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Alessandro GENAZZANI

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

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Pubblicazioni

2023 - Combined oral contraceptive with estetrol plus drospirenone: from pharmacokinetics to clinical applications [Articolo su rivista]
Battipaglia, C.; Feliciello, L.; Genazzani, A. D.; Facchinetti, F.; Grandi, G.
abstract

Introduction: Drospirenone/estetrol (DRSP/E4) is a combined oral contraceptive (COC) recently approved in several countries. It is composed of 15 mg of E4, a natural estrogen produced by human fetal liver throughout pregnancy, and 3 mg of DRSP, the first synthetic progestin used in oral contraception derived from 17-α-spirolactone. E4 and DRSP synergistically prevent pregnancy by inhibiting ovulation. E4 differs from 17-β-estradiol or ethinylestradiol because it represents a native estrogen with selective action in tissues (NEST), therefore it displays both agonist and antagonist estrogenic effects in different tissues. Areas covered: In this paper, we reviewed the scientific literature published in English prior to April 2023 and gathered information on the pharmacodynamics and pharmacokinetics of DRSP, E4 and their combination for contraception. We also proposed possible clinical applications based on the characteristics of the components of this COC. Expert opinion: E4/DRSP-based COC has shown high tolerability, safety and satisfaction and may represent a viable choice in young girls in need of oral contraception and pill users who suffer from high cholesterol, breast tenderness or water retention. Moreover, this new COC shows higher scheduled bleeding rate compared to other pills containing natural estrogens. All the data are reassuring, permitting long-term use.

2022 - Familial diabetes predisposes PCOS patients to insulin resistance (IR), reproductive impairment and hepatic dysfunction: effects of d-chiro inositol (DCI) and alpha lipoic acid (ALA) administration on hepatic insulin extraction (HIE) index [Articolo su rivista]
Genazzani, A. D.; Battipaglia, C.; Petrillo, T.; Piacquadio, N.; Ambrosetti, F.; Arnesano, M.; Semprini, E.; Sponzilli, A.; Tomatis, V.; Simoncini, T.
abstract

Objective PCOS is a syndrome is characterized by 2 out of 3 of the criteria established during the Rotterdam Consensus Conference. Recently the issue of insulin resistance (IR) has caught attention. Subjects A group of overweight/obese PCOS patients (n = 30) have been evaluated before and after 3 months of daily integrative administration of d-chiro inositol (DCI) (500 mg) and alpha lipoic acid (ALA) (300 mg). Methods Hormonal and metabolic profiles, oral glucose tolerance test (OGTT) for glucose, insulin and C-peptide response were performed in baseline conditions and after DCI plus ALA treatment. Hepatic Insulin Extraction (HIE) index was computed along the OGTT to evaluate the liver ability in degrading insulin. Results The treatment decreased LH, Androstenedione (A), insulin plasma levels, BMI, HOMA index, AST and ALT. Considering patients for the presence (n = 17) or absence of familial diabetes (n = 13), the greatest improvements occurred in the former patients. Insulin response to OGTT was greatly reduced after the treatment interval in PCOS with familial diabetes. HIE computation disclosed that in presence of familial diabetes liver degradation of insulin is reduced thus leaving a higher amount of circulating insulin. DCI plus ALA administration decreased AST and ALT and restored hepatic insulin clearance since HIE profile was improved. Conclusion Our study demonstrates that in overweight/obese PCOS the predisposition to familial diabetes triggers IR not only through the endogenous impaired DCI and ALA synthesis but also through a reduced hepatic clearance of insulin. DCI plus ALA administration positively improved hormonal, metabolic profiles as well as liver function.

2022 - Putative Complementary Compounds to Counteract Insulin-Resistance in PCOS Patients [Articolo su rivista]
Petrillo, T.; Semprini, E.; Tomatis, V.; Arnesano, M.; Ambrosetti, F.; Battipaglia, C.; Sponzilli, A.; Ricciardiello, F.; Genazzani, A. R.; Genazzani, A. D.
abstract

Polycystic ovary syndrome (PCOS) is the most frequent endocrine-metabolic disorder among women at reproductive age. The diagnosis is based on the presence of at least two out of three criteria of the Rotterdam criteria (2003). In the last decades, the dysmetabolic aspect of insulin resistance and compensatory hyperinsulinemia have been taken into account as the additional key features in the etiopathology of PCOS, and they have been widely studied. Since PCOS is a complex and multifactorial syndrome with different clinical manifestations, it is difficult to find the gold standard treatment. Therefore, a great variety of integrative treatments have been reported to counteract insulin resistance. PCOS patients need a tailored therapeutic strategy, according to the patient’s BMI, the presence or absence of familiar predisposition to diabetes, and the patient’s desire to achieve pregnancy or not. The present review analyzes and discloses the main clinical insight of such complementary substances.

2021 - D-Chiro-Inositol Regulates Insulin Signaling in Human Adipocytes [Articolo su rivista]
Montt-Guevara, M. M.; Finiguerra, M.; Marzi, I.; Fidecicchi, T.; Ferrari, A.; Genazzani, A. D.; Simoncini, T.
abstract

D-Chiro-Inositol (D-Chiro-Ins) is a secondary messenger in the insulin signaling pathway. D-Chiro-Ins modulates insulin secretion, the mitochondrial respiratory chain, and glycogen storage. Due to these actions D-Chiro-Ins has been proposed to correct defective insulin function in a variety of conditions characterized by metabolic dysfunction, such as polycystic ovary syndrome (PCOS), obesity, gestational diabetes and fat accumulation at menopause. Since it is unclear whether D-Chiro-Ins directly acts on adipocytes, we aimed to study D-Chiro-Ins’s actions on adipocyte viability, proliferation, differentiation, and insulin-related protein expression using a human adipocyte cell line derived from Simpson–Golabi–Behmel Syndrome (SGBS) which fully differentiates to mature adipocytes. Throughout differentiation, cells were treated with D-Chiro-Ins, 17β-estradiol (E2) or Insulin. Cell viability and proliferation were not affected by D-Chiro-Ins, then D-Chiro-Ins promoted cell differentiation only during the final days of the process, while E2 enhanced it from the first phases. D-Chiro-Ins stimulated lipid storage and the production of big lipid droplets, thus reducing the content of free fatty acids. We also found that D-Chiro-Ins, either alone or in combination with insulin and E2 increased the expression and activation of insulin receptor substrate-1 (IRS1) and glucose transporter type 4 (GLUT4). In conclusion, this work shows that D-Chiro-Ins plays a direct role in the differentiation and in the function of human adipocytes, where it synergizes with insulin and estrogen through the recruitment of signal transduction pathways involved in lipid and glucose storage. These findings give clear insights to better understand the actions of D-Chiro-Ins on fat metabolism in women in physiology and in a variety of diseases.

2021 - Neuroendocrine effects of carnitines on reproductive impairments [Articolo su rivista]
Petrillo, T.; Battipaglia, C.; Virmani, M. A.; Genazzani, A. R.; Genazzani, A. D.
abstract

Carnitines are quaternary amines involved in various cellular processes such as fatty acid uptake, β‐oxidation and glucose metabolism regulation. Due to their neurotrophic activities, their integrative use has been studied in several different physio‐pathological conditions such as anorexia nervosa, chronic fatigue, vascular diseases, Alzheimer’s disease and male infertility. Being metabol-ically active, carnitines have also been proposed to treat reproductive impairment such as functional hypothalamic amenorrhea (FHA) and polycystic ovary syndrome (PCOS) since they improve both hormonal and metabolic parameters modulating the neuroendocrine impairments of FHA. Moreo-ver, they are capable of improving the lipid profile and the insulin sensitivity in patients with PCOS.

2021 - Pathogenesis of PCOS: From Metabolic and Neuroendocrine Implications to the Choice of the Therapeutic Strategy [Capitolo/Saggio]
Prati, A.; Genazzani, A. R.; Genazzani, A. D.
abstract

PCOS is a quite frequent reproductive disease that affects 5–20% of the female population. Though specific diagnostic criteria have been established, probably they need an update according to the new insights recently ascertained, that is, insulin resistance (IR) and compensatory hyperinsulinemia. In addition, new specific insights have been demonstrated in animal models of PCOS that suggest a clear role of a neuroendocrinological impairment that might occur during prenatal life and/or after birth affecting the regular function of the reproductive axis. All these aspects suggest that PCOS might have a certain grade of epigenetic origins that might be implemented by familial predisposition to specific dismetabolic diseases such as diabetes. We will try to focus on these aspects to give an update on the putative therapeutical possibilities.

2021 - Polycystic Ovary Syndrome: Considerations About Therapeutic Strategies Choices from Fertile Life to Menopause [Capitolo/Saggio]
Genazzani, A. D.; Fedora, A.; Giulia, D.; Alba, M.; Martina, C.; Melania, A.; Tabatha, P.; Veronica, T.; Genazzani, A. R.
abstract

Polycystic ovary syndrome (PCOS) is a very frequent endocrine disorder in women since it occurs in as many as 8–10% of women of reproductive age [1, 2]. Due to the multiple heterogeneity of the syndrome [3], there has been no agreement on the criteria on which to base the diagnosis of PCOS.

2021 - Prolactin as a neuroendocrine clue in sexual function of women across the reproductive life cycle: an expert point of view [Articolo su rivista]
Nappi, R. E.; Di Ciaccio, S.; Genazzani, A. D.
abstract

Prolactin is a proteic hormone best known for its role in enabling the production of milk by female mammals. Secreted by the pituitary gland in response to the stimuli of eating, estrogen treatment, mating, ovulation and nursing, prolactin is involved in over 300 separate processes in a range of vertebrates, including humans. The hormone is released in a pulsatile manner and plays an essential role in metabolism, as well as in the regulation of the immune system and pancreatic development. Nevertheless, prolactin exerts other relevant roles, as it acts at the central nervous system level to modulate behavior, arousal and sexuality. In this experts’ opinion, we aim to give insights into the main activities of prolactin to advance the ability of medical doctors and specialists in obstetrics and gynecology to provide more emphasis in their clinical practices to the link between prolactin and sexuality.

2021 - Subclinical Atherosclerosis at Peripheral Arteries in Obese Individuals. [Articolo su rivista]
Farinetti, A; Castaniere, I; Clini, E; Migaldi, M; Gelmini, R; Scaringi Raspagliesi, F; Ara, N; Serra, F; Spatafora, F; Genazzani, A; Mattioli, Av.
abstract

Evidence on relationship between obesity and peripheral arterial disease (PAD) are controversial. The aim of the present study is to evaluate the presence of subclinical atherosclerosis at all level of the explorable vascular segments with a systematic method in a selected population of young obese submitted to a comprehensive rehabilitation course. A group of 50 consecutive morbidly obese (BMI>30) was included. All patients underwent Doppler evaluation including intima media thickness (IMT) and presence/absence of plaques. We found that vessels in the upper segment of the body demonstrate the presence of thickening and/or plaques at the level of the carotid segments but not of the subclavian arteries. The IMT of the right Common Carotid Artery (CCA) (1.49 + 1.38 versus 0.62 + 0.23; p=0.037) and of the left CCA (1.66 + 1.89 versus 0.45 + 0.26; p=0.034) was greater in patients. Vessels of the lower segment demonstrate the presence of thickening and/or plaques at the iliac but not at femoral level. The control group did not present vessel thickening at any level. In conclusions asymptomatic vascular damage may be present in different segment of peripheral vessels, thus suggesting an early risk for developing an overt vascular disease over time in obese.

2021 - The relevance of inositols treatment for PCOS before and during ART [Articolo su rivista]
Artini, P. G.; Malacarne, E.; Tomatis, V.; Genazzani, A. D.
abstract

Polycystic ovary syndrome (PCOS) is an endocrine disorder that occurs in 8-10% of women of reproductive age. It is characterized by oligo or anovulation, hyperandrogenism and/or polycystic ovaries, but also by an increased insulin plasma level especially in overweight/obese women or in those with familial diabetes. In the last years, among the insulin sensitizers, the use of the two active isoforms of inositols (myo-inositol and d-chiro-inositol) has been spreading for the treatment of PCOS insulin resistance. Several studies have shown a positive role of inositols both on the metabolic profile of PCOS patients, but also on hormonal parameters. Hence, inositols can positively affect the infertility that characterizes many PCOS patients, acting both on ovarian function and spontaneous ovulation and during IVF procedures, in terms of oocyte quality and pregnancy rate.

2020 - Cranberry, D-mannose and anti-inflammatory agents prevent lower urinary tract symptoms in women undergoing prolapse surgery [Articolo su rivista]
Russo, E.; Montt Guevara, M.; Giannini, A.; Mannella, P.; Palla, G.; Caretto, M.; Pancetti, F.; Genazzani, A. D.; Simoncini, T.
abstract

Objective: We assessed the effect on lower urinary tract symptoms (LUTS) of a supplement containing cranberry, D-mannose and anti-inflammatory molecules in postmenopausal women undergoing surgery for cystocele. Study design: Forty postmenopausal women were randomized 1:1 to an active group receiving the nutritional supplement twice a day for 2 weeks starting from surgery, or to a control group receiving surgery only. Primary outcomes were the effectiveness in the postoperative LUTS and urinary tract infections (UTI). LUTS were investigated by a validated questionnaire (ICIQ-FLUTS) at baseline and at week 4. Secondary outcomes were the safety and tolerability of the supplement and other perioperative outcomes. Results: No significant differences were found in perioperative outcomes and in incidence of UTI. After surgery, women treated with the supplement experienced significantly better scores on the filling domain of the questionnaire. A non-significant decrease in voiding scores was also found. No adverse events were detected. Conclusion: The use of an oral supplement containing cranberry, D-mannose and anti-inflammatory molecules decreases the perception of LUTS in postmenopausal women after anterior colporraphy. Our data suggest that perioperative use of nutritional supplements may be useful in the management of postoperative LUTS.

2020 - Inositols: reflections on how to choose the appropriate one for PCOS [Articolo su rivista]
Genazzani, A.
abstract

2020 - Kisspeptin and LH pulsatility in patients with functional hypothalamic amenorrhea [Articolo su rivista]
Podfigurna, A.; Maciejewska-Jeske, M.; Meczekalski, B.; Genazzani, A. D.
abstract

Purpose: Functional hypothalamic amenorrhea (FHA) occurs in response to exaggerated stressors with or without body weight loss. Various hormones, neurotransmitters, and neuromodulators are involved in the control of GnRH and kisspeptin is one of them. Our study aimed to evaluate the putative temporal coupling between kisspeptin and GnRH-induced LH pulsatile secretion. Methods: In total, 71 patients with FHA were selected for this study. All patients undergo to a pulsatility study for LH and kisspeptin evaluation (120 min, sampling every 10 min), and to an endocrine evaluation for prolactin (PRL), estradiol (E2), androstenedione (A), 17-hydroxy-progesterone (17OHP), TSH, fT3, fT4, insulin, cortisol and testosterone (T), glucose, total cholesterol, triglycerides. Results: Our data demonstrated kisspeptin and LH pulsatile secretions and that both hormones are co-secreted and temporally coupled at time 0 (p < 0.05). When patients were subdivided in hypo-LH (≤3 mIU/ml, n = 58) and normo-LH (>3 mIU/ml, n = 13), more insights were observed on the specific correlations of metabolic and hormone profiles with pulsatility indexes of LH and kisspeptin. Conclusions: Our study demonstrated the presence of a distinct kisspeptin episodic secretion in patients with FHA, and showed the temporally coupling of kisspeptin with LH secretory episodes thus supporting that though in amenorrhea, the reproductive axis is still relying on kisspeptin to drive GnRH discharge. In addition, correlations among hormonal data sustain the hypothesis that stress-induced compensatory events are the main direct and indirect promoters of the reproductive blockade in patients affected by FHA.

2019 - Differential insulin response to oral glucose tolerance test (OGTT) in overweight/obese polycystic ovary syndrome patients undergoing to myo-inositol (MYO), alpha lipoic acid (ALA), or combination of both [Articolo su rivista]
Genazzani, A. D.; Prati, A.; Marchini, F.; Petrillo, T.; Napolitano, A.; Simoncini, T.
abstract

Polycystic ovary syndrome is characterized by several endocrine impairments, insulin resistance and hyperinsulinemia. We aimed to evaluate the effects of myo-inositol (MYO), alpha-lipoic acid (ALA) and a combination of both. Setting: retrospective study. Ninety overweight/obese patients were considered. Presence or absence of first grade diabetic relatives was checked. Patients were administered MYO (1 g/die per os), ALA (400 mg/die per os), MYO (1 gr/die) + ALA (400 mg/die) per os. Only 76 out of 90 patients completed the 12 weeks of treatment. Patients were evaluated before and after the treatment interval for LH, FSH, E2 (estradiol), A (androstenedione), T (testosterone) plasma levels, oral glucose tolerance test (OGTT). All treatments demonstrated specific positive effects: MYO modulated more hormonal profiles and OGTT in polycystic ovary syndrome (PCOS) with no familial diabetes, ALA improved insulin response to OGTT and metabolic parameters in all patients with no effects on reproductive hormones, MYO + ALA improved hormonal and metabolic aspects and insulin response to OGTT in all patients. Presence of familial diabetes is a relevant clinical aspect. MYO is less effective when familial diabetes is present, ALA improved only metabolic aspects while MYO + ALA was effective on all PCOS patients independently from familial diabetes.

2019 - Metabolism, Obesity, Thinness, and Reproduction [Capitolo/Saggio]
Prati, A.; Napolitano, A.; Despini, G.; Manzo, A.; Caroli, M.; Genazzani, A. D.
abstract

The physiology of reproduction is ruled by neuroendocrine signals that originate in many regions of the brain. Additionally, such signals are greatly modulated or affected by relevant signals derived from the periphery of our body. All such peripheral signals are concerned with specific sensorial and metabolic information that might positively or negatively modulate specific responses from the brain and from the affective neuroendocrine pathways of the endocrine glands. Such interconnections are at the basis of the modulation, which might block or restart reproductive functions by means of hypothalamus-pituitary control of ovarian function in humans either by body weight loss, as from anorexia nervosa, or by excessive body mass, as in obesity. The understanding of these mechanisms is of tremendous value to clinicians who face and resolve reproductive impairment.

2019 - Oral dehydroepiandrosterone restores ß-endorphin response to OGTT in early and late postmenopause [Articolo su rivista]
Giannini, A.; Genazzani, A. D.; Napolitano, A.; Caretto, M.; Stomati, M.; Simoncini, T.; Genazzani, A. R.
abstract

ß-endorphin is a neuropeptide involved in several brain functions: its plasma levels are higher in obese women and its release increases after oral glucose tolerance test (OGTT) in normal or obese women. The study included 46 healthy women and evaluated the effect of oral dehydroepiandrosterone [DHEA] (50 mg/day) in early postmenopausal women (50–55 years) both of normal weight (group A, n = 12, BMI = 22.1 ± 0.5) and overweight (group B, n = 12, BMI = 28.2 ± 0.5), and late postmenopausal women (60–65 years) both normal weight (group C, n = 11, BMI = 22.5 ± 0.6) and overweight (group D, n = 11, BMI = 27.9 ± 0.4) undergone OGTT, in order to investigate if DHEA could restore/modify the control of insulin and glucose secretion and ß-endorphin release in response to glucose load. The area under the curve (AUC) of OGTT evaluated plasma levels of different molecules. DHEA, DHEAS, and ß-endorphin plasma levels were lower in baseline conditions in older women than younger women. Considering the AUC of ß-endorphin response to OGTT, all groups showed a progressive significant increase after 3 and also after 6 months of treatment in comparison to baseline and 3 months of treatment.

2018 - From Menopause to Aging: Endocrine and Neuroendocrine Biological Changes [Capitolo/Saggio]
Genazzani, A. D.; Giannini, A.; Napolitano, A.
abstract

Aging is strongly related to the female hormonal status; indeed it is well known how relevant the impact of the hormonal deficiency in the postmenopause is on the general health of the woman. Aging and in particular the menopause transition are associated with the occurrence of the typical symptoms related to estrogen deficiency such as vasomotor, genitourinary, and musculoskeletal symptoms [1–3]. In this period women become markedly vulnerable to cardiovascular diseases and neurodegenerative disorders that, at this moment of women’s life, occur more frequently than in men [4]. With the increase of life expectancy, in 2025 it is expected that there will be more than 1.1 billion in postmenopausal women and most of them will suffer from eating disorders and menopausal-related symptoms (Fig. 2.1).

2018 - Kisspeptin and LH pulsatile temporal coupling in PCOS patients [Articolo su rivista]
Katulski, K.; Podfigurna, A.; Czyzyk, A.; Meczekalski, B.; Genazzani, A. D.
abstract

Purpose: To evaluate the temporal coupling between spontaneous kisspeptin and luteinizing hormone (LH) pulsatile releases in polycystic ovary syndrome (PCOS) patients. Methods: We examined 71 patients diagnosed with PCOS. A 2 h pulsatility study was performed to evaluate serum kisspeptin and LH pulse frequency and concentration, sampled every 10 min; baseline follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), cortisol, 17-hydroksy-progesterone (17OHP), testosterone (T), free testosterone index (FTI, and insulin levels were also measured. Detect and Specific Concordance (SC) algorithms were used to evaluate the temporal coupling associations between spontaneous episodic secretion of kisspeptin and LH. Results: All PCOS patients demonstrated LH and kisspeptin pulsatile secretions. When the SC index was calculated across the sample of PCOS patients (n = 71), no temporal coupling was observed between kisspeptin and LH pulses. When PCOS patients were subdivided according to their menstrual cyclicity, oligomenorrheic patients demonstrated elevated kisspeptin pulse frequency. Additionally, the SC index reveled a temporal coupling between kisspeptin and LH secretory peaks only in eumenorrheic patients (n = 30, intermenstrual interval < 45 days). Oligomenorrheic PCOS patients (intermenstrual interval > 45 days) did not demonstrate temporal coupling between kisspeptin and LH secretory peaks. Conclusions: The study of the endogenous kisspeptin and LH pulsatile release revealed the temporal coupling of kisspeptin with LH secretory pulses only in eumenorrheic. This data supports the hypothesis that neuroendocrine impairments in PCOS affect the coupling of kisspeptin with LH pulses and potentially worsen as the disease progresses, becoming unequivocally evident in oligomenorrheic PCOS patients.

2018 - Metabolic Changes and Metabolic Syndrome During the Menopausal Transition [Capitolo/Saggio]
Genazzani, A. D.; Prati, A.; Despini, G.
abstract

Please check the hierarchy of the section headings and confirm if correct.

2018 - Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients [Articolo su rivista]
Genazzani, Alessandro; Shefer, K; Della Casa, D; Prati, Alessia; Napolitano, Antonella; Manzo, Alba; Despini, Giulia; Simoncini, T
abstract

To evaluate the efficacy of alpha-lipoic acid (ALA) administration on hormonal and metabolic parameters of obese PCOS patients.

2018 - The role of kisspeptin/neurokinin B/dynorphin neurons in pathomechanism of vasomotor symptoms in postmenopausal women: from physiology to potential therapeutic applications [Articolo su rivista]
Szeliga, A.; Czyzyk, A.; Podfigurna, A.; Genazzani, A. R.; Genazzani, A. D.; Meczekalski, B.
abstract

Women during perimenopausal period experience a range of symptoms, which interfere with physical, sexual, and social life. About 65–75% of symptoms connected with postmenopausal period are vasomotor symptoms (VMS), such as hot flushes and night sweats. Hot flushes are subjective sensation of heat associated with cutaneous vasodilatation and drop in core temperature. It is suspected that VMS are strongly correlated with pulsatile oversecretion of gonadotropin-releasing hormone (GnRH) and subsequently luteinizing hormone (LH). Evidence has accumulated in parallel showing that lack of negative feedback of steroid hormones synthesized in ovary causes overactivation of hypertrophied kisspeptin/neurokinin B/dynorphin (KNDy) neurons, located in infundibular nucleus. Oversecretion of both kisspeptin (KISS1) and neurokinin B (NKB), as well as downregulation of dynorphin, plays dominant role in creation of GnRH pulses. This in turn causes VMS. Administration of senktide, highly potent and selective NK3R agonist, resulted in increase of serum LH concentration, induction of VMS, increase in heart rate, and skin temperature in postmenopausal women. These finding suggest that modulation of KNDy neurons may become new therapeutic approach in the treatment of VMS.

2018 - Ulipristal acetate interferes with actin remodeling induced by 17β-estradiol and progesterone in human endometrial stromal cells [Articolo su rivista]
Shortrede, J. E.; Montt-Guevara, M. M.; Pennacchio, G.; Finiguerra, M.; Giannini, A.; Genazzani, A. D.; Simoncini, T.
abstract

Ulipristal acetate (UPA) is a selective progesterone receptor modulator (SPRM) used for emergency contraception and for the medical management of symptomatic uterine fibroids (UF). Treatment with UPA turns in amenorrhea and UF volume reduction. Treatment with UPA is associated with the frequent development of benign, transitory endometrial changes known as SPRM-associated endometrial changes (PAECs). Why PAECs develop and their biological or cellular basis is unknown. Sex steroids, including estrogen and progesterone, are established modulators of the actin cytoskeleton in various cells, including endometrial cells. This explains several morphological and functional changes in endometrial cells. We thus hypothesized that UPA may alter the appearance of the endometrium by interfering with the actions of 17β-estradiol (E2) or progesterone (P4) on actin dynamics. We isolated and cultured human endometrial stromal cells (ESC) from endometrial biopsies from healthy fertile women. Treatment with E2 or P4 stimulated visible actin rearrangements with actin remodeling toward the membrane. Activation through phosphorylation of the actin regulatory proteins, Moesin, and focal adhesion kinase (FAK), hacked actin remodeling induced by E2 and P4. Membrane re-localization of Paxillin and Vinculin were also induced by E2 and P4, showing the formation of focal adhesion complexes. All these E2 and P4 actions were inhibited by co-treatment with UPA, which was otherwise inactive if given alone. The cytoskeletal changes induced by E2 and P4 turned into increased motility of ESC, and UPA again blocked the actions E2 and P4. In conclusion, we find that UPA interferes with the cytoskeletal actions of E2 and P4 in ESC. This finding helps understanding the mode of actions of SPRMs in the endometrium and may be relevant for other potential clinical applications of UPA.

2017 - Functional Hypothalamic Amenorrhea as Stress Induced Defensive System [Capitolo/Saggio]
Genazzani, A. D.; Despini, G.; Bonacini, R.; Prati, A.
abstract

Since the activity of the reproductive axis is quite complex and modulated and/or affected by several neurotransmitters, neuromodulators and hormones, it is easy to understand that minimal changes of the equilibrium of few of these substances might induce changes of the reproductive axis leading to the amenorrheic condition. Among secondary amenorrheas, hypothalamic amenorrhea (HA) is the one with no evidence of endocrine/systemic causal factors. HA is mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stressed conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It might be considered strange, but such negative hypothalamic response to stress is nothing else than a defensive system. In primate females and in human females in particular, an adaptive mechanism during stress is represented by the reduction of reproductive axis activity, blocking a function that is not essential to survive. Some intermediate steps, such as poly- or oligo-menorrhea can anticipate the occurrence of the amenorrheic condition, which is the last and worst stage of this clinical adaptive response to stress.

2017 - Inositol supplementation in women with polycystic ovary syndrome undergoing intracytoplasmic sperm injection: a systematic review and meta-analysis of randomized controlled trials [Articolo su rivista]
Mendoza, N.; Perez, L.; Simoncini, T.; Genazzani, A.
abstract

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous disease that involves menstrual dysfunction and reproductive difficulty, as well as metabolic problems. The aim of this study was to assess the effectiveness of myo-inositol (MYO) and d-chiro-inositol (DCI) on improving oocyte or embryo quality and pregnancy rates for women with PCOS undergoing intracytoplasmic sperm injection (ICSI). We searched the Web of Knowledge, MEDLINE, EMBASE, Pubmed, Scopus and Cochrane databases for all articles published in any language up to March 2017. The selection criteria were as follows: (population) patients with PCOS; (intervention) treatment with inositol (MYO, DCI, or both, with any dose and any duration) in conjunction with an ovulation-inducing agent versus the ovulation-inducing agent alone; (outcome) oocyte and embryo quality; (study design) randomized controlled trials. Of 76 identified studies, eight RCTs were included for analysis comprising 1019 women with PCOS. MYO supplementation was insufficient to improve oocyte quality (OR 2.2051; 95% CI 0.8260 to 5.8868), embryo quality (OR 1.6231, 95% CI 0.3926 to 6.7097), or pregnancy rate (OR 1.2832, 95% CI 0.8692 to 1.8944). Future studies of appropriate dose, size and duration of DCI are vital to clarify its the role in the management of PCOS.

2017 - Modulatory effects of l-carnitine plus l-acetyl-carnitine on neuroendocrine control of hypothalamic functions in functional hypothalamic amenorrhea (FHA) [Articolo su rivista]
Genazzani, Alessandro D; Despini, Giulia; Czyzyk, Adam; Podfigurna, Agnieszka; Simoncini, Tommaso; Meczekalski, Blazej
abstract

Functional hypothalamic amenorrhea (FHA) is a relatively frequent disease due to the combination of metabolic, physical, or psychological stressors. It is characterized by the low endogenous GnRH-induced gonadotropin secretion, thus triggering the ovarian blockade and a hypoestrogenic condition. Up to now various therapeutical strategies have been proposed, both using hormonal treatment as well as neuroactive compounds. Since carnitine, namely l-acetyl-carnitine (LAC), has been demonstrated to be effective in the modulation of the central hypothalamic control of GnRH secretion, we aimed to evaluate whether a combined integrative treatment for 12 weeks of LAC (250 mg/die) and l-carnitine (500 mg/die) was effective in improving the endocrine and metabolic pathways in a group of patients (n = 27) with FHA. After the treatment, interval mean LH plasma levels increased while those of cortisol and amylase decreased significantly. When patients were subdivided according to baseline LH levels, only hypo-LH patients showed the significant increase of LH plasma levels and the significant decrease of both cortisol and amylase plasma levels. The increased 17OHP/cortisol ratio, as index of the adrenal activity, demonstrated the reduced stress-induced adrenal activity. In conclusion, our data sustain the hypothesis that the integrative administration of LAC plus l-carnitine reduced both the metabolic and the neuroendocrine impairment of patients with FHA.

2016 - Androgens Regulate T47D Cells Motility and Invasion through Actin Cytoskeleton Remodeling [Articolo su rivista]
Montt-Guevara, Maria Magdalena; Shortrede, Jorge Eduardo; Giretti, Maria Silvia; Giannini, Andrea; Mannella, Paolo; Russo, Eleonora; Genazzani, Alessandro; Simoncini, Tommaso
abstract

The relationship between androgens and breast cancer is controversial. Androgens have complex effects on breast cancer progression and metastasis. Moreover, androgen receptor (AR) is expressed in approximately 70 to 90% of invasive breast carcinomas, which has prognostic relevance in basal-like cancers and in triple-negative breast cancers. Recent studies have associated the actin-binding proteins of the ezrin-radixin-moesin (ERM) family with metastasis in endocrine-sensitive cancers. We studied on T47D breast cancer cells whether androgens with different characteristics, such as testosterone (T), dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA) may regulate breast cancer cell motility and invasion through the control of actin remodeling. We demonstrate that androgens promote migration and invasion in T47D via Moesin activation. We show that T and DHEA exert their actions via the AR and estrogen receptor (ER), while the non-aromatizable androgen - DHT - only recruits AR. We further report that androgen induced significant changes in actin organization with pseudopodia along with membrane ruffles formation, and this process is mediated by Moesin. Our work identifies novel mechanisms of action of androgens on breast cancer cells. Through the modulation of Moesin, androgens alter the architecture of cytoskeleton in T47D breast cancer cell and promote cell migration and invasion. These results could help to understand the biological actions of androgens on breast cancer and, eventually, to develop new strategies for breast cancer treatment.

2016 - Inositol and human reproduction. From cellular metabolism to clinical use [Articolo su rivista]
Milewska, Ewa M; Czyzyk, Adam; Meczekalski, Blazej; Genazzani, Alessandro
abstract

Inositol is an organic compound of high biological importance that is widely distributed in nature. It belongs to the sugar family and is mainly represented by its two dominant stereoisomers: myo-inositol and D-chiro-inositol that are found in the organism in the physiological serum ratio 40:1. Inositol and its derivatives are important components of the structural phospholipids of the cell membranes and are precursors of the second messengers of many metabolic pathways. A high concentration of myoinositol is found in the follicular fluid and in semen. Inositol deficiency and the impairment of the inositol-dependent pathways may play an important role in the pathogenesis of insulin resistance and hypothyroidism. The results of the research also point out the potential beneficial role of inositol supplementation in polycystic ovarian syndrome and in the context of assisted reproduction technologies and in vitro fertilization. The main aim of the article is to overview the major inositol-dependent metabolic pathways and to discuss its importance for reproduction.

2016 - Inositol as putative integrative treatment for PCOS [Articolo su rivista]
Genazzani, Alessandro
abstract

Studies over the last decade have demonstrated that some polycystic ovary syndrome (PCOS) patients have abnormal insulin sensitivity (insulin resistance), independently from being overweight or obese. This induces the risk of developing type 2 diabetes in such PCOS patients. The use of insulin sensitizers (i.e. metformin), reduces such metabolic, and most hormonal, impairments. As metformin often induces side effects, new integrative strategies have been proposed to treat insulin resistance, such as the use of inositols. Such compounds are mainly represented in humans by two inositol stereoisomers: myo-inositol (MYO) and d-chiro-inositol (DCI). MYO is the precursor of inositol triphosphate, a second messenger that regulates thyroid-stimulating hormone (TSH) and FSH as well as insulin. DCI derives from the conversion of myo-inositol via an insulin-dependent pathway. Several preliminary studies have indicated possible benefits of inositol therapy in PCOS patients, but to date no meta-analysis has been performed. This review aims to give clinical insights for the clinical use of inositol in PCOS.

2016 - Insulin resistance, PCOS and obesity: from metformin to integrative treatments that can improve insulin sensitivity [Articolo su rivista]
Genazzani, Ad; Prati, A; Bonacini, R; Despini, G
abstract

2016 - Medical Treatment of Myomas [Capitolo/Saggio]
Genazzani, A. D.; Chierchia, E.; Despini, G.; Prati, A.
abstract

Uterine fibroids or myomas are the most frequent benign neoplasm during fertile life in women. It originates from the smooth muscle cells of the uterus (myometrium) [1], and it is frequently found at a gynecological examination or at ultrasound in almost 30 % of the women above 35 years of age. Myomas are usually asymptomatic, but in 30 % of the women, they can induce a variety of symptoms such as dysmenorrhea, menorrhagia, pelvic discomfort, infertility, recurrent abortion, and when there several myomas and/or when they are quite large and heavy, they can induce diseases for the compression of the tissues and/or organs close to the uterus, such as the bladder [2].

2016 - Pharmacological and Integrative Treatment of Stress-Induced Hypothalamic Amenorrhea [Capitolo/Saggio]
Genazzani, A. D.; Despini, G.; Chierchia, E.; Benedetti, C.; Prati, A.
abstract

Among secondary amenorrheas, hypothalamic amenorrhea (HA) is the one with no evidence of endocrine/systemic causal factors. HA is mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stressed conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It has to be investigated using the clinical history of the patient: occurrence of menarche, menstrual cyclicity, time and modality of amenorrhea, and it has to be excluded any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stressed situation induced by loss, family or working problems, weight loss or eating disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed but no absolute parameter can be proposed since HA is greatly dependent from individual response to stressors and/or the adaptive response to stress. This chapter aims to give insights into diagnosis and putative therapeutic strategies.

2016 - Short-term estriol administration modulates hypothalamo-pituitary function in patients with functional hypothalamic amenorrhea (FHA) [Articolo su rivista]
Genazzani, Alessandro; Podfigurna Stopa, Agnieszka; Czyzyk, Adam; Katulski, Krzysztof; Prati, Alessia; Despini, Giulia; Angioni, Stefano; Simoncini, Tommaso; Meczekalski, Blazej
abstract

Objective: To evaluate the influence of short-term estriol administration (10 d) on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by functional hypothalamic amenorrhea (FHA). Study design: Controlled clinical study on patients with FHA (n = 12) in a clinical research environment. Intervention(s): Hormonal determinations and gonadotropin (luteinizing hormone [LH] and FSH) response to a gonadotropin-releasing hormone (GnRH) bolus (10 μg) at baseline condition and after 10 d of therapy with 2 mg/d of estriol per os. Main outcome measure(s): Measurements of plasma LH, FSH, prolactin, estradiol, androstenedione, 17α-hydroxyprogesterone, insulin, cortisol, thyroid-stimulating hormone, free triiodothyronine, and free thyroxine. Result(s): After treatment, the FHA patients showed a statistically significant increase of both LH and FSH plasma levels and the significant increase of their responses to the GnRH bolus. Conclusion(s): Estriol short-term therapy modulates within 10 d of administration the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of both gonadotropins synthesis and secretion in hypogonadotropic patients with FHA.

2016 - Spontaneous endogenous pulsatile release of kisspeptin is temporally coupled with luteinizing hormone in healthy women [Articolo su rivista]
Meczekalski, Blazej; Katulski, Krzysztof; Podfigurna Stopa, Agnieszka; Czyzyk, Adam; Genazzani, Alessandro
abstract

Objective To evaluate the presence of a spontaneous pulsatile release of kisspeptin and whether it is temporally coupled to LH pulses. Design Experimental study. Setting Academic medical center. Patient(s) Thirty young healthy eumenorrheic women aged 20-37 years were included in the study group. All subjects were white women admitted to the Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland. Intervention(s) Kisspeptin, FSH, LH, E2, PRL, and insulin were evaluated in all subjects at baseline. Main Outcome Measure(s) All women underwent a pulsatility study measuring LH and kisspeptin plasma concentrations to assess the spontaneous episodic secretion of both hormones, sampling every 10 minutes for 2 hours from 9:00 to 11:00 a.m. for a total of 12 blood samples. Detection and specific concordance (SC) algorithms were used to detect pulses and their concordance. Result(s) A significant endogenous secretory pattern was demonstrated for both LH and kisspeptin over the 2-hour duration of the study (2.4 ± 0.1 peaks/2 h). The computation of the SC index showed for the first time that kisspeptin and LH are cosecreted and temporally coupled at time "0," and their peaks occur at the same point in time. Conclusion(s) The present study provides evidence supporting the hypothesis that kisspeptin is highly relevant in the regulation and modulation of reproductive functions in humans.

2015 - Effects of preoperative and perioperative administration of wobenzym vital on minimal-mild endometriosis [Articolo su rivista]
Giannini, A.; Palla, G.; Goglia, L.; Genazzani, A. R.; Genazzani, A.; Simoncini, T.
abstract

Background: Endometriosis is an estrogen-dependent chronic inflammatory disease associated with pelvic pain, inflammation and infertility. Drugs that modulate the release of chemokines and angiogenic and inflammatory molecules are under evaluation. The aim of the present randomized, double-blind, placebo-controlled study was to investigate the effects of Wobenzym Vital, an enzyme-flavonoids combination supplement with antiinflammatory activity, as supportive treatment in patients affected by minimal-moderate endometriosis selected for surgery. Methods: Thirty women suspected for endometriosis stage I-II were randomly assigned to receive Wobenzym Vital or placebo for a period of 40-60 days before surgery and 60 days thereafter. Visual analog scale (VAS) scores for pain at enrollment, time of surgery and 7 and 60 days afterwards were evaluated. Blood samples were taken at the same times for the assay of several inflammatory, angiogenic and growth factors and growth factor regulators. Results: Treatment with Wobenzym Vital was associated with lower VAS scores before surgery and perioperatively. Surgery further reduced VAS scores in all patients. Patients receiving placebo underwent increases in plasmatic concentrations of sCD40L, EGF, IGFBP-1, IL-6, IL-8, TGF-α and TNF-α in the perioperative period, while this was not noted in patients with active treatment. A trend for lower concentrations of several of the tested analytes in the peritoneal fluid was found in patients treated with Wobenzym Vital. Conclusions: In symptomatic patients affected by minimal-mild endometriosis undergoing surgery, preoperative and postoperative treatment with Wobenzym Vital results in reduced pain and lower concentrations of inflammatory and angiogenic factors in peripheral blood and the peritoneal cavity.

2015 - Estetrol modulates endothelial nitric oxide synthesis in human endothelial cells [Articolo su rivista]
Montt Guevara, Maria Magdalena; Giretti, Maria Silvia; Russo, Eleonora; Giannini, Andrea; Mannella, Paolo; Genazzani, Andrea Riccardo; Genazzani, Alessandro; Simoncini, Tommaso
abstract

Estetrol (E4) is a natural human estrogen that is present at high concentrations during pregnancy. E4 has been reported to act as an endogenous estrogen receptor modulator, exerting estrogenic actions on the endometrium or the central nervous system but presenting antagonistic effects on the breast. Due to these characteristics, E4 is currently being developed for a number of clinical applications, including contraception and menopausal hormone therapy. Endothelial nitric oxide (NO) is a key player for vascular function and disease during pregnancy and throughout aging in women. Endothelial NO is an established target of estrogens that enhance its formation in human endothelial cells. We here addressed the effects of E4 on the activity and expression of the endothelial nitric oxide synthase (eNOS) in cultured human umbilical vein endothelial cells (HUVEC). E4 stimulated the activation of eNOS and NO secretion in HUVEC. E4 was significantly less effective compared to E2, and a peculiar concentration-dependent effect was found, with higher amounts of E4 being less effective than lower concentrations. When E2 was combined with E4, an interesting pattern was noted. E4 antagonized NO synthesis induced by pregnancy-like E2 concentrations. However, E4 did not impede the modest induction of NO synthesis associated with postmenopausal-like E2 levels. These results support the hypothesis that E4 may be a regulator of NO synthesis in endothelial cells and raise questions on its peculiar signaling in this context. Our results may be useful to interpret the role of E4 during human pregnancy and possibly to help develop this interesting steroid for clinical use.

2015 - Insulin resistance and PCOS as metabolic disease [Articolo su rivista]
Genazzani, Ad; Prati, A; Despini, G; Chierchia, E
abstract

2015 - Obesity and Metabolic Syndrome: Impact and Relationship with Menopausal Transition [Capitolo/Saggio]
Santagni, S.; Rattighieri, E.; Chierchia, E.; Despini, G.; Prati, A.; Genazzani, A. D.
abstract

Western society predisposes to weight gain. We simply have too much food available. The real problem is the fact that human biology, especially in women, changes as people get to their 50s, when ageing and perimenopausal modifications take place little by little. Small changes in gonadal steroid production at the ovarian level together with some changes in the metabolic pathways and in the insulin sensitivity create the trigger for weight gain. Food intake and steroid modulation of the metabolic pathways are the basis for some of the relevant changes that facilitate the increase in body mass index and the occurrence of metabolic syndrome.

2015 - Ovulation induction with myo-inositol alone and in combination with clomiphene citrate in polycystic ovarian syndrome patients with insulin resistance [Articolo su rivista]
Kamenov, Zdravko; Kolarov, Georgi; Gateva, Antoaneta; Carlomagno, Gianfranco; Genazzani, Alessandro
abstract

Background: Insulin resistance plays a key role in the pathogenesis of polycystic ovarian syndrome (PCOS). One of the methods for correcting insulin resistance is using myo-inositol. Aim: The aim of the present study is to evaluate the effectiveness of myo-inositol alone or in combination with clomiphene citrate for (1) induction of ovulation and (2) pregnancy rate in anovulatory women with PCOS and proven insulin resistance. Patients and methods: This study included 50 anovulatory PCOS patients with insulin resistance. All of them received myo-inositolduring three spontaneous cycles. If patients remained anovulatory and/or no pregnancy was achieved, combination of myo-inositol and clomiphene citrate was used in the next three cycles. Ovulation and pregnancy rate, changes in body mass index (BMI) and homeostatic model assessment (HOMA) index and the rate of adverse events were assessed. Results: After myo-inositol treatment, ovulation was present in 29 women (61.7%) and 18 (38.3%) were resistant. Of the ovulatory women, 11 became pregnant (37.9%). Of the 18 myo-inositol resistant patients after clomiphene treatment, 13 (72.2%) ovulated. Of the 13 ovulatory women, 6 (42.6%) became pregnant. During follow-up, a reduction of body mass index and HOMA index was also observed. Conclusion: Myo-inositol treatment ameliorates insulin resistance and body weight, and improves ovarian activity in PCOS patients.

2015 - PCOS and Insulin Resistance (IR): From Lifestyle to Insulin Sensitizers [Capitolo/Saggio]
Genazzani, A. D.; Santagni, S.; Rattighieri, E.; Chierchia, E.; Despini, G.; Prati, A.; Ricchieri, F.
abstract

PCOS patients are typically characterized by chronic anovulation, hyperandrogenism, polycystic ovaries and these aspects are frequent in a high percentage of women during the repruductive life. PCOS frequently show overweight and/or obesity and are characterized by a higher production of androgens and reduced sensitivity to insulin. In fact it is of great importance to note that up to 60% of all PCOS patients are with modest up to exagerated overweight and that most of these patients show a modest up to an exagerated hyperinsulinism in response to the standard oral glucose tollerance test (OGTT). This reduced insulin sensitivity can be modified by a specific attention to life style, including not only a diet but also certain degree of physical activity. However, a specific effect on hyperinsulinemia can be achieved using glucose sensitizer drugs, such as metformin, so that to reduce the negative modulation exerted by hyperinsulinemia on the reproductive axis as well as on neuroendocrine control of reproduction with relevant effects also on adrenal function and neurosteroid production. Also specific integrative compounds have been proposed in recent years to counteract insulin resistance: myo-inositol (MYO) and d-chiro-inositol (DCI). These 2 compounds are tightly linked one to the other since MYO is transformed by an epimerase in DCI, having each tissue its own conversion rate, likely due to the specific needs for the two different molecules. In general both these compounds works as specific modulators of the intra cellular second messanger activated by the insulin linkage with its own membrane receptor. It remains clear that only the combination of life-style (diet & physical exercise) with one of the above mentioned treatments is able to solve the metabolic/endocrine impairment of overweight/obese PCOS.

2015 - Polycystic Ovary Syndrome: From Contraception to Hormone Replacement Therapy [Capitolo/Saggio]
Genazzani, A. R.; Genazzani, A. D.
abstract

Polycystic ovary syndrome (PCOS) is a common disease based on a combination of various endocrine impairments. The use of hormonal treatments permits the aesthetic disturbances to be counteracted (acne, hirsutism, alopecia), but greater attention has to be given to insulin resistance, which may induce more severe diseases, such as diabetes. The use of oral contraceptives is helpful, but a lifestyle change is considered essential so as to improve the natural ability to resist disease affecting the circulation and metabolism. When the menopausal transition starts, greater attention is given to those PCOS patients who demonstrated insulin resistance during their fertile life. The use of hormone replacement therapy is often suggested as it has been proven to be beneficial.

2015 - Surgical technique of endometrioma excision impacts on the ovarian reserve. Single-port access laparoscopy versus multiport access laparoscopy: a case control study [Articolo su rivista]
Angioni, Stefano; Pontis, Alessandro; Cela, Vito; Sedda, Federica; Genazzani, Alessandro; Nappi, Luigi
abstract

Several recent studies report the detrimental effect of endometrioma excision on the ovarian reserve. Surgical technique and the excessive use of bipolar coagulation could be the key factors. Single-port access laparoscopy (SPAL) ovarian cystectomy has been reported as a comparable procedure to conventional laparoscopy in terms of operative outcomes. The aim of this study was to evaluate whether the single-port surgery affects the ovarian reserve whilst performing laparoscopic ovarian cystectomy for unilateral endometrioma. This was a prospective, case-control study of 99 women with unilateral endometrioma. Forty-nine women underwent single-port cystectomy and 50 women underwent multiport laparoscopic (MPL) conventional cystectomy. The primary outcome was the assessment of the ovarian reserve. We evaluated the serum anti-Mullerian hormone (AMH) levels before, 4–6 weeks and 3 months after surgery. At T2 we performed an ultrasound assessment of the antral follicular count (AFC). We have drawn attention to a statistically significant decrease of the mean AMH value and AFC in the SPAL group at the 4–6-week and 3-month follow-up compared to the conventional laparoscopy group. In conclusion, our results suggest that SPAL cystectomy should not be recommended to patients undergoing surgery for endometrioma excision who want to preserve their fertility.

2014 - DHEA: A natural steroid for the treatment of menopausal women [Articolo su rivista]
Genazzani, A. D.; Prati, A.; Santagni, S.; Rattighieri, E.; Chierchia, E.; Marini, G.; Despini, G.; Genazzani, A. R.
abstract

DHEA is one of the main adrenal hormones that progressively reduces its plasmatic levels starting from the 30ies. This phenomenon implies not only the reduction of the plasmatic androgens, but also the decrease of a peculiar class of hormones, named neurosteroids, in particular allopregnanolone, the most powerful one, characterized by antidepressant and ansiolitic effect. During the latest years the putative role of the use of DHEA as replacement therapy for menopausal women has been under consideration, especially because of the failure of hormonal replacement therapy (HRT) in improving some discomforts of menopausal age, such as loss of libido and changes of mood. This review aims to elucidate the peculiar aspects of DHEA administration and its putative use as substitutive/integrative hormonal treatment alone or in combination with the traditional HRT. © Copyright 2014, CIC Edizioni Internazionali.

2014 - Dall'uso del solo DHEA alla sua associazione con la terapia ormonale sostitutiva [Articolo su rivista]
Prati, Alessia; Santagni, Susanna; Rattighieri, Erika; Campedelli, Annalisa; Ricchieri, Federica; Chierchia, Elisa; Despini, Giulia; Genazzani, A. R.; Genazzani, Alessandro
abstract

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2014 - Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats [Articolo su rivista]
Pluchino, N.; Santoro, A. N.; Casarosa, E.; Giannini, A.; Genazzani, A.; Russo, M.; Russo, N.; Petignat, P.; Genazzani, A. R.
abstract

Introduction Estetrol (E4), a naturally occurring estrogen only produced by the human fetal liver, is being evaluated in human studies for potential use in contraception and menopausal care. The present study was designed to profile E4 in the central nervous system, to assess the in vivo effects of E4 administration on allopregnanolone (AP) synthesis in specific brain structures and to evaluate whether E4 has synergic or antagonistic effects on estradiol-mediated AP synthesis. Material and methods Intact female adult rats received different doses of E4, and ovariectomized OVX rats received different doses of E4 or E2V or combinations of both drugs. The concentrations of AP were assessed in the frontal and parietal cortex, hippocampus, hypothalamus, anterior pituitary, and serum. Results E4 did not alter AP in intact animals in any region. E4 at a dosage of 5 mg/kg/day increased AP levels in different brain areas and in the serum of OVX animals. However, in the presence of estradiol, E4 showed an estrogen-antagonistic effect on the brain and serum levels of AP. Conclusion E4 increases the CNS and peripheral levels of AP, behaving as a weak estrogen-agonist in OVX rats. The antagonistic effect observed with E2V co-administration further profile E4 as a natural SERM. © 2014 Elsevier Ltd.

2014 - Effects of a Combination of Alpha Lipoic Acid and Myo-Inositol on Insulin Dynamics in Overweight/Obese Patients with PCOS. [Articolo su rivista]
Genazzani, Alessandro; Despini, Giulia; Santagni, Susanna; Prati, Alessia; Rattighieri, Erica; Chierchia, Elisa; Simoncini, Tommaso .
abstract

Myo-inositol increases insulin sensitivity in insulin resistant patients with PCOS since it improves the insulin postreceptor pathways. Since previous reports suggested that also alpha lipoic acid has specific positive effects on glucose control, we aimed to evaluate the specific effects of a combination of alpha lipoic acid and myo-inositol on insulin resistance in obese patients with PCOS. We studied a group of obese PCOS patients (n=34, BMI= 30.1 ± 0.9) according to the revised 2003 Rotterdam consensus diagnostic criteria. Among the PCOS patients, 16 out of 34 had diabetic type II relatives (parents and/or grandparents). Patients were administered a combination of alpha lipoic acid (400 mg) and myo-inositol (1 gr.) (Sinopol, Laborest, Italy) every day for at least 12 weeks. Patients underwent to baseline hormone determination and to an oral glucose tolerance test (OGTT) before and at the 12th week of treatment. After the treatment interval, HOMA index decreased significantly as well as the glucose-induced insulin response with no changes of BMI. Interestingly the treatment did not change insulin dynamics in normo-insulinemic PCOS while significant insulin decrease was observed in hyperinsulinemic PCOS patients. 87.5% (14 out of 16) of the PCOS patients with diabetic relatives resulted to be among the hyperinsulinemic patients. Hyperinsulinemic PCOS patients showed the significant decrease of the insulin plasma levels (from 14 ± 2.1 to 9.5 ± 0.8 μU/ml, p<0.05), of HOMA index (from 3.3 ± 0.4 to 2.1 ± 0.1, p<0.05) and showed the significant decrease of insulin response to glucose load. In conclusion, the combination of alpha lipoic acid plus MYO was effective in improving insulin sensitivity in obese PCOS patients that resulted to be hyperinsulinemic under OGTT. Moreover the more peculiar and relevant positive changes were observed in obese PCOS with diabetic first grade relatives.

2014 - Effects of estetrol on migration and invasion inT47-D breast cancer cells through the actin cytoskeleton [Articolo su rivista]
Maria, Silvia Giretti; Guevara, Maria Magdalena Montt; Cecchi, Elena; Mannella, Paolo; Palla, Giulia; Spina, Stefania; Bernacchi, Guja; Bello, Silvia Di; Genazzani, Andrea Riccardo; Genazzani, Alessandro; Simoncini, Tommaso
abstract

Estetrol (E4) is a natural human estrogen present at high concentrations during pregnancy. Due to its high oral bioavailability and long plasma half-life, E4 is particularly suitable for therapeutic applications. E4 acts as a selective estrogen receptor (ER) modulator, exerting estrogenic actions on the endometrium or the central nervous system, while antagonizing the actions of estradiol in the breast. We tested the effects of E4 on its own or in the presence of 17β-estradiol (E2) on T47-D ER+ breast cancer cell migration and invasion of three-dimensional matrices. E4 administration to T47-D cells weakly stimulated migration and invasion. However, E4 decreased the extent of movement and invasion induced by E2. Breast cancer cell movement requires a remodeling of the actin cytoskeleton. During exposure to E4, a weak, concentration-dependent, re-distribution of actin fibers toward the cell membrane was observed. However, when E4 was added to E2, an inhibition of actin remodeling induced by E2 was seen. Estrogens stimulate ER+ breast cancer cell movement through the ezrin-radixin-moesin family of actin regulatory proteins, inducing actin and cell membrane remodeling. E4 was a weak inducer of moesin phosphorylation on Thr(558), which accounts for its functional activation. In co-treatment with E2, E4 blocked the activation of this actin controller in a concentration-related fashion. These effects were obtained through recruitment of estrogen receptor-α. In conclusion, E4 acted as a weak estrogen on breast cancer cell cytoskeleton remodeling and movement. However, when E2 was present, E4 counteracted the stimulatory actions of E2. This contributes to the emerging hypothesis that E4 may be a naturally occurring ER modulator in the breast.

2014 - Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients [Articolo su rivista]
Genazzani, Alessandro; Santagni, Susanna; Rattighieri, Erika; Chierchia, Elisa; Despini, Giulia; Marini, Giulia; Prati, Alessia; Simoncini, Tommaso
abstract

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2014 - Myo-inositol modulates insulin and luteinizing hormone secretion in normal weight patients with polycystic ovary syndrome [Articolo su rivista]
Genazzani, Alessandro; Santagni, Susanna; Ricchieri, Federica; Campedelli, Annalisa; Rattighieri, Erika; Chierchia, Elisa; Marini, Giulia; Despini, Giulia; Prati, Alessia; Simoncini, Tommaso
abstract

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2014 - PCOS from Lifestyle to the Use of Inositol and Insulin Sensitizers [Capitolo/Saggio]
Genazzani, A. D.; Prati, A.; Despini, G.; Marini, G.; Ricchieri, F.
abstract

PCOS patients are typically characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries, and these aspects are frequent in a high percentage of women during the reproductive life. PCOS frequently show overweight and/or obesity and are characterized by a higher production of androgens and reduced sensitivity to insulin. In fact it is of great importance to note that more than 40–45% of all PCOS patients show overweight up to obesity and that these patients have a modest up to an exaggerated hyperinsulinism in response to the standard oral glucose tolerance test (OGTT). What is relevant to point out is that such reduced insulin sensitivity can be observed also in 10–15% of the normal weight PCOS, thus confirming that hyperinsulinism can show up not only in relation to obesity or to excess of fat tissue but also as an intrinsic abnormal ability to control glucose metabolism. Recent data clearly demonstrated that reduced insulin sensitivity can be gained with a specific attention to lifestyle, including not only a diet but also certain degree of physical activity. However, a specific effect on hyperinsulinemia can be achieved using glucose sensitizer drugs, such as metformin, so that to reduce the negative modulation exerted by hyperinsulinemia on the reproductive axis as well as on neuroendocrine control of reproduction with relevant effects also on adrenal function and neurosteroid production. The evolution of therapeutical approach to PCOS proposed in recent years the use of inositol in two of the isomers at present available, that is myo-inositol (MYO) and D-chiro-inositol (DCI). These two compounds are tightly linked one to the other since MYO is transformed by an epimerase in DCI, having each tissue its own conversion rate, likely due to the specific needs for the two different molecules. In general both these compounds work as specific modulators of the intracellular second messenger activated by the insulin linkage with its own membrane receptor. Recent data demonstrated also that integrative administration of MYO in lean PCOS ameliorated insulin response to OGTT and that both MYO and DCI reduced insulin response to OGTT in overweight or obese PCOS. Both isomers have been demonstrated to improve also ovarian function and LH response to GnRH stimulation, typically abnormal in PCOS patients. Though impossible to state what of the two isomers play the main role, it appears clear that the metabolic impairment(s) are great part of the casual factor(s) of the abnormal reproductive function in PCOS.

2014 - Pathophysiology and Clinical Assessment of Hyperandrogenic States [Capitolo/Saggio]
Santagni, S.; Rattighieri, E.; Chierchia, E.; Despini, G.; Genazzani, A. D.
abstract

2013 - Advances in neurosteroids: Role in clinical practice [Articolo su rivista]
Pluchino, N.; Santoro, A.; Casarosa, E.; Wenger, J. M.; Genazzani, Alessandro; Petignat, P.; Genazzani, A. R.
abstract

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2013 - Endocrine and clinical effects of myo-inositol administration in policystyc ovary syndrome. A randomized study. [Articolo su rivista]
Artini, Pg; Di Berardino, Om; Papini, F; Genazzani, Alessandro; Simi, G; Ruggiero, M; Cela, V.
abstract

Objective: To evaluate the effects the administration of myo-inositol (MYO) on hormonal parameters in a group of polycystic ovary syndrome (PCOS) patients. Design: Controlled clinical study. Setting: PCOS patients in a clinical research environment. Patients: 50 overweight PCOS patients were enrolled after informed consent. Interventions: All patients underwent hormonal evaluations and an oral glucose tolerance test (OGTT) before and after 12 weeks of therapy (Group A (n=10): MYO 2 g plus folic acid 200 mg every day; Group B (n=10): folic acid 200 mg every day). Ultrasound examinations and Ferriman-Gallwey score were also performed. Main outcome measures: Plasma LH, FSH, PRL, E2, 17OHP, A, T, glucose, insulin, C peptide concentrations, BMI, HOMA index and glucose-to-insulin ratio. Results: After 12 weeks of MYO administration plasma LH, PRL, T, insulin levels and LH/FSH resulted significantly reduced. Insulin sensitivity, expressed as glucose-to-insulin ratio and HOMA index resulted significantly improved after 12 weeks of treatment. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic subjects. No changes occurred in the patients treated with folic acid. Conclusions: MYO administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.

2013 - Hypothalamic amenorrhea in a Camurati-Engelmann disease-a case report [Articolo su rivista]
Meczekalski, Blazej; Czyzyk, Adam; Podfigurna Stopa, Agnieszka; Rydzewski, Bogdan; Sroczynski, Jakub; Lipinska, Małgorzata; Sokalski, Jerzy; Krawczynski, Maciej; Jamsheer, Aleksander; Katulski, Krzysztof; Genazzani, Alessandro
abstract

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2013 - PCOS as a metabolic impaired disease [Articolo su rivista]
Genazzani, A. D.; Prati, A.; Santagni, S.; Rattighieri, E.; Chierchia, E.; Campedelli, A.; Marini, G.; Despini, G.; Farinetti, A.; Ricchieri, F.
abstract

2012 - Actin Cytoskeleton Remodelling by Sex Steroids in Neurones [Articolo su rivista]
Sanchez, Am; Flamini, Mi; Polak, K; Palla, G; Spina, S; Mannella, P; Genazzani, Alessandro; Simoncini, T.
abstract

Cell morphology and its interaction with the extracellular environment are integrated processes involving a number of intracellular controllers orchestrating cytoskeletal proteins and their interaction with the cell membrane and anchorage proteins. Sex steroids are effective regulators of cell morphology and tissue organisation, and recent evidence indicates that this is obtained through the regulation of the actin cytoskeleton. Intriguingly, many of these regulatory actions related to cell morphology are achieved through the rapid, nonclassical signalling of sex steroid receptors to kinase cascades, independently from nuclear alteration of gene expression or protein synthesis. The identification of the mechanistic basis for these rapid actions on cell cytoskeleton has special relevance for the characterisation of the effects of sex steroids under physiological conditions, such as for the development of neurone/neurone interconnections and dendritic spine density. This is considered to be critical for gender-specific differences in brain function and dysfunction. Recent advancements in the characterisation of the molecular basis of the extranuclear signalling of sex steroids help to clarify the role of oestrogen and progesterone in the brain, and may turn out to be of relevance for clinical purposes. This review highlights the regulatory effects of oestrogens and progesterone on actin cytoskeleton and neurone morphology, as well as recent progresses in the characterisation of these mechanisms, providing insights and working hypotheses on possible clinical applications for the modulation of these pathways in the central nervous system.

2012 - Bollettino di Endocrinologia Ginecologia [Direzione o Responsabilità Riviste]
Genazzani, Alessandro
abstract

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2012 - Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients [Articolo su rivista]
Genazzani, Alessandro; Prati, Alessia; Santagni, Susanna; Ricchieri, Federica; Chierchia, Elisa; Rattighieri, Erica; Campedelli, Annalisa; Simoncini, Tommaso; Artini, Paolo G.
abstract

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, chronic anovulation, polycystic ovaries at ultrasound evaluation, and quite frequently by insulin resistance or compensatory hyperinsulinemia. Attention has been given to the role of inositol-phosphoglycan (IPG) mediators of insulin action and growing evidences suggest that a deficiency of D-chiro-inositol (DCI) containing IPG might be at the basis of insulin resistance, frequent in PCOS patients. On such basis, we investigated the efficacy on insulin sensitivity and hormonal parameters of 8 weeks treatment with myo-inositol (MYO) (Inofert, ItalPharmaco, Milano, Italy) at the dosage of 2 g day in a group (n = 42) of obese PCOS patients,. After the treatment interval body mass index (BMI) and insulin resistance decreased together with luteinizing hormone (LH), LH/FSH and insulin. When subdividing the patients according to their fasting insulin levels, Group A (n = 15) insulin below 12 mu U/ml and Group B (n = 27) insulin above 12 mu U/ml, MYO treatment induced similar changes in both groups but only patients of Group B showed the significant decrease of both fasting insulin plasma levels (from 20.3 +/- 1.8 to 12.9 +/- 1.8 mu U/ml, p < 0.00001) and of area under the curve (AUC) of insulin under oral glucose tolerance test (OGTT). In conclusion, our study supports the hypothesis that MYO administration is more effective in obese patients with high fasting insulin plasma levels.

2012 - Dydrogesterone exerts endothelial anti-inflammatory actions decreasing expression of leukocyte adhesion molecules [Articolo su rivista]
Fu, Xd; Garibaldi, S; Gopal, S; Polak, K; Palla, G; Spina, S; Mannella, P; Genazzani, Ar; Genazzani, Alessandro; Simoncini, T.
abstract

Clinical observations and basic studies show that progesterone and progestins have a variable influence on endothelial function. Dydrogesterone (DG) is a widely used progestin, but its endothelial actions have not been thoroughly assessed. In this study, we investigated the effects of DG and its metabolite 20-alpha-dihydro-dydrogesterone (DHD), natural progesterone as well as medroxyprogesterone acetate, on the expression of leukocyte adhesion molecules in human endothelial cells using an in vitro experimental endothelial inflammation system. Our findings show that all progestins significantly suppress endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and inter-cellular adhesion molecule-1 (ICAM-1) induced by bacterial lypopolysaccharide (LPS). These inhibitory effects of DG and DHD require activation of progesterone receptor. DG and DHD decrease adhesion molecule expression associated with LPS administration by preventing nuclear translocation of the pro-inflammatory transcription factor nuclear factor-kappa B. In addition, DG and DHD do not alter the anti-inflammatory effects of 17 beta-estradiol. In conclusion, DG and DHD decrease endothelial inflammatory responses induced by LPS, via reduced expression of the pro-atherogenic adhesion molecules VCAM-1 and ICAM-1. These actions may be relevant for the vascular effects of DG.

2012 - Effects of red clover extracts on breast cancer cell migration and invasion [Articolo su rivista]
Mannella, P; Tosi, V; Russo, E; Zullino, S; Pancetti, F; Gompal, S; Polak, K; Genazzani, Ar; Genazzani, Alessandro; Simoncini, T.
abstract

Postmenopausal hormone therapy is associated with increased incidence of breast cancer. For this reason alternativetherapeutic options to treat menopausal symptoms have been developed. Red clover extracts (RCE) are rich in isoflavones,particularly genistein and daidzein and they have been proved to be effective in reducing vasomotor symptoms in a number ofstudies. Due to their partial selectivity of action on estrogen receptors (ERs) these compounds have been claimed to be saferon the breast. In this article, we explored the action of RCE on motility and invasion of ER positive breast cancer cells and wepartially characterized the signaling mechanisms. The principal isoflavones contained in RCE acted as weak estrogeniccompounds when administered alone. However, when provided in association with physiological amounts of estradiol, RCEacted as estrogen antagonist on remodeling of actin cytoskeleton that are requested to enact cell movement and with relatedmodifications of the activity of actin-binding proteins, such as moesin. These results offer novel information on the molecularactions of isoflavones contained in red clover on breast cancer cells, supporting a possible action of these molecules as naturalselective estrogen receptor modulators in the presence of physiological amounts of estrogens.

2012 - Estriol administration modulates luteinizing hormone secretion in women with functional hypothalamic amenorrhea [Articolo su rivista]
Genazzani, Alessandro; Meczekalski, B; Podfigurna Stopa, A; Santagni, Susanna; Rattighieri, Erika; Ricchieri, Federica; Chierchia, Elisa; Simoncini, T.
abstract

Objective: To evaluate the influence of estriol administration on the hypothalamus-pituitary function and gonadotropins secretion in patients affectedby functional hypothalamic amenorrhea (FHA).Design: Controlled clinical study.Setting: Patients with FHA in a clinical research environment.Patient(s): Twelve hypogonadotropic patients affected by FHA.Intervention(s): Pulsatility study of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and a gonadotropin-releasing hormone (GnRH)test (10 mg in bolus) at baseline condition and after 8 weeks of therapy with 2 mg/day of estriol.Main Outcome Measure(s): Measurements of plasma LH, FSH, estradiol (E2), androstenedione (A), 17a-hydroxyprogesterone (17-OHP), cortisol,androstenedione (A), testosterone (T), thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and insulin, and pulsedetection.Result(s): After treatment, the FHA patients showed a statistically significant increase of LH plasma levels (from 0.7 0.1 mIU/mL to 3.50.3 mIU/mL)and a statistically significant increase of LH pulse amplitude with no changes in LH pulse frequency. In addition, the LH response to the GnRH bolus wasa statistically significant increase.Conclusion(s): Estriol administration induced the increase of LH plasma levels in FHA and improved GnRH-induced LH secretion. These findingssuggest that estriol administration modulates the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of LHsynthesis and secretion in hypogonadotropic patients with FHA.

2012 - Estrogen regulates endothelial migration via plasminogen activator inhibitor (PAI-1) [Articolo su rivista]
Gopal, S; Garibaldi, S; Goglia, L; Polak, K; Palla, G; Spina, G; Genazzani, Ar; Genazzani, Alessandro; Simoncini, T.
abstract

Endothelial plasminogen activator inhibitor (PAI-1) controls vascular remodeling, angiogenesis and fibrinolysis. PAI-1 blood levels in women are related to estrogen. The aim of this study was to characterize the signaling pathways through which estrogen regulates PAI-1 in endothelial cells. Furthermore, we aimed to investigate whether PAI-1 is implicated in the control of endothelial migration by estrogen. Cultured human umbilical vein endothelial cells (HUVECs) and ovariectomized rats were used to test the effects of 17b-estradiol (E2) on PAI-1 expression and its role on endothelial migration. At physiological concentrations, E2 increases the expression of PAI-1 in HUVEC within 6–12 h through activation of a signaling cascade initiated by estrogen receptor a and involving G proteins, phosphatidylinositol-3-OH kinase and Rho-associated kinase II. ROCK-II activation turns into an over-expression of c-Jun and c-Fos that is required for E2-induced expression of PAI-1. Estrogen-induced PAI-1 expression is implicated in HUVEC horizontal migration. PAI-1 regulation is found also in vivo, in female rats, where ovariectomy is associated with reduced PAI-1 expression, while estrogen replacement counteracts this change. In conclusion, E2 increases PAI-1 synthesis in human endothelial cells and in rodent aorta through a G protein-initiated signaling that targets earlyimmediate gene expression. This regulatory pathway is implicated in endothelial cell migration. These findings describe new mechanisms of action of estrogens in the vessels, which may be important for vascular remodeling and hemostasis.

2012 - PCOS and metformin: from pharmacology to clinical use for women’s health [Articolo su rivista]
Genazzani, Alessandro; Ricchieri, Federica; Prati, A; Chierchia, Elisa; Rattighieri, Erika; Bosco, G; Despini, G; Campedelli, Annalisa; Farinetti, Alberto; Santagni, Susanna
abstract

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2012 - Progestinici e fibromatosi uterina [Articolo su rivista]
Campedelli, Annalisa; Santagni, Susanna; Chierchia, Elisa; Alessia, Prati; Giovanna, Bosco; Giulia, Despini; Ricchieri, Federica; Genazzani, Alessandro
abstract

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2011 - Acetyl-L-Carnitine (ALC) administration positively affects reproductive axis in hypogonadotropic women with functional hypothalamic amenorrhea [Articolo su rivista]
Genazzani, Alessandro; Lanzoni, Chiara; Ricchieri, Federica; Santagni, Susanna; Rattighieri, Erika; Chierchia, E; Monteleone, P; Jasonni, Valerio
abstract

Background: Hypothalamic amenorrhea (HA) is characterized by neuroendocrine impairment that, in turn, negatively modulates endocrine function, mainly within the reproductive axis. HA presents withs hypoLH, hypoestrogenism and, until now, a definite therapeutic strategy has not yet been found.The aim of the following study was to test the efficacy of Acetyl-L-Carnitine (ALC)administration in HA-affected subjects.Population: A group of 24 patients affected by stress-induced HA were divided in 2 groups according to LH plasma levels. Group A, hypo LH (LH < 3 mIU/ml) (n=16) and group B, normoLH (LH > 3 mIU/ml), (n=8) were treated with Acetyl-L-Carnitine (ALC) (1 g/day, per os) for 16 weeks.Design: Patients underwent baseline hormonal assessment, pulsatility test (for LH and FSH), naloxone test (for LH, FSH and cortisol) both before and after 16 weeks of treatment.Results: Under ALC administration hypo LH patients showed a significant increase in LH plasma levels (from 1.4±0.3 to 3.1±0.5, p<0.01) and in LH pulse amplitude (p< 0.001). No changes wereobserved in the normo LH group. LH response to naloxone was restored under ALC therapy. Maximal LH response and AUC under naloxone were significantly increased (p<0.05 and p<0.01,respectively). No changes were observed in the normo LH patients.Conclusions: Our data support the hypothesis of a specific role of ALC on counteracting the stressinduced abnormalities in hypo LH patients affected by hypothalamic amenorrhea.

2011 - Analgesia and endocrine surgical stress: effect of two analgesia protocols on cortisol and prolactin levels during abdominal aortic aneurysm endovascular repair. [Articolo su rivista]
Barbieri, Alberto; Giuliani, Enrico; Genazzani, Alessandro; Baraldi, E; Ferrari, Anna; D'Amico, Roberto; Coppi, Gioachino
abstract

OBJECTIVES:Endovascular abdominal aortic aneurysm (AAA) repair was performed with local anaesthesia and intravenous analgesia. The objective of the study was to evaluate how two analgesia protocols affected stress response, measured as cortisol, 17-OH progesterone (17OHP) and prolactin (PRL) concentration during the procedure.METHODS:44 patients undergoing elective AAA endovascular repair were included to either receive regular boluses of fentanyl midazolam or remifentanil continuous infusion, analgesia was monitored by Visual Analogue Scale (VAS) measurement; cortisol, 17OHP and PRL were sampled preoperatively, at skin incision, endovascular prosthesis release and skin suture.RESULTS:42 patients were included. Mean VAS values were lower in the remifentanil group 0.50±0.68 vs 1.48±1.20, p=0.002 at incision, 0.24±0.58 vs 1.45±1.18, p<0.001 prosthesis release, 0.51±0.90 vs 1.73±1.45, p=0.002 suture. No statistically significant difference was found among cortisol and 17OHP levels; PRL was significantly lower in the fentanyl-midazolam group (23.83±16.92 ng/ml vs 40.81±22.45 p=0.009 at prosthesis release and 28.23±15.05 vs 41.37±14.54, p=0.007 at suture).CONCLUSIONS:Although statistically significant VAS difference had a limited clinical impact due to its small entity. The group that experienced less pain showed a more intense PRL response, while cortisol and 17OHP did not reach statistical significance.

2011 - Bollettino di Endocrinologia Ginecologica [Direzione o Responsabilità Riviste]
Genazzani, Alessandro
abstract

2011 - DHEA as a putative replacement therapy in the elderly [Capitolo/Saggio]
Genazzani, A. D.; Lanzoni, C.
abstract

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2011 - Estimation of instantaneous secretory rates and intrinsic characteristics of luteinizing hormone secretion in women with Kallmann syndrome before and after estriol administration. [Articolo su rivista]
Genazzani, Alessandro; Santagni, Susanna; Chierchia, Elisa; Rattighieri, Erika; Campedelli, Annalisa; Prati, A; Ricchieri, Federica; Simoncini, T.
abstract

Three Kallmann syndrome (KS) patients were examined to assess characteristics of LH response to GnRH bolus, with and without GnRH sensitization using Instantaneous Secretory Rate (ISR) computation before and after estriol treatment (60 days, 2 mg/day). Six healthy women were enrolled as controls and underwent GnRH bolus during the early follicular phase (days 3-5 of the menstrual cycle). After estriol treatment, the KS patients showed a higher LH response to GnRH bolus and similar LH pulse duration to healthy controls. These data support the hypothesis that the administration of weak estrogen improves LH response to GnRH in hypogonadotropic women with KS.

2011 - Estrogen-like effects of wine extracts on nitric oxide synthesis in human endothelial cells [Articolo su rivista]
Simoncini, T; Lenzi, E; Zochling, A; Gopal, S; Goglia, L; Russo, E; Polak, K; Casarosa, E; Jungbauer, A; Genazzani, Alessandro; Genazzani, Ar
abstract

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2011 - Metabolismo osseo nelle amenorreaa ipotalamiche da basso peso: il ruolo del trattamento con estroprogestinici [Articolo su rivista]
Ricchieri, Federica; Chierchia, Elisa; Campedelli, Annalisa; Rattighieri, Erika; Prati, A; Santagni, Susanna; Genazzani, Alessandro
abstract

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2011 - Modificazioni della citologia cervicovaginale nella donna in menopausa e possibili trattamenti [Articolo su rivista]
Santagni, Susanna; Rattighieri, Erika; Campedelli, Annalisa; Prati, A; Chierchia, Elisa; Genazzani, Alessandro
abstract

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2010 - Bollettino di Endocrinologia Ginecologica [Direzione o Responsabilità Riviste]
Genazzani, Alessandro
abstract

2010 - Effects of Klamath Algae extract on psychological disorders and depression in menopausal women: a pilot study [Articolo su rivista]
Genazzani, Alessandro; Chierchia, Elisa; Lanzoni, Chiara; Santagni, Susanna; Veltri, F; Ricchieri, Federica; Rattighieri, Erika; Nappi, R. E.
abstract

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2010 - Effetto degli estratti di alga Klamath sul benessere e sui fenomeni di stress ossidativo nelle pazienti in menopausa [Articolo su rivista]
Genazzani, Alessandro; Santagni, Susanna; Chierchia, Elisa; Canestrari, F; Lanzoni, Chiara; Scoglio, S.
abstract

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2010 - Hypothalamic amenorrhea: from diagnosis to therapeutical approach. [Articolo su rivista]
Genazzani, Alessandro; E., Chierchia; Santagni, Susanna; Rattighieri, Erika; Farinetti, Alberto; Lanzoni, Chiara
abstract

Among secondary amenorrheas, hypothaIamic amenorrhea (HA) is the ODe with 00 evidence of endocrine/systemic causai factors. HA is maioly related to various stressors affectiog neuroendocrine cootrol of the reproductive axis. In clinicaI practice, HA is maioly associated with metabolic,physical, or psychological stress. Stress is the adaptive respoose of our body through ali its homeostatic systems, to extemal and/or internai stimuli that activate specific and ooospecific physiological pathways. HA occurs generally after severe stressed conditions/situations such as dieting, heavytraining, or intense emotional events, ali situatioos that cao induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In faci, the diagnosis is essentialIy based on a good aoamnestic investigatioo. It has to be investigated using the clinicaIhistory of the patient: occurrence of meoarche, menstrual cyclicity, time and modality of amenorrhea, aod it has to be excluded aoy enOOcrine disease or aoy metabolic (i.e., diabetes) aod systemic disorders. It is necessary to identify any stressed situation induced by 10ss, famity or working problems, weight loss or eatiog disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed bui 00 absolute parameter cao be proposed since HA is greatly dependent from individuai response to stressors and/or the adaptive response to stress. This chapter aims to give iusights into diagnosis and putative therapeutic strategies.

2010 - La Sindrome Premestruale: clinica, fisiopatologia e indicazioni terapeutiche [Articolo su rivista]
Santagni, Susanna; Chierchia, E.; Rattighieri, Erika; Lanzoni, Chiara; Campedelli, Annalisa; Genazzani, Alessandro
abstract

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2010 - Metformin administration restores allopregnanolone response to adrenocorticotropic hormone (ACTH) stimulation in overweight hyperinsulinemic patients with PCOS [Articolo su rivista]
Genazzani, Alessandro; Chierchia, Elisa; Rattighieri, Erika; Santagni, Susanna; Casarosa, E; Luisi, M; Genazzani, A. R.
abstract

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2010 - Use of metformin in the treatment of polycystic ovary syndrome [Articolo su rivista]
Genazzani, Alessandro; Ricchieri, Federica; Lanzoni, Chiara
abstract

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2009 - Aspetti endocrini, diagnostici e terapeutici delle menimetrorragie in età perimenopausale. [Articolo su rivista]
Rattighieri, Erika; Lanzoni, Chiara; Santagni, Susanna; Chierchia, Elisa; Campedelli, Annalisa; Jasonni, Valerio; Genazzani, Alessandro
abstract

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2009 - Bollettino di Endocrinologia Ginecologica [Direzione o Responsabilità Riviste]
Genazzani, Alessandro
abstract

2009 - Effect of a 2-month treatment with Klamin®, a Klamath algae extract, on the general well-being, antioxidant profile and oxidative status of postmenopausal women [Articolo su rivista]
Scoglio, S; Benedetti, S; Canino, C; Santagni, Susanna; Rattighieri, Erika; Chierchia, E; Canestrari, F; Genazzani, Alessandro
abstract

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2009 - L'amenorrea da basso peso. [Abstract in Atti di Convegno]
Genazzani, Alessandro; C., Lanzoni; Farinetti, Alberto; V. M., Jasonni
abstract

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2009 - PCOS e diabete mellito tipo II. [Articolo su rivista]
Chierchia, Elisa; Santagni, Susanna; Rattighieri, Erika; Lanzoni, Chiara; Ricchieri, Federica; Genazzani, Alessandro
abstract

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2008 - Bollettino di Endocrinologia Ginecologica [Direzione o Responsabilità Riviste]
Genazzani, Alessandro
abstract

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2008 - Effect of short term sibutramine on gonadotropin spontaneous pulsatile release in normogonadotropinemic amenorrheic subjects [Articolo su rivista]
Genazzani, Alessandro; Lanzoni, Chiara; Ricchieri, Federica; Campedelli, Annalisa; Rattighieri, Erika; Santagni, Susanna; Jasonni, Valerio
abstract

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2008 - Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome [Articolo su rivista]
Genazzani, Alessandro; Lanzoni, Chiara; Ricchieri, Federica; Jasonni, Valerio
abstract

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2008 - Obesità e benessere: i rischi per la salute della donna obesa [Articolo su rivista]
Ricchieri, Federica; Lanzoni, Chiara; Campedelli, Annalisa; Rattighieri, Erika; Santagni, Susanna; Chierchia, Elisa; Jasonni, Valerio; Genazzani, Alessandro
abstract

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2008 - One-year therapy with 10 mg/day DHEA alone or in combination with HRT in postmenopausal women: effects on hormonal milieu [Articolo su rivista]
Pluchino, N.; Ninni, F.; Stomati, M.; Freschi, L.; Casarosa, E.; Valentino, V.; Luisi, S.; Genazzani, Alessandro; Potì, E.; Genazzani, A. R.
abstract

The purpose of this study was to evaluate the effects on hormonal milieu of 1-year therapy with 10 mg/day oral dehydroepiandrosterone(DHEA) or 50 g transdermal estradiol plus 100 mg/day oral micronized progesterone in a group of 20healthy postmenopausal women (age = 50–58 and years since menopause (ysm) = 1–6) and also the effects observed by combiningthese two therapies in a group of 12 postmenopausal women (age = 54–61 and ysm = 6–10) characterized by lower baselineDHEA and DHEAS levels (<2.40 and <0.55 g/ml, respectively).DHEA produced a significant rise in androgens levels, whereas HRT did not. Moreover, DHEA alone induced a significantlylower increase in estrogens and beta-endorphin levels and a higher decrease in cortisol levels than HRT. DHEA and HRT alsoproduced a significant similar increase in allopregnanolone levels.DHEA plus HRT induced a significantly higher increase in testosterone and estradiol and a lower increase in allopregnanoloneand beta-endorphin levels and a significantly lower decrease in cortisol levels than HRT alone treated group. A similar increasewas observed in progesterone and SHBG levels in all groups.These results suggest that 10-mg DHEA seems to be the proper dose to replace androgen deficiency in subjects with reducedDelta-5 androgens plasma levels. However, the aging process and the number of years since menopause may further modulatethe effects of hormone therapy on hormonal milieu.© 2008 Elsevier Ireland Ltd. All rights reserved.

2007 - Bollettino di Endocrinologia Ginecologica [Direzione o Responsabilità Riviste]
Genazzani, Alessandro
abstract

2007 - Efficacy on menopausal neurovegetative symptoms and some plasma lipids blood levels of an herbal product containing isoflavones and other plant extracts [Articolo su rivista]
Cancellieri, F.; De Leo, V.; Genazzani, Alessandro; Nappi, C.; Parenti, G. L.; Polatti, F.; Ragni, N.; Savoca, S.; Teglio, L.; Finelli, F.; Nichelatti, M.
abstract

Objectives: To assess the efficacy of a product containing isoflavones and other plant extracts (1310) on whole menopausal symptomatology and plasma lipids profile. Methods: Multicente, randomized, double blind, placebo controlled clinical investigation on 125 menopausal women randomly assigned to two groups treated for 6 months with placebo or one tablet daily of an herbal product containing 72 mg/dose of isoflavones of different plants origin and other plant extracts (1310). Primary end-point: Kupperman Menopause Index (KI) variations; secondary end-point: activity on plasma lipids profile and clinical global impression (CGI) on efficacy and tolerability by investigators and patients. The usual parametric test (paired Student t test) was performed to evaluate the significance. In case of non-applicability of parametric tests, the non-parametric Mann-Whitney U test was used. The differences where considered significant at p < 0.05 level. Results: At the end of treatment in both groups KI showed a significant decrease (p < 0.001). However, in the BIO group the KI reduction was significantly higher (p=0.0265) than in the placebo group after 4 and 6 months of treatment. In the BIO treated patients the LDL cholesterol showed a borderline but not significant reduction compared to placebo (p = 0.0608) and triglyceride (TG) a significant (p = 0.0151) decrease compared to placebo. The investigator's and patient's CGI on BIO group where superior as compared to placebo. Clinical tolerability was good in booth groups. Conclusion: On the basis of positive effects on HI and lipids profile as well as of good clinical tolerability, BIO can be considered one of the possible alternative therapy for conventional HRT. (c) 2007 Published by Elsevier Ireland Ltd.

2007 - Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor [Articolo su rivista]
Begliomini, S; Casarosa, E; Pluchino, N; Lenzi, E; Centofanti, M; Freschi, L; Pieri, M; Genazzani, Alessandro; Luisi, S; Genazzani, A. R.
abstract

Brain-derived neurotrophic factor (BDNF) is a mediator of neuronal plasticity and influenceslearning, memory and cognitive behaviour. The aim of this study is to assess plasma BDNF variations according tohormonal status. METHODS: A total of 60 subjects were included: 20 fertile ovulatory women, 15 amenorrhoeicwomen and 25 postmenopausal women. Blood samples were collected after overnight fasting. For 5 out of the 20fertile women, samples were collected every 2 days throughout the whole menstrual cycle. Following basal evaluation,10 out of 25 postmenopausal women were administered a hormone replacement therapy (HRT) and reevaluated after6 months of treatment. Plasma BDNF concentrations were measured by enzyme-linked immunosorbent assay. Infertile women, estradiol (E2), progesterone and gonadotrophins were also assessed. RESULTS: In fertile women,luteal phase levels of plasma BDNF were significantly higher than follicular phase levels (P < 0.001). BDNF increasedfrom early follicular phase up to Day 14 of the cycle, reaching a pre-ovulatory peak, similar to E2. A second rise tookplace during mid-luteal phase, with a peak on Day 24. Amenorrhoeic subjects, as well as postmenopausal women,showed significantly lower plasma BDNF levels compared with fertile females (P < 0.001). BDNF was positively correlatedwith E2 and progesterone and negatively correlated with menopausal age. HRT restored BDNF levels to thosepresent in fertile women during the follicular phase. CONCLUSIONS: Plasma BDNF levels are influenced by hormonalstatus. Modifications in BDNF circulating levels during the menstrual cycle suggest a potential role for gonadal sexhormones (E2 and progesterone) in regulating neurotrophin expression.

2007 - Metformin administration is more effective when non-obese patients with polycystic ovary syndrome show both hyperandrogenism and hyperinsulinemia [Articolo su rivista]
Genazzani, Alessandro; Lanzoni, Chiara; Ricchieri, Federica; Baraldi, E.; Casarosa, E.; Jasonni, Valerio
abstract

Background. Polycystic ovary syndrome (PCOS) is a common endocrine disease that is frequently observed to be related to increased insulin resistance independent of body weight. The use of insulin-sensitizer compounds, such as metformin, permits great improvement of such metabolic abnormality, restoring ovarian function and gonadal steroid synthesis and reducing insulin resistance. Aim. On this basis we aimed to evaluate a group of non-obese amenorrheic PCOS patients before and after 6 months of metformin administration (500 mg orally twice daily) to better understand upon which basis of clinical and endocrine parameters metformin administration might be chosen as a putative therapeutic tool. Method. A group of non-obese PCOS patients (n = 42) was enrolled after informed consent. They underwent an oral glucose tolerance test for insulin, glucose and C-peptide levels and provided blood samples for determination of plasma levels of luteinizing hormone (LH), follicle-stimulating hormone, prolactin, estradiol, androstenedione, 17-hydroxyprogesterone, insulin, cortisol and testosterone levels on two occasions: before and on day 7 of the first menstrual cycle occurring after the 5th month of treatment. Results. Plasma LH, estradiol, insulin and C-peptide were decreased significantly by metformin treatment in the entire group of PCOS patients. When subdividing PCOS patients according to insulin sensitivity (i.e. hyper- and normoinsulinemic subjects), a greater rate of positive endocrine changes was observed in hyperinsulinemic patients and the highest rate was observed in hyperinsulinemic hyperandrogenic subjects. Menstrual cyclicity was recovered in all patients under treatment. Conclusions. Our data show that metformin modulates ovarian function and greatly affects LH secretion through reduction of the hyperandrogenic condition. The highest rate of endocrine changes was observed in the hyperinsulinemic hyperandrogenic non-obese PCOS patients. Our study demonstrates that metformin administration is more appropriate in hyperinsulinemic hyperandrogenic non-obese PCOS patients.

2007 - Might DHEA be Considered a Beneficial Replacement Therapy in the Elderly ? [Articolo su rivista]
Genazzani, Alessandro; Lanzoni, C; Genazzani, A. R.
abstract

Dehydroepiandrosterone (DHEA) [prasterone] is typically secreted by the adrenal glands and its secretory rate changes throughout the human lifespan.When human development is completed and adulthood is reached, DHEA and DHEA sulphate (DHEAS) [PB-008] levels start to decline so that at 70–80 years of age, peak DHEAS concentrations are only 10–20% of those in young adults.This age-associated decrease has been termed ‘adrenopause’, and since many agerelated disturbances have been reported to begin with the decline of DHEA/DHEAS levels, this provides a potential opportunity for use of DHEA as replacementtherapy.For these reasons, use of DHEA as a replacement therapy in aging men and women has been proposed and this paper outlines the reported beneficial effects ofsuch treatment in humans. Many interesting results have been obtained in experimental animals suggesting that DHEA positively modulates most age-related disturbances. However, renewed interest in DHEA has arisen as a result of recentstudies suggesting that DHEA appears to be beneficial in hypoandrogenic men as well as in postmenopausal and aging women. Menopause is the event in awoman’s life that induces a dramatic change in the steroid milieu, and use of DHEA as ‘replacement treatment’ has been reported to restore both the androgenic and estrogenic environment and reduce most of the symptoms of this change.As menopause is the beginning of the biological transition of women towards senescence, it is of great interest to better understand how DHEA might help to solve and/or overcome the problems of this complex stage of life. In men withadrenal insufficiency and hypogonadism without androgen replacement, DHEA administration results in a significant increase in circulating androgens.Though most data are suggestive for use of DHEA as hormonal replacement treatment, more defined and specific clinical trials are needed to uncover all of the ‘secrets’ and features of this steroid before it can be used as a standard treatment.Furthermore, DHEA is perceived differently around the world, being considered only a ‘dietary supplement’ in the US, while in many European countries it isconsidered a ‘true hormone’ that has not been approved for use as a hormonal treatment by the European health authorities. This overview offers some points of view on use of DHEA as an experimental hormonal replacement therapy.

2006 - Clinical evaluation of patients with weight loss-related amenorrhea: Neuropeptide Y and luteinizing hormone pulsatility [Articolo su rivista]
Meczekalski, B; Genazzani, Ar; Genazzani, Alessandro; Warenik Szymankiewicz, A; Luisi, M.
abstract

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2006 - Diagnostic and therapeutic approach to hypothalamic amenorrhea. [Articolo su rivista]
Genazzani, Alessandro; Ricchieri, Federica; Lanzoni, Chiara; Strucchi, Claudia; Jasonni, Valerio
abstract

Hypothalamic amenorrhea (HA) is a secondary amenorrheawith no evidence of endocrine/systemic causal factors, mainly related tovarious stressors affecting neuroendocrine control of the reproductiveaxis. In clinical practice, HA is mainly associated with metabolic, physical,or psychological stress. Stress is the adaptive response of our bodythrough all its homeostatic systems, to external and/or internal stimulithat activate specific and nonspecific physiological pathways. HA occursgenerally after severe stressant conditions/situations such as dieting,heavy training, or intense emotional events, all situations that caninduce amenorrhea with or without body weight loss and HA is a secondaryamenorrhea with a diagnosis of exclusion. In fact, the diagnosisis essentially based on a good anamnestic investigation. It has to be investigatedusing the clinical history of the patient: occurrence of menarche,menstrual cyclicity, time and modality of amenorrhea, and it has to beexclude any endocrine disease or any metabolic (i.e., diabetes) and systemicdisorders. It is necessary to identify any stressant situation inducedby loss, family or working problems, weight loss or eating disorders, orphysical training or agonist activity. Peculiar, though not specific, endocrineinvestigations might be proposed but no absolute parameter canbe proposed since HA is greatly dependent from individual response tostressors and/or the adaptive response to stress. This article tries to giveinsights into diagnosis and putative therapeutic strategies.

2006 - Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback [Articolo su rivista]
Rochira, Vincenzo; Zirilli, Lucia; Genazzani, Alessandro; A., Balestrieri; Claudio, Aranda; Bibiana, Fabre; Paula, Antunez; Diazzi, Chiara; Carani, Cesare; Laura, Maffei
abstract

Background: In men, the feedback of gonadotropins is regulated by estrogens that come from the aromatization of testosterone, but the relative contribution to the inhibition of LH and FSH secretion by the amount of locally produced estrogens within the hypothalamus and/or the pituitary, and the amount of circulating estrogens still remains unknown. Objective: In order to evaluate the effect of regulation induced by estradiol on the hypothalamic-pituitary-gonadal (HPG) axis, we studied the pulsatility of LH and FSH in two aromatase-deficient men (called subject 1 and subject 2), in which the production rate of estrogen (both local and circulating) is completely, or at least severely, impaired. Design: FSH and LH were evaluated in terms of their pulsated secretion and as GnRH-stimulated secretion in two phases: phase 1, before estrogen treatment; and phase 2, during estrogen treatment with 25 mu g transdermal estradiol twice weekly. Methods: Blood samples were taken during phase I and phase 2 at 0800 h for basal measurements of LH, FSH, inhibin B, testosterone, and estradiol. The analysis of the pulsatility of LH and FSH was performed by sampling every 10 min for 8 h in the two phases. Gonadotropin response to GnRH-stimulation test was studied by serial standard sampling after 100 mu g GnRH i.v. bolus in phases 1 and 2. Results: Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5 +/- 0.7 in phase 1, 4.5 +/- 0.7 in phase 2) and amplitudes (3.5 +/- 0.006 in phase 1, 1.9 +/- 0.4 in phase 2) of peaks, whereas FSH showed only a conspicuous reduction in serum levels and a trend towards the reduction of the amplitudes of its peaks without modification of the frequency of the pulses. Both testosterone and gonadotropins decreased during phase 2, whereas estradiol reached the normal range in both subjects. Transdermal estradiol treatment significantly lowered the peaks of both serum LH and FSH after GnRH as well as the incremental area under the curve after GnRH administration in both subjects. Basal serum inhibin B levels were slightly higher before transdermal estradiol treatment (phase 1) than during estrogen treatment (phase 2) in both subjects. Conclusions: The administration of estrogen to aromatase-deficient men discloses the effects of circulating estrogens on LH secretion, exerted both at pituitary level, as shown by the decrease of basal and GnRH-stimulated secretion of LH and the LH pulsed amplitude, and at hypothalamic level as shown by the reduction of the frequency of LH pulses. The present study, coupling the outcomes of basal, GnRH-stimulated and the pulsatile evaluation of LH and FSH secretion in two aromatase-deficient men, demonstrates that circulating estrogens play an inhibitory role in LH secretion by acting on the hypothalamus and the pituitary gland of men. The discrepancy among testosterone levels, the arrest of spermatogenesis and a slightly inappropriate respective increase of serum FSH (lower than expected) suggests a possible role of estrogens in the priming and the maturation of HPG axis in men, an event that has never occurred in these two subjects as a consequence of chronic estrogen deprivation.

2006 - Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women [Articolo su rivista]
Genazzani, A. R.; Pluchino, N.; Begliuomini, S.; Stomati, M.; Bernardi, F.; Pieri, M.; Casarosa, E.; Palumbo, M.; Genazzani, A. D.; Luisi, M.
abstract

Objective. The aging process is associated with a decline in the circulating Δ5-androgen dehydroepiandrosterone (DHEA) and its sulfate ester, dehydroepiandrosterone sulfate (DHEAS). The present study aimed to evaluate the effects of a long-term (12 months) oral DHEA administration (25 mg/day) on adrenal function, before and after 3, 6 and 12 months of treatment. Method. Postmenopausal women belonging to two age groups, 50-55 years (n = 10) and 60-65 years (n = 10), were studied. Adrenal function was assessed in basal conditions, after suppression with dexamethasone (DXM) and following a stimulation test with adrenocorticotropic hormone (ACTH) (10 μg bolus). Serum levels of DHEA, DHEAS, androstenedione (Δ4-A), allopregnanolone, 17-hydroxyprogesterone (17-OHP) and cortisol were measured and the effects of DHEA supplementation on specific adrenal enzymatic pathways were evaluated by calculating precursor/product ratios (17-OHP/cortisol, 17-OHP/Δ4-A, DHEA/Δ4-A and DHEA/DHEAS). Results. DHEA supplementation annulled the age-related differences in DHEA and DHEAS levels and induced a marked increase in all steroids, except for cortisol, after 3-6 months of treatment. Serum cortisol levels decreased from the 3rd month, both in younger and older subjects. DHEA supplementation did not affect DXM-induced suppression of adrenal steroidogenesis. During the treatment period all adrenal androgens and progestins showed a significant increase in their response to ACTH, while the cortisol response decreased significantly. The results suggest a significant DHEA-induced change in adrenal enzymatic activities, as also evidenced by the change in precursor/product ratios during therapy. Conclusion. Chronic DHEA administration is capable of modifying circulating levels of androgens and progestins in both early and late postmenopausal women by modulating the age-related changes in adrenal function. © 2006 Informa UK Ltd.

2006 - Metformin administration modulates neurosteroids secretion in non-obese amenorrhoic patients with polycystic ovary syndrome [Articolo su rivista]
Genazzani, Alessandro; Strucchi, C; Luisi, M; Casarosa, E; Lanzoni, C; Baraldi, E; Ricchieri, F; Mehmeti, H; Genazzani, Ar
abstract

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2005 - Alla scoperta dei minerali dell'Isola d'Elba: itinerari e note per la ricerca sulle pegmatiti del Monte Capanne [Monografia/Trattato scientifico]
Genazzani, Alessandro
abstract

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2005 - Effect of dehydroepiandrosterone on central and peripheral levels of allopregnanolone and beta-endorphin. [Articolo su rivista]
Bernardi, F; Casarosa, E; Pluchino, N; Palumbo, M; Genazzani, Alessandro; Luisi, S; Genazzani, A. R.
abstract

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2005 - Effects of hormone replacement therapy on plasma viscosity and Doppler variations in postmenopausal non-smokers and heavy smokers [Articolo su rivista]
Mancini, F; Persico, N; Genazzani, Alessandro; Volpe, Annibale; Battaglia, C; De Aloysio, D.
abstract

Objectives. To evaluate the effects of transdermal hormone replacement therapy (HRT) on some biological cardiovascular risk factors, specifically thromboxane B-2 level and plasma viscosity. Furthermore, we investigated Doppler flow modifications at the level of the uterine, internal carotid, ophthalmic and bladder wall arteries, and evaluated whether there were significant differences, in the examined parameters, between postmenopausal women who were non-smokers and heavy smokers. Methods. Forty-three postmenopausal women (age 53.6 +/- 3.3 years, mean +/- standard deviation) participated in the study and were divided into two groups (Group I: n = 21, normal controls; and Group II: n = 22, heavy smokers). Patients were treated with continuous estradiol transdermal supplementation and 12-day courses of medroxyprogesterone acetate every 2 months. They were studied at baseline and after 6 months (in the estrogen-only phase of the cycle). Results. Results showed a beneficial effect of hormone substitution after 6 months of therapy. Plasma viscosity decreased significantly after 6 months of therapy both in non-smokers and heavy smokers (-18% and -14%, respectively). Plasma levels of thromboxane 132, which were similar at baseline, underwent a dramatic reduction in both Group I and Group II (-93% and -88%, respectively). Doppler assessment of pulsatility index at the level of the uterine, internal carotid, ophthalmic and bladder wall arteries showed a significant reduction in vascular impedance at the end of treatment in both groups. However, the treatment was significantly less beneficial, in terms of the analyzed factors, in heavy smokers. Conclusions. Cigarette smoking represents a cardiovascular risk factor that can only partially be modified by the administration of transdermal HRT.

2005 - Female precocious puberty, obesity and polycystic-like ovaries [Articolo su rivista]
C., Battaglia; P., De Iaco; Iughetti, Lorenzo; F., Mancini; N., Persico; Genazzani, Alessandro; Volpe, Annibale; D., De Aloysio
abstract

Objective To evaluate the characteristics of obese girls with gonadotropin releasing hormone-dependent precocious puberty with and without polycystic-like ovaries. Methods Forty-seven overweight (> 75(th) centile of the Italian reference data) girls with a diagnosis of isosexual precocious puberty underwent auxological analysis, hormonal assay and utero-ovarian sonographic and Doppler evaluation. On the basis of sonography the patients were subdivided into two groups, girls presenting normal ovaries (Group 1; n = 31) and those with polycystic-like ovaries (Group II; n = 16). Results The mean body weight was significantly higher (P = 0.003) in Group II than it was in Group I. In addition, the patients with polycystic-like ovaries fell within our definition of superobese (>= 97(th) centile of the Italian reference data) in 44% of cases. The uterine and ovarian volumes were significantly greater in Group II compared with Group I patients. The Doppler evaluation showed intraparenchymal ovarian vascularization and low downstream impedance to flow in all patients in Group II. Conclusions Girls with precocious puberty and polycystic ovaries, compared with those without polycystic ovaries, have a higher incidence of body weight exceeding the 85(th) centile of the Italian reference data (obesity). Copyright

2005 - Menopausal metabolic syndrome [Articolo su rivista]
Genazzani, A. D.; Vito, G.; Lanzoni, C.; Strucchi, C.; Mehemeti, H.; Ricchieri, F.; Mbusnum, M. N.
abstract

2005 - Neuroendocrine aspects of amenorrhea related to stress [Articolo su rivista]
Genazzani, Alessandro
abstract

Reproductive functions are controlled by a very sophisticated system that is composed by the perfect syncronization of neuronal end endocrinological functions. Hypothalamus is the neuroendocrine gland that discharges GnRH that stimulates LH and FSH secretion from pituitary thus promoting ovarian function. Whatever affects the hypothalamic activity might be able to interfere with the reproductive axis. In fact changes in such sophisticated stimulatory system is able to negatively affect the periodical function of the ovary and may induce amenorrhea. Stressant situations, due to physical, psychologic or metabolic stressors, are able to negatively modulate the hypothalamus-pituitary-ovarian axis (HPO) mainly acting through an impairment of the many neuromodulators and neuropeptides that are produced inside the brain and in the hypothalamic areas. Stress induced amenorrhea is usually called hypothalamic amenorrhea (HA) and affect a consistent percentage of women, independently from the age. Nevertheless, quite often HA is diagnosed in adolescents or in girls below 20 years of age. Undernutrition, excess of training, psychological stress, are able to induce HA and then hypo-estrogenism due to the reduced ovarian activity. When sports or exaggerated training is performed before or during the onset of menarche, a specific delay of menarche might occur, as direct consequence of the unbalance between feeding, energy consumption and psychological stress. Osteopenia and osteoporosis are possible consequence of such situation. Clinicians have to pay great attention to all kind of delay of occurrence of meanarche or of amenorrhea, especially if related to lost of weight, since these might mask adverse environmental situations that might induce HA through an exaggerated stress-induced neuroendocrine response.

2005 - Tibolone, transdermal estradiol or oral estrogen-progestin therapies: Effects on circulating allopregnanolone, cortisol and dehydroepiandrosterone levels [Articolo su rivista]
Pluchino, N; Genazzani, Alessandro; Bernardi, F; Casarosa, E; Pieri, M; Palumbo, M; Picciarelli, G; Gabbanini, M; Luisi, M; Genazzani, A. R.
abstract

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2004 - Aging and the central nervous system [Articolo su rivista]
Genazzani, A. D.; Malavasi, B.; Strucchi, C.; Tortolani, F.
abstract

2004 - Conjugated equine estrogens reverse the effects of aging on central and peripheral allopregnanolone and beta-endorphin levels in female rats. [Articolo su rivista]
Genazzani, A. R.; Stomati, M; Bernardi, F; Luisi, S; Casarosa, E; Puccetti, S; Genazzani, Alessandro; Palumbo, M; Luisi, M.
abstract

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2004 - Different concentrations of interleukins in the peritoneal fluid of women with endometriosis: relationships with lymphocyte subsets [Articolo su rivista]
Gallinelli, A.; Chiossi, G.; Giannella, L.; Marsella, T.; Genazzani, Alessandro; Volpe, Annibale
abstract

The present study explored the possible relationships between immune cell subsets and interleukin (IL)-12 or IL-13 levels in the peritoneal fluid of patients with and without endometriosis. Peritoneal fluid samples were obtained from 80 women while they were undergoing laparoscopy for pain, infertility, tubal ligation or re-anastomosis. The American Fertility Society scoring system was used to determine the extension of endometriosis. The peritoneal fluid mononuclear cells were analyzed for immunophenotyping using cytometry, whereas peritoneal fluid concentrations of interleukins were measured using two ultrasensitive commercially available enzyme-linked immunosorbent assay kits. Significantly higher peritoneal fluid IL-12 levels were found in women with moderate or severe endometriosis (stages III and IV) than in healthy controls (p < 0.01). Conversely, subjects with endometriosis showed remarkably lower peritoneal fluid IL-13 concentrations than controls, independent of the severity of the disease (p < 0.05). Considering immune system effectors, patients with endometriosis presented a significantly higher peritoneal fluid CD8(+)/CD4(+) ratio when compared with healthy controls. Moreover, the number of peritoneal fluid CD8(+) and CD4(+) activated T cells was significantly lower in the former than in the latter group, independent of the endometriosis stage. Connections were observed between peritoneal fluid interleukins and peritoneal fluid T cells: both patients with endometriosis and controls presented an inverse correlation between peritoneal fluid activated T cells and IL-13 levels, and a direct correlation between peritoneal fluid T cells and IL-12 concentrations. These data seem to suggest that a reciprocal modulation exists between peritoneal fluid cytokines and T lymphocyte subsets in patients with endometriosis.

2004 - Endocrinologia Ginecologica [Monografia/Trattato scientifico]
Genazzani, Alessandro
abstract

Testo di clinica e diagnostica di endocrinologia ginecologica

2004 - Long-term low dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency. [Articolo su rivista]
Genazzani, A. R.; Inglese, S; Lombardi, I; Pieri, M; Bernardi, F; Genazzani, Alessandro; Rovati, L; Luisi, M.
abstract

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2004 - Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome [Articolo su rivista]
Genazzani, Alessandro; C., Battaglia; B., Malavasi; C., Strucchi; F., Tortolani; O., Gamba
abstract

Objective: To evaluate the effects of metformin administration on spontaneous LH episodic release in a group of nonobese polycystic ovary (PCOS) patients. Design: Controlled clinical study. Setting: PCOS patients in a clinical research environment. Patient(s): Twenty nonobese PCOS patients were enrolled after informed consent. Intervention(s): All patients underwent hormonal evaluations and a pulsatility study (sampling every 10 minutes for 4 hours) before and at the sixth month of therapy (metformin, 500 mg, p.o. b.i.d.). Ultrasound examinations and Ferriman-Gallwey scoring were also performed. Main Outcome Measure(s): Measurements of plasma LH, FSH, estradiol (E-2), androstenedione (A), 17-hydroxy-progesterone (17-OHP), and testosterone (T), glucose, insulin, and C-peptide concentrations. Result(s): After 6 months of metformin administration, the plasma LH, 17-OHP, A, and T levels and LH/FSH ratio were significantly reduced. Insulin sensitivity, expressed as the glucose-to-insulin ratio, was significantly improved under glucose load after 6 months of treatment. Spontaneous LH episodic release showed a significant reduction in pulse amplitude with no changes in pulse frequency. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic women. The ovarian volume and Ferriman-Gallwey scores also were significantly reduced. Conclusion(s): Metformin administration improves reproductive axis functioning in hyperandrogenic nonobese PCOS patients. By acting on the ovary and restoring nortnal ovarian activity, metformin positively modulates the reproductive axis (namely GnRH-LH episodic release). ((C) 2004 by American Society for Reproductive Medicine.)

2004 - Sterss nel paziente odontoiatrico [Articolo su rivista]
Barbieri, Alberto; Ghirardini, A. M.; Pinna, C.; Giannetti, L.; Genazzani, Alessandro
abstract

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2003 - Adrenal function under long-term raloxifene administration [Articolo su rivista]
Genazzani, A. R; Lombardi, I; Borgioli, G; di Bono, I; Casarosa, E; Gambacciani, M; Palumbo, M; Genazzani, Alessandro; Luisi, M.
abstract

The aim of the present study was to evaluate the effect of long-term (12 months) administration of raloxifene hydrochloride (60 mg/day) on the steroid production of the adrenal cortex and on the hypothalamic-pituitary-adrenal axis in postmenopausal women. We performed a basal evaluation, a corticotropin releasing factor (CRF) (100 microg i.v. bolus) test and a dexamethasone (DXM) (0.25 mg) suppression-adrenocorticotropic hormone (ACTH) (10 microg i.v. bolus) stimulation test in 11 postmenopausal women, before and after 3, 6 and 12 months of raloxifene treatment. Raloxifene administration significantly modified circulating levels of adrenal steroids, decreasing cortisol (-24%), dehydroepiandrosterone (DHEA) (-36%), and its sulfate (DHEAS) (-41%), and androstenedione (-29%), and increasing circulating allopregnanolone (+39%) levels. Progesterone and 17OH-progesterone levels remained unmodified, while estradiol and estrone levels showed a significant decrease (-51% for estradiol and -61% for estrone). We also observed an increase in circulating ACTH (+58%) and beta-endorphin (+120%). No modifications in the hormonal responses to CRF were observed during the treatment. DXM significantly suppressed circulating steroids at any time with a lower suppression of cortisol from the third month and a higher suppression of DHEA at 12 months. ACTH administration was associated with a significantly blunted cortisol response from the sixth month and a significantly increased response of allopregnanolone from the third month. The present data exclude a raloxifene effect on pituitary sensitivity to CRF and demonstrate a reduced adrenal sensitivity to ACTH, sustained by the opposite changes in basal cortisol and Delta5 androgens, which were reduced, and in ACTH and beta-endorphin, which were increased, as well by the reduced response of cortisol to the direct ACTH stimulus. The reduction of circulating cortisol levels and cortisol response to the ACTH challenge suggests that raloxifene protects against the neurotoxic effects of endogenous glucocorticoids. Furthermore, the progressive increase in basal allopregnanolone and its increased response to ACTH indicate that chronic raloxifene administration exerts direct effects on the pattern of adrenal enzymes, leading to specific changes in the circulating levels of this anxiolytic progesterone metabolite. The important reduction in the circulating levels of estradiol and estrone under long-term raloxifene administration may represent a further mechanism by which this molecule may exert a protective effect against breast and endometrial malignancies.

2003 - Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuractive steroids [Articolo su rivista]
Genazzani, Alessandro; Stomati, M; Bernardi, F; Pieri, M; Rovati, L; Genazzani, A. R.
abstract

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2002 - Assessment of the QoL in Italian menopausal women: Comparison between HRT users and non-users [Articolo su rivista]
A. R., Genazzani; A., Nicolucci; C., Campagnoli; P., Crosignani; C., Nappi; G. B., Serra; E., Bottiglioni; A., Cianci; D. D., Aloysio; C. D., Sarti; M., Gambacciani; P., Monteleone; Genazzani, Alessandro; S., Guaschino; G., Palumbo; F., Petraglia; S., Schonauer; Volpe, Annibale; T. D., Paolantonio; M., Nagni; A., Tempesta; G. A., Coronel; P. D., Qualità
abstract

The aim of this cross-sectional study was to describe QoL in a large sample of women attending menopause centres and compare untreated postmenopausal women and matched HRT users by employing the Women's Health Questionnaire (WHQ) and two generic instruments, the SF-36 and the EQ-5D.Overall, 2906 women were recruited by 64 menopause centres throughout Italy, of whom 2160 filled in the questionnaire (1093 on HRT and 1067 not on HRT; response rate: 74\%).HRT users tended to be younger, healthier and with shorter menopause duration as opposed to non users, while no major socio-economic differences were present. At multivariate analysis, the presence of chronic diseases, low socio-economic status and living in Southern Italy represented the most important predictors of poor QoL. Furthermore, HRT users showed a lower probability of reporting problems in usual activities and pain/discomfort (EQ-5D), role limitations due to emotional problems (SF-36) and anxiety/fears (WHQ). HRT users also showed highly significant better outcomes in those areas that are more directly attributable to hormonal changes of mid age, namely vasomotor symptoms and sexual problems.Although QoL is mainly influenced by socio-economic and cultural factors, HRT has the potential for improving not only symptoms, but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women.

2002 - Conjugated equine estrogens, estrone sulphate and estradiol valerate oral administration in ovariectomized rats: effects on central and peripheral allopregnanolone and beta-endorphin [Articolo su rivista]
Stomati, Massimo; Bernardi, Francesca; Luisi, Stefano; Puccetti, Simone; Casarosa, Elena; Liut, Martina; Quirici, Barbara; Pieri, Matteo; Genazzani, Alessandro; Luisi, Michele; Genazzani, Andrea R.
abstract

Several natural or synthetic estrogenic molecules are commonly used in oral hormone replacement therapy for the relief of menopausal complaints and for the primary prevention of cardiovascular disease and osteoporosis. Little information is available concerning the comparative efficacy of different compounds on neuroendocrine function. The opioid peptide beta-endorphin (beta-EP), and the neurosteroid allopregnanolone are considered markers of neuroendocrine function and their synthesis and action is regulated by gonadal steroids. The present study aimed to investigate the effects of a 2-week oral treatment with estradiol valerate (EV), estrone sulphate (ES), or conjugated equine estrogen (CEE) on central and peripheral beta-EP and allopregnanolone levels in ovariectomized (OVX) female rats.

2002 - Pulsatile secretory characteristics of allopregnanolone, a neuroactive steroid, during the menstrual cycle and in amenorrheic subjects [Articolo su rivista]
Genazzani, Alessandro; Luisi, Michele; Malavasi, Barbara; Strucchi, Claudia; Luisi, Stefano; Casarosa, Elena; Bernardi, Francesca; Genazzani, Andrea R; Petraglia, Felice
abstract

To investigate whether allopregnanolone, a neuroactive steroid involved in modulating behavioural and neuroendocrine functions, shows episodic secretion in eumenorrheic women, during the follicular and luteal phases of the menstrual cycle, and in women with stress-induced amenorrhea.

2002 - Validation of italian version of the Women's Health Questionnaire: Assessment of quality of life of women from the general population and those attending menopause centers [Articolo su rivista]
A. R., Genazzani; A., Nicolucci; C., Campagnoli; P., Crosignani; C., Nappi; G. B., Serra; E., Bottiglioni; A., Cianci; D. D., Aloysio; C. D., Sarti; M., Gambacciani; P., Monteleone; M., Ciaponi; Genazzani, Alessandro; S., Guaschino; G., Palumbo; F., Petraglia; S., Schonauer; Volpe, Annibale; G. A., Coronel; T. D., Paolantonio; M., Nagni; A., Tempesta; P. D., Qualità
abstract

The Women's Health Questionnaire has been developed and validated in Anglo-Saxon and Swedish populations. The purpose of this study was to evaluate the Italian version of the questionnaire to determine whether cross-cultural differences exist in the perception of quality of life, and to use it to compare the quality of life in women attending menopause centers with that of women in the general population.An Italian version of the Women's Health Questionnaire (WHQ) was produced, using the forward-backward translation method to ensure conceptual equivalence, and approved by the originator. Women were recruited by random selection from the general population and from menopause centers, those taking hormone replacement therapy being ineligible. The questionnaire was completed anonymously at home and mailed to the co-ordinating center. Psychometric evaluation included tests of item convergent and discriminant validity, internal-consistency reliability, test-retest reliability, construct validity and the discriminative properties of the questionnaire.The completeness of the data was good, with missing-value rates consistently low for most items. Item-scale correlations, used to evaluate internal consistency, were also good and the scaling success rate, used to measure item discriminant validity, was high for all scales. Scale scores were reliable for seven out of nine scales and test-retest reliability was excellent. There were few significant differences between the two populations of women in most of the WHQ areas. A comparison of Italian data with published data on English women showed great similarity.The Italian version of the WHO is valid and reproducible. The subjective perception of the menopause and its related problems is similar in geographically and culturally different populations.

2001 - Effects of cyproheptadine clorhydrate, a serotonin receptor antagonist, on endocrine parameters in weight-loss related amenorrhea [Articolo su rivista]
Genazzani, Alessandro; Strucchi, C; Malavasi, B; Tortolani, F; Vecchi, F; Luisi, S; Petraglia, F.
abstract

The aim of the study was to evaluate the possible interactions and/or modulations of the serotoninergic system on hormonal parameters and the reproductive axis in amenorrheic subjects, Hypogonadotropic, underweight, amenorrheic patients (n=8) were studied before and during cyproheptadine clorhydrate administration (4 mg/day for 3 months). A pulsatility study (4 hours, sampling every 10 minutes) and a naloxone test were performed before and after 4 and 12 weeks of treatment. Plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), estradiol, thyroid-stimulating hormone (TSH), free tri-iodothyronine (fT(3)), free thyroxine (fT(4)) and total tri-iodothyonine (total T-3), insulin-like growth factor-I (IGF-I) concentrations were determined. Pulse detection analysis was performed using the DETECT program. Serotoninergic receptor blockade affected neither the naloxone-inducted LH response nor the gonadotropin pulsatile parameters. Body mass index (BMI) did not vary; conversely, integrated mean gonadotropins, CH and fT(3) concentrations increased during the treatment. In conclusion, cyproheptadine administration affects some of the abnormal endocrine parameters of underweight amenorrheic subjects with no modulation of the opioidergic system. It is likely that the gonadotropin and the fT(3) increases take place owing to a change in the metabolic signals modulating hypothalamic function and/or an increased energy availability. Our study suggests a specific central effect of cyproheptadine on the serotonergic pathway controlling food intake at the hypothalamic level.

2001 - Increased adrenal steroid secretion in response to CRF in women with hypothalamic amenorrhea [Articolo su rivista]
Genazzani, Alessandro; Bersi, C; Luisi, S; Fruzzetti, F; Malavasi, B; Luisi, M; Petraglia, F; Genazzani, Ar
abstract

Objectie: To evaluate adrenal steroid hormone secretion in response to corticotropin-releasing factor (CRF) or to adrenocorticotropin hormone in women with hypothalamic amenorrhea. Design: Controlled clinical study. Setting: Department of Reproductive Medicine and Child Development, Section of Gynecology and Obstetrics, University of Pisa, Italy. Patient(s): Fifteen women with hypothalamic amenorrhea were enrolled in the study. Eight normal cycling women were used as control group. Interention(s): Blood samples were collected before and after an injection of ovine CRF (0.1 g/kg iv bolus) or after synthetic ACTH (0.25 mg iv). Main outcome measure(s): Plasma levels of ACTH, 17-hydroxypregnenolone (17OHPe), progesterone (P), dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone (17OHP), cortisol (F), 11-deoxycortisol (S) and androstenedione (A). Result(s): Basal plasma concentrations of ACTH, cortisol, 11-deoxycortisol, DHEA and 17OHPe were significantly higher in patients than in controls, whereas plasma levels of progesterone and 17-OHP were significantly lower in patients than in controls. In amenorrheic women the ratio of 17-OHPe/DHEA, of 17-OHPe/17-OHP and of 11-deoxycortisol/cortisol were significantly higher than in controls, while a significant reduction in the ratio of 17-OHP/androstenedione, of 17-OHP/11-deoxycortisol was obtained. In response to corticotropin-releasing factor test, plasma levels of ACTH, cortisol, 17-OHP, 11-deoxycortisol, DHEA and androstenedione were significantly lower in patients than in controls. In response to adrenocorticotropin hormone, plasma levels of 17-OHP, androstenedione and androstenedione/cortisol were significantly higher in patients than in controls. Conclusions: Patients suffering for hypothalamic amenorrhea showed an increased activation of hypothalamus-pituitaryadrenal (HPA) axis, as shown by the higher basal levels and by augmented adrenal hormone response to corticotropin-releasing factor administration. These data suggest a possible derangement of adrenal androgen enzymatic pathway.

2001 - Neuroendocrine effects of raloxifene hydrocloride in postmenopausal women [Articolo su rivista]
Florio, P; Quirici, B; Casarosa, E; Lombardi, I; Luisi, M; Genazzani, Alessandro; Petraglia, F; Genazzani, Ar
abstract

..

2001 - Oral dehydroepiandrosterone supplementation modulates spontaneous and growth factor hormone-releasing hormone-induced growth hormone and insulin-like growth factor-1 secretion in early and late postmenopausal women [Articolo su rivista]
Genazzani, Alessandro; Stomati, M; Strucchi, C; Puccetti, S; Luisi, S; Genazzani, Ar
abstract

..

2001 - Severe intraabdominal bleeding after transvaginal oocyte retrieval for IVF-ET and coagulation factor XI deficiency: A case report [Articolo su rivista]
Battaglia, C; Regnani, G; Giulini, S; Madgar, L; Genazzani, Alessandro; Volpe, Annibale
abstract

..

2000 - Allopregnanolone and dehydroepiandrosterone response to corticotropin-releasing factor in patients suffering from Alzheimer's disease and vascular dementia [Articolo su rivista]
Bernardi, F; Lanzone, A; Cento, R. M; Spada, R. S; Pezzani, I; Genazzani, Alessandro; Luisi, S; Luisi, M; Petraglia, F; Genazzani, A. R.
abstract

Neurosteroids have been suggested to be involved in the regulation of cognitive performances. A major neurosteroid gamma-aminobutyric acid (GABA) agonist is allopregnanolone: the main source of circulating allopregnanolone is the adrenal cortex. Studies indicated that a disturbance of the central regulation of the hypothalamic-pituitary-adrenocortical axis occurs in both senile (Alzheimer's disease: AD) and vascular dementia (VD).

2000 - Allopregnanolone concentrations and premenstrual syndrome [Articolo su rivista]
Monteleone, P; Luisi, S; Tonetti, A; Bernardi, F; Genazzani, Alessandro; Luisi, M; Petraglia, F; Genazzani, A. R.
abstract

To evaluate basal allopregnanolone and progesterone in both phases of the menstrual cycle in women suffering from premenstrual syndrome (PMS) and their response to a GnRH test.

2000 - Il tibolone [Capitolo/Saggio]
Genazzani, Alessandro
abstract

N/A

2000 - Modificazioni neuroendocrine in pre e postmenopausa. [Capitolo/Saggio]
Genazzani, Alessandro
abstract

N/A

2000 - Perifollicular Doppler flow and follicular fluid vascular endothelial growth factor concentrations in poor responders [Articolo su rivista]
Battaglia, C; Genazzani, Alessandro; Regnani, G; Primavera, Mr; Petraglia, F; Volpe, Annibale
abstract

Objective: To prospectively evaluate follicular fluid levels of vascular endothelial growth factor in women undergoing IVF cycles and to investigate the correlation of these levels with ovarian response to gonadotropins and with uterine or ovarian Doppler findings. Design: Prospective study. Setting: University hospital. Patient(s): 41 patients undergoing ART were divided into two groups according to response to ovarian stimulation protocols: poor responders (n = 18) and normoresponders (n = 23). Intervention(s): Doppler analysis of perifollicular arteries and assay of follicular fluid vascular endothelial growth factor. Main Outcome Measure(s): During ovarian stimulation, patients underwent hormonal (E2), ultrasonographic (follicular number and diameter, endometrial thickness) and Doppler (uterine and perifollicular arteries) evaluation. Serum and follicular fluid concentrations of vascular endothelial growth factor were assayed in each female patient. Result(s): Compared with poor responders, more oocytes were collected and more embryos were transferred but follicular fluid levels of vascular endothelial growth factor levels were lower in normoresponders. Follicular fluid levels of vascular endothelial growth factor were inversely correlated with number of oocytes retrieved. Poor responders had significantly higher uterine and perifollicular Doppler flow resistances. The pregnancy rate per cycle was significantly higher in normoresponders (26%) than poor responders (6%). Conclusion(s): Elevated follicular fluid levels of vascular endothelial growth factor concentrations are associated with poor ovarian response and a very low pregnancy rate. (Fertil Steril (R) 2000;74:809-12. (C) 2000 by American Society for Reproductive Medicine.).

2000 - Pivagabine decreases stress-related hormone secretion in women with hypothalamic amenorrhea [Articolo su rivista]
Genazzani, Alessandro; Stomati, M; Bersi, C; Luisi, S; Fedalti, M; Santuz, M; Esposito, G; Petraglia, F; Genazzani, A. R.
abstract

Stress-induced neuroendocrine activities influence the regulation of endocrine glands and axes. Weight loss-related hypothalamic amenorrhea is a typical stress-induced physiopathological condition. It is characterized by increased adrenal cortex activation and by reduced GH, LH, FSH and gonadal steroid hormone levels. The aim of the present study was to investigate the effects of pivagabine, a neurotropic drug (1800 mg/day for 7 days) or placebo administration on ACTH, cortisol, GH, LH, FSH and PRL plasma levels in patients with hypothalamic amenorrhea related to weight loss. Hormonal parameters and the pulsatile release of cortisol (6-hour pulsatility, sampling every 10 minutes) were evaluated before and after 7 days of treatment. Pivagabine administration significantly reduced mean plasma ACTH (from 21.7+/-1.7 to 15.4+/-1.2 pg/ml, p<0.05) and cortisol levels (from 12.2+/-0.7 to 9.7+/-0.7 ng/ml, p<0.05) and increased GH levels (from 1.4+/-0.5 to 3.0+/-0.9 ng/ml, p<0.05). A significant reduction of cortisol pulse amplitude was observed (p<0.01) while no change in pulse frequency occurred. No changes were observed in placebo-treated subjects. LH, FSH and PRL levels were not modified by placebo or pivagabine administration. In conclusion, in patients with hypothalamic amenorrhea related to weight loss pivagabine induced a significant decrease of cortisol secretion and an increase of GH release by pivagabine administration, suggesting that this drug exerts a specific neuroendocrine modulatory role.

2000 - Polycystic ovary syndrome: A new ultrasonographic and color Doppler pattern [Articolo su rivista]
C., Battaglia; G., Regnani; P. G., Artini; S., Giulini; Genazzani, Alessandro; A. R., Genazzani; Volpe, Annibale
abstract

The aim of this study was to evaluate whether patients with partial bilateral polycystic ovaries show different ovarian and uterine blood flow to those with complete bilateral polycystic ovaries, and to investigate whether there is a correlation between ultrasonographic and hormonal parameters. Fifteen patients with partial polycystic ovaries and eighteen patients with complete bilateral polycystic ovaries underwent clinical, biochemical, gray-scale and color Doppler ultrasonographic evaluation. Hormonal (luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH concentration ratio, estradiol, prolactin, androstenedione, testosterone), clinical (body mass index, Ferriman-Gallwey score), ultrasonographic (ovarian volume, number and distribution of subcapsular follicles, stromal score) and Doppler (uterine artery and intraparenchymal vessels pulsatility index, ovarian stromal vascularization) parameters were evaluated, in the early follicular phase (cycle day 3-5) in oligomenorrheic patients, or at random in amenorrheic patients. Significantly higher androstenedione plasma levels and LH/FSH concentration ratios were observed in complete bilateral polycystic ovaries. In partial polycystic ovaries, gray-scale and color Doppler ultrasonography showed different features in affected and unaffected areas of the ovary, similar to polycystic and normal ovary appearance respectively. In conclusion, PCOS does not predetermine a single ultrasonographic or Doppler pattern.

2000 - Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause [Articolo su rivista]
Stomati, M; Monteleone, P; Casarosa, E; Quirici, B; Puccetti, S; Bernardi, F; Genazzani, Alessandro; Rovati, L; Luisi, M; Genazzani, A. R.
abstract

The adrenal production of the delta 5-androgens, dehydroepiandrosterone (DHEA) and its sulfate ester dehydroepiandrosterone sulfate (DHEAS), declines linearly with aging. The evidence that DHEA or DHEAS administration may alleviate some of the problems related to aging has opened new perspectives for clinical research. The present study aims to investigate the effects of a 6-month DHEA supplementation in early and late postmenopausal women, with normal or overweight body mass index (BMI), on the level of circulating steroids, sex hormone binding globulin (SHBG), beta-endorphin and gonadotropins, and on the adrenal gland response to dexamethasone suppression and adrenocorticotropic hormone (ACTH) stimulation. Early postmenopausal women (50-55 years) both normal weight (BMI 20-24, n = 9) and overweight (BMI 26-30, n = 9) and late postmenopausal women (60-65 years) both of normal weight and overweight, were treated with oral DHEA (50 mg/day). Circulating DHEA, DHEAS, 17-OH pregnenolone, progesterone, 17-OH progesterone, allopregnenolone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, SHBG, cortisol, luteinizing hormone, follicle stimulating hormone and beta-endorphin levels were evaluated monthly and a Kupperman score was performed. The product/precursor ratios of adrenal steroid levels were used to assess the relative activities of the adrenal cortex enzymes. Before and after 3 and 6 months of therapy, each women underwent an ACTH stimulating test (10 micrograms i.v. in bolus) after dexamethasone administration (0.5 mg p.o.) to evaluate the response of cortisol, DHEA, DHEAS, androstenedione, 17-OH pregnenolone, allopregnanolone, progesterone and 17-OH progesterone. The between-group differences observed before treatment disappeared during DHEA administration. Levels of 17-OH pregnenolone remained constant during the 6 months. Levels of DHEA, DHEAS, androstenedione, testosterone and dihydrotestosterone increased progressively from the first month of treatment. Levels of estradiol and estrone significantly increased after the first/second month of treatment. Levels of SHBG significantly decreased from the second month of treatment only in overweight late postmenopausal women, while the other groups showed constant levels. Progesterone levels remained constant in all groups, while 17-OH progesterone levels showed a slight but significant increase in all groups. Allopregnanolone and plasma beta-endorphin levels increased progressively and significantly in the four groups, reaching values three times higher than baseline. Levels of cortisol and gonadotropins progressively decreased in all groups. The product/precursor ratios of adrenal steroid levels at the sixth month were used to assess the relative activities of the adrenal cortex enzymes and were compared to those found before therapy. The 17,20-desmolase, sulfatase and/or sulfotransferase, 17,20-lyase and 5 alpha-reductase activities significantly increased, while the 3 beta-hydroxysteroid-oxidoreductase activity did not vary. On the contrary, the 11-hydroxylase and/or 21-hydroxylase activities showed a significant decrease after 6 months of treatment. In basal conditions, dexamethasone significantly suppressed all the adrenal steroids and this suppression was greater after 3 and 6 months of treatment for DHEA, DHEAS and allopregnanolone, while it remained unchanged for other steroids. Before treatment, ACTH stimulus induced a significant response in all parameters; after the treatment, it prompted a greater response in delta 5- and delta 4-androgens, progesterone and 17-OH progesterone, while cortisol responded less in both younger and older normal-weight women. The endometrial thickness did not show significant modifications in any of the groups of postmenopausal women during the 6 months of treatment. Treatment with DHEA was associated with a progressive improvement of the Kupperman score in all groups, with major effects on the vasomotor symptoms in

2000 - The use of a combined regimen of GnRH agonist plus a low-dose oral contraceptive improves the spontaneous pulsatile LH secretory characteristics in patients with polycycstic ovary disease after discontinuation of treatment [Articolo su rivista]
Genazzani, Alessandro; Battaglia, C; Gamba, O; Petraglia, F; Malavasi, B; Genazzani, A. R.
abstract

The fertility rate in women with polycystic ovary disease (PCOD) is influenced by the type of treatment received. The present study evaluated the possible correlation between treatment and pulsatile release of gonadotropins.

1999 - Controversie in ostetricia e ginecologia [Monografia/Trattato scientifico]
Volpe, Annibale; Battaglia, C; Cagnacci, Angelo; Genazzani, Alessandro
abstract

-

1999 - Doppler, ultrasonographic and endocrinological environment with regard to the number of small subcapsular follicles in polycystic ovary syndrome. [Articolo su rivista]
C., Battaglia; Genazzani, Alessandro; M., Salvatori; S., Giulini; P. G., Artini; A. R., Genazzani; Volpe, Annibale
abstract

The aim of this study was to evaluate how, in patients with polycystic ovary syndrome, the number of small subcapsular follicles correlates with uterine and ovarian blood flow and with specific hormonal parameters. At an ultrasonographic evaluation, 30 patients with polycystic ovary syndrome showed 5-10 (group I; n = 14) or > 10 (group II; n = 16) small follicles. These patients underwent ultrasonographic (ovarian volume and stroma echodensity; number, diameter and distribution of follicles) and color Doppler (uterine and intraovarian vessels) analyses, and hormonal assay. In group II, significantly lower pulsatility index values than in group I were observed in the ovarian stromal arteries. The Ferriman-Gallwey score, plasma androstenedione level and luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio results were significantly higher in group II than in group I. Androstenedione plasma levels correlated with the number of small follicles. Furthermore, the LH/FSH ratio correlated with both the number of small follicles and the stromal artery pulsatility index. The combined assessment of ovarian morphology by transvaginal ultrasound and color Doppler may provide insight into the pathological state of polycystic ovary syndrome.

1999 - Raloxifene analog LY 117018 effects on central and peripheral beta-endorphin [Articolo su rivista]
Genazzani, A. R; Bernardi, F; Stomati, M; Rubino, S; Giardina, L; Luisi, S; Monteleone, P; Genazzani, Alessandro; Luisi, M; Petraglia, F.
abstract

Raloxifene is a selective estrogen receptor modulator with a benzothiophene structure, that exerts an estrogen-like action on some target tissues and an anti-estrogenic action on the uterus and breasts. A limited number of data are available on the effect of raloxifene on neuroendocrine function. Since beta-endorphin (beta-EP) is considered a marker of neuroendocrine function, the aim of the present study was to evaluate the effects of a 14 day treatment with a raloxifene analog, LY 117018, on beta-EP content in the hypothalamus, hippocampus, anterior and neuro-intermediate pituitary lobe, and in the plasma of fertile and ovariectomized (ovx) rats. The effect of LY 117018 in ovx rats was compared to that of 17 beta-estradiol. beta-EP contents were measured by a specific radioimmunoassay. While ovariectomy determined a significant decrease in beta-EP levels in the anterior and neurointermediate pituitary lobe and plasma (p < 0.01), no changes of beta-EP content in the hypothalamus and hippocampus were found. The administration of 17 beta-estradiol or LY 117018 in ovx rats significantly increased beta-EP concentration in the anterior and neurointermediate pituitary lobe, in the hypothalamus and plasma (p < 0.01), though they did not significantly modify hippocampal beta-EP content. When LY 117018 was administered together with 17 beta-estradiol in ovx animals, a clear anti-estrogenic effect in all organs and in plasma was observed, resulting in significantly lower beta-EP content with respect to the group treated with 17 beta-estradiol alone (p < 0.01). The chronic administration of LY 117018 in fertile rats significantly decreased beta-EP content in the anterior pituitary, hippocampus and plasma (p < 0.01), while it increased beta-EP hypothalamic content and did not change beta-EP content in the neurointermediate lobe. In conclusion, raloxifene analog LY 117018 has an estrogen-like action on neuroendocrine opiatergic pathways when administered alone in ovx rats, while it exerts an anti-estrogen effect in fertile or in ovx rats treated with 17 beta-estradiol.

1998 - Acute infusion of naloxone, an opioid receptor antagonist, does not modify serum leptin concentrations in amenorrheic and healthy women [Articolo su rivista]
Genazzani, Alessandro; Menozzi, Renata; DEL RIO, Graziano; Luisi, Stefano; Petraglia, Felice; Genazzani, Andrea R.
abstract

Objective: To determine whether the opioidergic system is involved in the modulation of leptin secretion in healthy and amenorrheic subjects. Design: Prospective study. Setting: Department of Obstetrics and Gynecology, University of Modena, Modena, Italy. Patient(s): Healthy subjects (n = 8) and patients with hypothalamic amenorrhea (n = 17) or hyperandrogenism (n = 7) and low body mass index (BMI). Intervention(s): Acute infusion of naloxone (4-mg bolus) and blood sampling 15 minutes before infusion; at time of infusion; and 15, 30, 45, 60, 75, 90, and 120 minutes after infusion. Main Outcome Measure(s): Plasma leptin, LH, FSH, E2, and cortisol concentrations. Result(s): Plasma leptin concentrations were lower (P <.01) in both hypothalamic and hyperandrogenic amenorrheic subjects than in healthy controls. In all groups of subjects, no significant changes in leptin levels were observed after infusion of naloxone. A significant correlation was found between leptin concentrations and BMI when all subjects were considered together (P <.05) but was not found in the single groups. Conclusion(s): The present data do not support the hypothesis that opioidergic receptors are involved acutely in the modulation of leptin release in healthy and amenorrheic women.

1998 - Contraception as prevention and therapy: sex steroids and the brain [Articolo su rivista]
Stomati, M; Genazzani, Alessandro; Petraglia, F; Genazzani, A. R.
abstract

The brain is one of the specific target tissues for sex steroid hormones. Estrogens, progestins and androgens are able to induce several effects in brain areas of the central nervous system (CNS), through the binding with specific receptors. Specific receptors for gonadal steroids have been identified in the amygdala, hippocampus, basal forebrain cortex, cerebellum, locus ceruleus, midbrain rafe nuclei, glial cells, pituitary gland, hypothalamus and central gray matter. At the hypothalamic level, the principal target for sex steroids is those neurons producing the pulsatile release of the gonadotropin releasing hormone (GnRH), localized in the mediobasal hypothalamus and the arcuate nucleus. The GnRH release depends on the complex and co-ordinated interrelationships among gonadal steroids, pituitary gonadotropins and neuroactive transmitters, such as the noradrenaline, dopamine, opioid peptides (beta-endorphin), acetylcholine, serotonin, gamma-aminobutyrric acid, corticotropin releasing hormone and neuropeptide Y. The interplay of these control mechanisms is governed by peripheral feedback signals; as well as the input from higher brain centers they may modify the GnRH secretion. The anterior pituitary lobe is the best known target tissue for endogenous or exogenous sex steroid hormones, because it is possible to detect luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in blood, as the expression of the pituitary cells' activity. The synthesis and release of FSH and LH by the gonadotropic cells depend upon the peripheral control of gonadal hormones and the GnRH hypothalamic release. In summary, during a woman's reproductive life, the interaction between neurotransmitters, neuropeptides and gonadal hormones modulates the hypothalamo-pituitary-gonadal axis by acting selectively on the synthesis and release of GnRH and of pituitary gonadotropic hormones. The increased use of oral contraceptives in the last 30 years and, in general, of sex steroid hormone derivative therapies, has led to the study of the biochemical and metabolic properties of the different progestin molecules available in hormonal therapies by focusing attention on the interactions between estrogens and progestins in the modulation of the hypothalamo-pituitary-gonadal axis. The different kinds of estrogen and progestin molecules used in oral contraceptives inhibit the ovulatory process and may interfere with other sex steroid hormone receptors, thus exerting multiple effects in each target tissue.

1998 - Erratum: Neuroendocrine effects of different estradiol-progestin regimens in postmenopausal women (Maturitas (1997 28 (127) PII: S037851229700073X) [Articolo su rivista]
Stomati, M.; Bersi, C.; Rubino, S.; Palumbo, M.; Comitini, G.; Genazzani, A. D.; Santuz, M.; Petraglia, F.; Genazzani, A. R.
abstract

1998 - Estrogen replacement therapy modulates spontaneous GH secretion but does not affect GH-RH-induced GH response and low T3 syndrome in women with hypothalamic amenorrhea associated to weight-loss [Articolo su rivista]
Genazzani, Alessandro; Gamba, O; Petraglia, F.
abstract

Severe dieting and negative energy balance usually lead to the occurrence of amenorrhea together with several endocrine disturbances such as the low T3 syndrome and an abnormal GH secretion. To evaluate whether estrogen replacement therapy (ERT) affects thyroid hormones and GH secretion, two groups of patients affected by weight-loss-related amenorrhea and with low plasma T3 levels were treated with two different schedules of ERT using 50 or 100 mu g estradiol transdermal patches twice a week (Dermestril, Rottapharm, Monza, Italy). Before and after 5 weeks of therapy in each patient thyroid hormones, spontaneous GH secretion and GH-RH-induced GH release were evaluated. After ERT, plasma GH and IGF-1 levels increased in both groups and a consistent change in GH spontaneous release was observed. Conversely the low T3 plasma levels and GH-RH-induced GH response were not modified by ERT. Our present data suggest that in amenorrhea related to weight-loss, hormonal abnormalities are only in part dependent from the hypoestrogenic condition. (J. Endocrinol. Invest. 21: 353-357, 1998) (C)1998, Editrice Kurtis.

1998 - Low levels of serum inhibin A and inhibin B in women with hypergonadotropic amenorrhea and evidence of high levels of activin A in women with hypothalamic amenorrhea [Articolo su rivista]
Petraglia, F.; Hartmann, B.; Luisi, S.; Florio, P.; Kirchengast, S.; Santuz, M.; Genazzani, A. D.; Genazzani, A. R.
abstract

Objective: To examine serum levels of inhibin A, inhibin B, and activin A in women with secondary hypergonadotropic or hypothalamic amenorrhea. Design: Retrospective study. Setting: Universities of Udine, Pisa, and Modena in Italy, and of Wien in Austria. Patient(s): Forty women with idiopathic premature ovarian failure (POF), 23 women with hypogonadotropic hypothalamic amenorrhea, 40 healthy postmenopausal women, and 40 age-matched women with normal ovarian function (controls). Intervention(s): Blood samples were collected between 8 and 9 AM. Main Outcome Measure(s): Serum levels of inhibin A, inhibin B, and activin A. Result(s): Women with POF had lower concentrations of serum inhibin A and inhibin B than women with hypothalamic amenorrhea and fertile controls, and the difference between these concentrations was statistically significant. Levels of inhibin A and inhibin B were low in postmenopausal women and were no different than in women with POF. Serum levels of activin A were not significantly different among women with POF, fertile controls, and postmenopausal women. Women with hypogonadotropic hypothalamic amenorrhea had higher activin A values than did controls. No significant correlation was found between the level of inhibin A or inhibin B and the length of amenorrhea or the level of FSH. Conclusion(s): Low levels of circulating inhibins A and B, but not activin A, reflect ovarian failure in women with POF, whereas women with hypogonadotropic hypothalamic amenorrhea have normal levels of inhibins A and B and high levels of activin A.

1998 - Paracrine regulation of human placenta: control of hormonogenesis. [Articolo su rivista]
F., Petraglia; M., Santuz; P., Florio; T., Simoncini; S., Luisi; L., Plaino; A. R., Genazzani; Genazzani, Alessandro; Volpe, Annibale
abstract

There is much evidence indicating that the human placenta plays a very important role in modulating the endocrinology of pregnancy. Placental tissue produces cytokines, hormones and growth factors that are essential in the regulation of the feto-maternal unit. The production of these substances is regulated by a network of interactions within and between intra-uterine through paracrine and/or autocrine mechanisms. Communication between the gestational intra-uterine tissues is critical for successful pregnancy, from the earliest stage of implantation until the expulsive phase of delivery. This is confirmed by the demonstration that the human placenta directly controls the release of substances such as hCG, hPL, steroid hormones and prostaglandins. Furthermore, there is evidence that intra-uterine tissues also can regulate ACTH release and have effects on the hypothalamus-pituitary-gonadal axis and the hypothalamus-pituitary-adrenal axis. The set of data reported in this article confirms that the placenta must be considered an organ that is essential for the initiation, maintenance and successful conclusion of pregnancy and that an imbalance between the complex network of placental regulating systems may cause serious gestational disorders.

1998 - Pulsatile secretion of ACTH and cortisol in premenopausal women: effect of obesity and body fat distribution [Articolo su rivista]
Pasquali, R; Biscotti, D; Spinucci, G; Vicennati, V; Genazzani, Alessandro; Sgarbi, L; Casimirri, F.
abstract

OBJECTIVE There is emerging evidence that women with visceral obesity may have hyper-responsiveness of the hypothalamic-pituitary-adrenal axis. There are no studies on basal daily secretory pattern of ACTH and cortisol in subjects with different obesity phenotypes. DESIGN AND PATIENTS In this study we examined daytime pulsatile secretion of ACTH and cortisol in two groups of premenopausal obese women with visceral (V-BFD) (BMI 37.1 +/- 1.7) and subcutaneous (S-BFD) (BMI 38.8 +/- 1.5) body fat distribution (measured by CT scan) and in a group of normal weight healthy controls (BMI 21.1 +/- 0.5). After an overnight fast, blood samples were taken at 15-minute intervals for 12h (49 samples, from 0800h until 2000h). All women avoided breakfast but had a normal lunch and dinner, both containing similar food, energy and nutrient composition. ACTH and cortisol responses to mixed meals at noon and in the evening were also investigated. RESULTS Mean values of ACTH and cortisol did not differ between the groups. However, ACTH pulse frequency was significantly higher in V-BFD (P<0.06) and S-BFD (P<0.02) obese women than in controls, without any significant differences between the two obese subgroups. Mean ACTH pulse amplitude was lower in the V-BFD than in S-BFD obese (P<0.02) and control (P<0.05) groups. Cortisol episodic characteristics did not differ between V-BFD and S-BFD obese and controls. All differences in ACTH pulsatile parameters between obese and controls and between the two obese subgroups were evident only in the morning, with no further significant differences during the early and late afternoon. There were no significant differences in cortisol parameters during the three periods of the day between the various groups, apart from late afternoon cortisol pulse frequencies, which were significantly lower in V-BFD than in controls. After lunch, ACTH and cortisol levels significantly increased in all groups, but the cortisol increase tended to be more rapid in V-BFD than in the other two groups. After dinner, ACTH significantly increased in V-BFD and controls but not in the S-BFD group, whereas cortisol rose significantly in all groups, but significantly less in S-BFD than in V-BFD and controls. Cortisol(AUC) (but not ACTH(AUC)) after lunch was significantly higher than after dinner in all groups. ACTH response after each meal was similar in all groups, but cortisol(AUC) after dinner was significantly lower in S-BFD than in V-BFD women. CONCLUSION This study demonstrates that in premenopausal women, obesity, particularly the visceral phenotype, is associated with several abnormalities of ACTH pulsatile secretion, particularly in the morning. On the contrary, no major differences were present in either blood concentrations, diurnal rhythm or secretory pattern of cortisol between obese and controls. The responses to meals seem to indicate a much more rapid cortisol response after lunch in women with visceral obesity and a reduced activation of the hypothalamic-pituitary-adrenal axis after dinner in women with subcutaneous obesity.

1998 - The transition from pubertal development to postmenopause discloses a gonadotropin-releasing hormone-independent mechanism regulating follicle-stimulating hormone release [Articolo su rivista]
Genazzani, Alessandro; Nappi, L.
abstract

The reproductive function is tightly dependent on gonadotropin secretion and the optimal activity of the hypothalamus-pituitary axis. This study discusses evidence that supports the possible existence of a GnRH-independent modulator of FSH secretion in humans. Stich a hypothesis has been consistently reported in several experimental animals. To test the hypothesis specific times during the physiological development and activity of the hypothalamus-pituitary axis have been evaluated under the use of drugs acting directly on hypothalamic GnRH-secreting neurons, such as GnRH agonists. The possible presence also in humans of such an independent FSH stimulator might be important for the understanding of anovulation and infertility.

1998 - Ultrasonographic and color Doppler analysis in the treatment of polycystic ovary syndrome [Articolo su rivista]
Battaglia, C; Genazzani, Alessandro; Artini, Pg; Salvatori, M; Giulini, S; Volpe, A.
abstract

Objective To compare the effect of a gonadotropin releasing hormone (GnRH) analog plus 'add-back' oral contraceptive (OC) therapy with OC therapy alone on the clinical and hormonal parameters that are characteristic of polycystic ovary syndrome (PCOS). Design Prospective, randomized study. Subjects Thirty PCOS patients were randomly assigned to treatment with leuprolide acetate for depot suspension plus a combined monophasic OC (Group I) or to OC alone (Group II). Methods Hormonal (luteinizing hormone (LH), follicle stimulating hormone (FSH), LH:FSH concentration ratio, estradiol, androstenedione, testosterone), clinical (Ferriman-Gallwey score), ultrasonographic (ovarian volume, number of subcapsular follicles, stromal score) and Doppler (uterine artery and ovarian intraparenchymal vessels' pulsatility index, ovarian stromal vascularization) parameters were evaluated during 6 months' therapy and 6 months' follow-up. Results Significant changes in all the parameters analysed occurred as a result of therapy and the changes were more marked in the group undergoing treatment with GnRH analog plus OC. Conclusions GnRH analog plus OC use has a more rapid and marked effect on the hormonal milieu as well as the ovarian architecture and vascularization in patients with PCOS than OC used alone. The former treatment may be a more efficient therapy for PCOS.

1998 - Which form of HRT should we choose? [Articolo su rivista]
Genazzani, Alessandro
abstract

..

1997 - A long-term treatment with gonadotropin-releasing hormone agonist plus a low-dose oral contraceptive improves the recovery of the ovulatory function in patients with polycystic ovary syndrome. [Articolo su rivista]
Genazzani, Alessandro; F., Petraglia; C., Battaglia; O., Gamba; Volpe, Annibale; A. R., Genazzani
abstract

To evaluate the hormonal and clinical follow-up after the suspension of a longterm therapy with GnRH-agonist (GnRH-a) plus oral contraceptive (OC) in comparison to OC alone in patients with polycystic ovary syndrome (PCOS).Hormonal (plasma LH, FSH, sex steroid levels) and clinical (Ferriman-Gallwey score and ultrasound) parameters were monitored at various moments during the 6 months of treatment and during the 6 months after treatment suspension.Physiopathology of Human Reproduction, University of Modena, Italy.Thirty patients with PCOS were enrolled and randomly subdivided in two groups of 15 each.Group A was treated with 3.75 mg IM GnRH-a plus OC. Group B was treated only with OC.Both therapeutical regimens were effective in reducing androgenic milieu, Ferriman-Gallwey score, and ovarian volume within the 6th month of treatment. However, only patients treated with GnRH-a + OC showed a normal LH:FSH ratio, adequate plasma E2 and P levels, and ovulatory cycles during the 6 months of the after treatment follow-up. Patients treated with OC alone showed no beneficial effect after the 3rd month of the follow-up.These data support the evidence of a higher efficacy of the combined regimen (GnRH-a + OC) than OC alone in the treatment of patients with PCOS. In addition, the former regimen is associated with recovery of normal ovulatory cycles.

1997 - Color Doppler analysis in oligo and amenorrheic women with polycystic ovary syndrome [Articolo su rivista]
Battaglia, C; Artini, Pg; Genazzani, Alessandro; Gremigni, R; Salvatori, M; Sgherzi, Mr; Giulini, Simone; Lombardo, M; Volpe, Annibale
abstract

The objective of this study was to determine whether amenorrheic women have more severe blood flow variations and clinical-endocrinological patterns in comparison with oligomenorrheic polycystic ovary syndrome (PCOS) patients. Twenty oligomenorrheic women (cycle length > 35 days; Group I), and 20 amenorrheic women (no vaginal bleeding for at least 6 months; Group II) were submitted to ultrasonographic evaluation of ovarian volume, follicle distribution, number and diameter, color Doppler analysis of uterine and intraovarian blood flow, hormonal assay of different compartments, and plasma evaluation of lipid profile. The number of subcapsular small-sized follicles, and the ovarian volume, androstenedione and luteinizing hormone (LH) plasma levels, and the LH/follicle-stimulating hormone (FSH) ratio were significantly higher in the amenorrheic group compared with the oligomenorrheic patients. Furthermore, significantly lower high-density lipoprotein (HDL) and HDL/total cholesterol ratio were observed in Group II compared with Group I. In addition, in Group II, higher resistance in the uterine arteries and lower impedance to blood flow in the intraovarian arteries have been shown. The assessment of ovarian morphology by transvaginal ultrasound and Doppler flow analysis of both intraovarian and uterine arteries in patients with PCOS may provide an insight into the pathological state and the degree of progression of the disease.

1997 - Difference of LH and FSH secretory characteristics and degree of concordance between postmenopausal and aging women. [Articolo su rivista]
Genazzani, Alessandro; F., Petraglia; L., Sgarbi; V., Montanini; B., Hartmann; N., Surico; A., Biolcati; Volpe, Annibale; A. R., Genazzani
abstract

Several neuroendocrine changes occur at menopause and the present study aimed to verify whether the episodic release and the degree of concordance of LH and FSH differs between early and late postmenopausal women.Postmenopausal (n = 32) women were enrolled and subdivided in two groups according to the menopausal age: group A (n = 22), patients with more than 2 but less than 5 years from the occurrence of menopause; group B (n = 10), patients with more than 15 years from the occurrence of menopause. All subjects underwent a pulsatility study (4 h, sampling every 10 min) to assess LH and FSH secretory characteristics and their degree of concordance.Mean +/- S.E.M. LH and FSH plasma levels were lower in older women than in postmenopausal women (P < 0.01). The secretory pattern was pulsatile for both LH and FSH and their pulse amplitudes were lower in aged women (P < 0.01). No significant difference was observed in terms of pulse frequency between the two groups. LH and FSH pulses were co-secreted in early postmenopausal women while such a concordance was lost in older women.Late postmenopause is characterized by the reduction of the amplitude of gonadotropin pulses in comparison to women in early postmenopause, reflecting changes of both GnRH secretion and/or pituitary responsiveness to GnRH. The age-related loss of concordance between LH and FSH pulses discloses the existence of a hidden FSH stimulating system, which drives FSH episodic release independently and more promptly than GnRH.

1997 - Effects of sex steroid hormones on the neuroendocrine system [Articolo su rivista]
Genazzani, A. R.; Lucchesi, A.; Stomati, M.; Catarsi, S.; Genazzani, Alessandro; Criscuolo, M.; Petraglia, F.
abstract

Estrogen and progesterone are the most important ovarian steroid hormones regulating female fertility. They have a profound effect on the central nervous system. Target functions of sex steroids in the brain are: pituitary and hypothalamic hormone release, thermoregulatory and cardiocirculatory activities and behavior and mood changes. Furthermore, several studies have shown a correlation between brain neurotransmitters, neuropeptides and sex steroid hormones: they influence synthesis and release of norepinephrine, dopamine, serotonin, gonadotropin releasing hormone, β-endorphin, corticotropin releasing factor and prolactin. Thus, oral hormone contraceptives inhibit the ovulatory process by blocking the activity of the hypothalamus-pituitary-gonadal axis. This inhibitory effect seems to be due to the action of both estrogens and progestins.

1997 - Estrogens as neuromodulators [Articolo su rivista]
Petraglia, F; Stomati, M; Segrè, L. G; Genazzani, Alessandro; Luisi, M; Genazzani, A. R.
abstract

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1997 - Hypothalamic amenorrhea: Neuroendocrine mechanisms / stress-induced anomalies [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F.; Volpe, A.; Genazzani, A. R.
abstract

The importance of stress in the occurrence of amenorrhea is clear and it remains of fundamental importance the fact that whatever is the causal factor inducing the reduction of food intake the result is always an impairment of the central neuroendocrine modulation of the hypothalamus-pituiary-gonadel axis. In some cases, such as athletes or dancers excessive training and / or controlled / reduced feeding may induce amenorrhea later than in non- exercising women. This might depend on the fact that training enables to be physically more resistant to stressors and to stressful situations. In any case amenorrhea, especially the one related to weight loss, may be the prelude to anorexia or it may hide psychological or psychiatric diseases. The fact that amenorrhea is characterized by low estradiol plasma levels exposes all amenorrheic patients to all the risks of hypoestrogenemia: reduction of hone density till to osteopenia, increased total cholesterol, altered lipoproteins, abnormally reduced thyroid hormones. Hypothalamic amenorrhea associated with weight loss is considered a complex disease associated with severe stressful physical, psychological events, reduced food intake and neuromodulation of the human reproductive axis.

1997 - Modulatory effects of a synthetic steroid (tibolone) and estradiol on spontaneous and GH-RH-induced GH secretion in postmenopausal women [Articolo su rivista]
Genazzani, Alessandro; Gamba, O; Nappi, L; Volpe, Annibale; Petraglia, F.
abstract

Objective: Since hormonal replacement therapy (HRT) affects plasma GH levels, the present study aimed to verify the effect of tibolone, a synthetic steroid, on modulating spontaneous and growth hormone releasing hormone (GH-RH) induced GH secretion. Methods: Postmenopausal women (n = 30) were enrolled and randomly subdivided in three groups (n = 10 each group): (1) treated with transdermal estradiol (50 mu g) (Dermestrill, Rottapharm, Monza, Italy) biweekly; (2) treated with transdermal estradiol (100 mu g) (Dermestrill, Rottapharm, Monza, Italy) biweekly; (3) treated with tibolone 2.5 mg/day (Livial, Organon Italia, Pome, Italy). Patients underwent a GH-RH test (1 mu g/kg) and 15 of them underwent to a pulsatility study before and 5 weeks after treatment. Results: Mean(+S.E.M.) GH plasma levels increased in all patients after any type of HRT. GH response to GH-RH stimulation (expressed as maximal response to GH-RH or as delta value) was similar in the three groups while significant changes occurred in spontaneous pulsatile GH release. Tibolone and both dosages of transdermal estradiol significantly reduced GH pulse frequency and increased pulse amplitude. Conclusions: The reduced plasma GH levels observed during postmenopause are probably related to a reduced endogenous GH-RH and not to a reduced pituitary ability to respond to GH-RH. In addition tibolone, as well as transdermal estradiol, are effective in restoring the spontaneous GH episodic release.

1997 - Neuroendocrine effects of different estradiol-progestin regimens in postmenopausal women [Articolo su rivista]
Stomati, M; Bersi, C.; Rubino, S.; Palumbo, M.; Comitini, G.; Genazzani, Alessandro; Santre, M.; Petraglia, F.; Genazzani, A. R.
abstract

Objective: New regimens and routes of administration of hormonal, replacement therapy (HRT) in climateric women are becoming available. Since there is no information on the neuroendocrine effects of sequential combined treatment with 17β-estradiol and a progestin, the present study evaluated the neuroendocrine, clinical vasomotor and psychological changes before and after different sequential combined HRT regimens (17β-estradiol plus nomegestrol acetate, or cyproterone acetate, or vaginal progesterone). Vasomotor and behavioral effects were evaluated by using the Kupperman score, while changes in plasma endorphin (β-END) levels were used as marker of neuroendocrine effects. Methods: Postmenopausal women (n = 30) were randomly divided into three groups (ten women for each group); all women received continuous 17β-estradiol (50 mg, transdermal) and each group was sequentially treated with different progestins for 12 days/month: group A, cyproterone acetate (5 mg p.o.); group B, nomegestrol acetate (5 mg p.o.); and group C, progesterone (100 mg, vaginal cream). A group of healthy fertile women (n = 8) served as control. Before and after 6 months of HRT, postmenopausal women underwent an evaluation of subjective Kupperman score and two neuroendocrine tests: (a) naloxone (4 mg i.v.) and (b) clonidine (1.25 mg i.v.). Plasma β-END levels were measured before and at 15, 30, 45, 60 and 90 min after drug injection. Control women were studied by administering the two neuroendocrine tests only once. Results: Postmenopausal women before HRT showed a pathological Kupperman and no changes of plasma β-END levels in response to the clonidine and naloxone tests score. On the contrary the increase was significant in healthy women. In each of the three groups of treated women both naloxone and clonidine tests induced a significant increase in plasma β-END levels (P < 0.01). After 6 months of HRT, an improvement of vasomotor and psychological symptoms was shown by a decrease of Kupperman score. Conclusions: The present study indicates that sequential treatment with transdermal 17β-estradiol and progestin, no matter which progestin was used, restores the β-END release, improves vasomotor and psychological symptoms.

1997 - Neuroendocrinology of the menstrual cycle [Relazione in Atti di Convegno]
Genazzani, A. R.; Petraglia, F.; Gamba, O.; Sgarbi, L.; Greco, M. M.; Genazzani, A. D.
abstract

1997 - Neuromodulatory role of opioidergic system on hypothalamus-pituitary-gonadal axis during puberty [Articolo su rivista]
Genazzani, Alessandro; Gamba, O; Sgarbi, L; Gandolfi, A; Corazza, F; Surico, N; Petraglia, F.
abstract

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1996 - Bicuculline enhances the corticosterone secretion induced by lipopolysaccharide and interleukin-1 alpha in male rats [Articolo su rivista]
Guo, A. L; Petraglia, F; Nappi, R. E; Criscuolo, M; Ficarra, G; Salvestroni, C; Genazzani, Alessandro; Trentini, G. P; Genazzani, A. R.
abstract

Lipopolysaccharide (LPS)-induced inflammatory stress activates the hypothalamus-pituitary-adrenal (HPA) function. Interleukin-I (IL-1) is one of the key factors during this event; however, the mechanisms mediating IL-1 stimulation of HPA axis are still unclear. The present study evaluated the possible involvement of gamma-aminobutyric acid (GABA) in LPS-induced activation of HPA axis in adult male rats. In addition, the possible existence of diurnal changes of LPS-induced HPA axis activity was also investigated. Bicuculline (0.8 mg/kg BW), a GABA-A receptor antagonist and GABA (1 g/kg BW) were intraperitoneally (ip) injected 15 min before LPS (2 mg/kg BW, ip) or recombinant human IL-1 alpha (microgram/rat) administration in intact rats. Control animals received an equivalent volume of 0.9% saline. Rats were sacrificed at 60 min or 90 min after LPS, or IL-1 alpha or saline injection. Plasma corticosterone levels were measured by radioimmunoassay. Results showed that pretreatment with bicuculline enhanced both LPS- and IL-1-induced corticosterone secretion; while pretreatment with GABA significantly reduced the LPS-stimulated corticosterone release (p < 0.05, vs LPS alone). The effect is dependent on the time of sampling and such effect of bicuculline or GABA was not observed when rats were stimulated in the evening. In addition, the maximal changes of plasma corticosterone following LPS administration in the evening were significantly lower than in the morning (p < 0.01). The present study provides evidence that GABA is involved, at least in part, in the neuroendocrine regulation of LPS/interleukin-1a-induced corticosterone secretion via GABA-A receptor in rats. In addition, the response of plasma corticosterone to LPS has a diurnal variation, which corresponds to a diurnal change of GABAergic modulation of the immunoneuroendocrine response.

1996 - Chronobiological derangement of pituitary hormones in hypothalamic amenorrhea [Articolo su rivista]
Genazzani, A. D.; Petraglia, F.; Sgarbi, L.; Gamba, O.; Volpe, A.; Surico, N.; Genazzani, A. R.
abstract

1996 - Color Doppler analysis in lean and obese women with polycystic ovary syndrome. [Articolo su rivista]
C., Battaglia; P. G., Artini; Genazzani, Alessandro; M. R., Sgherzi; M., Salvatori; S., Giulini; A., Volpe
abstract

The objective of this study was to determine whether obese patients with polycystic ovary syndrome (PCOS) show different ovarian and uterine blood flow patterns in comparison with lean patients. Sixteen obese (body mass index: BMI = 31.4 +/- 3.6 kg/m2) and 22 lean (BMI = 21.1 +/- 1.3 kg/m2) PCOS patients underwent, in the early follicular phase if oligomenorrheic or randomly if amenorrheic, ultrasonographic evaluation of ovarian volume, echodensity and follicle number; transvaginal color Doppler evaluation of uterine and intraovarian blood flow; and radioimmunological assay of luteinizing hormone, follicle stimulating hormone, growth hormone, estradiol, progesterone, testosterone, androstenedione, insulin, insulin-like growth factor I, and other hormonal parameters. Hematocrit, plasma glucose, total cholesterol, high density lipoprotein and triglycerides were also evaluated. Insulin levels were significantly higher in the obese group, whereas levels of growth hormone were significantly lower. Moreover, a more adverse lipid profile was observed in overweight patients. This was associated with higher hematocrit values. At Doppler analysis, a significantly higher mean uterine artery pulsatility index (PI) was observed in the obese group. Furthermore, the PI was inversely correlated with high density lipoprotein values (r = -0.4820; p < 0.05). In both groups, androstenedione was correlated with the uterine PI. The above findings may, in part, explain the increased risk in women with PCOS of developing cardiovascular diseases, and emphasize that obesity may further increase the risk.

1996 - Color Doppler hysterosalpingography in the diagnosis of tubal patency. [Articolo su rivista]
C., Battaglia; P. G., Artini; G., D'Ambrogio; Genazzani, Alessandro; A. R., Genazzani; Volpe, Annibale
abstract

To assess tubal patency by color Doppler hysterosalpingography (HSG).Comparative study of color Doppler HSG with roentgenogram HSG and chromolaparoscopy in infertile women of childbearing age.Clinical environment.Sixty female patients (22 to 39 years) with long-lasting infertility problems.Sterile saline was transcervically injected into the uterine cavity through a catheter and color Doppler HSG was performed. All the patients were submitted to roentgenogram HSG and chromolaparoscopy.The diagnostic efficacy of color Doppler HSG and its concordance with "gold standard" chromolaparoscopy were analyzed.Correlation between color Doppler HSG and roentgenogram HSG with chromolaparoscopy occurred in 86\% versus 93\% of all women studied.Color Doppler HSG with its accuracy and safety results a promising alternative technique to roentgenogram HSG in diagnosing tubal status in infertile patients.

1996 - Corticotropin-releasing factor-binding protein: Origins and possible functions [Articolo su rivista]
Petraglia, F; Florio, P; Gallo, R; Salvestroni, C; Lombardo, M; Genazzani, Alessandro; Dicarlo, C; Stomati, M; Dambrogio, G; Artini, Pg
abstract

Corticotropin-releasing hormone-binding protein (CRFBP) is a 37-kD protein of 322 amino acids, containing one putative N-glycosylation site and 11 cysteines, 10 of which remain in the mature molecule (298 amino acids) and result essential for the action. CRFBP protein gene has been cloned and mapped to the distal region of chromosome 13 and loci5q in the mouse and human genomes. CRFBP is the only example of a neuropeptide-binding protein. It is produced in human and rat brain, and in human liver and placenta. In brain, the central distribution of CRFBP shares some regional overlap with CRF receptor-binding sites. Additionally, in hypothalamic and limbic structures, CRFBP has been identified in association with CRF-expressing cell groups. CRFBP has been also demonstrated in the human placenta and related membranes. Indeed, amniotic epithelium, chorionic cytotrophoblast, and maternal decidua also show intense positive CRFBP mRNA signals. Circulating CRFBP levels in healthy nonpregnant individuals show the same range values as in maternal plasma collected during the first and second trimesters of pregnancy. A rise in CRFBP levels at 30-35 weeks of pregnancy with a dramatic decrease at 38-40 weeks have been shown. At postpartum, CRFBP levels in maternal plasma reach the nonpregnant concentrations. Recombinant and native CRFBP neutralize the ACTH-releasing activity of human CRF in cultured pituitary or placental cells and, additionally, may block the activity of CRF on human pregnant endometrium prostaglandin release and on human myometrium contractility in vitro. These findings suggest that CRFBP may play a role in modulating the functions of CRF in human pregnancy.

1996 - Episodic secretion of activin A in pregnant women [Articolo su rivista]
Gallinelli, A; Gallo, R; Genazzani, Alessandro; Matteo, Ml; Caruso, A; Woodruff, Tk; Petraglia, F.
abstract

The aim of the present study was to determine the characteristics of activin A secretion in women with normal and abnormal pregnancy. With this purpose, a prospective study was done to evaluate the putative pulsatile pattern of serum activin A in serial specimens of blood collected during a certain amount of time (every 15 min for 3 h). A group of pregnant women (N=24) participated in a cross-sectional study. They were subdivided into three groups: healthy pregnant women (N=8), patients with preterm labor (N=8) and patients with gestational diabetes (N=8) before and after insulin therapy. Secretory pulses of serum activin A were determined in all patients with a specific frequency and amplitude by using two different computerized analyses, i.e. DETECT and CLUSTER, Mean+/-SEM values of serum activin A were significantly higher in patients with preterm labor and gestational diabetes than in controls (p <0.01), showing a significant decrease following insulin therapy in diabetic patients (p <0.01). Specific pulses of serum activin A levels were observed in all women, The mean pulse frequency did not change significantly between healthy controls and the different pathological groups, Patients with gestational diabetes after insulin therapy showed a pulse frequency that was significantly higher than in controls (p <0.05). When the mean peak amplitude of activin A pulses was evaluated, patients with preterm labor or gestational diabetes showed values that were significantly higher than in healthy pregnant women (p <0.01). A significant, inverse correlation between pulse frequency and amplitude was found both in healthy pregnant women (p <0.05) and in patients with gestational diabetes (p <0.001). The present study showed that circulating activin A levels in pregnant women change in a pulsatile pattern whose pulse amplitude is modified in the presence of gestational diseases, such as preterm labor or gestational diabetes.

1996 - Growth hormone (GH)-releasing hormone-induced GH response in hypothalamic amenorrhea: evidence of altered central neuromodulation [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Gastaldi, M; Gamba, O; Corazza, F; D'Ambrogio, G; Genazzani, A. R.
abstract

To evaluate the GH-releasing hormone (GH-RH)-induced response of GH in patients affected by hypothalamic amenorrhea.

1996 - Long-term GnRH-agonist administration revealed a GnRH-independent mechanism stimulating FSH discharge in humans [Articolo su rivista]
Genazzani, Alessandro; Massolo, Fausta; Ferrari, Elena; Gandolfi, Andrea; Petraglia, Felice; Genazzani, Andrea R.
abstract

The present study evaluated the FSH and LH episodic discharge in different physiopathological conditions undergoing chronic GnRH-agonist administration. Four girls with true precocious puberty and five postmenopausal women were administered GnRH-agonist (3.73 leuprolide acetate every 4 weeks; Takeda Italia, Rome, Italy) for at least 4 months. Plasma LH and FSH secretory profiles were assessed before and under GnRH-agonist administration (after 21 and 120 days). Pulsatility studies were conducted for 4 h in the girls and for 6 h in postmenopausal women, with blood sampling intervals of 10 min. Pubertal and postmenopausal patients showed the distinct episodic co-secretion of LH and FSH before GnRH-agonist administration; this co-secretion disappeared in both groups after;21 and 120 days of treatment. Moreover, while LH concentrations decreased to almost undetectable levels and LH episodic release disappeared, FSH plasma levels were only partially reduced and FSH episodic secretion was detectable in both groups. In conclusion, this study demonstrated that long-term GnRH-agonist administration blocked LH but not FSH episodic release. These data enforce the hypothesis that FSH episodic discharge might be dependent not only on hypothalamic GnRH, but also on a GnRH-independent stimulatory pathway.

1995 - Allopregnanolone concentration in hippocampus of prepubertal rats and female rats throughout estrous cycle [Articolo su rivista]
Palumbo, M. A; Salvestroni, C.; Gallo, R.; Guo, Ai Li; Genazzani, Alessandro; Artini, P. G.; Petraglia, F.; Genazzani, A. R.
abstract

Hippocampus plays an important role in cognition, neuroendocrine function and sexual behaviour. Changes of hippocampal neuropeptide and neurotransmitter concentrations are associated to behavioural changes occurring throughout reproductive life. The present study focused the attention on the presence of a neurosteroid, 5α-pregnan-3α-ol-20-one (termed allopregnanolone) in hippocampus. In particular, hippocampal allopregnanolone concentration in male and female prepubertal rats and in female rats throughout estrous cycle were evaluated. Hippocampal extracts were eluted on high pressure liquid chromatography and allopregnanolone concentration was measured by radioimmunoassay. Prepubertal male and female rats (15 days old) showed highest values which significantly decreased with advancing age (25 and 60 days) (p<0.01); the lowest hippocampal concentration of allopregnanolone was found in adult rats. Female rats on proestrus morning and afternoon showed an hippocampal allopregnanolone concentration significantly higher than on diestrus or on estrus (p<0.01), while rats on estrus showed hippocampal allopregnanolone concentration significantly lower than during other days of estrus cycle (p<0.01). These data indicate differences in hippocampal concentration of allopregnanolone between prepubertal and adult rats and throughout estrous cycle in female rats. This finding suggest a putative role of neurosteroids in the modulation of behavioral changes occurring throughout reproductive life. © 1995, Italian Society of Endocrinology (SIE). All rights reserved.

1995 - Changes in Dopaminergic control of circulating melanocyte- stimulating hormone-related peptides at puberty. [Articolo su rivista]
Facchinetti, Fabio; S., Bernasconi; Iughetti, Lorenzo; Genazzani, Alessandro; L., Ghizzoni; A. R., Genazzani
abstract

Desacetyl alpha-melanocyte-stimulating hormone (MSH) (ACTH 1-13) is the main form of immunoreactive alpha-MSH circulating in human plasma. This study evaluates the possibility that a dopaminergic inhibitory mechanism could be operative during human development. Thus, alpha-MSH and ACTH 1-13 plasma levels were measured after dopaminergic blockade (domperidone (0.3 mg/kg body weight, maximum 10 mg, p.o.) in 13 prepubertal (aged 4.5-12.3 y) and 12 pubertal (aged 10.2-16.9 y) children. Both peptides were measured by RIA after plasma extraction on Sep-pak C-18 cartridges and reverse phase HPLC. The chromatographic profile of alpha-MSH immunoreactivity falls into two main peaks, corresponding to the retention time of alpha-MSH and ACTH 1-13. Moreover, in prepubertal children domperidone induced a significant increase of alpha-MSH from 1.7 (median) to 5.0 pmol/L, whereas no changes in alpha-MSH plasma levels were found in pubertal subjects (from 5.0 to 4.1 pmol/L). Similarly, ACTH 1-13 plasma levels significantly increased from 3.0 to 19.8 pmol/L in prepubertal children remaining stable in pubertal ones (from 7.8 to 4.6 pmol/L). Moreover, a significant negative correlation was found between basal DHEA-S levels and the plasma alpha-MSH increase after domperidone. These data demonstrate that: 1) ACTH 1-13 is the main form of immunoreactive alpha-MSH in prepubertal life and 2) the dopaminergic inhibition of both ACTH 1-13 and alpha-MSH plasma levels is apparent only in prepubertal subjects.

1995 - EFFECT OF CORTICOTROPIN-RELEASING FACTOR-BINDING PROTEIN ON PROSTAGLANDIN RELEASE FROM CULTURED MATERNAL DECIDUA AND ON CONTRACTILE ACTIVITY OF HUMAN MYOMETRIUM IN-VITRO [Articolo su rivista]
Petraglia, F; Benedetto, C; Florio, P; Dambrogio, G; Genazzani, Alessandro; Marozio, L; Vale, W.
abstract

Human placenta and uterine tissues are sites of production and local action of corticotropin-releasing factor (CRF). The recent evidence that CRF-binding protein (CRF-BP), a protein that blocks CRF-induced pituitary ACTH release, is produced by placental tissues suggested the present study to investigate the effects of CRF-BP on prostaglandin release land contractile activity of myometrial strips. Primary cultures of decidual cells were prepared using tissue collected from healthy women undergoing cesarean delivery at term. Mechanical and enzymatic cell dispersions were carried out, and experiments were performed 24-28 h after cell plating. The prostaglandin E(2)(PGE(2)) concentration in cultured medium was measured by RIA. Myometrial strips were obtained from the upper edge of the uterine incision during elective cesarean section at term. Dissected free of connective tissue, strips were mounted in a 30-mL two-chamber organ bath containing oxygenated Tyrode's buffer (37 C) and connected to a two-channel isometric smooth muscle transducer. Cultured decidual cells collected at term significantly increased the release of PGE(2) in the presence of CRF (P < 0.01). The addition of CRF-BP did not significantly modify PGE(2) release, but completely reversed the effect of CRF. When human myometrial strips were incubated in the presence of CRF and PGF(2 alpha), a significant increase in contractile activity was observed (P < 0.01); preincubation with CRF-BP prevented the increased contractile activity induced by CRF. The present data show that CRF-BP is able to counteract the biological effect of CRF on human pregnancy endometrium and myometrium and suggest that CRF-BP may be a regulatory protein that plays a role in the local function of uterine tissues during pregnancy.

1995 - Maternal plasma and placental immunoreactive corticotrophin-releasing factor concentrations in infection-associated term and pre-term delivery [Articolo su rivista]
Petraglia, F; Aguzzoli, L.; Florio, P.; Baumann, P.; Genazzani, Alessandro; Di Carlo, C.; Romero, R.
abstract

The present study aimed to investigate whether microbial invasion of the amniotic cavity affects maternal plasma or placental immunoreactive corticotrophin releasing factor (ir-CRF) concentrations in pregnant women with pre-term or term labour. A cross-sectional study was conducted collecting blood samples in: (I) women with pre-term labour and intact membranes (25-36 weeks), with or without microbial invasion of the amniotic cavity (subdivided into three groups: IA, no microbial invasion of the amniotic cavity, delivery at term, n = 54; group IB, delivery &lt; 48 h, no microbial invasion of the amniotic cavity, n = IO; group IC, delivery &lt; 48 h, microbial invasion of the amniotic cavity, n = 8); (2) women at term, not in labour and without microbial invasion of the amniotic cavity (n = 15); (3) women in spontaneous active labour at term without (A) (n = 55) or with (B) (n = 16) microbial invasion of the amniotic cavity; and (4) healthy women not in labour at 25-36 weeks of gestation (n = 25). Specimens of trophoblast tissue were collected from pregnant women with pre-term labour (no microbial invasion of the amniotic cavity, n = 6; microbial invasion of the amniotic cavity, n = 4) or delivering at term (no microbial invasion of the amniotic cavity, n = 8; microbial invasion of the amniotic cavity, n = 4). A specific radioimmunoassay on acidic extracts of plasma or placental specimens was used. Patients with pre-term labour showed higher plasma ir-CRF concentration than healthy women at the same gestational age or at term not in labour, and those with microbial invasion of the amniotic cavity, had higher plasma ir-CRF concentrations than the ones without microbial invasion of the amniotic cavity (P &lt; 0.05). Term labour was associated with elevated plasma ir-CRF concentrations, not affected by, the presence or absence of microbial invasion of the amniotic cavity. Placental ir-CRF concentrations in women with pre-term labour, in absence of microbial invasion of the amniotic cavity, mere significantly lower than in women with pre-term labour associated with microbial invasion of the amniotic cavity (P &lt; 0.05). These findings showing a different pattern of maternal and placenta ir-CRF concentrations between pre-term labour with ol without microbial invasion of the amniotic cavity, support the hypothesis of an impact of infection on neuroendocrine activity, of human placenta.

1995 - Naltrexone administration modulates the neuroendocrine control of luteinizing hormone secretion in hypothalamic amenorrhoea. [Articolo su rivista]
Genazzani, Alessandro; M., Gastaldi; F., Petraglia; C., Battaglia; N., Surico; Volpe, Annibale; A. R., Genazzani
abstract

Because endogenous opioids have been considered to be deeply involved as a causal factor of hypothalamic amenorrhoea, this study was designed to evaluate the efficacy of the administration of naltrexone, an antagonist of opioid receptors, on luteinizing hormone (LH) secretion in patients with hypothalamic amenorrhoea. A total of 30 patients with hypothalamic amenorrhoea were studied. Patients were divided into two groups: group A, hypogonadotrophic (n = 15), and group B, normogonadotrophic (n = 15). All patients were administered naltrexone at a dose of 50 mg/ day per os for 6 months. A third group of 10 amenorrhoeic patients was treated with placebo per os with the same schedule. All patients were evaluated for LH spontaneous pulsatile release in baseline conditions and after 3 and 6 months of treatment. Plasma gonadal steroid concentrations increased significantly in all patients after 3 months of naltrexone therapy, but only hypogonadotrophic patients showed a sharp increase in both LH plasma concentrations and LH pulse amplitude within the first 3 months of treatment which remained unchanged until the sixth month of treatment. Plasma follicle stimulating hormone concentrations did not change significantly in any patient. Menstrual bleeding occurred within 90 days of the beginning of treatment in 24 out of the 30 patients. Patients treated with placebo did not show a significant change in gonadotrophin and gonadal steroid plasma concentrations. The results of our study support the efficacy of naltrexone administration on neuroendocrine pathways controlling LH secretion in patients with hypothalamic amenorrhoea.

1995 - Naltrexone treatment restores menstrual cycles in patients with weight loss-related amenorrhea [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F.; Gastaldi, M.; Volpogni, C.; Gamba, O.; Genazzani, A. R.
abstract

Objective: To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test. Design: Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients were divided in two groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule. Results: Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels. Conclusions: The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.

1995 - Prolonged treatment of hirsutism with flutamide alone in patients affected by polycystic ovary syndrome [Articolo su rivista]
Pucci, E; Genazzani, Alessandro; Monzani, F; Lippi, F; Angelini, F; Gargani, M; Barletta, D; Luisi, M; Genazzani, A. R.
abstract

Hirsutism is a common symptom of women affected by polycystic ovary syndrome (PCOS). The effectiveness of the antiandrogen flutamide alone was studied in 25 patients affected by PCOS with severe hirsutism for a period of 24 months. Seventeen of these patients had not been treated before and eight had had previous but unsatisfactory therapy. Nineteen patients showed a normal body weight (BMI < 25 kg/m2) whereas six were obese (BMI > 35 kg/m2). A chemical and endocrinological evaluation and an assessment of the degree of hirsutism, assigned by Ferriman-Gallwey score (mean 22 +/- 3.038), was performed under baseline conditions. Patients started treatment with flutamide (Eulexin, Schering-Plough, Kenilworth, USA) at the dose of 500 mg daily. A chronobiological assessment of gonadotropin episodic secretion and of gonadotropin response to GnRH challenge (10 micrograms in bolus) was done before and on day 7 of flutamide administration. During treatment, our patients showed a marked and significant reduction of hirsutism starting from a score of 6 and reaching the maximum (9.6 + 2.1) at 24 months of therapy. No relevant hormonal changes or side-effects were observed during therapy. Our data demonstrate that hirsutism in PCOS can rapidly and markedly respond to treatment with flutamide alone without important side-effects even if administered for a long period.

1995 - Spontaneous episodic release of adenohypophyseal hormones in hypothalamic amenorrhea. [Articolo su rivista]
Genazzani, Alessandro; M., Gastaldi; Volpe, Annibale; F., Petraglia; A. R., Genazzani
abstract

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1995 - The role of color doppler imaging in the diagnosis of polycystic ovary syndrome [Articolo su rivista]
Battaglia, Cesare; Artini, Paolo G.; D'Ambrogio, Gerardo; Genazzani, Alessandro; Genazzani, Andrea R.
abstract

OBJECTIVE: Our purpose was to evaluate whether intraovarian and uterine blood flow variations are associated with clinical, ultrasonographic, and endocrine polycystic ovary syndrome findings. Study DESIGN: Thirty-two hirsute, oligomenorrheic patients and 18 volunteer women underwent in the early follicular phase ultrasonographic evaluation of ovarian volume, echodensity, and follicle number; transvaginal color Doppler measurement of the uterine and intraovarian vessel variations; and radioimmunologic dosage of luteinizing hormone, follicle-stimulating hormone, estradiol, progesterone, testosterone, androstenedione, and other hormonel compartments. RESULTS: In the patients with polycystic ovary syndrome (increased luteinizing hormone/follicle-stimulating hormone ratio, elevated androstenodione levels, high number of subcapsular follicles by ultrasonography-augmented ovarian volume and echodensity) (n = 22) we observed, at Doppler analysis, significantly elevated uterine artery pulsatility index values associated with a typical low resistance index of stromal ovary vascularization. The pulsatility index was positively correlated with the luteinizing hormone/follicle-stimulating hormone ratio, and the resistance index was negatively correlated. The elevated uterine artery resistance was correlated with androstenedione levels. CONCLUSION: Doppler analysis can be a valuable additional tool for the diagnosis of polycystic ovary syndrome. © 1995.

1994 - Episodic changes of serum procollagen type I carboxy-terminal propeptide levels in fertile and postmenopausal women. [Articolo su rivista]
Sgherzi, Mr; Fabbri, G; Bonati, M; Maietta latessa, A; Segre, A; De Vita, D; De Leo, V; Genazzani, Alessandro; Petraglia, F; Genazzani, Ar
abstract

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1994 - Episodic release of prolactin in women with weight loss-related amenorrhea. [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Gastaldi, M; Volpogni, C; Surico, N; Genazzani, Ar
abstract

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1994 - Evidence suggesting an additional control mechanism regulating episodic secretion of luteinizing hormone and follicle stimulating hormone in pre-pubertal children and post-menopausal women [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Gastaldi, M; Volpogni, C; Gamba, O; Massolo, Fausta; Genazzani, A. R.
abstract

The possible differential regulation of pulsatile follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion in pre-pubertal children and in post-menopausal women was investigated. Children were studied for 4 h and post-menopausal women for 6 h; blood samples were taken every 10 min. Post-menopausal women were studied before and 21 days after administration of a single i.m. dose of gonadotrophin-releasing hormone (GnRH) analogue. Eight post-menopausal women and 18 children (nine boys and nine girls) were enrolled. The children were divided into two groups: A, at Tanner stages 0-1 (four boys and three girls); B, at Tanner stage 2-3 (five boys and six girls). Plasma LH and FSH concentrations were determined using an immunofluorimetric assay. Time series were analysed and the specific concordance (SC) index was computed to determine the degree of concordance between episodes of LH and FSH secretion. While children of group A had LH concentrations below the minimal detectable dose of 0.1 IU/l, group B showed measurable LH plasma concentrations (1.4 +/- 0.3 IU/l, mean +/- SEM). Plasma FSH concentrations were detectable in both groups. Group A showed FSH plasma concentrations significantly lower than those of group B (0.75 +/- 0.2 and 1.95 +/- 0.4 IU/l respectively; P < 0.05), but FSH pulse frequency was higher in group A (P < 0.05). Children of group B showed significant concomitance of LH and FSH secretory events at time 0 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

1994 - Intrinsic secretory characteristics of luteinizing hormone and prolactin episodic release during pubertal development [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F.; Gastaldi, M.; Massolo, F.; Cellini, M.; Iori, G.; Surico, N.; Genazzani, A. R.
abstract

The intrinsic characteristics of LH and prolactin (PRL) episodic secretion were evaluated in a group of 18 children (8M and 10F). The children were divided into two groups according to the Tanner stage: Group A (Tanner ≤ 1, N = 7, 3M and 4F, 6-10 years of age) and group B (Tanner 2-3, N = 11, 5M and 6F, 9-11 years of age). A pulsatility study of 4 h, sampling every 10 min, was carried out in all children. LH and PRL plasma levels were assayed by IFMA and RIA respectively. LH and PRL secretory episodes were then identified on plasma determinations using the program DETECT, Instantaneous secretory rates (ISR) were then computed for both LH and PRL using the specific algorithm within the DETECT program. Plasma LH levels were different between the two groups of children. Group A children showed undetectable LH plasma levels (below the minimal detectable dose of 0.1 mIU/ml), while group B demonstrated LH plasma levels in the normal range of values for age and sexual development (1.5 ± 0.3 mIU/ml, mean ± SEM). LH pulse frequency for group B was 3.2 ± 0.4 peaks/4h. No significant differences in mean plasma PRL levels, pulse frequency and pulse amplitude were observed between the two groups of children. Computation of ISR for LH (group B only) and PRL (both groups) identified the intrinsic episodic characteristics of the two hormones. No significant differences in LH and PRL pulse frequencies were observed when comparing the results estimated on ISR with those estimated on plasma concentrations. No significant changes in PRL pulse amplitude were observed between the two groups. Conversely, a shorter duration of LH and PRL secretory episodes was found. In conclusion, in children PRL, secretory bursts from lactotropes lasted the same number of minutes independently of the Tanner stages. Moreover, the LH secretory events were clearly detectable during the daytime only when puberty had already started. The duration of PRL and LH secretory events was similar to adult fertile subjects. These data indicate that the gonadal maturation does not modify LH and PRL secretory events from the pituitary.

1994 - Life events impact in patients with secondary amenorrhoea. [Articolo su rivista]
L., Fioroni; M., Fava; Genazzani, Alessandro; Facchinetti, Fabio; A. R., Genazzani
abstract

To evaluate the relationship between stressful life events and the onset of secondary amenorrhoea Paykel's semi-structured interview for Recent Life Events was administered to patients affected by secondary amenorrhea and also to healthy volunteers. The number, quality, and objective negative impact of life events were compared among different hormonal subtypes of secondary amenorrhoea and healthy normally menstruating women, as a control group. The number of life events in amenorrhoeic patients (N = 131) was significantly greater than those observed in the control group (N = 64) (45.9 vs 32.8\%). Moreover, where only hypothalamic hypogonadotrophic amenorrhoea was considered, the occurrence of life events was significantly higher (59.8\%) than in hyperandrogenic (26.6\%) or in normogonadotrophic (20.4\%) patients. The most prevalent events among hypothalamic hypogonadotrophic amenorrhoeic patients were those classified as 'undesirable', 'uncontrolled' and with 'Objective Negative Impact'. The present study supports the hypothesis of a cause-effect relationship between stressful personal life events and the onset of secondary amenorrhoea of hypogonadotrophic subtype.

1994 - Pulsatile fluctuations of plasma gonadotropin-releasing hormone and corticotropin-releasing factor levels in healthy pregnant women [Articolo su rivista]
Petraglia, F; Genazzani, Alessandro; Aguzzoli, L; Gallinelli, A; De Vita, D; Caruso, A; Genazzani, Ar
abstract

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1994 - Secretion and Putative Role of Activin and CRF in Human Parturition [Articolo su rivista]
Petraglia, F.; Florio, P.; Gallinelli, A.; Micheroux, A. A. D.; Ferrari, A.; Vita, D. V. D.; Aguzzoli, L.; Genazzani, A. D.; Carlo, C. D.
abstract

1994 - The duration of prolactin secretory bursts from the pituitary is independent from both prolactin and gonadal steroid plasma levels in women and in men [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F.; Volpogni, C.; Forti, G.; Surico, N.; Genazzani, A. R.
abstract

The intrinsic secretory characteristics of prolactin (PRL) have been investigated using newly developed algorhythms for instantaneous secretory rate (ISR) computation. PRL secretory rate, its intrinsic pulsatile characteristics and their possible dependance from gonadal steroids were investigated in five groups of subjects: a) 11 women during the follicular and luteal phase of the same menstrual cycle; b) 5 healthy postmenopausal women; c) 6 women affected by functional hyperprolactinemia; d) 5 normal men; e) 4 agonadal subjects before and during testosterone replacement therapy. All subjects underwent a 6 hours pulsatility study, from 08:00 to 14:00, sampling every 10 minutes. PRL plasma concentrations were determined using a RIA system and the presence of PRL secretory pulses was evaluated with program DETECT, both on plasma time series and after ISR computation. A distinct PRL episodic release was observed in all groups (follicular phase: 5.5±0.5, luteal phase: 6.5±0.6, postmenopause: 5±1, hyperprolactinemic women: 4.2±0.8, men: 4.8+0.4, agonadal before testosterone: 6±1, agonadal during testosterone administration: 5.3±0.3 peaks/6h), but mainly the computation of ISR allowed to demonstrate that the duration of the lactotropes secretory events was constant in all groups studied. PRL secretory bursts duration ranged between 23.1±1.8 and 25.4±2.5 minutes independently both on PRL or on sex steroid plasma levels. In conclusion, the present report shows that in different physiological conditions the intrinsic secretory bursts from lactotropes are constant in duration independently from the functional state, sex and the steroid hormone levels. 1 This paper was partially supported by the grant “Altri Intervene” (AI 92.00159.04) of C.N.R., Rome, Italy, given to Dr. A.D. Genazzani. © 1994, Italian Society of Endocrinology (SIE). All rights reserved.

1993 - . Hormonal treatments modulate pulsatile plasma growth hormone, gonadotrophin and osteocalcin levels in postmenopausal women [Articolo su rivista]
Mercuri, N; Petraglia, F; Genazzani, Alessandro; Amato, F; Sgherzi, Mr; Maietta Latessa, A; De Leo, V; Nappi, C; Genazzani, Ar
abstract

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1993 - . Opioid control of gonadotrophin secretion in humans. [Articolo su rivista]
Genazzani, Ar; Genazzani, Alessandro; Volpogni, C; Pianazzi, F; Guo, A. L.; Surico, N; Petraglia, F.
abstract

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1993 - A comparative study of three ovulation induction protocols in polycystic ovarian disease patients in an in vitro fertilization/embryo transfer program. [Articolo su rivista]
N. O., Turhan; P. G., Artini; G., D'Ambrogio; F., Droghini; C., Battaglia; Genazzani, Alessandro; Volpe, Annibale; A. R., Genazzani
abstract

This study compares the results of three ovulation induction protocols in polycystic ovarian disease (PCOD) patients undergoing an in vitro fertilization-embryo transfer (IVF-ET) program. A total of 85 cycles was studied. The patients were treated with clomiphene citrate (CC) plus human menopausal gonadotropin (hMG) (CC/hMG group), with purified menofollitropin (pFSH) plus hMG (pFSH/hMG group), and with pFSH/hMG plus gonadotropin releasing hormone analogue (GnRH-a) (analogue group). In the analogue group the suppression of luteinizing hormone (LH) with GnRH-a decreased the number of follicles < 12 mm on the day of human chorionic gonadotropin (hCG) administration and the number and percentage of immature oocytes retrieved and increased the percentage of mature oocytes retrieved.However, fertilization rates of oocytes, cleaved embryo rates, pregnancy rates following replacement, and pregnancy outcomes were not different.Although the suppression of the hypothalamic-pituitary-ovarian axis with GnRH-a in PCOD patients improved follicular synchrony and oocyte maturity, none of the ovulation induction protocols was superior to the others with respect to pregnancy rates and pregnancy outcomes.

1993 - Acetyl-L-Carnitine effect on pituitary and plasma *-endorphin responsiveness to different chronic intermittent stressors. [Articolo su rivista]
Bidzinska, B; Petraglia, F; Angioni, S; Genazzani, Alessandro; Criscuolo, M; Ficarra, G; Gallinelli, A; Trentini, Gp; Genazzani, Ar
abstract

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1993 - Cefalea ed alterazioni neuroendocrine e cronobiologiche. [Articolo su rivista]
Genazzani, Alessandro; Gastaldi, M; Facchinetti, Fabio; Nappi, G; Martignoni, E; Micieli, G; Genazzani, Ar
abstract

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1993 - Contraception in older woman. [Articolo su rivista]
Volpe, Annibale; M., Silferi; Genazzani, Alessandro; A. R., Genazzani
abstract

Oral contraception (OC) in the premenopause has been recently proposed as treatment for control and prevention of the putative symptoms typical of this period of life. Indeed, menstrual cycle disturbances and climacteric symptoms frequently occur at this age. The major aim of normal contraception is resultant maintenance of normal sexual activity. The effects of one OC containing 20 mcg ethinylestradiol and 150 mcg desogestrel (EE/DOG) were studied. Treatment did not significantly modify both lipid metabolism (triglycerides, total cholesterol, HDL, LDL, Apo A, Apo B) and clotting system (fibrinogen, PT, PTT, antithrombin III, fibrinopeptide A). No significant modifications of oral glucose tolerance test (OGGT) occurred after EE/DOG treatment. Also, bone density was not modified during estro-progestinic administration. From our experience, if there are no risk factors such as smoking, obesity or hypertension, the OCs could be used until menopause for absolute contraceptive efficacy, good tolerance and lack of side effects.At Cagliari Hospital in Italy, the department of obstetrics and gynecology studied the efficacy and safety of a combined oral contraceptive (OC) containing 20 mcg of ethinyl estradiol and 150 mcg of desogestrel in 61 nonsmoking women aged 41-48. The women were followed for up to five years. After the second cycle of treatment, the mean length of the menstrual cycle and menses standardized at 26 and 4 days, respectively. By 12 months of OC treatment, the slight side effects either had disappeared or had significantly declined. No woman gained weight. Blood pressure did not change significantly. Lipid metabolism did not change significantly. There were only small insignificant increases in high and low density lipoprotein cholesterol, triglycerides, and apolipoproteins A. After 6, 12, and 24 months of OC treatment, sex hormone binding globulin levels increased significantly (1.83 vs. 3.6 mcg/dl; p 0.05). The OC did not significantly affect blood coagulation markers (fibrinogen, prothrombin time, partial thromboplastin time, antithrombin III, and fibrinopeptide A). It had no effect on fasting blood glucose and insulin levels and their response to the oral glucose tolerance test. The researchers conducted bone density measurements in the lumbar spine (L2-L4) of 37 women aged 45-48. The OC did not alter bone density. These results suggest that this low-estrogen-dose combined OC is a safe and effective contraceptive in perimenopausal women and has good acceptability and good cycle control without considerable side effects. The OC also exhibited the capability of further minimizing the thrombogenic effects of low-dose OCs.

1993 - Corticotropin-releasing-hormone modulates cytokines release in cultured human peripheral blood mononuclear cells. [Articolo su rivista]
Angioni, S; Petraglia, F; Gallinelli, A; Cossarizza, Andrea; Franceschi, C; Muscettola, M; Genazzani, Alessandro; Surico, N; Genazzani, Ar
abstract

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1993 - DERANGEMENT OF LH EPISODIC SECRETION IN CLUSTER HEADACHE SUFFERERS [Articolo su rivista]
Genazzani, Alessandro; Micieli, G; Martignoni, E; Facchinetti, Fabio; Rodbard, D; Nappi, G.
abstract

In patients with cluster headache (CH) testosterone plasma levels have been consinstently reported to be lower than in normal males. Thus, we studied LH pulsatile secretory pattern in a group of 29 males suffering from CH. Ten of them were studied longitudinally, while 19 were studied cross-sectionally only during active (n=9) or attack free (n=10) phases. Nine healthy, age-matched males were studied as reference group. All subjects underwent a pulsatility study of 6 hours, sampling every 15 minutes. CH patients resulted to have a lower LH pulsatile release both during active (3.6+/-0.9 peaks/6h, p<0.0001) and attack free (4.1+/-0.9 peaks/6h, p<0.004) phases than normal males (5.2+/-0.6 peaks/6h). When longitudinally studied, CH patients (n=10) showed lower LH secretory episodes during the active than during the attack free phase (3.3+/-0.9 and 4.1+/-0.7 peaks/6h, p<0.05). Testosterone plasma levels did not differ between active and free phases (4.3+/-1 and 4.7+/-0.8 ng/ml, respectively), while, in patients they were significantly lower than in controls (6.8+/-0.9 ng/ml, p<0.01)). These data demonstrate an impaired function of the hypothalamo-pituitary axis possibly due to an overactivity of the opioid neuromodulation.

1993 - Effect of different chronic intermittent stressors and acetyl-l-carnitine on hypothalamic beta-endorphin and GnRH and on plasma testosterone levels in male rats [Articolo su rivista]
Bidzinska, B; Petraglia, F; Angioni, S; Genazzani, Alessandro; Criscuolo, M; Ficarra, G; Gallinelli, A; Trentini, Gp; Genazzani, Ar
abstract

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1993 - FSH SECRETORY PATTERN AND DEGREE OF CONCORDANCE WITH LH IN AMENORRHEIC, FERTILE, AND POSTMENOPAUSAL WOMEN. [Articolo su rivista]
Genazzani, Alessandro; F., Petraglia; C., Volpogni; G., D'Ambrogio; Facchinetti, Fabio; A. R., Genazzani
abstract

Pulsatile secretion of gonadotropin was investigated in amenorrheic patients and in fertile and postmenopausal women to assess both follicle-stimulating hormone (FSH) episodic secretion and its temporal coupling with luteinizing hormone (LH). Three groups of amenorrheic patients were studied: hyperandrogenic (n = 20), hypogonadotropic (n = 51), and normogonadotropic (n = 31). Nineteen fertile women (during the follicular and luteal phases of the cycle) and sixteen postmenopausal women were investigated as reference groups. All subjects demonstrated the presence of a distinct pulsatile pattern with LH and FSH pulses/4 h as follows: hyperandrogenic 3.95 +/- 0.26 and 3.85 +/- 0.2, hypogonadotropic 3.76 +/- 0.26 and 3.9 +/- 0.16, normogonadotropic 3.5 +/- 0.2 and 3.9 +/- 0.17 LH and FSH pulses/4 h, respectively (means +/- SE). Normal controls showed 4.1 +/- 0.2 and 3.1 +/- 0.2 pulses/4 h for LH (P < 0.05) and 3.2 +/- 0.1 and 3.6 +/- 0.3 pulses/4 h for FSH, during follicular and luteal phases, respectively. Postmenopausal women showed 3.6 +/- 0.2 and 3.0 +/- 0.3 pulses/4 h for LH and FSH, respectively. Specific concordance (SC) index demonstrated that LH and FSH were significantly and simultaneously secreted in all groups. Conversely, LH and FSH were not temporally related during the luteal phase. In conclusion, we report a distinct FSH episodic secretion and its temporal linkage with LH pulses irrespective of plasma concentrations of gonadal steroids in secondary amenorrhea

1993 - Growth hormone treatment affects plasma LH pulsatile release in women with secondary amenorrhea. [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Volpogni, C; Pianazzi, F; Montanini, V; D'Ambrogio, G; Genazzani, A. r.
abstract

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1993 - Hypothalamic amenorrhea: evidence for a central derangement of hypothalamic-pituitary-adrenal cortex axis activity. [Articolo su rivista]
Nappi, Re; Petraglia, F; Genazzani, Alessandro; D'Ambrogio, G; Zara, C; Genazzani, Ar
abstract

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1993 - Long-term naltrexone treatment modifies luteinizing hormone secretory amplitude in polycistic ovary syndrome [Articolo su rivista]
Nappi, R. E.; Petraglia, F.; Bacchi-Modena, A.; Benassi, L.; Genazzani, A. D.; Comitini, G.; Nappi, C.; Genazzani, A. R.
abstract

Objective: To evaluate the neuroendocrine effect of naltrexone in the long-term treatment of polycystic ovary syndrome. Methods: The chronobiological secretory characteristics of the pituitary hormones FSH, LH, PRL, and cortisol were investigated over a period of 8 hours in a group of polycystic ovary syndrome patients before and after treatment with naltrexone (50 mg per os daily for 28 days). Results: No significant changes in integrated LH mean values and mean LH pulse frequency were found, whereas the mean LH pulse amplitude was significantly lower (p&lt;0.05) after 28 days of naltrexone therapy. The characteristics of pulsatile FSH, PRL and cortisol secretory patterns were not significantly different before and after treatment with naltrexone. Conclusion: This study shows that long-term naltrexone therapy reduces the LH pulse amplitude probably through central and peripheral mechanisms without affecting the overall LH secretion. Thus, naltrexone can represent a useful tool in the clinical management of polycystic ovary syndrome.

1993 - Modulatory role of estrogens and progestins on growth hormone episodic release in women with hypothalamic amenorrhea. [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Volpogni, C; Gastaldi, M; Pianazzi, F; Montanini, V; Genazzani, Ar
abstract

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1993 - Neuroendocrine changes in luteal function in patients with premenstrual syndrome. [Articolo su rivista]
Facchinetti, Fabio; Genazzani, Alessandro; E., Martignoni; L., Fioroni; G., Nappi; A. R., Genazzani
abstract

The present study evaluates the luteal progesterone (P) and LH secretions in 14 patients affected by premenstrual syndrome (PMS) and in 14 asymptomatic controls through the evaluation of their episodic release. PMS was prospectively confirmed in two consecutive menstrual cycles using Moos' Menstrual Distress Questionnaire. A pulsatility study was performed during the luteal phase. Blood samples were drawn every 10 min for 12 h, beginning at 0800 h. Statistically significant pulses were detected using the Detect program, and the degree of concordance of LH and P pulses was estimated. Similar mean 12-h P levels were found in controls (mean +/- SD, 13.9 +/- 9.3 nmol/L) and patients (14.2 +/- 10.1). LH levels were also similar in the two groups. Patients showed a higher P pulse frequency (13.4 +/- 1.8 vs. 11.4 +/- 2.3; P < 0.02) and a reduced amplitude of secretory episodes (126.5 +/- 61.6\% vs. 187.1 +/- 126.7\%; P < 0.03) than controls. Similarly, PMS patients showed pulsatile LH release of increased frequency and reduced amplitude than controls. A significant degree of concordance between LH and P pulses was observed in both groups, with a time lag of 0-10 min; that is, P secretory episodes follow LH with a delay of 0-10 min. These findings demonstrate that despite the fact that integrated P levels in PMS patients are similar to those in control subjects, the episodic secretion of the hormone is characterized by pulses of increased frequency and reduced amplitude. This phenomenon is temporally related to LH secretion, thus reinforcing the concept of PMS as a neuroendocrine disorder.

1993 - Stressful life events and affective disorders inhibit pulsatile LH secretion in hypothalamic amenorrhea. [Articolo su rivista]
Facchinetti, Fabio; M., Fava; L., Fioroni; Genazzani, Alessandro; A. R., Genazzani
abstract

The aim of this study was to evaluate relationships between emotional state and hypothalamic activity in patients with hypothalamic secondary amenorrhea. Sixty-seven normal weight patients with hypothalamic amenorrhea were submitted to concomitant psychological and LH pulsatility evaluation. Structured clinical interview for anxiety and depressive disorders (DSM III-R) as well as life events investigations (Paykel test) were performed. LH pulses (blood sampling every 10 min for 4 hr) were analyzed through DETECT program and Instantaneous Secretory Rate were computed. Twenty-one patients reporting life events associated to the onset of amenorrhea had LH pulse frequency (2.28 +/- 1.10 pulses/4 hr) lower than those without life events (3.40 +/- 1.46 p = .007). LH pulses amplitude was lower in patients meeting a DSM III-R (21 cases: 1.22 +/- 0.96 mIU/ml) diagnosis than in those without (1.99 +/- 1.20 p = .04) diagnosis. Plasma estradiol and FSH levels as well as duration of amenorrhea and Body Mass Index were similar among groups. It is concluded that psychogenic factors (namely the presence of life events related to the onset of menstrual disorder) are associated with significant and specific changes of hypothalamic activity which could be involved in determining hypogonadism.

1993 - The concomitant release of androstenedione with cortisol and luteinizing hormone pulsatile releases distinguishes adrenal from ovarian hyperandrogenism. [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Pianazzi, F; Volpogni, C; Genazzani, Ar
abstract

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1992 - FREQUENCY OF PROLACTIN PULSATILE RELEASE IN NORMAL MEN AND IN AGONADAL PATIENTS IS NEITHER COUPLED TO LH-RELEASE NOR INFLUENCED BY ANDROGEN MODULATION [Articolo su rivista]
Genazzani, Alessandro; Forti, G; Guardabasso, V; Maggi, M; Milloni, M; Cianfanelli, F; Serio, M.
abstract

OBJECTIVE We wished to examine and characterize the prolactin pulsatile secretory pattern in both normal and agonadal males in order to assess whether there was any concordance with LH secretion. DESIGN Patients were sampled every 5 minutes for 12 hours. PATIENTS We studied five normal and four agonadal men, the latter group before and on testosterone enanthate (TE) (200 mg i.m. every 15 days) treatment. MEASUREMENTS Prolactin and luteinizing hormone plasma levels were determined using commercial RIA systems. Pulse detection was performed using the DETECT program and the degree of concordance between luteinizing hormone and prolactin was established computing the specific concordance index. RESULTS We demonstrated the presence of a frequent PRL secretory pattern in normal men (22.8 +/- 1.8 peaks/12h; mean +/0 SEM) and in agonadal patients, both in basal conditions and during testosterone treatment (20.5 +/- 2.8 and 18 +/- 1.6 peaks/12h, respectively). The testosterone treatment in agonadal men significantly reduced luteinizing hormone pulse frequency (baseline: 27.5 +/- 2, testosterone administration: 18 +/- 1.3 peaks/12h, P < 0.01) but did not affect pulsatile prolactin release. Using a 10 and 15 minute sampling protocol, we observed that prolactin pulse frequency significantly decreased (P < 0.01) and was similar to the frequencies estimated in previous reports. When luteinizing hormone and prolactin time series were studied to evaluate the possible presence of a specific concordance (SC) between the secretory events of the two hormones, no significant degree of concomitancy was observed neither using the specific concordance index or the cross-correlation analysis. CONCLUSONS This report demonstrates (a) the presence of frequent pulsatile release of prolactin in both controls and agonadal patients (baseline and on testosterone enanthate), (b) the use of an appropriate sampling interval (5 minutes) to unmask the prolactin pulsatile release, (c) that in men, luteinizing hormone secretory events are not temporally linked to prolactin secretion, and (d) that androgens, even if reducing luteinizing hormone pulse frequency in agonadal patients, do not significantly affect prolactin pulsatile secretion, suggesting that testosterone and its metabolites do not affect lactotroph activity.

1992 - Melatonin treatment delays reproductive aging of female rat via the opiatergic system. [Articolo su rivista]
Trentini, Gp; Genazzani, Ar; Criscuolo, M; Petraglia, F; De Gaetani, C; Ficarra, G; Bidzinska, B; Migaldi, Mario; Genazzani, Alessandro
abstract

In female rat age-related reproductive decline is accompanied by progressive impairment of the neuroendocrine mechanisms that regulate LH secretion. The biosynthetic activity of the pineal gland is markedly depressed and the nocturnal secretion of melatonin decreases significantly. The aim of the present study was to evaluate whether the nocturnal administration of melatonin via the drinking water (0.4 micrograms/ml) throughout the course of aging from 14 to 24 months of age could (1) influence the age-related changes that occur in basal serum levels of LH and in the LH response to GnRH or to naloxone stimulation at 16, 18 and 20 months of age, and (2) delay the onset of the postreproductive constant estrous-anovulatory state as evaluated by the daily recording of vaginal smears and by occurrence of polyfollicular ovaries at 24 months of age. Our results demonstrate that melatonin replacement delays the increase in LH serum levels and the decrease in LH response to GnRH that occur in 18-month-old control animals. Furthermore, they show that melatonin treatment prevents the loss of LH response to naloxone manifested in control rats between 16 and 20 months of age. Melatonin also appears to prevent the progressive increase in the monthly occurrence of estrus phases as well as to decrease the number of rats with polyfollicular ovaries at 24 months of age in comparison to control animals. These results suggest that the age-related decrease in circulating melatonin during the night may contribute to the reproductive decline of aging, and that this effect may involve the central opioid system.

1992 - PULSATILE SECRETION OF GONADOTROPINS AND PROLACTIN DURING THE FOLLICULAR AND LUTEAL PHASES OF THE MENSTRUAL-CYCLE - ANALYSIS OF INSTANTANEOUS SECRETION RATE AND SECRETORY CONCOMITANCE [Articolo su rivista]
Inaudi, P; Reymond, Mj; Rey, F; Genazzani, Alessandro; LEMARCHAND BERAUD, T.
abstract

Objective: To characterize the pulsatile secretions of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) during the menstrual cycle and to statistically evaluate their secretory concomitance. Design: Pulsatility study performed during the midfollicular and midluteal phases of a same menstrual cycle, blood samples being collected every 10 minutes for 6 hours. Setting: Participants investigated in the Division of Endocrinology, University Hospital. Participants: Nine healthy women (22 to 38 years) with regular menstrual cycles. Main Outcome Measures: Plasma LH, FSH, and PRL values were analyzed as raw and deconvoluted data, and the specific (nonrandom) secretory concomitance was evaluated statistically. Results: The pulsatile secretion of LH was confirmed, and that of FSH and PRL was clearly established during both phases of the cycle by characterization of peak frequency, period, and amplitude. A specific secretory concomitance was assessed between LH and FSH in the follicular but not the luteal phase, and a tight concomitance between LH and PRL was demonstrated during both phases. Conclusions: These results are supportive of significant pulsatile secretions of the three hormones during the menstrual cycle, and they are demonstrative of a definite copulsatility of these hormones, suggestive of common regulatory factors in the complex temporal patterns of gonadotropin and PRL secretions along the cycle.

1992 - The brain as a target organ of gonadal steroids. [Articolo su rivista]
Genazzani, Ar; Gastaldi, M; Bidzinska, B; Mercuri, N; Genazzani, Alessandro; Nappi, Re; Segre, A; Petraglia, F.
abstract

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1991 - Acetyl-l-carnitine as possible drug in the treatment of hypothalamic amenorrhea. [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Algeri, I; Gastaldi, M; Calvani, M; Botticelli, G; Genazzani, Ar
abstract

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1991 - Correlati endocrini della amenorrea ipotalamica [Articolo su rivista]
Genazzani, Alessandro; Botticelli, G; Petraglia, F; Gastaldi, M; Pianazzi, F; Prandi, B; Genazzani, Ar
abstract

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1991 - Cytokines in placental physiology. [Articolo su rivista]
Angioni, S; Botticelli, G; Galassi, Mc; Genazzani, Alessandro; Mancini, Ac; Amato, F; Petraglia, F; Genazzani, Ar
abstract

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1991 - Diagnosi endocrina dei disturbi riproduttivi nell'adolescente [Articolo su rivista]
Petraglia, F; Angioni, S; Tommaselli, G; Prandi, B; Amato, F; Botticelli, G; Genazzani, Alessandro; Mercuri, N; Segre, Alberto
abstract

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1991 - Hormonal pulsatile release and computerized techniques for pulse detection [Relazione in Atti di Convegno]
Genazzani, A. D.; Petraglia, F.; Benatti, R.; Angioni, S.; Amato, F.; Genazzani, A. R.
abstract

1991 - INHIBIN AND ACTIVIN MODULATE HUMAN MONOCYTE CHEMOTAXIS AND HUMAN LYMPHOCYTE INTERFERON-GAMMA PRODUCTION [Articolo su rivista]
Petraglia, F; Sacerdote, P; Cossarizza, Andrea; Angioni, S; Genazzani, Alessandro; Franceschi, C; Muscettola, M; Grasso, G.
abstract

Inhibin and activin are referred to as gonadal glycoprotein hormones whose function is the control of FSH release from the pituitary gland. However, several observations indicate that inhibin and activin are produced in various organs and serve multiple functions. Because bone marrow and spleen produce inhibin and activin, our aim was to evaluate their possible effect on cell-mediated immune function. For this reason we studied 1) monocyte chemotaxis, 2) lymphocyte interferon-gamma production, 3) phytohemagglutinin-induced lymphocyte proliferation, and 4) nonmajor histocompatibility complex-restricted and lymphokine-activated lymphocyte cytotoxicity. All studies were performed on human peripheral blood cells in the absence or presence of various doses of inhibin, activin, or inhibin plus activin. A significant dose-related increase in monocyte chemotaxis was induced by inhibin. Activin increased the migrational activity of monocytes, but via random, not directed, migration. Inhibin significantly decreased interferon-gamma production, and its effect was reversed by activin. Inhibin and/or activin had no significant effect on either phytohemagglutinin-induced lymphocyte proliferation or lymphocyte cytotoxic capability. The present demonstration that inhibin and activin may affect some immune parameters suggests a possible involvement of these hormones in regulating cell-mediated immune function.

1991 - Luteinizing hormone (LH) secretory burst duration is independent from LH, prolactin, or gonadal steroid plasma levels in amenorrheic women. [Articolo su rivista]
Genazzani, Alessandro; F., Petraglia; R., Benatti; Montanini, Vanna; I., Algeri; Volpe, Annibale; A. R., Genazzani
abstract

The possible presence of LH pulsatile secretion has been studied in patients with hypothalamic amenorrhea [LH plasma levels, less than 3 (n = 35) or greater than 3 IU/L (n = 18)], amenorrhea associated with hyperandrogenemia (n = 31), or hyperprolactinemia (n = 10). Patients were sampled every 10 min for 4 h, and LH plasma concentrations were determined by the use of an immunofluorimetric assay. The program Detect was used for both pulse detection and data deconvolution, i.e. for instantaneous secretory rate computation, on LH time series. The presence of episodic LH secretion was observed in all patients, and LH pulse frequency ranged between 3.5 +/- 0.3 and 3.8 +/- 0.2 peaks/4 h among the four groups. LH pulse amplitude was significantly reduced in patients affected by hypothalamic amenorrhea with LH plasma levels lower than 3 IU/L (0.7 +/- 0.1 IU/L; P less than 0.01) and significantly increased in patients with hyperandrogenic amenorrhea (6.8 +/- 0.3 IU/L; P less than 0.01) compared to levels in the other groups under study. Instantaneous secretory rate computation permitted the optimal resolution of the secretory events and demonstrated that the duration of gonadotrope secretory bursts ranged from 22.8 +/- 1.4 to 26.8 +/- 2.3 min in amenorrheic patients and did not depend on LH, PRL, or sex steroid plasma levels. In conclusion, the present study shows the presence of significant LH pulsatile release in amenorrheic patients, suggesting that in amenorrheic, as in normally cycling, women the secretory bursts from the gonadotropes have the same duration, despite the plasma LH, PRL, or steroid hormone levels.

1991 - Neuroendocrine Correlates of Stress‐Related Amenorrhea [Articolo su rivista]
Genazzani, A. R.; Petraglia, F.; De RAMUNDO, B. M.; Genazzani, A. D.; Amato, F.; Algeri, I.; Galassi, M. C.; Botticelli, G.; Bidzinska, B.
abstract

1991 - Neuroendocrine mechanisms regulating placental hormone production [Capitolo/Saggio]
Petraglia, F.; Angioni, S.; Coukos, G.; Uccelli, E.; Didomenica, P.; De Ramundo, B. M.; Genazzani, A. D.; Garuti, G. C.; Segre, A.
abstract

1991 - OBJECTIVE ASSESSMENT OF CONCORDANCE OF SECRETORY EVENTS IN 2 ENDOCRINE TIME-SERIES [Articolo su rivista]
Guardabasso, V; Genazzani, Alessandro; Veldhuis, Jd; Rodbard, D.
abstract

A new objective method is presented for investigating the presence of a temporal relationship between episodic release of two hormones. The two time series of hormone concentrations are first analysed by an objective method for peak detection. Both data series are then transformed into quantized or discretized series by recording the occurrence of a hormone pulse as an event, characterized by the onset, the maximum, or another unique feature. The two quantized series are then matched, and the number of concordant events and discordant events are counted. Each point in series A is compared with a time-window of a selected number of points in series B, to accommodate small degree of mismatch between events in the two series. An index of concordance is computed, compensating for any spurious random coincidence: the Specific Concordance, to evaluate the frequency of concordant events in excess of those expected on the basis of chance alone. This calculation is systematically repeated, interposing a range of time-lags between the two series. A graph of Specific Concordance versus time-lag indicates the time-lag corresponding to a maximal concordance. Simulations of random series of events are performed, and their degree of concordance is evaluated in a similar fashion, thus generating frequency distributions of Specific Concordance values under the null hypothesis of no temporal relationship. This permits the selection of criteria for statistical significance at any desired p-level, for one or many lag times, and for one or multiple subjects. Various degrees of concordance can also be simulated to evaluate the performance (sensitivity, statistical power) of this approach. These methods have been implemented as a collection of short microcomputer programmes, and applied to the study of the temporal relationship between beta-endorphin and cortisol in normal subjects sampled every 10 min for 24 h. This analysis demonstrated concordance between events in the two series, with synchronous occurrence of beta-endorphin and cortisol release events significantly more frequently than expected on the basis of random association (p < 0.01).

1991 - Prevalence of different types of human papillomavirus in cervical infections of North Italian women [Articolo su rivista]
Garuti, G; Boselli, F; Genazzani, Alessandro; Genazzani, Ar
abstract

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1991 - Reduced spinal bone density in young women with amenorrhea. [Articolo su rivista]
Fabbri, G; Petraglia, F; Segre, A; Maietta Latessa, A; Galassi, Mc; Cellini, M; Sardelli, S; Massolo, F; Genazzani, Alessandro; Genazzani, Ar
abstract

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1991 - Specific concordance index defines the physiological lag between LH and progesterone in women during the midluteal phase of the menstrual cycle. [Articolo su rivista]
Genazzani, Alessandro; Guardabasso, V; Petraglia, F; Genazzani, Ar
abstract

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1991 - The effect of varoius drugs with neuroendocrine activity and transdermal estradiol on plasma gonadotropin concentrations after ovariectomy in reproductive-aged women. [Articolo su rivista]
Nappi, C; Petraglia, F; De Chiara, Bm; Genazzani, Alessandro; Montemagno, R; Genazzani, Ar; Montemagno, U.
abstract

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1991 - Use of receiver operating characteristic curve to evaluate sensitivity, specificity, and accuracy of methods for detection of peaks in hormone time series. [Articolo su rivista]
Genazzani, Alessandro; Rodbard, D.
abstract

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1990 - Acetyl-L-Carnitine restores the daily pattern of hypothalamic beta-endorphin in rats exposed to continuous light [Articolo su rivista]
Genazzani, Ar; De Ramundo, Bm; Criscuolo, M; De Gaetani, C; Ficarra, G; Genazzani, Alessandro; Petraglia, F; Trentini, Gp
abstract

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1990 - Effect of steroid hormones and antihormones on hypothalamic beta-endorphin concentrations in intact and castrated female rats. [Articolo su rivista]
A. R., Genazzani; F., Petraglia; N., Mercuri; G., Brilli; Genazzani, Alessandro; M., Bergamaschi; B. M., Deramundo; Volpe, Annibale
abstract

The aim of the present study was to evaluate the effects of estrogens and androgens on hypothalamic beta-endorphin (beta-EP) concentrations. Intact or castrated female rats were chronically (2 weeks) treated with estrogen (estradiol benzoate) and/or antiestrogens (clomiphene, cyclophenil or epimestrol), and with androgens (dihydrotestosterone or dehydroepiandrosterone sulphate) and/or antiandrogen (cyproterone acetate). A group of rats treated with vehicle were studied as comparison. The beta-EP concentrations were measured by radioimmunoassay on acidic extracts of rat hypothalami. The administration of clomiphene and cyclophenil significantly reduced hypothalamic beta-EP concentrations in intact rats, while both drugs or estradiol benzoate increased the peptide concentration in castrated rats. Both intact and castrated rats treated with epimestrol showed hypothalamic beta-EP concentrations higher than vehicle treated rats. The estradiol-induced increase of beta-EP was not changed by the concomitant administration of antiestrogens. The administration of dihydrotestosterone significantly decreased beta-EP concentrations in both intact and castrated female rats, while the treatment with dehydroepiandrosterone sulphate only slightly decreased beta-EP levels in intact female rats. The cyproterone acetate-chronically treated rats showed higher beta-EP concentrations than vehicle-treated rats and these changes were reversed by the concomitant addition of dihydrotestosterone or dehydroepiandrosterone sulphate. These results showed that estrogens play a positive role while androgens negatively influence the hypothalamic beta-EP concentrations in female rats, supporting the view that central beta-EP might be a target of gonadal steroid feedback signals.

1990 - Effects of inhibition of norepinephrine synthesis on spontaneous and growth hormone-releasing hormone-induced GH secretion in cynomologus macaques: evidence for increased hypothalamic somatostatin tone. [Articolo su rivista]
Malozowski, S; Hao, E; Ren, Sg; Genazzani, Alessandro; Kalogeras, K; Merriam, G.
abstract

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1990 - Estimation of instantaneous secretory rate of luteinizing hormone in woman during the menstrual cycle and in man. [Articolo su rivista]
GENAZZANI, Alessandro; Rodbard, D; Forti, G; Petraglia, F; Baraghini, Gf; Genazzani, Ar
abstract

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1990 - Evidence of luteinizing hormone pulsatile secretion in hypothalamic amenorrhea associated with weight loss. [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Fabbri, G; Monzani, A; Montanini, V; Genazzani, Ar
abstract

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1990 - Interazioni tra l'asse ipotalamo-ipofisi-ovaio e l'asse ipotalamo-ipofisi-surrene. [Articolo su rivista]
Petraglia, F; Amato, F; De Ramundo, Bm; D'Ambrogio, G; Genazzani, Alessandro; Mercuri, N; Volpe, A; Genazzani, Ar
abstract

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1990 - Neuroendocrine correlates of premenstrual syndrome: changes in the pulsatile pattern of plasma LH. [Articolo su rivista]
Facchinetti, Fabio; Genazzani, Alessandro; E., Martignoni; L., Fioroni; G., Sances; A. R., Genazzani
abstract

Some studies suggest that patients suffering from premenstrual syndrome (PMS) may be affected by an endogenous opioid dysfunction. Since opioids are the main modulators of the pulsatile LH secretion, we evaluated plasma LH pulsatility in 13 patients with PMS (aged 33.1 yr) and in six asymptomatic control volunteers (aged 31.5 yr), in the late luteal phase (-7, -5 days before their next menses). The patients were prospectively evaluated for two menstrual cycles with the Menstrual Distress Questionnaire; the main symptoms which worsened during the premenstrual period were mood swings and water retention. The pulsatility of plasma LH secretion was studied by collecting blood samples every 10 min for 12 hr, starting at 0800h. The presence of LH pulses was estimated using the program DETECT on the raw data. This program also allows the computation of the instantaneous secretory rate (ISR). Ovulation was ascertained in all the controls and in nine PMS patients by means of urinary LH assay and luteal progesterone (P) determination. The remaining four patients did not ovulate. Both the ovulatory and the anovulatory PMS patients had an increased number of LH pulses/12 hr (10.3 +/- 2.4 and 11.5 +/- 4.4, mean +/- SD, respectively) in comparison with the controls (7.0 +/- 1.3 pulses, p less than 0.01), together with a reduced amplitude and duration. Similar findings were obtained with the ISR computation. Plasma P levels were similar in both the ovulatory patients and controls. The increased frequency and reduced amplitude of LH pulses in the PMS patients most likely reflect a dysfunction of hypothalamic Gn-RH release, possibly linked to a reduction of opioid inhibition.

1990 - Oppioidi ed attivazione puberale: regolazione della funzione surrenalica e riproduttiva e della secrezione gonadotropinica. Ginecologia dell'Infanzia e dell'adolescenza [Articolo su rivista]
Genazzani, Alessandro; Petraglia, F; Angioni, S; Amato, F; Genazzani, Ar
abstract

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1990 - PLASMA ß-ENDORPHIN AND ß-LIPOTROPIN LEVELS INCREASE IN WELL TRAINED ATHLETES AFTER COMPETITION AND NON COMPETITIVE EXERCISE. [Articolo su rivista]
Petraglia, F; Bacchi Modena, A; Comitini, G; Scazzina, D; Facchinetti, Fabio; Fiaschetti, D; Genazzani, Alessandro; Barletta, C; Scavo, D; Genazzani, Ar
abstract

Plasma beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) levels were measured in 15 healthy trained marathon runners. These hormones were evaluated in two different conditions: 1-before (1h) and after a marathon race (n = 10); 2-before, during and after a prolonged (90 min) submaximal exercise (bicycle ergometer at 50% VO2 max) (n = 5). In these latter group plasma beta-EP and beta-LPH levels were measured every 15 min for 165 min. In all the athletes, both plasma beta-EP and beta-LPH levels were significantly higher after the end of the marathon race than in basal conditions (p less than 0.01). The prolonged exercise with bicycle ergometer significantly stimulated plasma beta-EP and beta-LPH levels. Starting 60 min after the beginning of the exercise, plasma beta-EP and beta-LPH levels resulted significantly higher than basal values until the end of the exercise (p less than 0.01 at 60, 75 and 90 min). These data confirming that marathon running is a potent stress stimulus, showed that the duration and related factors but not the work load may be considered critical in stimulating beta-EP and beta-LPH release during physical exercise

1990 - Progestins modulate the action of estrogen on gonadotropin-releasing hormone, luteinizing hormone and prolactin in the rat. [Articolo su rivista]
A. R., Genazzani; F., Petraglia; M., Silferi; A. M., Lattesa; G., Coukos; Genazzani, Alessandro; P., Artini; C., Nappi; Volpe, Annibale
abstract

The aim of the present study was to evaluate the effect of progesterone and of various synthetic progestins on hypothalamic gonadotropin-releasing hormone (GnRH) and on pituitary and plasma LH and prolactin (Prl) concentrations in ovariectomized rats. Groups of 6 rats were treated for 2 weeks with a pharmacological dose of progesterone, desogestrel, medroxyprogesterone acetate or norethisterone enanthate (NET). The same treatment was also repeated in association with estradiol benzoate (EB). Groups of ovariectomized rats were also treated with EB only or vehicle. Ovariectomized rats showed hypothalamic concentrations of GnRH significantly higher than control rats. Progesterone and NET significantly increased GnRH concentrations and reversed the EB-induced changes. Rats treated with progesterone and NET also showed reduced pituitary LH concentration, with high plasma LH levels. All progestins blocked the increase of pituitary LH induced by EB, but were inactive in influencing the inhibitory effect of EB on plasma LH levels. The administration of progesterone and progestins did not induce significant changes of pituitary or plasma Prl, but reversed the EB-induced increase. These results showed that progesterone and progestins have a marked effect on hypothalamic and pituitary hormone secretion and that they modulate estrogen-induced effects.

1990 - Pulsatile secretion of LH in agonadal men before and during testosterone replacement therapy [Articolo su rivista]
Genazzani, Alessandro; Forti, G; Maggi, M; Milloni, M; Cianfanelli, F; Guardabasso, V; Toscano, V; Serio, M; Rodbard, D.
abstract

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1990 - Vasopressin receptors in human seminal vesicles: identification, pharmacologic characterization, and comparison with the vasopressin receptors present in the human kidney. [Articolo su rivista]
Maggi, M; Baldi, E; Genazzani, Alessandro; Giannini, S; Natali, A; Costantini, A; Rodbard, D; Serio, M.
abstract

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1989 - Aging modifies the hormonal responses in women. [Articolo su rivista]
Fabbri, G; Petraglia, F; Stacca, R; Benatti, L; Monzani, A; Montanini, V; Genazzani, Alessandro; Alessandrini, G; Genazzani, Ar
abstract

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1988 - Detection of Chlamydia trachomatis in cytological samples by a biotinylated DNA probe test [Articolo su rivista]
Garuti, G.; Boselli, F.; Genazzani, A.; Comanducci, M.; Silvestri, S.; Ratti, G.
abstract

An in situ DNA hybridization test which uses a Chlamydia trachomatis (CT) specific plasmid was employed to detect CT infection on cytological samples obtained from 160 patients. Eighteen (11.3%) samples were positive, and the subjects could be considered infected by CT. The tested procedure appears to be simple and rapid, and suitable for routine clinical application.

1988 - Similarity of vasopressin receptors in seminal vesicles and renal medulla of pigs. [Articolo su rivista]
Maggi, M; De Rossi, M; Amenta, F; Genazzani, Alessandro; Rodbard, D; Serio, M.
abstract

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1988 - Vasopressin and oxitocin receptors in vagina, myometrium, and oviduct of rabbits [Articolo su rivista]
Maggi, M; Genazzani, Alessandro; Giannini, S; Torrisi, C; Baldi, E; Di Tomasso, M; Munson, Pj; Rodbard, D; Serio, M.
abstract

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1987 - Effects of Org OD 14 on pituitary and peripheral beta-endorphin in castrated rats and post-menopausal women. [Articolo su rivista]
A. R., Genazzani; F., Petraglia; Facchinetti, Fabio; Genazzani, Alessandro; M., Bergamaschi; A., Grasso; Volpe, Annibale
abstract

The aim of the first part of this study was to evaluate the effects of a new synthetic steroid (7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14), on anterior pituitary (AP) and neurointermediate pituitary lobe (NIL) contents and on circulating levels of beta-endorphin (beta-EP) in rats. Three weeks after ovariectomy, groups of 9 rats were treated with either Org OD 14 (2 or 10 micrograms/day/rat for 14 days) or a placebo. In addition, 2 groups of ovariectomized rats were also treated with oestradiol benzoate (EB) (2 or 10 micrograms/day/rat for 14 days) to compare the effectiveness of the new steroid with that of a classical oestrogenic substance. beta-Ep concentrations were measured in plasma and in AP and NIL extracts by means of double-antibody radioimmunoassay (RIA), employing a specific anti-camel beta-EP (C-terminal fragment). Both doses of Org OD 14 induced a significant dose-related increase in plasma and pituitary lobe beta-EP concentrations as compared with the results on placebo treatment. By comparison, EB was active only at a dose of 10 micrograms/day. Despite the common stimulatory effects of EB and Org OD 14 on pituitary beta-EP, these findings suggest that the two steroids have different modes of action. The second part of the study investigated the changes in beta-EP and beta-lipotrophin (beta-LPH) plasma levels in a group of post-menopausal women treated for 6 months with Org OD 14 (2.5 mg/day) in comparison with the levels in a placebo-treated group. The clinical efficacy of Org OD 14 treatment in post-menopausal symptoms was confirmed, as well as its lack of or only transient effect on plasma lipids and lipoproteins. beta-EP and beta-LPH plasma levels were significantly higher in the Org OD 14-treated group than in the placebo group as from the second month until the end of the observation period.

1987 - Naloxone administration does not affect gonadotropin secretion in patients with Klinefelter's syndrome. [Articolo su rivista]
Forti, G; De Feo, Ml; Maggi, M; Genazzani, Alessandro; Fazzi, V; Delitala, G.
abstract

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1987 - Progesterone and progestins modulate beta-endorphin concentrations in the hypothalamus and in the pituitary of castrated female rats. [Articolo su rivista]
A. R., Genazzani; F., Petraglia; M., Bergamaschi; Genazzani, Alessandro; Facchinetti, Fabio; Volpe, Annibale
abstract

Hypothalamic and pituitary beta-endorphin (B-EP) concentrations are modified by ovariectomy and estrogen treatments, supporting a direct interaction between this peptidergic system and gonadal steroids. Because the use of progestins is becoming even more diffuse in clinical practice, we evaluated the effect of progesterone and of the synthetic progestins medroxyprogesterone acetate (MPA), norethisterone acetate (NET) and desogestrel on the concentration of B-EP in the medial-basal hypothalamus and the anterior and neurointermediate pituitary lobes in ovariectomized rats (OVX), treated or untreated with estradiol benzoate (EB). B-EP concentrations were significantly increased by desogestrel in the anterior lobe and by progesterone, desogestrel and medroxyprogesterone acetate in the neurointermediate lobe. Progesterone and progestins significantly reduced B-EP increase induced by estradiol benzoate in the anterior lobe. Estradiol benzoate treatment did not modify the effect of progesterone and desogestrel on B-EP in the neuro-intermediate pituitary lobe. Norethisterone acetate and progesterone increased B-EP concentrations in the medial-basal hypothalamus, while the other steroids were inactive. In contrast, in the hypothalamus all progestins attenuated the increase of B-EP induced by estradiol benzoate (p less than 0.01). These data indicate that progesterone and progestins modulate the hypothalamic and pituitary B-EP concentrations in concert with estrogens. The capacity of progestins to modify the hypothalamic contents of B-EP may represent one of the mechanisms of action of these steroids in influencing brain function.

1987 - Seminal fluid androgen levels in infertile patients. [Articolo su rivista]
Facchinetti, Fabio; G., Comitini; Genazzani, Alessandro; C., Bakalakis; A. R., Genazzani; S., Loche
abstract

Seminal fluid concentrations of testosterone (T), dihydrotestosterone (DHT), androstenedione (A), and 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) were measured in 34 male patients of infertile couples. Patients were subdivided into oligospermic (less than 20 X 10(6)/mL) and asthenospermic (typical motility less than 20\%; total motility less than 40\%) groups. Steroids were measured by specific radioimmunoassay after ether extraction and celite column chromatography. 3 alpha-Diol was present in seminal fluid, and its concentration was significantly correlated with DHT (r = .49, P less than .05). In oligospermic patients, seminal levels of T (78 +/- 29 pg/mL, mean +/- SD) and DHT (323 +/- 132 pg/mL) were significantly reduced in comparison with normospermic men (T, 119 +/- 56, P less than .05; DHT, 557 +/- 255, P less than .01), while A and 3 alpha-diol concentrations were similar in the two groups. Seminal T and DHT levels were also reduced in asthenospermic specimens, which showed increased 3 alpha-diol concentrations (75 +/- 44 pg/mL) with respect to normokinetic samples (45 +/- 20, P less than .05). Finally, a positive linear relationship was observed between DHT and both sperm density (P less than .01) and total motility (P less than .01). These data demonstrate the existence of a significant amount of 3 alpha-diol in seminal plasma and suggest DHT as the androgen most closely related to sperm quality.

1986 - Naloxone administration does not affect gonadotropin secretion in agonadal men either basally or during testosterone treatment. [Articolo su rivista]
M. L., De; M., Maggi; V., Guardabasso; D., Rodbard; G., Delitala; V., Fazzi; Genazzani, Alessandro; Facchinetti, Fabio; G., Forti
abstract

Naloxone administration has no effect on plasma gonadotropin levels of agonadal men. The present study was designed to evaluate whether testosterone replacement therapy could restore LH responsiveness to naloxone in such men. We measured plasma LH and FSH levels at 15-min intervals during naloxone infusion (8 mg in 1 min followed by 12 mg in 3 h) and for the following 3 h in a group of agonadal men both before and after at least 2 months of three different schedules of testosterone replacement therapy: 1) testosterone undecanoate, 40 mg three times a day by mouth; 2) testosterone enanthate 200 mg im every 2 weeks; and 3) testosterone enanthate 100 mg im once a week. Mean plasma gonadotropin levels as well as LH pulse frequency did not vary during naloxone infusion vs. placebo either basally or during each testosterone regimen. These results suggest that long term testosterone therapy does not affect the altered opioid modulation of gonadotropin secretion which is present in agonadal men.