR 2039 A>G on serum FSH in women?

2013 - The impact of socioeconomic and anamnestic characteristics on quality of life and sexual function in women with endometriosis [Articolo su rivista]
Di Donato, Nadine; Montanari, Giulia; Benfenati, Arianna; Leonardi, Debora; Bertoldo, Valentina; Monti, Giorgia; Casadio, Paolo; La Marca, Antonio; Seracchioli, Renato
abstract

Purpose: The aim of this study is to evaluate the impact of sociodemographic and anamnestic characteristics of women with deep infiltrating endometriosis (DIE) on the quality of life and sexual function. Methods: It is a prospective cohort study including 200 women with preoperative clinical and ultrasound diagnosis of DIE. They completed a preoperative questionnaire regarding sociodemographic and anamnestic characteristics, a sexual activity questionnaire (Sexual Health Outcomes in Women Questionnaire [SHOW-Q]) and a quality of life questionnaire (Short Form-36 Health Survey [SF-36]). Results: The mean values obtained for the SF-36 (50.7 ± 21.1) and SHOW-Q (56.4 ± 21.1) questionnaire showed an impairment of quality of life and sexual function. Women with a history of previous surgery had significantly lower scores of SF-36 and SHOW-Q questionnaires than women without (p< 0.05). The increase of body mass index (BMI) was positively correlated with an improvement of sexual function (p = 0.008). Postsecondary education was significantly associated with a better quality of life (p = 0.001). Conclusions: Patients with DIE have an impairment of quality of life and sexual function. Educational level, BMI and previous surgery may influence quality of life and sexual function of women affected by DIE. © 2013 Wichtig Editore.

2013 - Whatever its variability, antimüllerian hormone remains the most stable hormonal predictor [Articolo su rivista]
LA MARCA, Antonio
abstract

amh variability

2012 - Anti-Müllerian hormone: clairvoyance or crystal clear? [Articolo su rivista]
Nelson, Scott M; Anderson, Richard A; Broekmans, Frank J; Raine Fenning, Nick; Fleming, Richard; LA MARCA, Antonio
abstract

The clinical use of anti-Müllerian hormone (AMH) has increased exponentially due to its unique relationship with the ovarian reserve and ability to predict ovarian response, facilitate pretreatment counselling and individualize treatment strategies to minimize the risk of ovarian hyperstimulation syndrome. There is now a rapidly increasing literature examining additional possibilities for AMH, all of which suggest that its reach extends far beyond the assisted conception clinic. The recognition that it is a significantly more accurate and reliable measure of ovarian reserve than the antral follicle count or FSH has led to its adoption by physicians to counsel women on their reproductive lifespan, the impact of gonadotoxic chemotherapy, radiotherapy and surgery on the ovarian reserve and allow polycystic ovarian syndrome to be diagnosed by primary care physicians. We propose that there is an adequate literature base to embrace this technology while continuing to develop and refine how AMH can optimize patient care.

2012 - Development of a nomogram based on markers of ovarian reserve for the individualisation of the follicle-stimulating hormone starting dose in in vitro fertilisation cycles [Articolo su rivista]
LA MARCA, Antonio; Papaleo, E; Grisendi, V; Argento, Cindy; Giulini, Simone; Volpe, Annibale
abstract

To elaborate a nomogram based on markers of ovarian reserve for the calculation of the appropriate starting dose of follicle-stimulating hormone (FSH).

2012 - Evaluation of the treatment with D-chiro-inositol on levels of oxidative stress in PCOS patients [Valutazione del trattamento con D-chiro-inositolo sui livelli di stress ossidativo nelle pazienti con PCOS] [Articolo su rivista]
De Leo, V; LA MARCA, Antonio; Cappelli, V; Stendardi, A; Focarelli, R; Musacchio, M. C; Piomboni, P.
abstract

Recent studies on the pathophysiology of infertility have shown that oxidative stress (OS) can be one of the causal factors. The OS is, by definition, an imbalance between the production of reactive oxygen species (ROS) and antioxidant defense systems. It seems that oxidative stress plays an important role in almost all phases of human reproduction. In fact, ROS are involved in the modulation of a large spectrum of reproductive functions such as oocyte maturation, ovarian steroidogenesis, corpus luteum functions and are involved in the processes of fertilization, embryo development and pregnancy, but also in some diseases that cause infertility. Polycystic ovary syndrome (PCOS) has recently been associated with increased oxidative stress, often put in relation to the syndrome's typical metabolic disorder. Inositol is an intracellular mediator of insulin, currently much used as a therapeutic agent in PCOS. While its main action takes place via insulin sensitization, little is known about the possible effects of other disorders, such as oxidative stress, associated with PCOS. The purpose of this study was therefore to assess the effect of D-chiro-inositol on the state of oxidative stress in the follicular fluid of women with PCOS.

2012 - LH and hCG Action on the Same Receptor Results in Quantitatively and Qualitatively Different Intracellular Signalling [Articolo su rivista]
Casarini, Livio; Lispi, M.; Longobardi, S.; Milosa, F.; LA MARCA, Antonio; Tagliasacchi, Daniela; Pignatti, Elisa; Simoni, Manuela
abstract

Human luteinizing hormone (hLH) and chorionic gonadotropin (hCG) act on the same receptor (LHCGR) but it is not known whether they elicit the same cellular and molecular response. This study compares for the first time the activation of cell-signalling pathways and gene expression in response to hLH and hCG. Using recombinant hLH and recombinant hCG we evaluated the kinetics of cAMP production in COS-7 and hGL5 cells permanently expressing LHCGR (COS-7/LHCGR, hGL5/LHCGR), as well as cAMP, ERK1/2, AKT activation and progesterone production in primary human granulosa cells (hGLC). The expression of selected target genes was measured in the presence or absence of ERK- or AKT-pathways inhibitors. In COS-7/LHCGR cells, hCG is 5-fold more potent than hLH (cAMP ED50: 107.1±14.3 pM and 530.0±51.2 pM, respectively). hLH maximal effect was significantly faster (10 minutes by hLH; 1 hour by hCG). In hGLC continuous exposure to equipotent doses of gonadotropins up to 36 hours revealed that intracellular cAMP production is oscillating and significantly higher by hCG versus hLH. Conversely, phospho-ERK1/2 and -AKT activation was more potent and sustained by hLH versus hCG. ERK1/2 and AKT inhibition removed the inhibitory effect on NRG1 (neuregulin) expression by hLH but not by hCG; ERK1/2 inhibition significantly increased hLH- but not hCG-stimulated CYP19A1 (aromatase) expression. We conclude that: i) hCG is more potent on cAMP production, while hLH is more potent on ERK and AKT activation; ii) hGLC respond to equipotent, constant hLH or hCG stimulation with a fluctuating cAMP production and progressive progesterone secretion; and iii) the expression of hLH and hCG target genes partly involves the activation of different pathways depending on the ligand. Therefore, the LHCGR is able to differentiate the activity of hLH and hCG.

2012 - Nitric Oxide concentration in endometrial washing throughout the menstrual cycle [Articolo su rivista]
S., Giulini; M. M., Carbone; LA MARCA, Antonio; A., Tirelli; Radi, Daniele; Volpe, Annibale
abstract

PURPOSE: Nitric oxide (NO) intrauterine production has been shown to have an important role in the reproductive system in females. The objective of the present study was to evaluate NO concentration in endometrial washing throughout the menstrual cycle. METHODS: Observational study at Institute of Obstetrics and Gynecology, Mother-Infant Department, University Hospital. The study included 40 healthy fertile women, aged 21-40, with regular menstrual cycle, undergoing endometrial washing by hydrosonography for the assessment of NO concentration. RESULTS: Nitric oxide concentration in endometrial washing were low in early to mid proliferative phase (4.73 ± 1.57 mcM/L), but significantly higher (p < 0.05) in late proliferative phase (7.30 ± 3.37 mcM/L) early secretory phase (8.05 ± 1.97 mcM/L) and late secretory phase (8.69 ± 4.12 mcM/L) of menstrual cycle. CONCLUSIONS: Endometrial washing by hydrosonography is a simple, minimally invasive, and effective tool to use in the evaluation of cyclical NO intrauterine production. Nitric oxide concentrations increased during the late proliferative and secretory phase of menstrual cycle.

2012 - Normal serum anti-Müllerian hormone levels in the general female population and the relationship with reproductive history [Articolo su rivista]
La Marca, Antonio; Spada, Elena; Grisendi, Valentina; Argento, Cindy; Papaleo, Enrico; Milani, Silvano; Volpe, Annibale
abstract

Objective: Anti-Müllerian hormone (AMH) has been evaluated by several groups as a potential novel clinical marker of ovarian reserve. Considering the wide use of AMH measurement in daily clinical practice and the large number of conditions in which it may be used, it is essential to establish reference values in the healthy female population. In this study we aim to calculate the age-by-age normal values of circulating AMH. In addition, we report on AMH levels in women according to BMI, smoking status and reproductive history. Study design: The study was performed at the Institute of Obstetrics and Gynecology, University of Modena, between January 2008 and December 2010. A total of 416 healthy women (aged 18-51) were recruited and serum AMH levels were measured for all of them. The centiles of AMH distribution were estimated with the CG-LMS method. The relationship between AMH levels and the womens' characteristics such as BMI, smoking status and reproductive history was analysed by using the uni- and multi-variable regression analysis and the Chi-square test. Results: Serum AMH concentrations show a progressive decline with female ageing. Age-related nomograms for the 5th, 25th, 50th, 75th, and 95th percentiles of AMH were produced. Mean AMH concentrations were not modified by smoking habit and BMI and were independent of parity of the women. Conclusion: In the present study, we established age-specific reference values for circulating AMH levels in the eumenorrheic female population. AMH measurement produces new information on ovarian pathophysiology and ovarian reserve and the establishment of reference values for AMH is the first step for a correct interpretation of the assay. © 2012 Elsevier Ireland Ltd.

2012 - Possibilities and Limits of Ovarian Reserve Testing in ART [Articolo su rivista]
LA MARCA, Antonio; C., Argento; G., Sighinolfi; V., Grisendi; M., Carbone; G., D'Ippolito; A. C., Artenisio; G., Stabile; Volpe, Annibale
abstract

Markers of ovarian reserve are associated with ovarian aging as they decline with chronologic age, and hence may predict stages of reproductive aging including the menopause transition. Assessment of ovarian reserve include measurement of serum follicle stimulating hormone (FSH), anti-Müllerian hormone (AMH), and inhibin-B. Ultrasound determination of antral follicle count (AFC), ovarian vascularity and ovarian volume also can have a role. The clomiphene citrate challenge test (CCCT), exogenous FSH ovarian reserve test (EFORT), and GnRH-agonist stimulation test (GAST) are dynamic methods that have been used in the past to assess ovarian reserve. In infertile women, ovarian reserve markers can be used to predict low and high oocyte yield and treatment failure in women undergoing in vitro fertilization. However the markers may have limitations when an in depth analysis of their accuracy, cost, convenience, and utility is performed As ovarian reserve markers may permit the identification of both the extremes of ovarian stimulation, a possible role for their measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in the ovarian reserve testing before initiation of an IVF cycle and whether the ovarian reserve markers-determined strategy of ovarian stimulation for assisted conception may be associated to improved live birth rate.

2012 - Reply: The Bologna criteria for poor ovarian response; Has the job been accomplished? [Articolo su rivista]
Ferraretti, A. P.; Marca, A. L.; Fauser, B.; Tarlatzis, B.; Nargund, G.; Gianaroli, L.
abstract

2012 - Reply: The definition of 'poor response': Bologna criteria [Articolo su rivista]
Ferraretti, A. P.; La Marca, A.; Fauser, B. C. J. M.; Tarlatzis, B.; Nargund, G.; Gianaroli, L.
abstract

N/A

2012 - Understanding the perceptions of and emotional barriers to infertility treatment: a survey in four European countries [Articolo su rivista]
Domar, Alice; Gordon, Keith; Garcia Velasco, Juan; LA MARCA, Antonio; Barriere, Paul; Beligotti, Fabiola
abstract

Infertility can significantly impact women's lives and personal relationships. Despite the negative impact of infertility, a significant number of women who are struggling to conceive do not consult a physician. This cross-sectional survey was conducted to determine the emotional impact of infertility on women to identify which aspects of fertility treatment contribute to the psychological stress experienced by so many patients and to identify barriers to seeking treatment.

2011 - Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study [Articolo su rivista]
Almog, Benny; Shehata, Fady; Suissa, Sami; Holzer, Hananel; Shalom Paz, Einat; La Marca, Antonio; Muttukrishna, Shanthi; Blazar, Andrew; Hackett, Richard; Nelson, Scott M; Cunha Filho, Joao Sabino; Eldar Geva, Talia; Margalioth, Ehud J; Raine Fenning, Nick; Jayaprakasan, Kannamannadiar; Mcilveen, Myvanwy; Wunder, Dorothea; Freour, Thomas; Nardo, Luciano G; Balasch, Juan; Peñarrubia, Joana; Smeenk, Jesper; Gnoth, Christian; Godehardt, Erhard; Lee, Tsung Hsien; Lee, Maw Sheng; Levin, Ishai; Gamzu, Ronni; Tulandi, Togas
abstract

To produce age-related normograms for serum antimüllerian hormone (AMH) level in infertile women without polycystic ovaries (non-PCO).

2011 - Age-specific nomogram for the decline in antral follicle count throughout the reproductive period [Articolo su rivista]
LA MARCA, Antonio; E., Spada; G., Sighinolfi; C., Argento; A., Tirelli; S., Giulini; S., Milani; Volpe, Annibale
abstract

To investigate the relationship between antral follicle count (AFC) and chronological age and to establish normal values for AFC in women with regular menstrual cycles.Cross-sectional study.University hospital.Four hundred fifteen premenopausal women were recruited for the study. Data from 362 patients were available for the statistical analysis.AFC was measured by transvaginal ultrasound examination.Estimating the relationship between AFC and age and developing the AFC nomogram.The analysis showed a linear decline in AFC with age; for every year increase in age, the median AFC decreases by 0.4. The AFC corresponding to the 5th, 25th, 50th, 75th, and 95th centiles for each age have been calculated.A linear relationship of AFC to age was found. For the first time, a nomogram reporting normal and interquartile values for AFC, age by age, throughout the reproductive period has been provided. Until now, the interpretation of the measurement was mainly based on the individual experience of the operator, because no normative data were present. Therefore, the establishment of a nomogram of AFC values is the first step to counsel patients on a scientific basis.

2011 - Anti-Müllerian hormone-based prediction model for a live birth in assisted reproduction [Articolo su rivista]
LA MARCA, Antonio; S. M., Nelson; G., Sighinolfi; M., Manno; E., Baraldi; L., Roli; S., Xella; T., Marsella; D., Tagliasacchi; D'Amico, Roberto; Volpe, Annibale
abstract

Prediction of assisted reproduction treatment outcome has been the focus of clinical research for many years, with a variety of prognostic models describing the probability of an ongoing pregnancy or a live birth. This study assessed whether serum anti-Müllerian hormone (AMH) concentrations may be incorporated into a model to enhance the prediction of a live birth in women undergoing their first IVF cycle, by analysing a database containing clinical and laboratory information on IVF cycles carried out between 2005 and 2008 at the Mother-Infant Department of University Hospital, Modena. Logistic regression was used to examine the association of live birth with baseline patient characteristics. Only AMH and age were demonstrated in regression analysis to predict live birth, so a model solely based on these two criteria was generated. The model permitted the identification of live birth with a sensitivity of 79.2\% and a specificity of only 44.2\%. In the prediction of a live birth following IVF, a distinction, however moderate, can be made between couples with a good and a poor prognosis. The success of IVF was found to mainly depend on maternal age and serum AMH concentrations, one of the most relevant and valuable markers of ovarian reserve.

2011 - ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria [Articolo su rivista]
Ferraretti, A. P; LA MARCA, Antonio; Fauser, B. C. J. M; Tarlatzis, B; Nargund, G; Gianaroli, L.
abstract

The definition presented here represents the first realistic attempt by the scientific community to standardize the definition of poor ovarian response (POR) in a simple and reproducible manner. POR to ovarian stimulation usually indicates a reduction in follicular response, resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to define the poor response in IVF, at least two of the following three features must be present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and (iii) an abnormal ovarian reserve test (ORT). Two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ORT. By definition, the term POR refers to the ovarian response, and therefore, one stimulated cycle is considered essential for the diagnosis of POR. However, patients of advanced age with an abnormal ORT may be classified as poor responders since both advanced age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of ovarian stimulation cycle outcome. In this case, the patients should be more properly defined as 'expected poor responder'. If this definition of POR is uniformly adapted as the 'minimal' criteria needed to select patients for future clinical trials, more homogeneous populations will be tested for any new protocols. Finally, by reducing bias caused by spurious POR definitions, it will be possible to compare results and to draw reliable conclusions.

2011 - Hormonal and ultrasound markers of ovarian function in a woman with a balanced 1;11 translocation [Articolo su rivista]
G., D'Ippolito; A., Tirelli; S., Giulini; Volpe, Annibale; LA MARCA, Antonio
abstract

To present a case of a poor responder woman with a rare balanced autosomal translocation.Case report.Infertility center in a university teaching hospital.A 34-year-old white woman with primary infertility.Laboratory and ultrasound evaluation, karyotype analysis, ovarian stimulation with gonadotropins.Markers of ovarian reserve and ovarian response to gonadotropin stimulation.The patient was a carrier of a balanced translocation (1;11) (q23;p11.2). The hormone ovarian reserve markers (FSH, anti-Mullerian hormone, inhibin B) were within the normal range. The antral follicle count (AFC) was measured twice and only in one occasion did it reach the lower limit of the normal range. Furthermore, the patient had regular menstrual cycles. However, ovarian response to the administration of a maximal dose FSH was extremely poor.Patients with balanced autosomal translocations should be counseled regarding their increased risk for poor response even if markers of ovarian reserve are in the range of normality.

2011 - Periodontal disease and nitric oxide levels in low risk women with preterm labor [Articolo su rivista]
L., Giannella; Giulini, Simone; L. B., Cerami; LA MARCA, Antonio; Forabosco, Andrea; Volpe, Annibale
abstract

The aims of the study were to evaluate the possible association between periodontal disease (PD) and preterm labor (PTL), to assess whether the presence of periodontal disease in women with PTL increases the risk of preterm birth (PTB), and to evaluate the role of nitric oxide (NO) in this possible association.This study included 820 nulligravid women with low risk socioeconomic status: 400 cases with PTL and 420 controls with normal pregnancy, between 25 and 33 weeks+6 days of weeks' gestation. At enrollment, periodontal examination and detection of plasma, gingival and cervical NO levels were performed. We compared the periodontal status of the two groups; we detected the presence of PD and compared NO levels. We then followed the outcome of women with PTL and compared obstetric status and PTB rate between patients with and without PD.Logistic regression analysis revealed a strong association between PD and PTL (adjusted odds ratio: 2.83, 95\% confidence interval (CI) 1.86-4.23; P<0.0001). Non parametric Mann-Whitney U-test demonstrated significant differences in gingival and cervical NO levels between women with PTL and controls (respectively, median 85.1 μmol/L, interquartile range (i.r.) 51.2-177 vs median 50.5 μmol/L, i.r. 34.5-109.65, P<0.0001; and median 102 μmol/L, i.r. 53.05-182.7 vs median 38.9 μmol/L, i.r. 32.87-46.1, P<0.0001). The ability of mean-gingival NO levels to predict PTL was examined by ROC curve analysis: the area under the curve was 0.817 (95\% CI 0.774-0.854; P<0.0001). The cut-off level for the greatest sensitivity and specificity for mean-gingival NO levels was 116.04 μmol/L (sensitivity 0.57, specificity 0.94). Positive and negative predictive values were, respectively, 90.65\% and 69.73\%. Among women with PTL, the risk of PTB increased in women with PD (adjusted relative risk: 3.85, 95\% CI 2.11-6.06; P<0.0001).In this tested population, PTL is associated with PD. The presence of PD in women with PTL increases the risk of premature delivery. NO may be a new marker to explain this association.

2011 - Predizione della menopausa basata su AMH, body mass index e fumo [Altro]
Sighinolfi, G; Cagnacci, Angelo; Toniolo, D; Volpe, Annibale; LA MARCA, Antonio
abstract

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2011 - The journey from the old to the new AMH assay: how to avoid getting lost in the values [Articolo su rivista]
Nelson, S. M; LA MARCA, Antonio
abstract

Anti-Müllerian hormone (AMH) is set to dominate reproductive endocrinology because of its unique relationship with the ovarian reserve. To date half of the published articles have used the Diagnostic Systems Lab (DSL) assay and the other half the Immunotech (IOT) assay. Unfortunately, these assays utilize two different primary antibodies against AMH and different standards, and consequently the crude values reported can differ substantially, with the IOT assay giving values for AMH that are higher than those obtained with the DSL assay. With the recent consolidation of these two companies by Beckman Coulter, and their sole ownership of the patent to measure mammalian AMH, there is finally a single commercially available assay - the AMH Gen II assay, which will fully replace the DSL and IOT assays. The aim of this article is to briefly focus on the different assays for AMH evaluation in order to give readers hopefully helpful suggestions for a correct interpretation of the AMH measurement. A brief overview on the development and performance characteristics of the new assay, how it relates to previous values and previously developed nomograms and where the future lies for AMH is also provided.

2011 - The ovarian follicular pool and reproductive outcome in women. [Articolo su rivista]
LA MARCA, Antonio; Papaleo, E; D'Ippolito, G; Grisendi, V; Argento, C; Volpe, Annibale
abstract

Both quantitative and qualitative aspects of the ovarian reserve are inversely related to age, hence the relationship existing between low quantity and low quality may be only indirect and depending on their strong relationship with the third variable, namely women's age. However the possibility exists that they may also be directly related. The objective of this study was to investigate the relationship between ovarian reserve and female reproductive outcome. Eight published studies reporting histological data on the human ovaries have been carefully reviewed. Only studies where the reproductive history of women was reported have been included for the analysis. The non-growing follicle count was plotted versus age and the best fit line through the data was calculated. All patients were assigned as to be above or below the calculated median hence differentiating women with high or low ovarian reserve for their age. A similar number of pregnancies ended in miscarriage in women with low and high ovarian reserve. The number of deliveries per woman in both the groups was not statistically different. The results of the study do not support the hypothesis that quality and quantity of the follicular pool are directly related.

2011 - Two hormone for one receptors: dissecting out LH and hCG activity with an in vitro approach [Abstract in Atti di Convegno]
Casarini, Livio; LA MARCA, Antonio; Pignatti, Elisa; Simoni, Manuela
abstract

Introduction: LH and hCG act on the same receptor (LHCGR), have different half-lives and in vivo biopotency. It is not known whether they elicit the same cellular and molecular response. The aim of this study was to compare the kinetics of cAMP response to recombinant LH and hCG. Design: In COS-7 cells permanently expressing the human LHCGR (COS-7/LHCGR) we evaluated LH and hCG dose-response curves, by measuring total cAMP after 3 h of incubation. We then evaluated the time-course of intracellular cAMP production in the presence of ED50 doses of LH and hCG over 3 h. Finally we evaluated the long-term response to LH and hCG by exposing human primary granulosa lutein cells (hGLC) to ED50 doses over 12 h. All incubations were performed in the presence of IBMX. Results: In COS-7/LHCGR cells, we observed significantly different ED50 for LH (475.75±137.33 pM, mean±S.D.) and hCG (101.75±44.63 pM) (Mann–Whitney’s U-test, P=0.029; n=4). Maximal LH stimulation of intracellular cAMP, about 50 fold over control, reached a plateau in 10 min, while maximal hCG stimulation at similar levels was attained only after 1 h (Anova; P<0.05; n=3). In hGLC continuous exposure to LH and hCG resulted in a repetitive, pulsatile increase of intracellular cAMP with peaks every 3–4 h and significantly higher levels of stimulation in the presence of hCG vs LH (Anova; P<0.05; n=3). Conclusions: Equimolar concentrations of human recombinant LH and hCG result in significantly higher in vitro biopotency of hCG (about 5-fold). Equipotent concentration (ED50) of LH and hCG stimulate a faster response to LH within the first 3 h, but a quantitatively higher response to hCG over 12 h. hGLC respond to constant LH/hCG stimulation in a pulsatile fashion, suggesting a novel control of gonadotropins action at the receptor level.

2010 - Adnexal Torsion during Pregnancy after Oocyte In Vitro Maturation and Intracytoplasmic Sperm Injection Cycle. [Articolo su rivista]
S., Giulini; G., Dante; S., Xella; Marca, A. L.; T., Marsella; Volpe, Annibale
abstract

We report a case of right adnexal torsion during pregnancy after an oocyte in vitro maturation and intracitoplasmic sperm injection cycle in patient with polycystic ovary syndrome. A 31-year-old woman with a typical clinical disorder of polycystic ovarian syndrome was included in an oocyte in vitro maturation program. Right adnexal torsion occurred two days after embryo transfer, and laparoscopy detorsion was successfully performed with preservation of adnexa. The patient had a full-term pregnancy and delivered a healthy infant at 40 weeks of gestation. To our knowledge this is the first report of adnexal torsion after an oocyte in vitro maturation and intracitoplasmic sperm injection program.

2010 - Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). [Articolo su rivista]
Marca, A. L.; G., Sighinolfi; Radi, Daniele; C., Argento; E., Baraldi; A. C., Artenisio; G., Stabile; Volpe, Annibale
abstract

BACKGROUND: In women, anti-Müllerian hormone (AMH) levels may represent the ovarian follicular pool and could be a useful marker of ovarian reserve. The clinical application of AMH measurement has been proposed in the prediction of quantitative and qualitative aspects in assisted reproductive technologies (ART). In men AMH is secreted in both the serum and seminal fluid. Its measurement may be useful in clinical evaluation of the infertile male. METHODS: The PubMed database was systematically searched for studies published until the end of January 2009, search criteria relevant to AMH, ovarian reserve, ovarian response to gonadotrophin stimulation, spermatogenesis and azoospermia were used. RESULTS: AMH seems to be a better marker in predicting ovarian response to controlled ovarian stimulation than age of the patient, FSH, estradiol and inhibin B. A similar performance for AMH and antral follicular count has been reported. In clinical practice, AMH measurement may be useful in the prediction of poor response and cycle cancellation and also of hyper-response and ovarian hyperstimulation syndrome. In the male, the wide overlap of AMH values between controls and infertile men precludes this hormone from being a useful marker of spermatogenesis. CONCLUSIONS: As AMH may permit the identification of both the extremes of ovarian stimulation, a possible role for its measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in ovarian reserve testing. Regarding the role of AMH in the evaluation of infertile men, AMH as single marker of spermatogenesis does not seem to reach a satisfactory clinical utility.

2010 - Embryo quality and implantation rate in two different culture media: ISM1 versus Universal IVF Medium. [Articolo su rivista]
S., Xella; T., Marsella; Tagliasacchi, Daniela; S., Giulini; Marca, A. L.; A., Tirelli; Volpe, Annibale
abstract

OBJECTIVE: To compare the outcome of two different culture media marketed by the MediCult AS Company (Jyllinge, Denmark)-Universal IVF Medium and ISM1 Medium culture-which, in addition to glucose, pyruvate, and energy-providing components, also contain amino acids, nucleotides, vitamins, and cholesterol. DESIGN: Laboratory and retrospective clinical study. SETTING: University teaching hospital. PATIENT(S): A total of 726 patients, undergoing IVF-intracytoplasmic sperm injection procedure, comparable in mean age range, oocyte retrieval, and infertility indication, were included in the study. Laboratory quality and standard procedures were maintained unaffected. INTERVENTION(S): Oocyte retrieval, different embryo culture media. MAIN OUTCOME MEASURE(S): Embryo quality, ongoing pregnancy, and implantation rate. RESULT(S): The frequency of good-quality embryos (79\% vs. 74\%) and the percentages of ongoing pregnancy (27.5\% vs. 18\%) and implantation rate (15\% vs. 10\%) were significantly higher in the group treated with ISM1 Medium rather than Universal IVF Medium. CONCLUSION(S): ISM1 Medium culture seems to improve the performance of embryonic growth and development, as well as increasing the percentage of pregnancy.

2010 - Normal serum concentrations of anti-Müllerian hormone in women with regular menstrual cycles [Articolo su rivista]
A. L., Marca; G., Sighinolfi; S., Giulini; M., Traglia; C., Argento; C., Sala; C., Masciullo; Volpe, Annibale; D., Toniolo; LA MARCA, Antonio
abstract

Anti-Müllerian hormone (AMH) has become the 'molecule of the moment' in the field of reproductive endocrinology. Indeed, it is valuable as a means of increasing understanding of ovarian pathophysiology and for guiding clinical management across a broad range of conditions. However, no normative values have been established for circulating AMH in healthy women. In this cross-sectional study, 277 healthy females (aged 18-50 years) were included. AMH was measured by commercial enzyme-linked immunosorbent assay. Serum AMH concentrations show a progressive decline with female ageing. The age-related changes in AMH were best fitted by a polynomial function. Mean AMH concentrations were not modified by past use of oral contraceptive and were independent of parity of women. Age-specific normative values for circulating AMH concentration were established. AMH concentrations seem to be independent of the reproductive history of the patient.

2010 - Primary ovarian insufficiency: autoimmune causes. [Articolo su rivista]
Marca, A. L.; A., Brozzetti; Sighinolfi, Giovanna; S., Marzotti; Volpe, Annibale; A., Falorni
abstract

To review the pathogenesis of premature ovarian insufficiency due to steroid cell autoimmunity (SCA-POI).Autoimmune oophoritis is characterized by a selective mononuclear cell infiltration into the theca layer of large, antral follicles, with earlier stage follicles consistently free of lymphocytic infiltration. SCA-POI is caused by the selective autoimmune destruction of theca cells with preservation of granulosa cells that produce low amounts of estradiol because of lack of substrates. Typically, serum concentrations of inhibins are increased in women with SCA-POI, as compared to both healthy fertile women and women with other forms of ovarian insufficiency. Normal serum antimüllerian hormone (AMH) concentrations were detected in two-thirds of women with recently diagnosed SCA-POI, which demonstrates that this form of ovarian insufficiency is associated with a preserved pool of functioning follicles.The combined measurement of autoantibodies and markers of ovarian reserve (as inhibin B and AMH) may permit to identify women with POI due to steroid cell autoimmunity with a preserved proportion of primordial and primary follicles. In the future the development of techniques of in-vitro folliculogenesis may permit new treatment strategies for women with SCA-POI-related infertility.

2010 - Rectus abdominis muscle endometriosis: Case report and review of the literature [Articolo su rivista]
Giannella, Luca; La Marca, Antonio; Ternelli, Giliana; Menozzi, Glennis
abstract

The abdominal wall is an uncommon site of extrapelvic endometriosis, which usually develops in a previous surgical scar and it should be considered in the differential diagnosis of any abdominal swelling. Endometriosis involving the rectus abdominis muscle is a very rare event and its rarity explains the incomplete nature of the reports in the literature. Up to the present, 18 cases with lesions contained entirely within the rectus abdominis muscle were clearly documented in medical literature with only four cases as a primary location. We report a case, which came to our observation, of primary endometriosis of the rectus abdominis muscle. The patient underwent only surgery without any medical treatment. Currently, the patient is in follow up for four years with no recovery of the disease. In our experience, surgery is the treatment of choice and it is decisive. We reviewed the literature and summarized all reported cases. © 2010 Japan Society of Obstetrics and Gynecology.

2009 - Anti-Mullerian hormone (AMH): what do we still need to know? [Articolo su rivista]
Marca, A. L.; F. J., Broekmans; Volpe, Annibale; B. C., Fauser; N. S., Macklon; E. S., H.
abstract

In the ovary, Anti-Müllerian hormone (AMH) is produced by the granulosa cells of early developing follicles and inhibits the transition from the primordial to the primary follicular stage. AMH levels can be measured in serum and have been shown to be proportional to the number of small antral follicles. In women serum AMH levels decrease with age and are undetectable in the post-menopausal period. In patients with premature ovarian failure AMH is undetectable or greatly reduced depending of the number of antral follicles in the ovaries. In contrast, AMH levels have been shown to be increased in women with polycystic ovary syndrome (PCOS). AMH levels appear to represent the quantity of the ovarian follicle pool and may become a useful marker of ovarian reserve. AMH measurement could also be useful in the prediction of the extremes of ovarian response to gonadotrophin stimulation for in vitro fertilization, namely poor- and hyper-response. Although AMH has the potential to increase our understanding of ovarian pathophysiology, and to guide clinical management in a broad range of conditions, a number of important questions relating to both the basic physiology of AMH and its clinical implications need to be answered.

2009 - MATER protein as substrate of PKCepsilon in human cumulus cells. [Articolo su rivista]
Maraldi, Tullia; Riccio, Massimo; Sena, Paola; Marzona, Laura; A., Nicoli; Marca, A. L.; Marmiroli, Sandra; Bertacchini, Jessika; LA SALA, Giovanni Battista; DE POL, Anto
abstract

High activity of the phosphoinositide 3-kinase/Akt pathway in cumulus cells plays an important role in FSH regulation of cell function and Protein Kinase C epsilon (PKCepsilon) collaborates with these signalling pathways to regulate cell proliferation. Relevant roles in follicular development are played by Maternal Antigen That Embryos Require (MATER) that is a cumulus cell- and oocyte-specific protein dependent on the maternal genome. We recently demonstrated that human MATER localizes at specific domains of oocytes and, for the first time, also in cumulus cells. MATER contains a carboxy-terminal leucine-rich repeat domain involved in protein-protein interactions regulating different cellular functions. Here we investigated the functional role of MATER. Thus, we performed coimmunoprecipitation experiments using HEK293T cells expressing human MATER; a similar approach was then followed in human cumulus/follicular cells. In MATER(+)HEK293T cells, we observed that this protein acts as a phosphorylation substrate of PKCepsilon. Western blot experiments indicate that, unlike oocytes, human cumulus cells express PKCepsilon. Immunoprecipitation and confocal analysis suggest for the first time that MATER protein interacts with this protein kinase in cumulus cells under physiological conditions. Since PKCepsilon is known to collaborate with antiapoptotic signalling pathways, this suggests a novel mechanism for the function of MATER in follicular maturation.

2009 - Primary ovarian insufficiency due to steroidogenic cell autoimmunity is associated with a preserved pool of functioning follicles [Articolo su rivista]
La Marca, Antonio; Marzotti, Stefania; Brozzetti, Annalisa; Stabile, Gaspare; Artenisio, Alfredo Carducci; Bini, Vittorio; Giordano, Roberta; De Bellis, Annamaria; Volpe, Annibale; Falorni, Alberto
abstract

Context: Primary ovarian insufficiency (POI) is defined as hypergonadotropic amenorrhea before the age of 40 yr. In 4-5% of patients with POI, an ovarian autoimmune process is present. Design: Serum concentrations of antimüllerian hormone (AMH) have been determined in 26 women with POI due to steroidogenic cell autoimmunity (SCA-POI), 66 with nonautoimmune idiopathic POI (iPOI), 40 postmenopausal women (PMW), and 44 healthy fertile women (HW). SCA-POI was diagnosed according to presence of steroidogenic enzyme autoantibodies (17α-hydroxylase, side chain cleavage, and 21-hydroxylase autoantibodies). Results: AMH concentrations were significantly higher in women with SCA-POI than women with iPOI (P = 0.018) orPMW(P = 0.03) but significantly lower thanHW(P < 0.0001). AMH was detected in 11 of 26 women with SCA-POI (42%) and seven of 66 with iPOI (11%) (P = 0.002). Serum concentrations above the fifth percentile of the normal range (0.6 ng/ml) were detected in nine of 26 women with SCA-POI (35%) and four of 66 with iPOI (6%) (P = 0.001). Eight of 12 women with SCA-POI with less than 5 yr (67%) and one of 14 with longer disease duration (7%) had AMH concentrations within the normal range (P = 0.003). AMH concentrations correlated inversely with disease duration in women with SCA-POI (rho = -0.563, P = 0.003) but not women with iPOI. AMH correlated inversely with FSH serum concentrations inHW(rho = -0.584, P < 0.001) but not PMW or women with POI. Conclusions: Two thirds of women with recent-onset SCA-POI had normal AMH concentrations. Women with SCA-POI, differently from those with iPOI, present a preserved ovarian follicle pool for several years after diagnosis of ovarian insufficiency. Copyright © 2009 by The Endocrine Society.

2009 - Seminal plasma total antioxidant capacity and semen parameters in patients with varicocele [Articolo su rivista]
Giulini, Simone; Sblendorio, Valeriana; Xella, Susanna; La Marca, Antonio; Palmieri, Beniamino; Volpe, Annibale
abstract

Total antioxidant capacity (TAC) was evaluated in the seminal plasma of infertile patients with varicocele in relation to their semen parameters. The study recruited 60 patients affected by varicocele and 10 fertile non-varicocele subjects as controls. Controls had normal semen parameters and proven fertility. On the basis of semen parameters, patients with varicocele were grouped into normozoospermic (n = 12), asthenozoospermic (n = 8), oligoasthenozoospermic (n = 40). The group with oligosthenozoospermia was divided into mild (<20 × 106/ml; ≥ 15 × 106/ml),moderate (<15 × 106/ml; ≥5 × 106/ml), and severe (<5 × 106/ml), based on sperm count. Antioxidant activity was measured in seminal plasma and peripheral blood using the free oxygen radicals defence test. No significant differences were observed in peripheral blood TAC concentrations between controls and groups. In patients with varicocele and moderate oligoasthenozoospermia or severe oligoasthenozoospermia, seminal plasma TAC concentrations were significantly lower (P < 0.05) than in controls and normozoospermic patients with varicocele. Moreover, in patients with severe oligosthenozoospermia, seminal plasma TAC concentrations were also significantly lower (P < 0.05) than in asthenozoozpermic patients with varicocele. In all subjects, concentrations of TAC showed a positive correlation with sperm concentration (r = 0.93, P < 0.05) and motility (r = 0.92, P < 0.05). © 2009 Published by Reproductive Healthcare Ltd.

2008 - Human ovarian tissue cryopreservation: effect of sucrose concentration on morphological features after thawing [Articolo su rivista]
Marsella, Tiziana; Sena, Paola; Xella, Susanna; LA MARCA, Antonio; Giulini, Simone; DE POL, Anto; Volpe, Annibale; Marzona, Laura
abstract

Recent improvements in techniques in clinical assisted reproduction have led to an increased interest in the cryopreservation of human ovarian tissue as a way of preserving fertility and ovarian steroidogenic activity in young cancer patients. Acceptable follicular survival in frozen-thawed human ovarian tissue has generally been reported. Since a 0.3 mol/l sucrose concentration in cryopreservation solutions evidently increases human oocyte survival after cryopreservation, the aim of this study was to observe the effect of sucrose concentrations of 0.2 mol/l and 0.3 mol/l on human ovarian tissue survival after thawing. Ovarian cortical slices from 10 patients, 22-36 years of age, were cryopreserved slowly using 0.2 mol/l or 0.3 mol/l sucrose with 1,2-propanediol (1.5 mol/l) as the cryoprotectants. Light and electron microscopy were used for the histological analyses. Results showed that both treatments produced an increase in damaged cells; however, the use of 0.3 mol/l sucrose showed a smaller percentage of damaged germ cells than 0.2 mol/l sucrose, and therefore was less detrimental to the thawed ovarian tissue. However as the damage occurred principally in the stroma and follicular cells rather than in the oocytes, the suitability of these cryopreservation protocols must be further evaluated prior to considering the use of stored ovarian cortex for autografting after thawing.

2007 - Anti-Mullerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology [Articolo su rivista]
LA MARCA, Antonio; Giulini, S; Tirelli, A; Bertucci, Emma; Marsella, T; Xella, S; Volpe, Annibale
abstract

BACKGROUND: Recently, a new marker, the anti-Mullerian hormone (AMH), has been evaluated as a marker of ovarian response. Serum AMH levels have been measured at frequent time-points during the menstrual cycle, suggesting the complete absence of fluctuation. The aim of this study was to evaluate whether serum AMH measurement on any day of the menstrual cycle could predict ovarian response in women undergoing assisted reproductive technology (ART). METHODS: This study included 48 women attending the IVF/ICSI programme. Blood withdrawal for AMH measurement was performed in all the patients independently of the day of the menstrual cycle. RESULTS: Women in the lowest AMH quartile (&lt; 0.4 ng/ml) were older and required a higher dose of recombinant FSH than women in the highest quartile (&gt; 7 ng/ml). All the cancelled cycles due to absent response were in the group of the lowest AMH quartile, whereas the cancelled cycles due to risk of ovarian hyperstimulation syndrome (OHSS) were in the group of the highest AMH quartile. This study demonstrated a strong correlation between serum AMH levels and ovarian response to gonadotrophin stimulation. CONCLUSION: For the first time, clinicians may have a reliable serum marker of ovarian response that can be measured independently of the day of the menstrual cycle.

2007 - Structural sperm and aneuploidies studies in a case of spermatogenesis recovery after the use of androgenic anabolic steroids [Articolo su rivista]
Moretti, E.; Collodel, G.; La Marca, A.; Piomboni, P.; Scapigliati, G.; Baccetti, B.
abstract

Purpose: Azoospermia may sometimes be related to the use of androgenic anabolic steroids. We report the case of an azoospermic man who had abused androgenic anabolic steroids and who recovered spermatogenesis six months after cessation of abuse and the administration of hormonal therapy. Methods: An azoospermic 34-year-old man came to Regional Referral Center for Male Infertility. The recovery of spermatogenesis was observed after the cessation of abuse of steroids and the administration of hormonal therapy. Ultrastructural analysis of sperm was carried out by transmission electron microscopy, and the meiotic segregation of chromosomes 1, 9, 18, X, Y was investigated. Results: Mathematically elaborated transmission electron microscopy data highlighted seminal features close to normal fertility. Fluorescence in situ hybridisation showed a high frequency of XY disomy in sperm. Conclusions: Our findings confirm the recovery of spermatogenesis but suggest a possible relationship between altered meiotic segregation and the abuse of androgenic anabolic steroids. © 2007 Springer Science+Business Media, Inc.

2007 - The Anti-Müllerian hormone and ovarian cancer [Articolo su rivista]
La Marca, Antonio; Volpe, Annibale
abstract

The Anti-Mullerian hormone (AMH), which is produced by fetal Sertoli cells, is responsible for regression of Mullerian ducts, the anlagen for uterus and Fallopian tubes, during male sex differentiation. Ovarian granulosa cells also secrete AMH from late in fetal life. The patterns of expression of AMH and its type II receptor in the post-natal ovary indicate that AMH may play an important role in ovarian folliculogenesis. Recent advances in the physiological role of AMH has stimulated interest in the significance of AMH as a diagnostic marker and therapeutic agent for ovarian cancer. Currently, AMH has been shown to be a circulating marker specifically for granulosa cell tumour (GCT). Its diagnostic performance seems to be very good, with a sensitivity ranging between 76 and 93%. In patients treated for GCT, AMH may be used post-operatively as marker for the efficacy of surgery and for disease recurrence. Based on the physiological inhibitory role of AMH in the Mullerian ducts, it has been proposed that AMH may inhibit epithelial ovarian cancer cell both in vitro and in vivo. These observations will be the basis for future research aiming to investigate the possible clinical role of AMH as neo-adjuvant, or most probably adjuvant, therapy for ovarian cancer. © The Author 2007. Published by Oxford University Press.

2007 - The management of vaginal agenesis: report of 104 cases [Articolo su rivista]
Jasonni, Valerio M.; La Marca, Antonio; Naldi, Silvia; Matonti, Giuseppe; D'Anna, Rosario
abstract

Objective: To present the results obtained in 104 cases of vaginal aplasia resolved with self-dilatation or with surgical procedures such as the McIndoe or Williams operations. Design: Retrospective study. Setting: Departments of obstetrics and gynecology of universities in Bologna, Modena, and Messina, Italy. Patient(s): One hundred four cases of vaginal aplasia. Intervention(s): Self-dilatation and surgical procedures such as the McIndoe or Williams operations. Main Outcome Measure(s): Outcome of the treatment. Result(s): From 1977 to 2002, 104 cases of vaginal agenesis were treated. The mean age of the treated patients was 16.5 years old (range, 13-18 years). After 6 months of self-dilatation, 41 subjects obtained a new cavity of about 10-12 cm in length. In 14 patients, a space ranging from 3 to 5 cm was obtained. The technique failed in 49 patients. Fourteen patients underwent the Williams surgical procedure, while the remaining 49 patients underwent to the McIndoe procedure. All patients were successfully treated, and the only complication, a rectovaginal fistula that was repaired, occurred in one case of the McIndoe operation. Conclusion(s): Self-dilatation should be the first approach because of its high success rate; the Williams surgical approach should be chosen when self-dilatation partially fails or when previous surgical attempts are unsuccessful. Finally, the McIndoe procedure and its variants should be used when self-dilatation completely fails. © 2007 American Society for Reproductive Medicine.

2007 - Utero-vaginal anastomosis in the treatment of cervical atresia [Articolo su rivista]
Jasonni, Valerio M.; La Marca, Antonio; Matonti, Giuseppe
abstract

Cervical atresia is an extremely rare malformation. Its incidence is not well known and management is controversial. The surgical technique and results of utero-vaginal anastomosis in 3 women affected by cervical atresia are described. © 2007 Taylor & Francis.

2006 - Anti-Mullerian hormone (AMH) in female reproduction: is measurement of circulating AMH a useful tool? [Articolo su rivista]
LA MARCA, Antonio; Volpe, Annibale
abstract

Anti-Mallerian hormone (AMH) is a dimeric glycoprotein, a member of the transforming growth factor (TGF) superfamily. It is produced exclusively in the gonads and is involved in the regulation of follicular growth and development. In the ovary AMH is produced by the granulosa cells of early developing follicles and seems to be able to inhibit the initiation of primordial follicle growth and FSH-induced follicle growth. As AMH is largely expressed throughout folliculogenesis, from the primary follicular stage towards the antral stage, serum levels of AMH may represent both the quantity and quality of the ovarian follicle pool. Compared to other ovarian tests, AMH seems to be the best marker reflecting the decline of reproductive age. AMH measurement could be useful in the prediction of the menopausal transition. It could also be used to predict poor ovarian response and possibly the prognosis of in vitro fertilization (IVF) cycles. AMH has been shown to be a good surrogate markers for polycystic ovary syndrome (PCOS). Finally, its use as a marker for granulosa cell tumours has been proposed. A clearer understanding of its role in ovarian physiology may help clinicians to find a role for AMH measurement in the field of reproductive medicine.

2006 - Anti-Mullerian serum levels during pregnacy [Articolo su rivista]
LA MARCA, Antonio; Volpe, Annibale
abstract

..

2006 - AntiMüllerian serum levels during pregnancy [2] [Articolo su rivista]
La Marca, A.; Volpe, A.
abstract

2006 - L'induzione della crescita follicolare nelle donne con anovulazione [Ovulation induction in anovulatory women] [Articolo su rivista]
LA MARCA, Antonio; Bertucci, Emma; Giulini, Simone; Tirelli, Alessandra; Malavasi, Barbara; Volpe, Annibale
abstract

Ovulation induction therapy is administered to stimulate follicular growth and induce ovulation in anovulatory infertile women. In anovulatory women with polycystic ovary syndrome, the treatment of choice is clomiphene citrate, whereas in clomiphene nonresponders, gonadotrophins are given as secondary therapy. Currently, insulin-sensitizing agents are used in the treatment of polycystic ovary syndrome to restore menstrual cyclicity. In selected patients, laparoscopic drilling has also been suggested. In anovulatory patients affected with hypogonadotropic hypogonadism, treatment is based on gonadotrophin replacement therapy or pulsatile gonadotrophin-releasing hormone infusion. In ovulation induction therapy the clinician's attention should be directed at restoring normal ovary function. When pharmacotherapy is required, monofollicular growth should be induced to reduce the risk of multiple pregnancy.

2006 - Rectovaginal fistula repair using fascia graft of autologous abdominal muscles [Articolo su rivista]
Jasonni, V. M.; La Marca, A.; Manenti, A.
abstract

N/A

2006 - Serum anti-Mullerian hormone levels in women with secondary amenorrhea [Abstract in Atti di Convegno]
La Marca, A; Giulini, S; Pati, M; Levratti, Paolo; Tirelli, A; Mehmeti, I; Volpe, A
abstract

N/A

2006 - Serum anti-Mullerian hormone throughout the human menstrual cycle [Articolo su rivista]
LA MARCA, Antonio; Stabile, G; Artenisio, Ac; Volpe, Annibale
abstract

BACKGROUND: The anti-Mullerian hormone (AMH) is a member of the transforming growth factor (TGF) superfamily. In women, AMH serum levels can be almost undetectable at birth, with a subtle increase noted after puberty. Data are lacking with regard to menstrual cycle day-to-day fluctuations. This longitudinal study was designed to investigate the pattern of secretion of AMH throughout the menstrual cycle in regularly cycling women. METHODS: Twelve healthy female subjects aged 18-24 years participated in this study. Blood samples were taken every other day throughout one menstrual cycle. Serum FSH, LH, estradiol (E-2), progesterone, inhibin B and AMH levels were assayed by double-antibody radioimmunoassay using commercial kits. RESULTS: Serum AMH in the first days of the menstrual cycle (days -14 to -12) was 3.8 +/- 1.2 ng/ml (mean +/- SD). No significant changes were observed in serum AMH levels throughout the menstrual cycle. The highest value was 3.9 +/- 1.3 ng/ml at day -12 and the lowest value was 3.4 +/- 1.1 ng/ml at day 14, and the difference was not significant. CONCLUSION: In this study, we demonstrated that serum AMH levels do not change significantly throughout the menstrual cycle. Hence, AMH exhibits a relatively stable expression during the menstrual cycle, making it an attractive determinant of ovarian activity.

2006 - Serum anti-mullerian hormone levels in women with secondary amenorrhea [Articolo su rivista]
LA MARCA, Antonio; Pati, M; Orvieto, R; Stabile, G; Artenisio, Ac; Volpe, Annibale
abstract

Anti-mullerian hormone (AMH) appears to regulate follicular growth. The aim of this study was to investigate AMH serum levels in patients affected by secondary amenorrhea. The AMH was significantly lower (or undetectable) in patients with premature ovarian failure (POF) and significantly higher in patients affected by polycystic ovary syndrome (PCOS). We suggest that Serum AMH evaluation Could be associated with that of established hormones., Such as FSH, LH. and E-2 when the activity of hypothalamo-pituitary-ovarian axis is investigated.

2006 - Soluble CD40 ligand levels during controlled ovarian hyperstimulation - A possible culprit of systemic inflammation [Articolo su rivista]
Orvieto, Raoul; Schachter, Benny; Yulzari-roll, Vered; La Marca, Antonio; Bar, Jacob; Fisch, Benjamin
abstract

Aim: To investigate the behavior and association of serum sex-steroids and serum CD40 ligand in patients undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). Design: Prospective, observational study. Setting: The IVF unit of an academic medical center. Patients and methods: Blood was drawn three times during the COH cycle from 17 patients undergoing the long gonadotropin-releasing hormone-analog protocol: (i) day on which adequate suppression was obtained (Day-S); (ii) day of or prior to administration of human chorionic gonadotropin (Day-hCG); and (iii) day of ovum pick-up (Day-OPU). Levels of sex steroids and serum CD40 ligand were compared among the three time points. Results: During gonadotropin treatment, serum ovarian sex steroids (estradiol, progesterone, free testosterone and androstenedione) significantly increased while CD40 ligand levels nonsignificantly decreased. After hCG administration, there was a significant increase in the levels of serum CD40 ligand, ovarian androgens, and progesterone, with a significant decrease in estradiol levels. No correlations were observed between CD40 ligand and ovarian sex-steroid levels or other treatment variables. Conclusion: The administration of hCG leads to activation of systemic inflammation, as reflected by CD40 ligand levels. This, in turn, may lead to the development of ovarian hyperstimulation syndrome via several mechanisms, including an increase in several angiogenic factors. © 2006 The Authors Journal compilation © 2006 Blackwell Munksgaard.

2006 - Sperm chromosome aneuploidy and gonadotrophin treatment [Abstract in Atti di Convegno]
De Leo, V; La Marca, A; Piomboni, P; Morgante, G; Pitaro, M; Fratoni, A; Collodel, G; Petraglia, F
abstract

N/A

2006 - Substituting human chorionic gonadotropin by gonadotropin-releasing hormone agonist to trigger final follicular maturation, during controlled ovarian hyperstimulation, results in less systemic inflammation [Articolo su rivista]
Orvieto, Raoul; Zagatsky, Irina; Yulzari-Roll, Vered; La Marca, Antonio; Fisch, Benjamin
abstract

Background. To investigate the degree of systemic inflammation, as reflected by serum C-reactive protein (CRP) levels, associated with controlled ovarian hyperstimulation (COH) with human chorionic gonadotropin (hCG) or gonadotropin-releasing hormone (GnRH) agonist for the induction of final follicular maturation.Design. Prospective, observational study.Setting. An in vitro fertilization (IVF) unit of an academic medical center.Patients. Twenty-four women undergoing COH and IVF with the flexible GnRH antagonist protocol were prospectively assigned to receive hCG or GnRH agonist for the induction of final follicular maturation.Methods. Blood was drawn three times during COH for measurement of sex-steroid and CRP levels: the day on which adequate suppression was obtained (Day-0); the day of or prior to administration of hCG (Day-hCG); and (3) the day of ovum pick-up (Day-OPU). Levels were compared among the three time points in the two groups.Results. No between-group differences were observed in terms of patient age, gonadotropin dosage, duration of stimulation or number of oocytes retrieved. Serum CRP levels were significantly higher on Day-OPU than on Day-hCG and Day-0, but the difference was significant only in the hCG group (p<0.03 for both). The percentage change in CRP levels after hCG administration (Day-OPU vs. Day-hCG) (96%) was higher than that after GnRH administration (23%).Conclusion. Administration of GnRH agonist in patients undergoing COH for IVF yields a lesser degree of systemic inflammation, as reflected by CRP levels, than hCG. © 2006 Informa UK Ltd.

2006 - Ultrastructural and DNA fragmentation analyses in swim-up selected human sperm [Articolo su rivista]
Piomboni, P.; Bruni, E.; Capitani, S.; Gambera, L.; Moretti, E.; La Marca, A.; De Leo, V.; Baccetti, B.
abstract

□ Seventeen sperm samples were evaluated by transmission electron microscopy (TEM) before and after swim-up separation. DNA-fragmentation was tested by terminal d-UTP nick end labeling (TUNEL) in unselected and selected semen samples, and the results were analyzed in relation to sperm ultrastructural characteristics detected by TEM. A significant improvement in mean numbers and percentages of structurally normal sperm was observed after swim-up selection, corresponding to a significant decrease in the percentage of necrotic and apoptotic sperm, while the percentage of sperm with immature nuclei did not change significantly. TUNEL indicated a significant decrease in chromatin-fragmented sperm after swim-up. Swim up selection based on sperm motility excludes many sperm with ultrastructural evidence of necrosis (absent or reacted acrosome, disrupted chromatin, broken plasma membrane) and apoptosis (misshapen nuclei with marginated chromatin), as confirmed by TUNEL analysis. Nevertheless, immature sperm with elliptical or roundish nuclei, misshapen acrosomes and uncondensed chromatin remain part of fertilizing pool. Copyright © Taylor & Francis LLC.

2005 - Anti-Mullerian hormone concentrations in maternal serum during pregnancy [Articolo su rivista]
LA MARCA, Antonio; S., Giulini; R., Orvieto; V., DE LEO; Volpe, Annibale
abstract

BACKGROUND: In females, anti-Mullerian hormone (AMH) is expressed only by the ovary. AMH is secreted by the granulosa cells of ovarian follicles and appears to regulate early follicle development. AMH is detected in serum from women of reproductive age and its levels vary slightly with the menstrual cycle, reaching the peak value in the late follicular phase. This study investigated serum AMH levels throughout gestation and after delivery in healthy pregnant women. METHODS: This cross-sectional study recruited pregnant women and healthy non-pregnant women, 84 in total. AMH, FSH and E-2 were measured in the follicular phase, in the three trimesters of pregnancy and in early puerperium. RESULTS: Estradiol and FSH levels followed the expected patterns during gestation. During the follicular phase of the menstrual cycle AMH levels were 1.9 +/- 0.5 ng/ml. In the three trimesters of pregnancy and in early puerperium AMH levels were: 2.1 +/- 0.56, 2.4 +/- 0.64, 1.95 +/- 0.6 and 2.05 +/- 0.55 ng/ml respectively. No significant modifications were found in AMH levels during pregnancy and in the early puerperium. CONCLUSIONS: This study has obtained information on AMH and on the possible relationship with FSH. We hypothesize that the profile of the new marker of ovarian activity AMH may indicate that initial non-cyclic ovarian follicular activity during pregnancy is not abolished. Moreover FSH, does not seem to play a direct role on AMH synthesis and secretion.

2005 - Anti-mullerian hormone in premenopausal women and after spontaneous or surgically induced menopause [Articolo su rivista]
LA MARCA, Antonio; De Leo, V; Giulini, S; Orvieto, R; Malmusi, S; Giannella, L; Volpe, Annibale
abstract

Objective: The objectives of this study were: (1) to determine anti-Mullerian hormane (AMH) levels in menopausal women, and (2) to confirm the source of AMH in cycling women and its disappearance after the removal of the source. Methods: An observational and prospective study was conducted. Results: A total of 47 women were recruited for the study. The study population consisted of the following group of patients: (A) women of late reproductive age (n = 24; mean age +/- SD, 44 +/- 2.8 years); (B) menopausal women (n = 14: mean age, 56 +/- 4 years); and (C) regularly cycling women undergoing surgical menopause (n = 9; mean age, 43 +/- 4 years). Blood samples were obtained from all patients. In patients undergoing surgery, blood samples were obtained before and after surgery. AMH was undetectable in 13 of 14 postmenopausal women, whereas it was undetectable in only two of 24 women of late reproductive age. A significant negative correlation has been found between AMH and age or follicle-stimulating hormone (FSH) in women of late reproductive age. In women who were candidates for oophorectomy, samples were obtained 3-5 days after surgery. AMH was undetectable after the surgery in all women. Conclusions: We found that AMH levels decreased in women in the late reproductive period and that menopause and ovariectomy in regularly cycling women are associated to undetectable AMH in serum. These observations confirm that the ovary could be the only source of AMH in women and that it is a novel marker for ovarian aging.

2005 - Clinical applications of nimesulide in pain, arthritic conditions and fever [Capitolo/Saggio]
Bianchi, M.; Ehrlich, G. E.; Facchinetti, F.; Huskisson, E. C.; Jenoure, P.; La Marca, A.; Rainsford, K. D.
abstract

Conclusions: In comparison with conventional NSAIDs (with COX-1 as well as COX-2 inhibitory effects) and the coxibs, nimesulide has been shown in a large number of studies to be equivalent to, or in some cases more effective in relieving pain and inflammatory signs and symptoms. Recent evidence suggesting that nimesulide may have fast onset of action in acute pain may be an advantage for the drug in certain clinical situations. Nimesulide has proven to be an effective drug in comparison with other NSAIDs including the coxibs.

2005 - Comparison of a gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist flare-up regimen in poor responders undergoing ovarian stimulation [Articolo su rivista]
Malmusi, S; LA MARCA, Antonio; Giulini, S; Xella, S; Tagliasacchi, D; Marsella, T; Volpe, Annibale
abstract

Objective: To compare the efficacy of flare-up and GnRH-antagonist treatment in poor-responder patients. Design: Randomized prospective study. Setting: Assisted reproduction center. Patient(s): Fifty-five poor-responder patients undergoing intracytoplasmic sperm injection (ICSI). Intervention(s): Thirty patients received GnRH agonist on the 1st day of menstruation, followed by exogenous gonadotropins from the 2nd day. Twenty-five patients received exogenous gonadotropins starting on the second day of menstruation, followed by GnRH antagonist when the leading follicle reached 14 mm in diameter. Main Outcome Measure(s): The total dose of FSH administered during the ovarian stimulation, as well as the number of mature oocytes retrieved, embryo quality, fertilization, implantation, and pregnancy rates were evaluated. Result(s): The number of ampules and units of FSH administered were significantly less in the flare-up than in the antagonist group. The fertilization rate (8.4% vs. 63%) was significantly higher in the flare-up than in the GnRH-antagonist group. The implantation and pregnancy rate were similar in the two groups. Conclusion(s): The flare-up protocol appears to be more effective than the GnRH-antagonist protocol in terms of mature oocytes retrieved, fertilization rate, and top-quality embryos transferred in poor-responder patients.

2005 - Does plasma insulin level affect ovarian response to exogenous administration of follicle-stimulating hormone in women without polycystic ovary syndrome? [Articolo su rivista]
LA MARCA, Antonio; Pati, Mariangela; Giulini, S; Levratti, Paola; Caretto, S; Volpe, Annibale
abstract

Background. Raised insulin levels have been shown to contribute to ovarian overproduction of androgens. Hyperinsulinemia, usually associated with polycystic ovary syndrome (PCOS), brings about greater ovarian endocrine and morphological responses to ovulation induced by follicle-stimulating hormone (FSH). This indicates that elevated levels of insulin play a role in the endocrine and paracrine control of the ovaries. Objective. The aim of the present study was to investigate whether basal insulin levels influence ovarian response to FSH in healthy women (non-PCOS) undergoing assisted reproduction by in vitro fertilization-embryo transfer (IVF-ET). Methods. The study included 36 consecutive women, 27-45 years old, undergoing IVF-ET for tubal-factor or male-factor infertility. Serum insulin levels were determined on the day of administration of gonaclotropin-releasing hormone analog (GnRHa) and on the first day of FSH administration. Results. Mean insulin levels were 6 +/- 3 and 7 +/- 3 mu U/ml on the day of GnRHa and FSH administration, respectively. No correlations were found between basal insulin level, days of treatment, total FSH dose, estradiol level and the number of oocytes retrieved. Conclusions. The results of the present study show that normal levels of insulin do not seem to influence ovarian response to FSH in non-PCOS women. In all patients included in our study, serum insulin levels did not correlate with IVF stimulation data (days of stimulation, total FSH dose) nor with IVF-ET outcome. Thus the study demonstrates that, in patients who are not insulin-resistant, insulin does not correlate with ovarian response to FSH administration.

2005 - Evidence for cycle-dependent expression of follicle-stimulating hormone receptor in human endometrium [Articolo su rivista]
LA MARCA, Antonio; Stabile, G; Rivasi, Francesco; Volpe, Annibale; Carducci Artenisio, A
abstract

Objective. It was the purpose of the present study to investigate whether human endometrium expresses follicle-stimulating hormone (FSH) receptor mRNA and peptide, and whether this expression is regulated in a cycle-dependent manner in endometrium derived from various phases of the menstrual cycle. Methods. FSH receptor mRNA and peptide expression were evaluated by reverse transcription-polymerase chain reaction and by immunohistochemistry in endometrium from 15 women undergoing hysteroscopy to evaluate the morphology of the uterine cavity or hysterectomy for leiomyomas. Results. FSH receptor mRNA was expressed by human endometrium, and its peptide was located immunohistochemically in both proliferative and secretory endometrial epithelial and stromal cells. A significant increase in immunoreactive FSH receptor was observed during the secretory phase. Conclusions. We have shown the presence of FSH receptor in human endometrium and demonstrated that FSH receptor immunostaining is upregulated in the secretory phase of the menstrual cycle. The dynamic pattern of receptor expression indicates that FSH may play a role in the regulation of endometrial function and possibly in the embryo-endometrium interaction.

2005 - Metformin treatment of PCOS during adolescence and the reproductive period [Articolo su rivista]
LA MARCA, Antonio; Artensio, Ac; Stabile, G; Volpe, Annibale
abstract

Insulin resistance is a common feature of PCOS. Hyperinsulinemia has been causally linked with all features of the syndrome, such as hyperandrogenism, reproductive disorders, and metabolic disturbances. Several insulin-sensitizing agents have been tested in the management of PCOS. Metformin is the only drug currently in widespread clinical use for PCOS. In a high percentage of patients, treatment with metformin is followed by regularization of the menstrual cycle, less pronounced hyperandrogenism and cardiovascular risk factors, and some improvement in the response to therapies aimed at induction of ovulation. In adolescent girls who are anovulatory and moderately obese, metformin administration can have a normalizing effect on multiple aberrations within the endocrine-metabolic status. During the reproductive period, metformin administration can improve reproductive function and the establishment of pregnancy. A role of metformin in prevention of gestational diabetes and hypertensive complications of pregnancy has yet to be shown. Finally, any real benefit of insulin-lowering treatment in terms of lesser cardiovascular risk in women with PCOS women remains to be demonstrated.

2005 - Ovarian androgens but not estrogens correlate with the degree of systemic inflammation observed during controlled ovarian hyperstimulation [Articolo su rivista]
Orvieto, Raoul; Fisch, Naama; Yulzari-Roll, Vered; La Marca, Antonio
abstract

Aim. To investigate the behavior and association of serum androgen and serum C-reactive protein (CRP) in patients undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). Design. Prospective, observational study. Setting. An IVF unit of an academic medical center. Patients and methods. Blood was drawn three times during the COH cycle from 15 patients undergoing the long gonadotropin-releasing hormone-analog protocol: the day on which adequate suppression was obtained (Day-S); the day of or prior to administration of human chorionic gonadotropin (Day-hCG); and the day of ovum pick-up (Day-OPU). Levels of sex steroids and serum CRP were compared among the three time points. Results. There was a significant increase in serum ovarian androgen levels during gonadotropin treatment. After hCG administration, there was a significant increase in the levels of both serum CRP and ovarian androgens (testosterone, androstenedione), with no significant change in adrenal androgen (dehydroepiandrosterone). Significant correlations were observed between CRP and ovarian androgen levels but not with dehydroepiandrosterone sulfate or estradiol levels. Conclusion. In patients undergoing COH for IVF, ovarian androgen levels increase in correlation with the degree of inflammation, as reflected by CRP levels. Further studies are necessary to elucidate whether androgens play a role in or are predictive of the systemic inflammatory response in COH. © 2005 Taylor & Francis.

2005 - Progestin effects on epidermal growth factor receptor (EGFR) endometrial expression in normal and hyperplastic endometrium [Articolo su rivista]
Jasonni, V. M.; La Marca, A.; Santini, D.
abstract

N/A

2005 - Pyrexia, leukocytosis and elevated circulating platelets associated to uterine stromal sarcoma with rhabdoid differentiation [Articolo su rivista]
Jasonni, Valerio; LA MARCA, Antonio; G., Vito; M., Crotti; Rivasi, Francesco
abstract

Fever of unknown origin can be associated to soft tissues sarcoma and two cases are reported in the literature regarding sarcoma and pyrexia sustained by the tumor [1]. In the present report, we describe a case of uterine sarcoma associated to fever, leukocytosis and circulating elevated levels of platelets.A 46-year-old women with diagnosis of severe anemia (Hb 5.9 gr/dl) and uterine leiomyoma was admitted as an emergency to our hospital. The patient experienced normal cycles until 5 months before when cyclic menhorragia appeared.An office endometrial biopsy showed proliferative endometrium and the patient was submitted to progestins administration in order to reduce the cyclic bleeding. During the last 5 months, pyrexia of unknown origin appeared and the laboratory examination showed leukocytosis and increased platelets.On presentation, the physical exam was notable for an enlarged irregularly shaped uterus. There was no inguinal, axillary or supraclavicolar adenopathy.

2005 - Serum androgen levels in patients undergoing controlled ovarian hyperstimulation for in vitro fertilization cycles [Articolo su rivista]
Orvieto, Raoul; Yulzari-Roll, Vered; La Marca, Antonio; Ashkenazi, Jacob; Fisch, Benjamin
abstract

Aim. To investigate androgen behavior during controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). Design. A prospective, observational study. Setting. An IVF unit of an academic medical center. Patients and methods. Blood was drawn three times during the COH cycle from 17 consecutive patients undergoing the long gonadotropin-releasing hormone-analog protocol: the day on which adequate suppression was obtained (Day-S); the day of or prior to administration of human chorionic gonadotropin (Day-hCG); and (3) the day of ovum pick-up (Day-OPU). Results. There was a significant increase in serum sex steroid levels during gonadotropin treatment. After hCG administration, there was a significant increase in levels of serum 17-hydroxyprogesterone (17-OHP) and ovarian androgens (total and free testosterone and androstenedione), with no significant change in adrenal androgen (dehydroepiandrosterone sulfate). Significant correlations were observed between plasma estradiol (E2) and androgen levels during COH and until hCG administration, but not after hCG administration. The E2/testosterone ratio increased significantly during COH and until hCG administration, and then decreased significantly. The number of oocytes retrieved correlated significantly with serum 17-OHP, E2and E2/testosterone ratio. The number of gonadotropin ampoules used correlated inversely only with serum E2levels. Conclusion. In patients undergoing COH for IVF, androgen levels increase in response to gonadotropin, and then again after hCG administration. Although the E2/testosterone ratio correlates with the number of oocytes retrieved, androgen levels do not. © 2005 Taylor & Francis.

2005 - The influence of urinary versus recombinant gonadotropin on serum P-selectin levels in vivo [Articolo su rivista]
Orvieto, Raoul; La Marca, Antonio; Badir, Walid; Golan, Oren; Bar, Jacob; Fisch, Benjamin
abstract

Objective. To determine the levels of serum P-selectin in patients undergoing controlled ovarian hyperstimulation (COH) cycles with urinary (uGn) versus recombinant gonadotropins (rGn) and their possible correlation with COH variables. Methods. This study was carried out in a large university-based infertility and in vitro fertilization unit. A total of 14 consecutive patients underwent our routine COH protocol for unexplained infertility with either uGn or rGn. Blood was drawn three times during the COH cycle: on day 2 or 3 of the menstrual cycle and before gonadotropin treatment (day-0); on the day of or prior to human chorionic gonadotropin (hCG) administration (day-hCG); and on the day of ovulation (day-OVU). Levels of sex steroids and serum P-selectin were compared among the three time points between the uGn and rGn subgroups. P-selectin was measured with a commercial quantitative sandwich immunoassay technique. Results. In both Gn subgroups, there was a non-significant increase in P-selectin level between day-hCG and day-0. In the rGN subgroup, no significant difference was observed in P-selectin levels between day-OVU and day-hCG. In the uGn subgroup, P-selectin levels were significantly lower in day-OVU as compared to day-hCG (p < 0.04) and day-0 (p < 0.04). No differences were noted between the uGn and rGn subgroups in patient age, number of gonadotropin ampules used or estradiol and progesterone levels during the COH cycle or P-selectin on day-0 or day-hCG. However, on day-OVU, P-selectin levels were significantly lower in the uGn than the rGn subroups (p < 0.01). Conclusion. The increase in serum P-selectin level during COH until the peak of estradiol level was significantly attenuated after hCG administration in patients pretreated with uGn, but not rGN. It would therefore be prudent in patients at risk of developing thromboembolism undergoing COH to use uGN rather than rGN in order to attenuate platelet activation. © 2005 Taylor & Francis Group Ltd.

2004 - Anti-Mullerian hormone plasma levels in spontaneous menstrual cycle and during treatment with FSH to induce ovulation [Articolo su rivista]
LA MARCA, Antonio; Malmusi, S; Giulini, S; Tamaro, Lf; Orvieto, R; Levratti, P; Volpe, Annibale
abstract

Background: Anti-Mullerian hormone (AMH) is member of the transforming growth factor-beta superfamily of growth factors. AMH is detected in serum from women of reproductive age and its levels vary slightly with the menstrual cycle, reaching the peak value in the late follicular phase. The present study was undertaken to assess the effect of controlled ovarian stimulation on AMH secretion by the ovary in healthy women in order to obtain more insight into the relationship between this peptide and gonadal steroids. Methods: Twenty-four normally cycling women attending the infertility clinic volunteered for this study and AMH was measured in blood samples obtained during both spontaneous and FSH-treated cycles. Results: AMH plasma levels did not change significantly from day 2 to day 6 in spontaneous cycles. On the contrary, AMH levels decreased progressively from day 2 to day 6 in FSH-treated cycles. A significant positive correlation was found between the decrease in AMH and the increase in estradiol plasma levels in FSH-treated cycles and between basal AMH and the peak estradiol (E-2) during exogenous FSH administration. Conclusions: The present study demonstrated that AMH plasma levels did not change during the follicular phase of the menstrual cycle and that exogenous FSH administration is followed by a significant reduction in AMH levels which is probably secondary to the gonadotrophin effect on the process of follicular development.

2004 - Gestrinone in the treatment of uterine leiomyomata: effects on uterine blood supply [Articolo su rivista]
Marca, A. L.; S., Giulini; G., Vito; R., Orvieto; Volpe, Annibale; V. M., Jasonni
abstract

Gestrinone has been shown to reduce uterine volume and stop bleeding in women with uterine leiomyomata. In the present study, we demonstrated a reduction in the volume of uterine myomas and in the uterine artery blood perfusion over a 6-month period of gestrinone administration in premenopausal women.

2004 - Menopause, the cardiovascular risk factor homocysteine, and the effects of treatment [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Morgante, Giuseppe; Musacchio, Maria Concetta; Luisi, Stefano; Petraglia, Felice
abstract

Since the identification of homocysteine (Hcy) as a risk factor for cardiovascular disease, it has been the subject of much research. As with other cardiovascular risk factors, a gender difference exists for Hcy. Plasma levels are lower in women of reproductive age than in men and postmenopausal women. This has led to the hypothesis that the increased risk of cardiovascular disease documented in postmenopausal women may be related to the increase in Hcy levels. Factors affecting total plasma levels of Hcy include genetic factors, nutritional factors, and lifestyle. Many studies appear to support the ability of estrogen replacement therapy to significantly lower both basal levels of Hcy and levels following methionine loading. A mean reduction of 10-15% in Hcy levels after 6 months of hormone therapy has been reported. Similarly, raloxifene and tamoxifen and low-dose folic acid administration induce reductions in plasma Hcy levels of the same degree observed for hormone therapy. The reduction occurs after a few months of therapy and is sustained, suggesting the potential for cardioprotective effects. Although there is a positive effect of estrogen therapy and hormone therapy on Hcy levels, recent studies do not recommend the use of estrogen or hormone replacement therapy for the primary or secondary prevention of cardiovascular disease. Further research is therefore needed to identify strategies to maximize the efficacy of hormone replacement therapy, while minimizing the risks.

2004 - Müllerian-inhibiting substance in women with polycystic ovary syndrome: Relationship with hormonal and metabolic characteristics [Articolo su rivista]
Marca, A. L.; R., Orvieto; S., Giulini; V. M., Jasonni; Volpe, Annibale; V. D., Leo
abstract

The aim of the present study was to examine the relationship between Mullerian-inhibiting substance (MIS) levels and metabolic characteristics in women with polycystic ovary syndrome. Increased ovarian MIS production may exert a paracrine negative control on follicle growth sufficiently to prevent selection of a dominant follicle.

2004 - Polycystic ovary syndrome and type 2 diabetes mellitus [Articolo su rivista]
De Leo, V.; Musacchio, M. C.; Morgante, G.; La Marca, A.; Petraglia, F.
abstract

Polycystic ovary syndrome (PCOS) is a medical condition that has brought multiple specialists together. Gynecologists, endocrinologists, cardiologists, pediatricians, and dermatologists are all concerned with PCOS patients and share research data and design clinical trials to learn more about the syndrome. Insulin resistance is a common feature of PCOS and is more marked in obese women, suggesting that PCOS and obesity have a synergistic effect on the magnitude of the insulin disorder. It leads to increased insulin secretion by β-cells and compensatory hyperinsulinemia. Hyperinsulinemia associated with insulin resistance has been causally linked to all features of the syndrome, such as hyperandrogenism, reproductive disorders, acne, hirsutism and metabolic disturbances. If β-cell compensatory response declines, relative or absolute insulin insufficiency develops which may lead to glucose intolerance and type 2 diabetes. Moreover, insulin resistance in PCOS may be considered a risk factor for gestational diabetes (GD).

2004 - Recombinant human leptin in women with hypothalamic amenorrhea. [Articolo su rivista]
LA MARCA, Antonio; Volpe, Annibale
abstract

..

2004 - Serum P-selectin level during controlled ovarian hyperstimulation - A preliminary report [Articolo su rivista]
Orvieto, Raoul; Badir, Walid; Bar, Jacob; La Marca, Antonio; Ashkenazi, Jacob; Avrech, Ori M.; Fisch, Benjamin
abstract

Objective: To measure levels of serum P-selectin in patients undergoing controlled ovarian hyperstimulation (COH) cycles and to determine their possible correlation to COH variables. Setting: Large university-based infertility and in vitro fertilization unit. Patients: Fourteen consecutive patients undergoing our routine COH protocol for unexplained infertility. Interventions and Main Outcome Measures: Blood was drawn three times during the COH cycle: (1) day 2 or 3 of the menstrual cycle, before gonadotropin treatment (Day-0); (2) day of or prior to human chorionic gonadotropin (hCG) administration (Day-hCG); and (3) day of ovulation (Day-OVU). Serum levels of sex steroids and P-selectin were compared among the three time points. P-selectin was measured with a commercial quantitative sandwich immunoassay technique. To reduce interpatient variability, the percent difference between the Day-0 (non-stimulated, basal) level and the Day-hCG and Day-OVU levels was calculated. Results: P-selectin level on Day-hCG was significantly higher than on Day-0 (P < 0.05) and non-significantly higher than on Day-OVU (P < 0.12). No significant correlations were observed between serum P-selectin and patient age, amount of gonadotropins used, or estradiol or progesterone level. Conclusion: The increase in serum P-selectin level during COH until peak estradiol suggests that COH may potentiate a state of platelet activation which is substantially attenuated after hCG administration. © Blackwell Munksgaard, 2004.

2004 - Veralipride administered in combination with raloxifene decreases hot flushes and improves bone density in early postmenopausal women [Articolo su rivista]
Morgante, G.; Farina, Marco; Cianci, Antonio; La Marca, A.; Petraglia, F.; De Leo, V.
abstract

We evaluated the administration of raloxifene and veralipride in postmenopausal women with high osteoporosis risk and hot flushes in whom hormone replacement therapy (HRT) was contraindicated. A group of early postmenopausal women (n = 29) (mean age 51.8 ± 4.1), complaining of severe vasomotor symptoms and with a bone mineral density (BMD) T-score between -1.5 and -2.5 were evaluated. They were randomly assigned to two treatment groups: raloxifene (60 mg/day) continuously in association with veralipride (100 mg/day) on alternate days (n = 17); or on alternate months (n = 12). BMD, serum prolactin concentration and endometrial thickness were assessed at baseline and after 6 months of therapy. Kupperman Index and hot flushes were assessed before and after 3 and 6 months of therapy. BMD was significantly higher at the end of therapy with an increase of 1.1%. Kupperman Index was significantly reduced after 3 months and a further decrease at 6 months was observed with both protocols. Both treatments led to a significant reduction of hot flushes after 3 and 6 months. No significant changes of prolactin levels were observed in either protocol. We found that the combined raloxifene-veralipride treatment, both every other day and every other month, led to a significant improvement in bone density and was effective in hot flushes and other menopause-associated symptoms. These protocols could represent a new way to administer raloxifene in early postmenopausal women at high osteoporosis risk with HRT contraindication.

2003 - Combination of statins and hormone replacement therapy in postmenopausal women is associated with increased bone mineral density [Articolo su rivista]
De Leo, V.; Morgante, G.; La Marca, A.; Lanzetta, D.; Cobellis, L.; Petraglia, F.
abstract

Recent studies have shown that statins might be potent inhibitors of bone resorption and osteoclast number, and there is evidence for their bone anabolic effects. Statin treatment seems to protect against non-pathological fractures in older women. However, contradictory findings have been obtained. In this retrospective study we found that post-menopausal women on statins and hormone replacement therapy (HRT) showed higher bone mineral density than women on HRT alone. This evidence provides further confirmation of the effect of statins on bone turnover and shows that the combination of HRT and statins reduces the risk of bone fracture by virtue of the antiresorptive effect of HRT and the anabolic and antiresorptive effects of statins.

2003 - Effects of estradiol alone or in combination with cyproterone acetate on carotid artery pulsatility index in postmenopausal women [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Orlandi, Roberto; Crippa, Donatella; Setacci, Carlo; Petraglia, Felice
abstract

Ojectives: The incidence of cardiovascular disease (CVD) increases dramatically with the loss of ovarian function. Observational studies indicate that the risk of CVD may be reduced by up to 50% in postmenopausal women who take estrogen replacement therapy. Estrogen therapy reduces internal carotid artery pulsatility index (PI). The improvement in carotid PI following HRT has been proposed as a marker of the cardioprotective effect of estrogen therapy. Cyclical progesterone addition to ERT partially antagonizes the reduction on the carotid artery PI. As progesterone, androgens has been shown to decreases arterial vasodilatation and carotid PI. To our knowledge no information is available regarding the effect of CPA addition on the carotid artery PI in women taking estrogen replacement therapy. Methods: We recruited a total of 30 women in postmenopause for at least 12 months and were in good health. Fifteen women were postmenopausal following surgical bilateral oophorectomy for benign condition. Fifteen postmenopausal women received estradiol valerate for 21 days and CPA (1 mg) for 10 days for 3 months (Group E/CPA). Ovarectomized women (n = 15) received estradiol hemihydrate (2 mg) for 3 months (Group E). The main factor investigated was PI, an indicator of impedence to blood flow down stream. Doppler US were performed before the start and at the end of the therapy. Results: The mean reductions respect to basal values were 11.5% in women treated with E and 10.8% in women treated with E/CPA. No significant difference was found between treatment values. Conclusions: The results of the present study demonstrate that cyproterone acetate addition to E do non-antagonize the effect of estrogen on carotid artery PI. The present study demonstrate that both estradiol hemihydrate and estradiol valerate plus cyproterone acetate lead to similar improvement in carotid artery; through this mechanism both treatments could potentially reduce the incidence of cerebrovascular disease in postmenopausal women. © 2003 Elsevier Ireland Ltd. All rights reserved.

2003 - Hemodynamic effect of danazol therapy in women with uterine leiomyomata [Articolo su rivista]
La Marca, Antonio; Musacchio, Maria Concetta; Morgante, Giuseppe; Petraglia, Felice; De Leo, Vincenzo
abstract

N/A

2003 - Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Petraglia, Felice
abstract

Polycystic ovary syndrome (PCOS) is a medical condition that has brought multiple specialists together. Gynecologists, endocrinologists, cardiologists, pediatricians, and dermatologists are all concerned with PCOS patients and share research data and design clinical trials to learn more about the syndrome. Insulin resistance is a common feature of PCOS and is more marked in obese women, suggesting that PCOS and obesity have a synergistic effect on the magnitude of the insulin disorder. Hyperinsulinemia associated with insulin resistance has been causally linked to all features of the syndrome, such as hyperandrogenism, reproductive disorders, acne, hirsutism, and metabolic disturbances. Women with PCOS should be evaluated for cardiovascular risk factors, such as lipid profile and blood pressure. Modification of diet and lifestyle should be suggested to those who are obese. Several insulin-lowering agents have been tested in the management of PCOS. In particular, metformin is the only drug currently in widespread clinical use for treatment of PCOS. In a high percentage of patients, treatment with metformin is followed by regularization of menstrual cycle, reduction in hyperandrogenism and in cardiovascular risk factors, and improvement in response to therapies for induction of ovulation.

2003 - Quantitative determination of sst2 and sst5 gene expression in uterine leiomyomata and the effect of treatment with somatostatin analogue [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Vegni, Virginia; Raggi, Claudia Casini; Maggi, Mario; Petraglia, Felice
abstract

N/A

2003 - Valutazione della somministrazione di isoflavoni di soia per via vaginale nel trattamento dei disturbi vulvovaginali in postmenopausa [Articolo su rivista]
Morgante, G.; La Marca, A.; Lanzetta, D.; Musacchio, M. C.; De Leo, V.
abstract

Aim. Hormonal replacement therapy (HRT) is safe and effective in the relief of postmenopausal symptoms. For the genital tract (vaginal dryness and thinning of genital tissue) a local estrogen therapy can be used. If the patient prefers to avoid hormones, there are some preparations with soy isoflavones extracts that locally applied induce relief of urogenital symptomatology caused by estrogen loss. Methods. Thirty healthy menopausal women (>1 year) with urogenital diseases were examined, randomly divided into 2 groups and treated for 3 months: group A, 18 women treated with soy isoflavones cream (1 vaginal application daily); group B, 12 women treated with a moisture gel. Local symptomatology was evaluated: dryness, dyspareunia e itch-burning. Results. Both groups showed improvement in symptomatology. In group A there was a significant reduction (p<0.005) compared to group B at the 1st and 3rd month of therapy for dyspareunia and itch-burning. Dryness showed the same reduction in both groups. Conclusion. The possibility to use a preparation like that used in the present study with an adequate dose of soy isoflavones makes it possible not only to treat, with a continued use, vulvo-vaginal symptomatology but to prevent its appearance.

2002 - A benefit-risk assessment of medical treatment for uterine leiomyomas [Articolo su rivista]
De Leo, Vincenzo; Morgante, Giuseppe; La Marca, Antonio; Concetta Musacchio, Maria; Sorace, Massimo; Cavicchioli, Chiara; Petraglia, Felice
abstract

The growth of a uterine leiomyoma stops and regresses after the menopause suggesting that leiomyoma growth is dependent on ovarian steroids. Therefore, estrogen has received much attention as the major factor responsible for the development of uterine leiomyomas, but progesterone also plays an important role in development of this disease. Cytogenetic analyses of resected samples has revealed that about 40 to 50% of leiomyomas show karyotypically detectable chromosomal abnormalities. Gonadotrophin releasing hormone (GnRH) agonists exert their action through the suppression of endogenous gonadotrophins and gonadal steroid secretion. Significant reductions of uterine/leiomyoma volume under GnRH agonist therapy has been reported in several studies. However, the leiomyoma generally returns to its pretreatment volume within a few months after discontinuation of the GnRH agonist. To minimise the adverse effects of hypoestrogenism during GnRH agonist treatment, add back therapy can be used (estrogen-progestin, progestin alone and recently tibolone). Antiprogestins have a potential clinical utility in uterine leiomyomas. Mifepristone is a synthetic steroid with both antiprogesterone and antiglucocorticoid activities, that may have an inhibitory effect on growth of leiomyoma. Danazol is an isoxazole of 17β-ethinyl testosterone, a synthetic steroid, which has a suppressive effect on sex hormone binding globulin concentrations, resulting in efficacy in the short-term treatment of uterine leiomyomas. Gestrinone is a tri-enic steroid with antiestrogen and antiprogesterone properties and has been shown to reduce uterine volume and stop bleeding. Growth factors play a relevant role on the pathophysiology of uterine leiomyoma and probably the inhibition of the action of growth factors on the myometrium will be the basis for future therapy. A number of agents are under investigation for treating uterine leiomyoma. Agents developed from increasing genetic knowledge of this condition could represent, in the next few years, new trends in the medical treatment of uterine leiomyomas.

2002 - Effects of the selective estrogen receptor modulator, raloxifene, on carotid artery pulsatility index in postmenopausal women [Articolo su rivista]
Setacci, Carlo; Marca, Antonio La; Agricola, Eustachio; Morgante, Giuseppe; Setacci, Francesco; Cappelli, Alessandro; Petraglia, Felice; De Leo, Vincenzo
abstract

OBJECTIVE: Estrogen replacement therapy after menopause reduces the incidence of arterial disease and cerebrovascular events. The reduced incidence also seems to be due to a positive effect of estrogens on brain blood flow as shown by a decrease in the carotid artery pulsatility index. Raloxifene, a second-generation selective estrogen receptor modulator, has aroused considerable interest because of its tissue-specific agonist-antagonist effect on estrogen receptors. However, there have been no studies on the effect of raloxifene on carotid blood flow after menopause. METHODS: A total of 66 healthy women in postmenopause for more than a year were divided randomly into 2 groups: the first group (n = 33; mean age ± SD, 53.3 ± 5.2 years) was treated with raloxifene (one 60-mg capsule per day) for 6 months, and the other group (n = 33; mean age ± SD, 51.9 ± 4 years) was untreated. Doppler ultrasonography was used to measure carotid artery pulsatility index (PI) at the beginning of the study and-at 2-month intervals. RESULTS: A reduction in carotid artery PI was observed in all patients receiving raloxifene. No significant changes were observed in the control group. The reduction with respect to baseline values was 6.1% (P < .05) after 2 months, 11.2% (P < .05) after 4 months, and 13.2% (P < .05) after 6 months of therapy. The higher the baseline PI, the greater was its reduction after therapy. CONCLUSIONS: After 6 months of therapy, raloxifene induced a reduction in PI similar to that reported after estrogen therapy. The present results further our understanding of the mechanisms by which raloxifene might reduce the incidence of cardiovascular disease in postmenopausal women.

2002 - Insulin-dependent diabetes in men is associated with hypothalamo-pituitary derangement and with impairment in semen quality [Articolo su rivista]
Baccetti, Baccio; La Marca, Antonio; Piomboni, Paola; Capitani, Serena; Bruni, Emanuele; Petraglia, Felice; De Leo, Vincenzo
abstract

Background: The objective of the study was to investigate the hypothalamo-pituitary-testicular axis and sperm structure at the transmission electron microscope (TEM) level in men affected by insulin-dependent diabetes. Methods: Twenty-two diabetic men and 24 controls were recruited. GnRH (100 μg) was administered and FSH- and LH-induced secretion was evaluated. Semen samples were collected and sperm concentration and motility were determined using a Makler chamber. Ejaculated sperm were fixed and observed with a TEM. Results: The response of gonadotrophins to GnRH was significantly lower in diabetics than in control men. Sperm motility was also significantly lower. At the electron microscope level, sperm from diabetics exhibited a higher percentage of immaturity- and apoptosis-related defects than sperm from controls. Conclusions: The reduced response of gonadotrophins to GnRH in diabetic men may indicate a decreased acute releasable pool of pituitary gonadotrophins. The results of TEM examination showed that sperm from men with diabetes presented severe structural defects in comparison with sperm from controls. It is possible that the reproductive impairment recognized in men with diabetes could be the result of interference by the disease on the hypothalamo-pituitary-testicular axis at multiple levels, as indicated by the reduced gonadotrophin response to appropriate stimuli and by the abnormal ultrastructure of ejaculated sperm. The defective spermatogenesis may be the consequence of a direct testicular effect of the disease.

2002 - Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome [Articolo su rivista]
La Marca, Antonio; Morgante, Giuseppe; Palumbo, Marco; Cianci, Antonio; Petraglia, Felice; De Leo, Vincenzo
abstract

Objective: To investigate the effects of reduction of insulin resistance and hyperinsulinemia associated with the polycystic ovary syndrome (PCOS) on FSH-stimulated ovarian aromatase activity. Design: Prospective study. Setting: Academic health center, Siena, Italy. Patient(s): Twenty women 18 to 26 years of age in whom PCOS was diagnosed on the basis of oligomenorrhea or amenorrhea and hyperandrogenemia. Intervention(s): Recombinant FSH was administered. The next day, therapy with metformin (500 mg t.i.d.) was begun. After 35 to 40 days of treatment, the pretreatment protocol was repeated. Main Outcome Measure(s): Plasma levels of estradiol (E2), androstenedione (A), and testosterone (T). The ratios of basal levels and areas under the curve (AUCs) of products and substrates were compared before and after metformin administration to detect differences in aromatase activity. Result(s): Metformin treatment was associated with significant reduction in basal free testosterone plasma levels, insulin plasma levels, and insulin response to oral glucose tolerance testing. Administration of FSH was followed by a significantly lesser E2response after metformin therapy than before this therapy. The ratios of AUCE2to AUCAand to AUCT, indicative of aromatase activity in response to FSH, were significantly lower after metformin therapy than before. Conclusion(s): Metformin therapy in women with PCOS is associated with a reduction in aromatase activity in response to FSH. Insulin affects production of both androgen and estrogen. Insulin therefore plays a central role in regulating the activity of thecal and granulosa cells. © 2002 by American Society for Reproductive Medicine.

2002 - Maternal serum levels of human chorionic somatotropin correlates with transferrin and erythropoietin in pregnancy [Articolo su rivista]
Carretti, Nicola; La Marca, Antonio
abstract

During pregnancy, plasma levels of erythropoietin (EPO) and transferrin (TSF) show a gradual increase till term, when a slight decrease occurs. Human chorionic somatotropin (hCS) is a peptide hormone with a direct effect on the function of the syncytiotrophoblast and on the mass of functional placental tissue. In order to understand the relationships between the placental functions, maternal erythropoiesis and iron transfer to the fetus, the relationships between EPO and hCS and between TSF and hCS were investigated. A group of healthy pregnant women (n = 190) attending the Obstetric Clinic of the University of Siena were studied. They were between 18 and 43 weeks pregnant. A single blood sample was taken from each patient by radial vein puncture on admission into the clinic before the beginning of any therapy, for the determination of haemoglobin, EPO, fer-ritin, serum iron, TSF and hCS. The highest correlation was that between hCS and TSF (r = 0.336, p < 0.0001). This correlation was significant in anaemic patients and lost its significance in non-anaemic patients. In our study, we also found a significant relationship between hCS and logEPO (r = 0.195; p < 0.01) which reached an elevated significance over the entire survey, but did not reach statistical significance in anaemic women. We hypothesise that in pregnancy chorionic villi develop a great capacity to respond to pathological maternal events with the result of regulating the transport of iron, the oxygen tension and the maternal-fetal transfer of oxygen through haemoglobin. Evidently, the response of the villi serves to balance the lack of iron in favour of the fetus, probably through a mechanism that links the variations of the iron transport on the maternal side and the increased use on the fetal side through a dynamic and consensual response by the chorionic villi. Copyright © 2002 S. Karger AG, Basel.

2002 - Metformin and FSH for induction of ovulation in women with polycystic ovarian syndrome [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio
abstract

N/A

2002 - The cardiovascular risk factor homocysteine is not elevated in young women with hyperandrogenism or hypoestrogenism [Articolo su rivista]
Morgante, Giuseppe; La Marca, Antonio; Setacci, Francesco; Setacci, Carlo; Petraglia, Felice; De Leo, Vincenzo
abstract

The aim of the present study was to determine whether the plasma concentrations of homocysteine (Hcy) are elevated in women with hypogonadotropic hypogonadism (a condition of chronic hypoestrogenism) and in women with polycystic ovarian syndrome (PCOS, a syndrome characterized by hyperandrogenemia). A cross-sectional study was performed. The plasma concentrations of Hcy were determined in 12 normal-cycling women, in 14 women with hypogonadotropic amenorrhea (HA), and in 20 women with PCOS. The plasma LH, FSH, E2, testosterone, free testosterone, and androstenedione levels were measured. The blood samples analyzed were taken during the early follicular phase in controls and without regard to the menstrual phase in the patients. Twelve normal-cycling women were compared with 14 women with HA and with 20 women with PCOS. Women with HA or PCOS have plasma concentrations of Hcy similar to those of healthy women with normal menstrual cycles. The results suggest that young women with chronic hypoestrogenism (HA) or hyperandrogenism (PCOS) have plasma concentrations of Hcy similar to those of healthy women with normal menstrual cycles. Copyright © 2002 S. Karger AG, Basel.

2002 - Ultrastructural sperm analysis in men with insulin-dependent diabetes [Relazione in Atti di Convegno]
By:piomboni, P; la Marca, A; Capitani, S; Bruni, E; Gambera, L; Serafini, F; Scapigliati, G; Moretti, E; De Leo, V; Petraglia, F; Baccetti, B
abstract

The sperm ultrastructure and the hypothalamo-pituitary-testicular axis, were analysed in 22 insulin-dependent diabetic men and 24 controls. GnRH was administered; subsequently FSH and LH induced-secretion was evaluated. Sperm concentration and motility were determined; TEM data were statistically evaluated with the mathematical formula of Baccetti et al. (1995). The gonadotropins response to GnRH was significantly lower in diabetics than in controls, indicating a decreased acute releasable pool of pituitary gonadotropins. In diabetic men sperm motility was significantly lower and TEM examination revealed severe structural defects, related to immaturity and apoptosis. The defective spermatogenesis may be the consequence of a direct testicular effect of the disease.

2001 - 8th World Congress of Gynecological Endocrinology [Relazione in Atti di Convegno]
La Marca, A.; Petraglia, F.
abstract

N/A

2001 - Administration of somatostatin analogue reduces uterine and myoma volume in women with uterine leiomyomata [Articolo su rivista]
De Leo, Vincenzo; Marca, Antonio; Morgante, Giuseppe; Severi, Filiberto Maria; Petraglia, Felice
abstract

N/A

2001 - Clinical, endocrine and metabolic effects of acarbose, an α-glucosidase inhibitor, in PCOS patients with increased insulin response and normal glucose tolerance [Articolo su rivista]
Ciotta, Lilliana; Calogero, Aldo E.; Farina, Marco; De Leo, Vincenzo; La Marca, Antonio; Cianci, Antonio
abstract

Background: The aim of this study was to evaluate whether treatment with acarbose, an α-glucosidase inhibitor, improved hyperandrogenic symptoms, insulin and androgen serum concentrations in hyperinsulinaemic patients with polycystic ovary syndrome (PCOS). Methods: 30 hyperinsulinaemic women with PCOS and 15 controls were evaluated. Patients were randomized, using a computer-generated randomization list, into two groups of 15 each and treated with placebo or 300 mg/day of acarbose for three months. Hirsutism and acne/seborrhoea scores, hormonal and sex hormone binding globulin serum concentrations, glycaemia and insulin responses to a standard oral glucose load (75g) were measured in all patients before and after three months of treatment. Results: A significant reduction of the acne/seborrhoea score was observed in patients treated with acarbose and eight of them resumed a regular menstrual rhythm. These clinical improvements were associated with a significant reduction of the insulin response to glucose load, a significant decrease of LH, total testosterone and androstenedione and with a significant increase of sex hormone binding globulin serum concentrations. The serum concentrations of FSH, dehydroepiandrosterone sulphate, prolactin and 17α-hydroxyprogesterone did not change significantly. No clinical, metabolic and hormonal modifications were observed in PCOS patients treated with placebo. Conclusions: This is the first report showing a reduction of the acne/seborrhoea score in hyperinsulinaemic patients with PCOS treated with acarbose. This improvement was associated with a significant decrease of the insulin response to oral glucose load and of LH and androgen serum concentrations and with a significant rise of sex hormone binding globulin concentration.

2001 - Comparison of biochemical markers of bone turnover and bone mineral density in different groups of climacteric women [Articolo su rivista]
Morgante, G.; La Marca, A.; Ditto, A.; Musacchio, M. C.; Cavicchioli, C.; Lanzetta, D.; Petraglia, F.; De Leo, V.
abstract

In the present study we evaluated plasma levels of two markers of bone turnover (osteocalcin (OC) and urinary pyridinium cross-links) in association with bone mineral density (BMI) in different groups of climacteric women. We have investigated 158 women in pre-, peri,- and postmenopause. Blood and urine samples for assay of hormones and markers were collected and bone mineral density (BMD) was measured by DEXA densitometry in the distal tenth of the non-dominant forearm. There was a significant increase in mean absolute levels of both markers in perimenopause and women in natural and surgical menopause, with respect to women in premenopause. There was a significant correlation between OC and deoxypyridoline (DPYR) in peri- and postmenopause groups. In peri- and postmenopause groups, BMD was correlated with an increase in the biochemical markers of bone remodeling. In the present study, OC and DPYR were found to have good sensitivity for identifying perimenopausal women with pathological BMD. The present results reveal a positive and significant correlation between DPYR and OC, inversely proportional to BMD, during hormone replacement therapy. These markers therefore turn out to be sensitive not only for monitoring severe pathology of bone turnover, but also for monitoring slight physiological deficits in bone equilibrium beginning in perimenopause.

2001 - Endocrine and metabolic effects of insulin sensitizers in the treatment of patients with polycystic ovary syndrome and hyperinsulinaemia [Articolo su rivista]
Ciotta, L.; De Leo, V.; Farina, M.; Pafumi, Carlo; La Marca, A.; Cianci, A.
abstract

We evaluated 16 women with polycystic ovary syndrome (PCOS) and 67 controls, aged 18-34 years. All subjects had an oral glucose tolerance test (OGTT), showing a normal response. They were subdivided into 2 groups (normoinsulinaemic, hyperinsulinaemic) undergoing 7 days of octreotide treatment. This caused modifications in body mass index, waist-hip ratio and blood pressure. No modifications were observed in basal luteinizing hormone (LH), follicle-stimulating hormone, androgens, 17α-hydroxyprogesterone, oestradiol, sex-hormone-binding globulin (SHBG), prolactin and cortisol serum concentrations in normoinsulinaemic patients. A significant decrease in the concentration of LH, androgens, and a significant increase in SHBG were observed in the hyperinsulinaemic patients. In hyperinsulinaemic patients, the treatment restored a regular insulinaemic response to an OGTT. No modifications of glycaemic response were detected in normoinsulinaemic ones. In hyperinsulinaemic patients, a decompensation of the glycaemic response was observed. Several agents (insulin sensitizers) decrease insulin secretion and androgen concentration. They could be considered an approachable long-term therapy for hyperinsulinaemic hyperandrogenic patients. In the next few years the pharmacotherapy for PCOS could be greatly expanded, allowing some patients, such as hyperinsulinaemic ones, to be treated with insulin sensitizers. Copyright © 2001 S. Karger AG, Basel.

2001 - Evaluation of combining kava extract with hormone replacement therapy in the treatment of postmenopausal anxiety [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Morgante, Giuseppe; Lanzetta, Danila; Florio, Pasquale; Petraglia, Felice
abstract

Objective: to evaluate the efficacy of combining kava extract with hormone replacement therapy in the treatment of menopausal anxiety. Materials and methods: HAMA score was evaluated before and after therapy in four groups of women in menopause (duration of menopause ranged from 1 to 12 years). The groups were treated with hormone replacement therapy (with and without progestogens) and kava extract or placebo for 6 months. Results: A significant reduction in HAMA score was observed in all four groups of women. The reduction was more significant in groups taking kava extract than in groups on hormones only. Discussion: The combined use of hormone replacement therapy and kava extract seems to be effective against menopausal anxiety. Kava extract accelerates resolution of psychological symptoms while hormone therapy safeguards against osteoporosis and cardiovascular disease. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

2001 - Evaluation of plasma levels of renin-aldosterone and blood pressure in women over 35 years treated with new oral contraceptives [Articolo su rivista]
De Leo, Vincenzo; la Marca, Antonio; Morgante, Giuseppe; Lucani, Barbara; Nami, Renato; Ciotta, Liliana; Cianci, Antonio; Petraglia, Felice
abstract

Increases in blood pressure and weight are consequences of increased fluid retention following oral contraceptives administration. Hypertension and weight increase are particularly frequent in women over 35 years of age. The aim of the present study was to evaluate the clinical and hormonal effects of a new extra-low dose oral contraceptive [15 μg ethinyl estradiol (EE) and 60 μg gestodene (GSD)] on the renin-aldosterone system in a group of women aged 35-39 years treated for 3 months compared with a formulation containing the same hormones at a higher dose. Eighteen healthy women, age 35-39 years, were divided into two groups. The first group (10 women) used Arianna®, Schering, 15 μg EE/60 μg GSD (EE15/GSD60); the second group (8 women) used Fedra®, Schering, 20 μg EE/75 μg GSD (EE20/GSD75). Blood samples were obtained before the study and after 3 months of contraceptive use for assay of renin and aldosterone. Blood pressure was also measured on both occasions. No significant changes in plasma renin activity (PRA) or plasma concentrations of aldosterone were observed between the two groups after 3 months of contraceptive use. The mean increase in body weight after 3 months of contraceptive use was 350 ± 100 g for EE20/GSD75 and 300 ± 50 g for EE15/GSD60. There was a mean increase of 4 mm Hg for systolic pressure and 2 mm Hg for diastolic pressure in women on EE20/GSD75 and corresponding increases of 3 and 2 mm Hg in women on EE15/GSD60. The changes were not significant in any case. The results of the present study show that the formulations were well tolerated and provided good control of the menstrual cycle in all 18 women. The contraceptive formulations EE20/GSD75 and EE15/GSD60 have no clinical impact on blood pressure, PRA, or aldosterone in this age group. © 2001 Elsevier Science Inc. All rights reserved.

2001 - Randomized control study of the effects of raloxifene on serum lipids and homocysteine in older women [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Morgante, Giuseppe; Lanzetta, Danila; Setacci, Carlo; Petraglia, Felice
abstract

OBJECTIVE(S): Raloxifene, a selective estrogen receptor modulator, has beneficial estrogen agonist effects on bone and cardiovascular risk factors and estrogen antagonist effects on the breast and uterus. Limited clinical data have shown a sustained decrease in total cholesterol, low-density lipoprotein cholesterol, and homocysteine levels; an elevated homocysteine level is an independent risk factor for atherosclerosis. All of these studies were conducted in relatively young populations of women (mean age, 52-54 years). Raloxifene does not affect hot flushes, a major immediate symptom of menopause. This drug may therefore be useful in older women to prevent osteoporosis and cardiovascular disease. The aim of this clinical study was to evaluate the effects of raloxifene on plasma lipids and homocysteine in older women. STUDY DESIGN: The subjects were 45 healthy postmenopausal women, aged 60 to 70 years. The women were randomly assigned to therapy with raloxifene or placebo, 60 mg/d for 1 year. Twenty-six women received raloxifene and 19 received placebo. Checkups were performed every 3 months. At baseline and after 3, 6, 9, and 12 months of treatment we measured homocysteine, total serum cholesterol, triglycerides, and both high-density lipoprotein and low-density lipoprotein cholesterol. RESULTS: An effect on lipids was evident by 3 months with no significant additional modification at 12 months. Mean low-density lipoprotein cholesterol levels were lowered by 15% and total cholesterol was lowered by 8.5%. No reduction in high-density lipoprotein cholesterol or triglycerides was observed. After 3 months of therapy, homocysteine was significantly lower than at baseline (9.9 ± 1.6 vs 11 ± 2.1 μmol/L; P < .05). The greatest reduction with respect to baseline was reached after 6 months of therapy (-19.5% ± 3%; P < .05). CONCLUSION(S): The results of our study show that raloxifene at a dose of 60 mg/d reduces serum concentrations of low-density lipoprotein cholesterol and total cholesterol in healthy older women. Our study shows that in older women raloxifene leads to a 19.5% ± 3% reduction in fasting homocysteine levels. Raloxifene may have a favorable effect on the incidence of cardiovascular disease in older women. © 2001 Mosby, Inc.

2001 - Soluble L-selectin levels during controlled ovarian hyperstimulation [Articolo su rivista]
Orvieto, R.; Ben-Rafael, Z.; Schwartz, A.; Abir, R.; Fisch, B.; La-Marca, A.; Bar-Hava, I.
abstract

We sought to determine whether neutrophil activation, as reflected by soluble L-selectin levels, plays a role in controlled ovarian hyperstimulation (COH) and the possible correlation between soluble L-selectin and serum sex steroid levels. The study population consisted of 14 consecutive patients undergoing our routine in vitro fertilization (IVF) long gonadotropin-releasing hormone (GnRH) analog protocol. Blood was drawn three times during the COH cycle: (1) on the day when adequate suppression was obtained (Day-S); (2) on the day of, or the day prior to, human chorionic gonadotropin (hCG) administration (Day-hCG); and (3) on the day of ovum pick-up (Day-OPU). Levels of sex steroids and plasma soluble leukocyte selectin (L-selectin) were compared among the three time points. Soluble L-selectin was measured with a commercial sandwich enzyme-linked immunosorbent assay (ELISA). The results showed significantly higher levels of soluble L-selectin on Day-OPU than on Day-S and Day-hCG, and significantly lower levels on Day-hCG than Day-S. Though no significant correlations were found between soluble L-selectin and serum estradiol or hCG levels, soluble L-selectin positively correlated with serum progesterone levels. We conclude that hCG administration leads to neutrophil activation, which correlates with the degree of luteinization. Further studies are required to elucidate the relationship between the immune system and COH. These may lead to new strategies for predicting and preventing complications of COH.

2000 - Administration of L-thyroxine does not improve the response of the hypothalamo-pituitary-ovarian axis to clomiphene citrate in functional hypothalamic amenorrhea [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Lanzetta, Danila; Morgante, Giuseppe
abstract

Objective: To investigate the hypothalamo-pituitary-ovarian axis in women with functional hypothalamic amenorrhea to determine whether the combination of L-thyroxine and clomiphene citrate produces a qualitative and quantitative increase in induced ovulatory cycles. Setting: Gynecological Endocrinology Research Center, University of Siena (Italy). Patients: 16 young women with functional hypothalamic amenorrhea and 15 women with normal cycles in early follicular phase. Design: Administration of 50 μg GnRH and 200 μg TRH. The women with functional hypothalamic amenorrhea were divided into groups A (n=8) and B (n=8). Both groups were given 100 mg/day clomiphene for 5 days/month for 3 months. Women in group A were also given 75 mcg/day thyroid hormone (L-thyroxine) for 3 months. Main outcome measures: Comparison of basal and stimulated levels of gonadotropins, TSH and Prl, in groups A and B. Qualitative and quantitative comparison of ovulatory cycles induced in the groups. Results: Administration of clomiphene and clomiphene plus L-thyroxine was evaluated in the second and third months of treatment and was followed by a total of 11 ovulatory cycles, six in group A and five in group B. No significant difference was found between groups. Mean progesterone concentrations measured 16 days after the last clomiphene tablet were 5.5±1.2 ng/ml in group A and 5.1±1.3 ngl/ml in group B. Conclusions: Administration of L-thyroxine with clomiphene does not improve the response of the hypothalamo-pituitary-ovarian axis to clomiphene citrate or the number of ovulatory cycles and does not reduce luteal phase defects. Copyright (C) 2000 Elsevier Science Ireland Ltd.

2000 - Bone mineral density and biochemical markers of bone turnover in peri- and postmenopausal women [Articolo su rivista]
De Leo, V.; Ditto, A.; La Marca, A.; Lanzetta, D.; Massafra, C.; Morgante, G.
abstract

Bone mineral density (BMD) measured by densitometry is the elective parameter for the diagnosis of osteopenia and osteoporosis. Biochemical markers have been proposed as sensitive indicators of high bone turnover and for monitoring response to antiresorptive treatment. We conducted a retrospective study to investigate the values of biochemical markers of bone metabolism with a view to early diagnosis of osteoporosis and monitoring of hormone replacement and calcitonin therapy. The subjects were 415 women, mean age 51 ± 8 years (43-62 years) in peri- and postmenopause, recruited at the Menopause Center of Obstetrics and Gynecology Department of Siena University and divided in five groups. Bone densitometry was performed in all subjects and blood samples were taken for assayed biochemical markers, that is, [osteocalcin (OC), parathyroid hormone (PTH), type 1 procollagen (PICP), and calcitonin (CT)]. Three groups of women were divided into two subgroups: those with normal and those with low BMD (<1 SD). Basal concentrations of PCP1, OC, PTH, and CT were compared in the various groups. Two groups of postmenopausal women with BMD below the normal were treated with estrogen replacement therapy and unmodified eel calcitonin. We evaluated whether some of these biochemical markers of bone turnover could help identify women with low BMD and whether they could be useful for monitoring the results of antiresorptive therapies. Markers of bone formation (PICP and OC) make it possible to distinguish women with high turnover who are at risk for osteoporosis from women with low turnover in menopause. A good correlation was also found between changes in levels of these markers and changes in BMD during treatments, which suggests that the PICP and OC would be useful for monitoring response to antiresorptive therapy.

2000 - Clomiphene citrate increases insulin-like growth factor binding protein-1 and reduces insulin-like growth factor-I without correcting insulin resistance associated with polycystic ovarian syndrome [Articolo su rivista]
De Leo, Vincenzo; Marca, Antonio La; Morgante, Giuseppe; Ciotta, Liliana; Mencaglia, Luca; Cianci, Antonio; Petraglia, Felice
abstract

The induction of ovulation by clomiphene could be the result of interaction of the drug at various levels: hypothalamus, pituitary and ovary. It was demonstrated that administration of clomiphene to women with polycystic ovarian syndrome (PCOS) is accompanied by a reduction in plasma concentrations of insulin-like growth factor-I (IGF-I). IGF-I seems to have an overall negative effect on normal folliculogenesis and ovulation. The aim of the present study was to evaluate the effect of clomiphene on plasma concentrations of IGF-I and IGF binding protein (IGFBP)-1 and on insulin resistance associated with PCOS. Fifteen patients diagnosed with PCOS were recruited. Clinical diagnosis was based on chronic oligomenorrhoea or amenorrhoea and hyperandrogenaemia. Clomiphene citrate was administered at a dose of 100 mg/day to all women from day 5 to day 9 of the spontaneous or medroxy-progesterone acetate (MAP)-induced menstrual cycle. Blood sampling and a 2 h oral glucose loading test (75 g) were performed the day before and after the course of clomiphene. Ovulation was confirmed in 13/15 PCOS patients. Plasma concentrations of IGF-I decreased by 31.5% (434 ± 84 versus 297 ± 71 ng/ml; P < 0.05) after 5 days of clomiphene therapy, whereas plasma concentrations of IGFBP-1 increased by ~28.1% (26.3 ± 4 versus 36.6 ± 7 ng/ml; P < 0.05). This gave a 56.6% reduction in the IGF-I:IGFBP-1 ratio (21.9 versus 9.53). No significant changes in basal plasma concetrations of fasting insulin or area under the insulin curve were observed in response to oral loading. The present results show that clomiphene does not cause changes in insulin resistance associated with PCOS but reduces plasma concentrations of IGF-I and increases those of IGFBP-1, with a consequent marked reduction in the IGF-I:IGFBP-1 ratio.

2000 - Controlled ovarian hyperstimulation - A state of endothelial activation [Articolo su rivista]
Orvieto, Raoul; Schwartz, Ariela; Bar-Hava, Itai; Abir, Ronit; Ashkenazi, Jacob; La-Marca, Antonio; Ben-Rafael, Zion
abstract

Problem: To aim of the study was to investigate whether controlled ovarian hyperstimulation (COH) causes endothelial activation and whether there is a correlation between endothelial activation and serum sex-steroid levels. Method of study: The study population consisted of 14 consecutive patients undergoing our routine IVF long gonadotropin-releasing hormone-analog protocol. Blood was drawn three times during the COH cycle: (1) day when adequate suppression was obtained (Day-S); (2) on the day of or the day prior to hCG administration (Day-hCG); and (3) on the day of ovum pick-up (Day-OPU). The levels of sex steroids and plasma soluble endothelial (E)-selectin were compared among the time points. Soluble E-selectin was measured with a commercial sandwich enzyme-linked immunosorbent assay. Results: Soluble E-selectin levels were significantly higher on Day-OPU than Day-S and Day-hCG, whereas no difference was observed between Day-hCG and Day-S. No significant correlations were found between soluble E-selectin level and patient age, number of gonadotropin ampoules used, number of oocytes retrieved, or serum estradiol, progesterone and human chorionic gonadotropin levels. Conclusions: Human chorionic gonadotropin administration leads to endothelial activation regardless of the degree of ovarian response. Further studies are required to elucidate the relationship between COH and endothelial activation. These findings may lead to new strategies for predicting and preventing complications of COH, such as severe ovarian hyperstimulation syndrome.

2000 - Effect of metforim on insulin-like growth factor (IGF) I and IGF-Binding protein I in polycystic ovary syndrome [Articolo su rivista]
De Leo, Vicenzo; La Marca, Antonio; Orvieto, Raoul; Morgante, Giuseppe
abstract

The objective of the present study was to investigate whether metformin affected plasma concentrations of insulin-like growth factor (IGF) I and IGF-binding protein I (IGFBP-I) in polycystic ovary syndrome (PCOS) patients. This was an open study conducted by the Department of Obstetrics and Gynecology at the University of Siena, Italy. Seventeen women with PCOS participated in the study and were administered metformin at a dose of 500 mg three times a day. Treatment was continued for 30-32 days, after which the pretreatment evaluation was repeated. Plasma concentrations of LH, FSH, estradiol, free testosterone, IGF-I, IGFBP-I, sex hormone-binding globulin, and insulin were evaluated. Metformin led to a significant reduction in areas under the insulin curves (9310 ± 1509 vs. 6520 ± 1108 mU/mL·min; P &lt; 0.05) and was associated with a decrease in plasma free testosterone levels (12.7 ± 1.7 vs. 10.3 ± 2 pg/mL; P &lt; 0.05) and an increase in plasma sex hormone-biding globulin concentrations (62 ± 8 vs. 94 ± 13 nmol/L; P &lt; 0.05). A nonsignificant increase in plasma IGF-I levels was observed after metformin (276 ± 48 vs. 291 ± 71 mcg/L), with a significant increase in plasma IGFBP-I levels (0.56 ± 0.2 vs. 0.98 ± 0.38 mcg/L; P &lt; 0.05). The IGF-I/IGFBP-I ratio was significantly lower (492.8 ± 117 vs. 296.9 ± 82; P &lt; 0.05) at the end of therapy than before treatment. In conclusion, it seems to be appropriate to intervene with an insulin-sensitizing agent such as metformin in an attempt to break the pathogenetic link between hyperinsulinemia and hormonal perturbations in PCOS.

2000 - Effects of human chorionic gonadotropin administration on testicular testosterone secretion during prolonged exercise [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Pasqui, Letizia; Zhu, Bin; Morgante, Giuseppe
abstract

N/A

2000 - Erratum: Metformin treatment reduces ovarian cytochrome P-450c17α response to human chorionic gonadotrophin in women with insulin resistance-related polycystic ovary syndrome (Hum. Reprod. (2000) 15 (21-23)) [Articolo su rivista]
La Marca, A.; Egbe, T. O.; Morgante, G.; Paglia, T.; Cianci, A.; De Leo, V.
abstract

N/A

2000 - Evaluation of the association of Kava-Kava extract and hormone replacement therapy in the treatment of anxiety in the postmenopause [Valutazione dell'associazione di estratto di Kava-Kava e terapia ormonale sostitutiva nel trattamento d'ansia in postmenopausa] [Articolo su rivista]
De Leo, V.; La Marca, A.; Lanzetta, D.; Palazzi, S.; Torricelli, M.; Facchini, C.; Morgante, G.
abstract

Background: Anxiety is one of the main symptoms in menopause. The aim of this study was to evaluate the efficacy of the association of Kava-Kava extracts with hormone replacement therapy (HRT) and to compare it with HRT alone in the treatment of postmenopausal anxiety. Methods: Forty women in physiological or surgical menopause for the past 1 to 12 years were enrolled in the study. Patients in physiological menopause were randomly assigned to one of the following protocols: TTS natural estrogens 50 μg/day with progestin and Kava-Kava extract at a dose of 100 mg (HRT+K, no. = 13); TTS natural estrogens 50 μg/day with progestin and a placebo product (HRT, no. = 9). Patients in surgical menopause were randomly assigned to one of the following protocols: TTS natural estrogens 50 μg/day and Kava-Kava extract at a dose of 100 mg (ERT+K, no. = 11); TTS natural estrogens 50 μg/day and a placebo product (ERT, no. = 7). Each treatment cycle lasted for 6 months. The outcome of the study was to evaluate changes in the MAMA score. Results: A significant reduction in the MAMA score was observed after 3 and 6 months' treatment in all four groups of women studied. The groups treated with the therapeutic association (HRT+K, ERT+K) showed a greater reduction in the HAMA score compared to patients in the groups treated with hormones alone. Conclusions: The results of this study show that the association of HRT and Kava-Kava extract may represent an excellent therapeutic tool for the treatment of women in stabilized menopause, in particular those suffering from anxiety and depression, given that Kava-Kava therapy accelerates the resolution of psychological symptoms without diminishing the therapeutic action of estrogens on organic disease, such as osteoporosis and cardiovascular disease.

2000 - Hormonal and clinical effects of GnRH agonist alone, or in combination with a combined oral contraceptive or flutamide in women with severe hirsutism [Articolo su rivista]
De Leo, V.; Fulghesu, A. M.; La Marca, A.; Morgante, G.; Pasqui, L.; Talluri, B.; Torricelli, M.; Caruso, A.
abstract

The objective of this prospective randomized study was to evaluate and compare the hormonal and clinical effects of long-acting gonadotropin-releasing hormone (GnRH) agonist and a combination of GnRH agonist with combined oral contraceptive (COC) or flutamide in women with polycystic ovary syndrome (PCOS). Thirty-five hirsute women with PCOS, ranging in age from 19-27 years, were randomly divided into three groups: group A treated with GnRH agonist (n = 12), group B (n = 12) treated with GnRH agonist plus COC and group C (n = 11) treated with GnRH agonist plus flutamide for 6 months. Before, at the end and 6 months after the end of treatment, blood samples were drawn from all women (in early follicular phase in those with menstrual cycles) to measure ovarian and adrenal androgens, gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), estradiol and estrone plasma levels. The results showed that all three protocols had good therapeutic efficacy. A significant reduction in hirsutism was observed in all patients after 6 months of therapy, the Ferriman - Gallwey scores dropping to 9 ± 3 in group A, 10 ± 4 in group B and 11 ± 5 in group C. Six months after the end of therapy, the hirsutism score continued to be significantly reduced in all groups. After 6 months of therapy, a reduction in plasma levels of LH, FSH, estrone, estradiol, testosterone, free testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS) was observed in all groups although this was more pronounced in group B and group C. These therapies may be the basis of future treatments that quickly reduce hirsutism and remove its causes by reducing the secretion of ovarian and adrenal androgens and by blocking androgen receptors.

2000 - Insulin sensitizing agents and their effect on adrenal androgens?: the reply [Articolo su rivista]
La Marca, Antonio; De Leo, Vincenzo
abstract

N/A

2000 - Low-dose folic acid supplementation reduces plasma levels of the cardiovascular risk factor homocysteine in postmenopausal women [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Morgante, Giuseppe; Ciani, Federica; Zammarchi, Enrico; Setacci, Carlo
abstract

OBJECTIVE: The aim of our randomized, controlled trial was to verify the effect of folic acid supplementation on homocysteine levels in postmenopausal women. STUDY DESIGN: Thirty-six women were divided randomly into 2 groups as follows: a placebo group (n = 18) and a group receiving 500 μg folic acid per day for 4 weeks (n = 18). To assess concentrations of plasma homocysteine, venous blood samples were taken on enrollment and after 4 weeks of treatment. RESULTS: Mean plasma homocysteine levels were 10.9 ± 2.7 μmol/L in the placebo group and 7.8 ± 2.35 μmol/L (P < .01) in the group receiving 500 μg folic acid per day for 4 weeks. The thirds (referred to as tertiles) of women with the highest baseline homocysteine plasma levels showed the greatest reduction in homocysteine, with a mean decrease of 4.35 μmol/L (32%; P < .01), in comparison with a decrease of 3.35 μmol/L (29%; P < .01) in the middle tertile and 1.3 μmol/L (22.4%; P = .09) in the lower tertile. CONCLUSIONS: The results show that low doses of folic acid are associated with a significant reduction in plasma concentrations of homocysteine. The highest initial levels of homocysteine showed the most important reduction after therapy.

2000 - Metformin and ovarian steroidogenesis in PCOS women [Articolo su rivista]
De Leo, V.; La Marca, A.; Morgante, G.
abstract

N/A

2000 - Metformin treatment reduces ovarian cytochrome P-450c17α response to human chorionic gonadotrophin in women with insulin resistance-related polycystic ovary syndrome [Articolo su rivista]
La Marca, Antonio; Egbe, Thomas Obinchemti; Morgante, Giuseppe; Paglia, Tiziana; Ciani, Antonio; De Leo, Vincenzo
abstract

It has recently been proposed that hyperinsulinaemic insulin resistance and increased ovarian cytochrome P-450c17α activity, two features of the polycystic ovary syndrome (PCOS), are pathogenetically linked. The aim of the present study was to test the hypothesis of the hyperinsulinaemia and supranormal cytochrome P-450c17α using the human chorionic gonadotrophin (HCG) challenge, which is a more direct ovarian stimulus than gonadotrophin-releasing hormone (GnRH) in detecting modifications in ovarian steroidogenesis. Eleven women with insulin resistance-related PCOS were studied, HCG (10,000 IU) was given i.m., and blood samples were obtained 0, 8, 12, 16 and 24 h thereafter. Next day, metformin was given at a dose of 500 mg three times a day for 30-32 days, at which time the pretreatment study was repeated. Two women ovulated after metformin treatment. The administration of metformin was associated with a decrease in area under the curve for insulin during a 2 h, 75 g oral glucose tolerance test, in plasma free testosterone concentrations and an increase in plasma sex hormone binding globulin concentration. The plasma 17-hydroxyprogesterone response to HCG was significantly lower after metformin treatment. The present study gives a direct demonstration that metformin leads to a reduction in stimulated ovarian cytochrome P-450c17α activity in women with polycystic ovary syndrome.

2000 - Prophylactic therapy in a pregnant woman with severe factor VII deficiency [Articolo su rivista]
De Leo, Vincenzo; Ditto, A.; Morgante, G.; La Marca, A.; Massafra, C.; Guidoni, C. G.
abstract

This paper reports a case of factor VII deficiency, a very rare autosomal recessive disorder, in a primipara at 37 weeks of gestation in whom we administered prophylactic therapy with factor VII every 12 h until 24 h after delivery. The prophylactic use of factor VII enabled the woman to deliver without hemorrhagic complications. Copyright (C) 2000 S. Karger AG, Basel.

2000 - Resting ECG is modified after oophorectomy and regresses with estrogen replacement therapy in premenopausal women [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Agricola, Eustachio; Morgante, Giuseppe; Mondillo, Sergio; Setacci, Carlo
abstract

Objective: To assess the effects of bilateral oophorectomy on the resting ECG and whether they regress with estrogen replacement therapy. Study design: Twenty-six premenopausal and 15 postmenopausal women were enrolled in the present study. All women had undergone hysterectomy and bilateral ovariectomy. All women underwent 12-lead ECG on admission to hospital. A second ECG was recorded 20-25 days after surgery. After this second ECG, premenopausal women were randomly divided into two groups. The women of Group A (n = 14) received transdermal ethinyl estradiol (EE). The women of Group B (n = 12) did not receive any therapy. A third ECG was performed in both groups 30-35 days after randomization. Results: Bilateral oophorectomy did not induce any significant modifications in the ECG parameters of the postmenopausal women whereas in the premenopausal women, we observed a significant increment in mean duration of the T wave, a significant decrease in its amplitude and significant reduction in ST depression in V2, V3, V4 and V5. The third ECG showed regression of the ECG modifications in Group A. In the women of Group B, the second and third ECGs were not substantially different, but there were statistically significant differences between the first and third ECGs. Conclusions: The results of the present study show that ovariectomy induces significant though not clinically evident modifications in resting ECG. These ECG changes are probably due to the sudden reduction in sex hormone plasma levels after ovariectomy. Administration of estradiol induced regression of the ECG modifications. (C) 2000 Elsevier Science Ireland Ltd.

1999 - Adrenal adenocarcinoma and empty sella syndrome in a 37-year-old woman [Articolo su rivista]
De Leo, V.; Morgante, G.; Ditto, A.; La Marca, A.
abstract

The case of a 37-year-old woman with secondary amenorrhea and clear signs of hyperandrogenism is reported. The patient underwent hormonal evaluation including circadian rhythm of cortisol, gonadotropin-releasing hormone/thyroid-stimulating hormone (GnRH/TRH) test, corticotropic-releasing hormone (CRH) test and dexamethasone suppression test. She also underwent pelvic and adrenal ultrasound examination, adrenal computed axial tomography (CAT) scan and cranial nuclear magnetic resonance (NMR). A mass about 10 cm in size was detected in the left adrenal region. The sella was empty and the pituitary displaced downward. Suspected adrenal adenocarcinoma was confirmed by histological examination after surgical removal of the mass. This case of interest for physicians because of the mixed androgen and cortisol secretion of the adenocarcinoma in a hyperprolactinemic patient with empty sella. Moreover, it suggests the need to investigate the adrenal gland in patients with hyperprolactinemia and hirsutism.

1999 - Comparison of two HRT regimens with bimonthly and monthly progestin administration in postmenopause [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Morgante, Giuseppe; Lanzetta, Danila
abstract

Objectives: Here we report the results of a study in which natural estrogens were given transdermally cyclically and continuously for 1 year, and a progestin of the latest generation, namely nomegestrol acetate, was given for 10 days every month and for 15 days every 2 months. Methods: The patients were a group of 34 post-menopausal women (51-56 years), 18 of whom (group A) were treated with continuous transdermal estradiol (50 μg/day) and cyclic oral nomegestrol at a dose of 5 mg/day for 15 days every 2 months for 1 year. The other 16 women (group B) were treated with cyclic transdermal estradiol for 3 weeks with oral nomegestrol for 10 days (12-21)/month. Endometrial thickness was evaluated by transvaginal ultrasonography before and after treatment. At the end of treatment, an endometrial biopsy was performed. Serum total cholesterol, HDL, LDL and triglycerides were assessed at baseline and every 4 months. The characteristics of the cycle were deduced from the diary cards recorded by the women. Results: No significant differences were found in the mean interval between the last dose of nomegestrol and the start of bleeding or in the duration of bleeding. The total number of days of bleeding per year was significantly lower in group A than group B (27±12 vs 52±18; P<0.01). Total serum cholesterol and LDL significantly decreased after 1 year of treatment in both groups, HDL-cholesterol and triglycerides were found increased at most of the time points studied. Conclusions: The present protocol involving continuous transdermal administration of estrogen combined with oral progestin every 2 months gave good control of the menstrual cycle, did not increase the risk of endometrial pathology and met with good patient compliance. Copyright (C) 1999 Elsevier Science Ireland Ltd.

1999 - Comparison of two malignancy risk indices based on serum CA125, ultrasound score and menopausal status in the diagnosis of ovarian masses [Articolo su rivista]
Morgante, Giuseppe; La Marca, Antonio; Ditto, Antonino; De Leo, Vincenzo
abstract

Objective To evaluate the ability of two malignancy risk indices (RMI 1 and Rh4I 2) incorporating menopausal status, serum CA125 level and ultrasound findings, to discriminate a benign from a malignant pelvic mass. Design A retrospective study. Setting Department of Obstetrics and Gynaecology, University of Siena, Italy. Population One hundred and twenty-four women over 30 years of age admitted consecutively between January 1995 and December 1997 for surgical excision of ovarian masses. Main outcome measures The sensitivity, specificity, and positive predictive value of serum CA125, ultrasound findings and menopausal status, separately and combined into the RMI 1 and RMI 2, to diagnose ovarian cancer. Results The RMI 1 and RMI 2 were more accurate than menopausal status, ultrasound findings, and CA125 separately in diagnosing cancer. For all cut off values between 80 and 250, RMI 2 performed better than RMI 1. The RMI 2 at a cut off level of 125 gave a sensitivity of 81%, specificity of 90%, and positive predictive value of 74%. Conclusions We found that RMI 2 was more reliable in discriminating benign and malignant ovarian disease than RMI 1. RMI is a simple method which can be used in gynaecology clinics and less specialised centres. © 1999 Blackwell Publishing Ltd.

1999 - Effects of dexamethasone and dexamethasone plus naltrexone on pituitary response to GnRH and TRH in normal women [Articolo su rivista]
La Marca, Antonio; Torricelli, Michela; Morgante, Giuseppe; Lanzetta, Danila; De Leo, Vincenzo
abstract

The hypothesis that glucocorticoids have a direct central inhibitory effect on the reproductive axis is sutained by the identification of glucocorticoid receptors on GnRH-secreting neurons and gonadotropic pituitary cells. It has been proposed that glucocorticoids and opioids interact centrally in the regulation of the GnRH-LH axis. The inhibitory effect of glucocorticoids may manifest not only directly through the hormone-receptor link, but also indirectly through an increase in opioid tone. The aim of this study was to evaluate the role of glucocorticoids and glucocorticoids combined with an opioid antagonist, in the regulation of basal and GnRH- and TRH-stimulated secretion of LH, FSH and Prl in 7 women with normal menstrual cycles. Blood samples were obtained every 10 min for an hour. GnRH (50 μg) and TRH (200 μg) were administered and blood sampling was continued every 15 min for 2 h (day 1). At 5 a.m. the next day, naltrexone (50 mg) was given and at 8 a.m. the GnRH-TRH test was repeated (day 2). At 5 a.m. on day 3, the patients took 2 mg oral dexamethasone and the test was repeated. At 5 a.m. on day 4, the patients took naltrexone and dexamethasone and at 8 a.m. the GnRH-TRH test was repeated. Administration of naltrexone did not cause significant changes in basal concentrations of LH and FSH and their response to GnRH. The area under the curve of the LH response to GnRH on day 3 was significantly less than on days 1, 2 and 4. Administration of naltrexone (day 2) did not cause any significant increase in basal and TRH-stimulated levels of Prl with respect to day 1. On day 3, dexamethasone caused a reduced response of Prl to TRH. Pretreatment with naltrexone (day 4) prevented this reduction. These results suggest that suppression of the response of LH to GnRH induced by dexamethasone may be partly mediated by endogenous opioids. Dexamethasone led to a reduction in the response of Prl to TRH, and naltrexone blocked this suppression. Hence the suppression of Prl and LH by dexamethasone must be partly mediated by endogenous opioids, which must therefore inhibit pituitary secretion of Prl.

1999 - Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome [Articolo su rivista]
La Marca, Antonio; Morgante, Giuseppe; Paglia, Tiziana; Ciotta, Liliana; Cianci, Antonio; De Leo, Vincenzo
abstract

Objective: To determine whether the administration of metformin, an insulin-sensitizing agent, is followed by changes in adrenal steroidogenesis in women with polycystic ovary syndrome (PCOS). Design: Prospective trial. Setting: Department of Obstetrics and Gynecology, University of Siena, Siena, Italy. Patient(s): Fourteen women with PCOS. Intervention(s): Blood samples were obtained before (-15 and 0 minutes) and after (15, 30, 45, and 60 minutes) the administration of ACTH (250 μg). Metformin then was given at a dosage of 500 mg three times a day for 30-32 days, at which time the pretreatment study was repeated. Main Outcome Measure(s): The adrenal androgen responses to ACTH before and after treatment with metformin. Result(s): Ovulation occurred in two women (14%) in response to metformin treatment. A significant reduction in basal concentrations of free testosterone and a significant increase in concentrations of sex hormone- binding globulin were observed. The administration of metformin was associated with a significant reduction in the response of 17α- hydroxyprogesterone, testosterone, free testosterone, and androstenedione to ACTH. The ratio of 17α-hydroxyprogesterone to progesterone, which indicates 17α-hydroxylase activity, and the ratio of androstenedione to 17α- hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly lower after a month of metformin treatment, indicating a reduction in the activities of these enzymes. Conclusion(s): The administration of metformin to unselected women with PCOS led to a reduction in the adrenal steroidogenesis response to ACTH. This finding supports the hypothesis that high insulin levels associated with PCOS may cause an increase in plasma levels of adrenal androgens.

1999 - Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome [Articolo su rivista]
De Leo, Vincenzo; Marca, Antonio La; Ditto, Antonino; Morgante, Giuseppe; Cianci, Antonio
abstract

Objective: To evaluate whether pretreatment with metformin improves FSH- induced ovulation in women with clomiphene-resistant polycystic ovary syndrome (PCOS). Design: Randomized prospective trial. Setting: Department of Obstetrics and Gynecology, University of Siena. Patient(s): Twenty women with clomiphene citrate-resistant PCOS. Intervention(s): The women were divided randomly into groups A and B (10 subjects each). Group B received 1,500 mg of metformin for at least a month before a single cycle of FSH stimulation. Group A underwent two cycles of FSH stimulation and then received metformin for a month before undergoing a third cycle. Main Outcome Measure(s): The number of FSH ampules, days of treatment, E 2 level on the day of hCG, number of follicles >15 mm, number of hyperstimulation, and the number of cycles with hCG withheld. Result(s): The number of follicles >15 mm in diameter on the day of hCG administration was significantly lower in cycles performed after metformin treatment. The percentage of cycles with hCG withheld because of excessive follicular development was significantly lower in cycles treated with metformin. Plasma levels of E 2 were significantly higher in cycles treated with FSH alone than in those treated with FSH and metformin. Conclusion(s): By reducing hyperinsulinism, metformin determines a reduction in intraovarian androgens. This leads to a reduction in E 2 levels and favors orderly follicular growth in response to exogenous gonadotropins.

1999 - Endocrine and metabolic effects of octreotide, a somatostatin analogue, in lean PCOS patients with either hyperinsulinaemia or lean normoinsulinaemia [Articolo su rivista]
Ciotta, Lilliana; De Leo, Vincenzo; Galvani, Fabiola; La Marca, Antonio; Cianci, Antonio
abstract

The effects on insulin secretion and on the glycaemic and androgen status before and after short-term treatment with octreotide were evaluated in 16 normal weight patients with polycystic ovarian syndrome (PCOS). Hyperinsulinaemia was determined by measuring the insulin response after oral glucose tolerance test (OGTT). Seven patients (group A) were classified as normoinsulinaemic, while nine patients (group B) were considered hyperinsulinaemic according to insulin response after OGTT. Octreotide treatment did not modify either glycaemic or insulinaemic response after OGTT, or androgen profile, in normoinsulinaemic patients. On the contrary, a significant decrease in the basal concentrations of luteinizing hormone (LH), testosterone and androstenedione, and a significant increase in serum concentrations of sex hormone-binding globulin (SHBG) were observed in the hyperinsulinaemic group of patients, in which we observed also a significant decrease of insulinaemic response and a decompensation of the glycaemic profile after OGTT. Our study is the first report showing that: (i) octreotide does not appear to significantly influence pituitary release of gonadotrophins in this group of PCOS patients; (ii) octreotide is able to reduce insulin release, LH and androgen concentrations in lean PCOS patients with hyperinsulinaemia. Due to the presence of a decompensation of glucose homeostasis during treatment, octreotide does not seem advisable for long-term therapy of hyperandrogenism in lean PCOS patients with hyperinsulinaemia.

1999 - Evaluation of hypothalamic-pituitary-adrenal axis in amenorrhoeic women with insulin-dependent diabetes [Articolo su rivista]
La Marca, A.; Morgante, G.; De Leo, V.
abstract

Diabetes is associated with a higher incidence of secondary hypogonadotrophic amenorrhoea. In amenorrhoeic women with insulin-dependent diabetes a derangement in hypothalamic-pituitary-ovary axis has been proposed. No data exist on hypothalamic-pituitary-adrenal function in these women. Gonadotrophin releasing hormone (GnRH), corticotrophin releasing hormone (CRH), metoclopramide and thyroid releasing hormone (TRH) tests were performed in 15 diabetic women, eight amenorrhoeic (AD) and seven eumenorrhoeic (ED). Frequent blood samples were taken during 24 h to evaluate cortisol plasma concentrations. There were no differences between the groups in body mass index, duration of diabetes, insulin dose and metabolic control. The AD women had lower plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, oestradiol, androstenedione and 17-hydroxyprogesterone (17-OHP) than the ED women. The responses of pituitary gonadotrophins to GnRH, and of thyroid stimulating hormone (TSH) to TRH, were similar in both groups. The AD women had a lower prolactin response to TRH and metoclopramide, and lower ACTH and cortisol responses to CRH, than the ED women. Mean cortisol concentrations >24 h were higher in the amenorrhoeic group. Significant differences in cortisol concentrations from 2400 to 1000 h were found between the two groups. Insulin-dependent diabetes may involve mild chronic hypercortisolism which may affect metabolic control. Stress-induced activation of the hypothalamicpituitary-adrenal axis would increase hypothalamic secretion of CRH. This would lead directly and perhaps also indirectly by increasing dopaminergic tonus to inhibition of GnRH secretion and hence hypogonadotrophic amenorrhoea. Amenorrhoea associated with metabolically controlled insulin-dependent diabetes is a form of functional hypothalamic amenorrhoea that requires pharmacological and psychological management.

1999 - Evaluation of treatment of hyperemesis gravidarum using parenteral fluid with or without diazepam. A randomized study [Articolo su rivista]
Ditto, A.; Morgante, G.; La Marca, A.; De Leo, Vincenzo
abstract

Objective: Hyperemesis gravidarum is a relatively unknown disease, and is generally self-limiting. In some women the symptoms are so severe as to threaten the health of the mother and fetus. Therapies proposed for hyperemesis gravidarum are therefore rather empirical. Medical treatment includes parenteral fluid replacement and nutrition, electrolytes, antiemetics, vitamins, sedation and psychological counseling. Diazepam and benzodiazepins have been widely studied in pregnancy but the results are contradictory. The aim of the present study was to investigate the efficacy of parenteral fluids with vitamins, with or without diazepam sedation. Methods: Fifty women with hyperemesis gravidarum were enrolled in the study. They were treated with infusions of normal saline, glucose, vitamins and randomly with diazepam. Results: The results show that the mean stay in the hospital was shorter in the diazepam group: 4.5 ± 1.9 vs. 6 ± 1.6 days (p < 0.05) and readmission to the the hospital was 4% in the diazepam group versus 27% in other group (p < 0.05). There was a significant reduction in nausea in the diazepam group (p < 0.05). A significant reduction in vomiting was observed in both groups. No side effects or congenital neonatal malformations were found in the diazepam group. Conclusions: Intravenous administration of fluids and vitamins is the standard treatment for women hospitalized for hyperemesis gravidarum. The addition of diazepam to the treatment is effective in reducing nausea and does not have teratogenic effects.

1999 - Low-dose danazol after combined surgical and medical therapy reduces the incidence of pelvic pain in women with moderate and severe endometriosis [Articolo su rivista]
Morgante, G.; Ditto, A.; La Marca, A.; De Leo, V.
abstract

The most effective therapy for endometriosis is a matter for debate. The aim of the present randomized study was to evaluate the efficacy of low doses of danazol on recurrence of pelvic pain in patients with moderate or severe endometriosis, who had undergone laparoscopic surgery and 6 months of gonadotrophin-releasing hormone analogue (GnRHa) therapy. After surgery, 28 patients with moderate or severe endometriosis underwent therapy for 6 months with GnRHa i.m. every 4 weeks. They were then randomized into two groups: group A (14 subjects) was treated with 100 mg/day danazol for 6 months; group B (14 subjects, control) did not receive any type of therapy. After 12 months of treatment, group A had a significantly (P < 0.01) lower pain score than group B. There was no significant difference between the groups in oestrogen concentrations, bone mineral density or side-effects. The results suggest that low-dose danazol therapy reduces recurrence of pelvic pain in patients with moderate or severe endometriosis, treated surgically, and has few or no metabolic side-effects.

1999 - Short-term treatment of uterine fibromyomas with danazol [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Morgante, Giuseppe
abstract

The aim of this study was to evaluate the effects of danazol in reducing the volume of fibromyomas and in the treatment of associated symptoms. Twenty women (34-42 years) with uterine fibromyomas were treated with 400 mg/day of danazol for 4-month periods. The women underwent ultrasound examination to determine their uterine volume at enrollment in the follicular phase and after 2 and 4 months. The examination was repeated by the same sonographer 3 and 6 months after the end of therapy. Blood samples were taken on the same days for LH, FSH, estradiol and progesterone assays. After therapy, fibromyoma volume decreased significantly (p < 0.01) by an average of 23.6 ± 5%. All patients experienced partial or complete relief of symptoms while using danazol. Three and six months after the end of treatment the fibromyoma volume had only increased slightly with respect to the volume at the end of therapy, but was still lower than the starting volume. The present study shows the efficacy of danazol at a dose of 400 mg/day for 4 months in reducing the volume of fibromyomas and associated symptoms. The mechanism by which danazol reduces the volume of fibromyomas may be due to reduced estrogen concentrations and to its antiprogesterone effects on uterine myomas.

1999 - The effect of menopause on blood lipid and lipoprotein levels [Articolo su rivista]
de aloysio, D; Gambacciani, M; Meschia, M; Pansini, F; Bacchi Modena, A; Bolis, Pf; Massobrio, M; Maiocchi, G; Peruzzi, E; Nencioni, T; Ciammella, M; Bonaccorsi, G; Morano, D; Viglino, S; Artoni, G; Grassini, E; Radici, G; De Cicco, F; Ronsisvalle, E; Marcacci, B; Perrone, P; De PAoli, D; Colacurci, N; De Franciscis, P; Lodico, G; Ferreri, R; Loizzi, V; Giacomelli, P; Benetello, E; Salmaggi, P; Coniglio, E; Giussani, E; Comi, R; Grimaldi, E; Mangino, Fp; Bucciantini, S; Checcucci, V; Nappi, C; Affinito, P; Campagnoli, C; Lanza, M; Galbiati, G; Albini, D; Lentini, G; Civallelci, S; Galbignani, E; Franchi, M; Terreni, Mg; Cicoli, C; Pulisca, S; Chionna, R; Marabini, R; Cordopatri, A; Spadaro, I; Cagnacci, Angelo; Volpe, A; De Leo, V; La MArca, A; Camanni, F; Manieri, C; Scognamiglio, P; Romani, L; Cargiaghe, S; Mannu, L; Masi, P; Fattorini, G; Bersellini, B; Bianicotti, L; Marchesoni, D; Dal Pozzo, M; Ramazzotto, F; Stegher, C; Molteni, B; Molteni, E; Lombardo, R; Galati, G; Sironi, A; Ranchet, G; Belloni, C; Proietti, C; Lorefice, R; Menozzi, G; Carunchio, P; Rovetta, E; Gallo, M; De Luigi, G; Righetti, G; Favaro, P; Gentile, E; Flangini, O; De Stefani, L; Sciacchitano, Sg; Catrini, R; Bartiromo, F; Bruno, M; Puggioni, Gf; Sionis, L; Agostinelli, D; Tajani, E; Mercuri, G; Petronio, P.
abstract

Cross sectional study across Italy to investigate lipoprotein modifications in the menopausal transition

1999 - Total abdominal hysterectomy: A randomized study comparing two techniques [Articolo su rivista]
De Leo, V.; De Palma, P.; Ditto, A.; Bifernino, V.; Molinari, BELEN SOL; La Marca, A.; Morgante, G.
abstract

Background: Abdominal hysterectomy is the most frequent operation performed by gynecologists. The most commonly used techniques are intrafascial, extrafascial and supracervical hysterectomy; in our department we mainly use the first method. A variant of this technique, because during the operation we use only an Allis clamp, simplifies the operation and maintains certain anatomical relationships between neighbouring pelvic structures. Methods: To compare two different surgical techniques between 1/1/1991 and 31/12/95, 262 women were randomized pre-operatively: 133 by the intrafascial technique of Richardson and 129 by the variant hysterectomy technique. The difference between the two techniques (Richardson versus variant hysterectomy technique), as performed in our department, was investigated regarding the clamping of uterine vessels, the resection of uterosacral and cardinal ligament. The two-tailed student test was used for continuous data and χ2analysis for discrete data. Results: Less blood loss occurred in the variant than in the Richardson group (P<0.01) and no intrasurgical complications occurred as compared to one case of ureter lesion in the Richardson group. There were no differences in the number of days of hospitalization. No particular post-surgical complications occurred in the follow-up period, which has now elapsed. After 36 months of follow-up the variant group showed a reduced incidence (not significant) of vaginal vault prolapse. The patients who underwent the variant hysterectomy technique reported better compliance with regard to sexual intercourse and urinary function than the Richardson group. Conclusion: We conclude that the variant hysterectomy technique is as valid as the Richardson technique, giving the surgeon the possibility of maintaining certain anatomical relationships between neighbouring pelvic structures. It also has minor delayed complications. Copyright (C) 1999.

1998 - Effect of ovarian steroid production on adrenal steroidogenesis? [6] (multiple letters) [Articolo su rivista]
La Marca, A.; Morgante, G.; De Leo, V.; Kelestimur, F.; Sahin, Y.; Azziz, R.; Rittmaster, R. S.; Fox, L. M.; Bradley E. L., Jr.; Potter, H. D.; Boots, L.
abstract

N/A

1998 - Effects of flutamide on pituitary and adrenal responsiveness to corticotrophin releasing factor (CRF) [Articolo su rivista]
De Leo, V.; La Marca, A.; Lanzetta, D.; Cariello, P. L.; D'Antona, D.; Morgante, G.
abstract

OBJECTIVE: Flutamide is a non-steroid antiandrogen that specifically blocks the androgen receptor. We have investigated the effect of flutamide treatment on the adrenal androgen response to corticotrophin releasing factor (CRF) in eight patients with polycystic ovary syndrome (PCOS). PATIENTS: Eight women with moderate to severe hirsutism, ranging in age from 19 to 23 years were enrolled in the study. Basal hormonal pattern showed anovulatory cycles, increased concentrations of LH, androstenedione and testosterone and increased LH/FSH ratio. A baseline ultrasound scan revealed polycystic ovaries in all patients. Each received 250 mg of Flutamide twice a day for 6 months. MEASUREMENTS: Before treatment and at the end of the sixth month, women were evaluated for hirsutism score and a CRF test was performed to evaluate ACTH, cortisol and adrenal androgen responses. RESULTS: Androstenedione (Δ4), DHEA-S, 17-hydroxyprogesterone, testosterone and free- testosterone showed significantly reduced responses after six months of flutamide therapy whereas ACTH and cortisol response were similar to those before treatment. Clinical improvement in the degree of hirsutism was observed in all patients. The Ferriman-Gallwey scores decreased from a mean of 22 ± 2 to 8 ± 1.5. CONCLUSION: Flutamide induces a significant reduction in adrenal androgen response to the CRF test but not in the response of ACTH and cortisol. The finding that flutamide does not alter the pituitary- adrenal axis shows that flutamide acts by reducing adrenal androgens. These results demonstrate that flutamide is not only effective in the treatment of hirsutism but also reduces adrenal androgen secretion.

1998 - Hormonal effects of flutamide in young women with polycystic ovary syndrome [Articolo su rivista]
De Leo, Vincenzo; Lanzetta, Danila; D'Antona, Donato; La Marca, Antonio; Morgante, Giuseppe
abstract

Anovulation in women with polycystic ovary syndrome (PCOS) is the direct effect of high local androgen concentrations on the ovary. Antiandrogens are substances that prevent androgens from expressing their activity on target tissues. Flutamide is a nonsteroid antiandrogen that has been found effective in hirsute patients, although its mechanism of action is unclear. Eight girls, ranging in age from 16-19 yr, with moderate to severe hirsutism and menstrual irregularities were enrolled in this study. The basal hormonal pattern showed anovulatory cycles; increased concentrations of LH, androstenedione, and testosterone; and increased LH/FSH ratio. A baseline ultrasound scan revealed polycystic ovaries in all patients. All were given 250 mg flutamide twice a day for 6 months. LH, FSH, androstenedione, testosterone, estradiol, and progesterone were evaluated before treatment, every 4 days during the third month of treatment, and on day 24 of the sixth month of treatment. Hirsutism improved, androgen levels dropped, and ovulatory cycles were restored in all subjects. Ultrasonographic examination in follicular phase showed a significant reduction in ovarian volume and ovaries of normal appearance with one dominant follicle. The most important result of the present study was that flutamide restored ovulation in anovulatory PCOS patients. This finding supports the hypothesis that flutamide reduces androgen synthesis through restoration of ovulation, although a direct block of the steroidogenic enzymes of androgen biosynthesis in ovarian thecal cells cannot be excluded.

1998 - Human chorionic gonadotropin, thyroid function, and immunological indices in threatened abortion [Articolo su rivista]
La Marca, A.; Morgante, G.; De Leo, Vincenzo
abstract

Objective: To evaluate the role of thyroid hormones in maintaining early pregnancy and to examine the association between thyroid physiological functions and immunological parameters. Methods: Forty-five pregnant women with a clinical diagnosis of threatened abortion and a live fetus and 30 normal pregnant women were included in the study. Blood samples were taken on admission to the hospital. The patients were divided retrospectively into two groups on the basis of outcome: 1) 31 women who did not miscarry (positive outcome) and 2) 14 women who miscarried (negative outcome). Plasma TSH, free triiodothyronine (fT3), free thyroxine (fT4), hCG, immunoglobulin (Ig) G and IgM concentrations and blood counts were determined in each patient. Results: Human chorionic gonadotropin was significantly higher in women who did not abort (39.4 ± 16.9 IU/mL) than in women who miscarried (17.6 ± 14.8 IU/mL, P < .001). Free thyroxine but not fT3 was lower in patients with negative outcome (1.25 ± 0.26 ng/mL compared with 1.98 ± 0.22 ng/mL, P < .001) and IgG and IgM plasma levels were higher (780 ± 500 ng/mL compared with 470 ± 300 ng/mL and 930 ± 400 ng/mL compared with 650 ± 280 ng/mL, respectively, P < .05). Plasma TSH levels were higher in patients with negative outcomes (1.72 ± 0.84 mIU/mL compared to 1.01 ± 0.41 mIU/mL, P < .001). Plasma concentrations of hCG and thyroid hormones were significantly correlated with peripheral blood lymphocyte and neutrophil counts only in the group of women who aborted. Conclusion: Our results indicate that maternal immune response, trophoblast function, and maternal thyroid function are somehow correlated. The presence of low concentrations of hCG and fT4 and high levels of TSH and gamma globulins in women with threatened abortion suggests a negative outcome for the pregnancy.

1998 - Hyperemesis gravidarum is not associated with hypofunction of the pituitary-adrenal axis [8] [Articolo su rivista]
La Marca, A.; Morgante, G.; De Leo, V.
abstract

N/A

1998 - Hypothalamo-pituitary-adrenal axis and adrenal function before and after ovariectomy in premenopausal women [Articolo su rivista]
De Leo, Vincenzo; La Marca, Antonio; Talluri, Beatrice; D'Antona, Donato; Morgante, Giuseppe
abstract

The hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few data exist on the relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone (CRH). The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of ACTH, cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in nine premenopausal women (44-48 years of age), before and after ovariectomy. The CRH test was performed before and 8 days after ovariectomy. A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed after ovariectomy. The ratio of Δ(max) androstenedione/17-OHP after CRH stimulation was substantially the same before and after ovariectomy, whereas Δ(max) 17-OHP/cortisol was significantly lower in ovariectomized women showing increased 21- and 11β- hydroxylase activity. The results show that the acute estrogen deficit induces changes in the HPA axis characterized by reduced stimulated secretion of ACTH and steroids but normal stimulated cortisol production.

1998 - Surgical treatment of ovarian dermoid cysts [Articolo su rivista]
Morgante, Giuseppe; Ditto, Antonino; La Marca, Antonio; Trotta, Valeria; De Leo, Vincenzo
abstract

Objective: To evaluate the efficacy of laparoscopic ovarian cystectomy and to compare the surgical course, post-surgical course and particularly post-surgical pain of the laparoscopic and laparotomic methods. Study design: We conducted a surgical study on dermoid cysts at the Gynecology Department of Siena University between 1 January 1992 and 31 December 1996. The selected cases were randomized into two groups based on surgical approach: via laparotomy (n=22) or laparoscopy (n=22). Surgical times, estimated blood loss, post-surgical pain, time in hospital, speed of recovery and complications were compared. Results: Mean blood loss was significantly less for laparoscopy (58.64±30.17 ml versus 103.84±38.45 ml, P<0.05). Mean hospitalization was 6.32±1.09 days for laparotomy and 3.18±0.39 days for laparoscopy (P<0.05). Post-surgical pain was significantly less in laparoscopy patients (P<0.05). The laparoscopic technique had fewer post-surgical complications. Conclusions: The laparoscopic approach had many advantages. Laparoscopy should be the elective treatment for women with dermoid cysts, because it has many advantages for the patient and lower costs for the national health system. Copyright (C) 1998 Elsevier Science Ireland Ltd.

1998 - Thyroid function in early pregnancy I: Thyroid-stimulating hormone response to thyrotropin-releasing hormone [Articolo su rivista]
De Leo, V.; LA MARCA, Antonio; Lanzetta, D.; Morgante, G.
abstract

Maternal thyroid function in pregnancy is influenced by many factors. This study was undertaken to clarify the mechanism of thyroid regulation in the first trimester of normal pregnancy. We performed the thyrotropin-releasing hormone (TRH) test in eight women in the first trimester (week 6-9) of pregnancy and ten normal women in early follicular phase. Basal plasma levels of free triiodothyronine and free thyroxine were within the normal range in both groups, whereas thyroid-stimulating hormone (TSH) was at the lower limit of the normal range in pregnant women. TRH stimulation evoked a TSH response with a peak of 14.1 ± 1.2 mIU/ml at 30 min. In control subjects TSH increased in response to TRH with a peak of 7.4 ± 1.1 mIU/ml at 30 min. Statistical analysis with Student's test revealed significantly higher TSH levels (p < 0.01) in pregnant women. The most striking finding was the enhanced responsiveness of TSH to TRH stimulation while the thyroid hormones, free triiodothyronine (fT3) and free thyroxine (fT4), remained in the normal range. This response was similar to that observed in central hypothyroidism. These results suggest that the reduction in maternal pituitary TSH levels is due to human chorionic gonadotropin (hCG) inhibition of TRH secretion.

1998 - Thyroid function in early pregnancy II: Paradoxical growth hormone response to thyrotropin-releasing hormone [Articolo su rivista]
De Leo, V.; La Marca, A.; Lanzetta, D.; Pasqui, L.; Morgante, G.
abstract

A variant of growth hormone (GH) known as human placental growth hormone (hpGH) is found in maternal serum during pregnancy. It is well established that during the second half of normal pregnancy, pituitary GH secretion is suppressed; however, there are no data about maternal GH secretion during the first trimester of pregnancy. The present study reports the response of GH to thyrotropin-releasing hormone (TRH) in eight pregnant women in the first trimester of pregnancy (weeks 6-9) who had previously requested voluntary interruption of pregnancy. The TRH test induced a significant paradoxical GH response with a peak of 9.4 ± 0.5 ng/ml (mean ± SD) at 30 min and a higher thyroid-stimulating hormone (TSH) response in pregnant women. The increment was observed until 120 min and no response was observed in the control group. These data show the paradoxical response of GH to TRH, a releasing factor to which the hormone does not normally respond. This paradoxical secretion may be due to direct pituitary stimulation and can be explained on the basis of a state of gestational hypothyroidism.