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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.

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 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.

Although the polycystic ovary syndrome (PCOS) is clinically defined by the presence of at least 2 out of 3 Rotterdam Consensus Conference criteria (i.e. hyperandrogenemia, oligo/amenorrhea, polycys...

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.

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.

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

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.

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.

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).Controlled clinical study on patients with FHA (n = 12) in a clinical research environment.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.Measurements of plasma LH, FSH, prolactin, estradiol, androstenedione, 17α-hydroxyprogesterone, insulin, cortisol, thyroid-stimulating hormone, free triiodothyronine, and free thyroxine.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.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.

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) 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.

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.摘要 围绝经期的妇女会出现一系列症状, 这些症状会干扰身体, 性生活和社交。绝经期间约65-75％的症状是血管舒缩症状（VMS）, 如潮热和盗汗。潮热是与皮肤血管舒张和核心温度下降相关的主观热感。VMS被怀疑与促性腺激素释放激素（GnRH）脉冲式释放过多和随后的黄体生成素（LH）分泌密切相关。同时研究显示, 卵巢中合成的类固醇激素缺乏负反馈导致位于漏斗核中的肥大Kisspeptin /神经激肽B /强啡肽（KNDy）神经元过度活化。 Kisspeptin（KISS1）和神经激肽B（NKB）的过度分泌以及强啡肽的下调在GnRH脉冲的产生中起主导作用, 反之导致VMS的发生。给予NK3受体特异性激动剂, 高效选择性NK3R激动剂导致绝经后妇女血清LH浓度增加, 诱导VMS发生, 心率增加和皮肤温度升高。这些发现表明, 对KNDy神经元的调节可能成为治疗VMS的新方法。.

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.

This paper provides a critical review of the data concerning the effects of combined hormonal contraceptives (CHC) for polycystic ovary syndrome (PCOS). The aim is to determine the best treatment option for each PCOS phenotype.A literature search of the PubMed database was conducted for randomized clinical trials (RCTs) and observational studies published in any language prior to October 2013. Hyperandrogenism (HA) is the essential diagnostic criterion for PCOS and is frequently associated with insulin resistance (IR) or obesity. The combinations of these criteria define the different PCOS phenotypes and establish the scale of metabolic and cardiovascular risks.19 RCTs and eight observational studies evaluated issues related to the current objectives. CHC represent an effective and safe treatment in women with any PCOS phenotype. In HA/PCOS patients, any CHC analyzed in this review can be used for symptom relief. For patients with metabolic risk, overweight or moderate IR that does not require metformin, a vaginal contraceptive ring appears to be preferred to oral EE/DRP. In these patients, the combination of CHC and myo-inositol may be more effective in controlling endocrine and metabolic profiles. However, further research is needed to define the optimal duration and to clarify the effects of treatment on long-term metabolic outcomes. Future research should also focus on new CHC.

A case report of a patient diagnosed with Camurati-Engelmann Disease (CED) in association with the functional hypothalamic amenorrhea disturbances. CED is a very rare genetically determined disorder classified as a type of bone dysplasia.Case report.Department of Gynecological Endocrinology, 3rd grade Medical University Hospital.Twenty-one years old female patient with CED admitted to the hospital because of primary amenorrhea. Her history revealed skeletal deformities and hearing impairment.Clinical examination, ultrasound, laboratory evaluations (including serum gonadotropins (FSH, LH) at basal state and after stimulation with gonadotropin-releasing hormone, serum basal estradiol) radiological studies (X-ray of the head, the lumbar spine and lower extremities; a computed tomography of the head), G-banding karyotype, polymerase chain reaction and DNA sequencing. Hormonal serum evaluations were made using an enzyme-linked immunosorbent assay. The exon 4 of the transforming growth factor beta 1 gene was amplified by a polymerase chain reaction and the product was directly sequenced.The hormonal analysis was characteristic for the hypogonadotropic hypogonadism. Radiological and molecular analyses confirmed CED diagnosis.The hypothalamic amenorrhea in a patient with CED may be explained as a consequence of fat hypotrophy and very low body mass index. Therefore, impairment within hypothalamic-pituitary axis in patients with CED should be treated with special attention.

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.

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 µU/ml and Group B (n = 27) insulin above 12 µU/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 µU/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.

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 50g transdermal estradiol plus 100 mg/day oral micronized progesterone in a group of 20 healthy postmenopausal women (age = 50–58 and years since menopause (ysm) = 1–6) and also the effects observed by combining these two therapies in a group of 12 postmenopausal women (age = 54–61 and ysm = 6–10) characterized by lower baseline DHEA and DHEAS levels (

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a mediator of neuronal plasticity and influences learning, memory and cognitive behaviour. The aim of this study is to assess plasma BDNF variations according to hormonal status. METHODS: A total of 60 subjects were included: 20 fertile ovulatory women, 15 amenorrhoeic women and 25 postmenopausal women. Blood samples were collected after overnight fasting. For 5 out of the 20 fertile 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 after 6 months of treatment. Plasma BDNF concentrations were measured by enzyme-linked immunosorbent assay. In fertile 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 increased from early follicular phase up to Day 14 of the cycle, reaching a pre-ovulatory peak, similar to E2. A second rise took place 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 correlated with E2 and progesterone and negatively correlated with menopausal age. HRT restored BDNF levels to those present in fertile women during the follicular phase. CONCLUSIONS: Plasma BDNF levels are influenced by hormonal status. Modifications in BDNF circulating levels during the menstrual cycle suggest a potential role for gonadal sex hormones (E2 and progesterone) in regulating neurotrophin expression.

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 age-related disturbances have been reported to begin with the decline of DHEA/DHEAS levels, this provides a potential opportunity for use of DHEA as replacement therapy. 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 of such 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 recent studies suggesting that DHEA appears to be beneficial in hypoandrogenic men as well as in postmenopausal and aging women. Menopause is the event in a woman'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 with adrenal 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 is considered 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.

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.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.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.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.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.

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, E 2 , 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.

Hypothalamic amenorrhea (HA) is a secondary amenorrhea with no evidence of endocrine/systemic causal factors, 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 stress 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 exclude any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stress 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 article tries to give insights into diagnosis and putative therapeutic strategies.

Polycystic ovary syndrome (PCOS) is a common endocrine disease that is observed frequently to be related to increased insulin resistance. The use of insulin-sensitizer compounds, such as metformin, permits great improvement of such metabolic abnormality and the restoration of normal ovarian function. Metformin administration reduces insulin resistance and androgen production both from the ovary and adrenal gland.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 per os twice daily) to better understand what changes might be induced by metformin on adrenal and ovarian function and in terms of temporal coupling of the pulsatile profiles of luteinizing hormone (LH), cortisol and allopregnanolone, the latter representative of the neurosteroid family.A group of non-obese PCOS patients (n = 8) was enrolled after informed consent and underwent to a pulsatility study for LH, cortisol and allopregnanolone, and an oral glucose tolerance test before and on day 7 of the first menstrual cycle occurring after the 5th month of treatment.Plasma androgen levels were decreased significantly by metformin treatment, as were plasma LH and allopregnanolone levels and insulin resistance. Metformin administration decreased LH pulse amplitude but not pulse frequency. On the contrary, cortisol and allopregnanolone showed a significant change in pulse frequency. When temporal coupling was tested between pulsatile profiles of LH or cortisol with allopregnanolone, cortisol pulses were temporally coupled to allopreganolone peaks both before and under metformin administration while LH pulses were temporally coupled to allopreganolone secretory peaks only under metformin treatment.Our data demonstrate that metformin administration modulates LH secretion as well as cortisol and allopregnanolone pulsatile release. In addition, the results demonstrate that adrenal and ovarian steroidogenic activity is greatly modulated by any change in insulin sensitivity.

The aim of the present study was to evaluate, in healthy postmenopausal women, the impact of tibolone (2.5 mg), transdermal estradiol (50 microg) (TE) and different oral estrogen-progestin regimens, conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (5 mg) (CEE + MPA) and estradiol (2 mg) plus norethisterone acetate (1 mg) (E2 + NETA) on circulating estradiol, progesterone, allopregnanolone, cortisol and dehydroepiandrosterone (DHEA) levels. Blood samples were collected before and after 1, 3, 6 and 9 months of treatment in 85 postmenopausal women. Estradiol levels increased (p < 0.001) in the TE, CEE + MPA and E2 + NETA groups after 1 month of therapy, but did not change in the tibolone group during the entire follow-up period. Both E2 + NETA and tibolone treatments induced an increase in progesterone levels (p < 0.05) after 1 year of therapy. Allopregnanolone levels showed an increase in all estrogen-based groups, being significant after 3 months of treatment (p < 0.01). Patients receiving tibolone showed a significant increase in allopregnanolone levels at 3 months (p < 0.05), but lower than in the other groups. Cortisol levels decreased significantly in the TE and CEE + MPA groups after 6 months and 12 months of treatment, respectively. Neither tibolone nor E2 + NETA treatments modified circulating cortisol levels. DHEA levels significantly (p < 0.05) decreased after 6 months of TE or estrogen-progestin therapies independently of the presence or the type of progestin used. In contrast, DHEA remained stable throughout the 12 months of treatment with tibolone. The increase of allopregnanolone, a steroid with sedative and anxiolytic properties, in response to these different treatments could underlie, at least in part, the central effects that hormone replacement therapy and tibolone have on anxiety, mood and behavior. Unlike estrogen-based therapy, tibolone treatment did not reduce the DHEA milieu in the menopause, and thus did not enhance the androgen deficiency syndrome in postmenopausal women.

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.

Objectives: 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 β-endorphin (β-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 β-EP and allopregnanolone levels in ovariectomized (OVX) female rats. Methods: Twelve groups of Wistar OVX rats received oral EV (0.05, 0.1, 0.5 and 1 mg/Kg/day) or ES (0.1, 0.5, 1 and 2 mg/Kg/day), or CEE (0.1, 0.5, 1 and 2 mg/Kg/day) for 14 days. One group of fertile and one group of OVX rats were used as controls. β-EP content was assessed in hypothalamus, hippocampus, anterior and neurointermediate pituitary, and plasma, while allopregnanolone content was assessed in hypothalamus, hippocampus, anterior pituitary, adrenals and serum. Results: Ovariectomy induced a significant decrease in β-EP and allopregnanolone content in hypothalamus, hippocampus, pituitary, and serum, while it increased allopregnanolone content in the adrenals. In OVX rats, the administration of each molecule reversed the ovariectomy-induced β-EP and allopregnanolone changes in a dose-dependent fashion, therefore completely restoring their concentration. At higher doses, the estrogenic compounds induced significantly higher levels of allopregnanolone and β-EP than in fertile rats. CEE induced higher allopregnanolone levels in hypothalamus, anterior pituitary and serum than the other estrogenic molecules, and in the hippocampus with respect to EV alone. CEE produced higher β-EP levels in the hippocampus and hypothalamus with respect to EV and ES. Conclusion : In the examined tissue and serum estrogens restore the ovariectomy induced changes in allopregnanolone and β-EP content in a dose-dependent manner; the magnitude of these effects is not uniform and it is related to the different tissues and the employed compounds.

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.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.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.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.Myo-inositol treatment ameliorates insulin resistance and body weight, and improves ovarian activity in PCOS patients.

Objective: To evaluate the effects of dehydroepiandrosterone (DHEA) supplementation on the growth hormone-releasing hormone–growth hormone (GHRH-GH) axis in lean and obese postmenopausal women. Design: Prospective study. Setting: Postmenopausal women in a clinical research environment. Patient(s): Thirty-one postmenopausal women were divided in two groups by age (50 to 55 and 60 to 65 years). Within each group, lean and obese patients were considered. Intervention(s): All patients underwent hormonal evaluations before and at the third and sixth month of therapy (50 mg of DHEA orally each day) and a GHRH test (1 μg/kg) before and at the sixth month of treatment. Ultrasound and bone mass density (BMD) examinations were performed before and after the sixth month of therapy. Main Outcome Measure(s): Plasma dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), E 1 , E 2 , androstenedione (A), testosterone (T), osteocalcin, GH, insulin-like growth factor 1 (IGF-1) concentrations. Result(s): The levels of all of the steroids that derived from DHEA metabolism (E 1 , E 2 , A, T, DHEAS) and osteocalcin were increased in plasma under DHEA supplementation. The supplementation protocol also increased the levels of GH and IGF-1. However, GHRH-induced GH and IGF-1 responses were not modified by DHEA supplementation. Conclusion(s): Administration of DHEA significantly affects several endocrine parameters in early and late postmenopausal women independently from body mass index. Our data support the hypothesis that DHEA treatment acts similarly to estrogen-progestin replacement therapy on the GHRH-GH-IGF-1 axis. This suggests that DHEA is more than a more than a simple "diet supplement" or "antiaging product"; rather it should be considered an effective hormonal replacement treatment.

Polycystic ovary syndrome (PCOS) is a common endocrine condition that affects fertility through oligo-ovulation, hyperandrogenism and polycystic morphology of the ovaries. Since it has been demonstrated a high incidence of insulin resistance in PCOS patients, our study aimed to evaluate the efficacy of the integrative treatment with D-chiro-inositol (DCI) (500 mg die, per os, for 12 weeks) on hormonal parameters and insulin sensitivity in a group of overweight/obese PCOS patients (body mass index; BMI 26). After the treatment, interval several endocrine parameters improved (luteinizing hormone [LH], LH/follicle stimulating hormone [FSH], androstenedione and insulin), insulin response to oral glucose tolerance test reported the significant improvement of insulin sensitivity as well as the gonadotropin-releasing hormone (GnRH)-induced (10 µg, in bolus) LH response. BMI decreased, though no lifestyle modification was requested. When data were analyzed according to the presence or absence of first-grade diabetic relatives, PCOS patients with diabetic relatives showed greater improvement after DCI administration. In conclusion DCI administration is effective in restoring better insulin sensitivity and an improved hormonal pattern in obese hyperinsulinemic PCOS patients, in particular, in hyperinsulinemic PCOS patients who have diabetic relatives.

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 μg) (Dermestrill, Rottapharm, Monza, Italy) biweekly; (2) treated with transdermal estradiol (100 μg) (Dermestrill, Rottapharm, Monza, Italy) biweekly; (3) treated with tibolone 2.5 mg/day (Livial, Organon Italia, Rome, Italy). Patients underwent a GH-RH test (1 μg/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.

The steroidogenic endocrine glands and local synthesis both contribute to the pool of steroids present in the central nervous system and peripheral nervous system. Although the synthesis of neurosteroids in the nervous system is now well established, the spectrum of respective functions in regulating neuronal and glial functions remains to be fully elucidated. From the concept of neurosteroids derives another treatment strategy: the use of pharmaceutical agents that increase the synthesis of endogenous neurosteroids within the nervous system. This approach has so far been hampered by lack of knowledge concerning the regulation of the biosynthetic pathways of neurosteroids and their relationship with sex steroids produced by the peripheral gland or with exogenous steroids. The present review summarizes some of the available clinical and experimental findings supporting the critical role of neurosteroids during fertile life and reproductive aging and their relationship with endogenous and exogenous sex steroids. The brain metabolism of synthetic progestins and the implications of DHEA treatment in postmenopausal women will also be discussed.

Objective To evaluate the GH-releasing hormone (GH-RH)-induced response of GH in patients affected by hypothalamic amenorrhea. Design Patients affected by weight-loss-related hypothalamic amenorrhea (n=28) were studied and compared with 20 healthy controls. Among patients with weight-loss amenorrhea, both hypogonadotropic and normogonadotropic conditions were present. All subjects underwent a GH-RH test (GEREF, Serono, Rome, Italy) (1 μ g/kg body weight IV). Plasma GH concentrations were determined using commercially available RIAs. Also, in selected samples insulinlike growth factor-I (IGF-I) levels were measured. Results Basal plasma IGF-I levels as well as body mass index (BMI) were lower in amenorrheic patients than in healthy controls. No significant correlation was found between BMI and IGF-I or E 2 plasma levels or between LH and IGF-I plasma levels. The basal GH plasma levels were comparable in all groups of subjects. The GH-RH-induced GH response evaluated as maximal release and as area under the curve (AUC) was higher in amenorrheic patients than in control subjects. Conclusions The amenorrheic condition associated with reduced BMI changes the GH-RH–induced GH response in hypothalamic amenorrhea, supporting a GH and a IGF-I disregulation in weight-loss–related amenorrhea.

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 17β-estradiol (E(2)) on PAI-1 expression and its role on endothelial migration. At physiological concentrations, E(2) increases the expression of PAI-1 in HUVEC within 6-12 h through activation of a signaling cascade initiated by estrogen receptor α 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 E(2)-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, E(2) increases PAI-1 synthesis in human endothelial cells and in rodent aorta through a G protein-initiated signaling that targets early-immediate 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.

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-α-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-κB. In addition, DG and DHD do not alter the anti-inflammatory effects of 17β-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.

Postmenopausal hormone therapy is associated with increased incidence of breast cancer. For this reason alternative therapeutic 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 of studies. Due to their partial selectivity of action on estrogen receptors (ERs) these compounds have been claimed to be safer on the breast. In this article, we explored the action of RCE on motility and invasion of ER positive breast cancer cells and we partially characterized the signaling mechanisms. The principal isoflavones contained in RCE acted as weak estrogenic compounds when administered alone. However, when provided in association with physiological amounts of estradiol, RCE acted as estrogen antagonist on remodeling of actin cytoskeleton that are requested to enact cell movement and with related modifications of the activity of actin-binding proteins, such as moesin. These results offer novel information on the molecular actions of isoflavones contained in red clover on breast cancer cells, supporting a possible action of these molecules as natural selective estrogen receptor modulators in the presence of physiological amounts of estrogens.

SUMMARY 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. Reproductive Biology 2011 11 3:284-293.

Objective To evaluate the influence of estriol administration on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by 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 μg 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 (E 2 ), androstenedione (A), 17α-hydroxyprogesterone (17-OHP), cortisol, androstenedione (A), testosterone (T), thyroid-stimulating hormone (TSH), free triiodothyronine (fT 3 ), free thyroxine (fT 4 ), and insulin, and pulse detection. Result(s) After treatment, the FHA patients showed a statistically significant increase of LH plasma levels (from 0.7 ± 0.1 mIU/mL to 3.5 ± 0.3 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 was a statistically significant increase. Conclusion(s) Estriol administration induced the increase of LH plasma levels in FHA and improved GnRH-induced LH secretion. These findings suggest that estriol administration modulates the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of LH synthesis and secretion in hypogonadotropic patients with FHA.

Endothelial dysfunction frequently ensues during the climacteric due to hormonal and metabolic changes. Non-pharmacological interventions such as lifestyle and dietary modifications are emerging as valuable strategies to counteract the cardiovascular consequences of ageing. A number of chemical components of wine, including alcohol and some polyphenols, are known to be active on the vessels. However, the molecular mechanisms through which they modulate endothelial function are largely unclear. The aim of this study was to investigate the effects of non-alcoholic wine fractions from five different wines on the synthesis of nitric oxide (NO) via the expression and enzymatic activation of the endothelial nitric oxide synthase (eNOS) in human endothelial cells. All non-alcoholic fractions studied increased NO synthesis, although with different potencies. All wine extracts maximally enhanced NO production at doses in the range achieved with a moderate wine intake, with decreasing effects with further increases of the dose. Interestingly, a part of these actions was recruited via estrogen receptors (ERs). Within the polyphenols with known binding activity for ERs contained in the tested wines, resveratrol, epicatechin, syringic acid, apigenin, malvidin and ellagic acid were largely responsible for eNOS activation. These findings show that some of the non-alcoholic components of wine enhance the production of NO by the vessels acting on ERs, and suggest that a moderate intake of wine may benefit the cardiovascular system through estrogen-like effects.

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; P0.02) and a reduced amplitude of secretory episodes (126.5 +/- 61.6% vs. 187.1 +/- 126.7%; P0.03) 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.

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.

Androstenedione secretory characteristics and its possible temporal correlation with luteinizing hormone (LH) and/or cortisol, intended as the markers of, respectively, ovarian stimulation and adrenal secretion, were evaluated in 24 patients affected by clinical hyperandrogenism. A pulsatility test was carried out for 8 h, with sampling every 10 min, and LH, cortisol and androstenedione profiles were determined by radioimmunoassay. Time series were analyzed with the computer program DETECT and with a program for specific concordance estimation. A distinct episodic release of LH, cortisol and androstenedione was observed in all patients (6.9 +/- 0.8, 5.2 +/- 0.6 and 5.5 +/- 1 peaks/8 h, respectively). When specific concordance was tested between LH and androstenedione, and between cortisol and androstenedione, two distinct groups of patients could be identified. Group A (n = 13) showed a significant specific concordance (SC) index only for LH and androstenedione while group B (n = 11) showed a significant SC also for cortisol and androstenedione, thus demonstrating a consistent adrenal participation in the androstenedione secretion in these patients. In addition, specific differences were observed on androstenedione secretory profiles of group B which showed a significant (p0.05) decrease of androstenedione plasma concentrations emulating cortisol behavior. No such observation was noted in group A, whose androstenedione plasma levels did not show any reduction. In conclusion, our data support the use of circulating androstenedione, LH and cortisol plasma levels and copulsatile assessment to distinguish the presence of two populations of hyperandrogenic patients: one whose hyperandrostenedionemia is mainly due to ovarian secretion (group A) and one which showed a hyperactivation of the adrenal gland (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective. To investigate the adrenal response in terms of allopregnanolone secretion in a group of hyperinsulinemic patients with polycystic ovary syndrome (PCOS). Design. Controlled clinical study. Setting. Patients with PCOS in a clinical research environment. Patients. Twenty-two overweight patients with PCOS with hyperinsulinism were enrolled after informed consent. Interventions. All patients underwent hormonal evaluations, oral glucose tolerance test (OGTT) and adrenocorticotropic hormone (ACTH) test before and after 4 months of metformin administration (500 mg p.o. bi-daily). Ultrasound examinations and Ferriman-Gallway score were also performed. Main outcome measures. plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol, 17-hydroxy-progesterone (17OHP), androstenedione (A), testosterone (T), allopregnanolone, glucose, insulin, C peptide concentrations, body mass index (BMI). Results. Metformin administration reduced significantly LH, A, T, insulin and BMI, while allopregnanolone was significantly increased with no change in progesterone plasma levels. Insulin response to OGTT decreased and allopregnanolone response to ACTH stimulation before while this was restored after the treatment interval. The Ferriman-Gallway score as well as the ovarian volume was significantly decreased after 4 months of metformin therapy. Conclusions. In overweight patients with PCOS with hyperinsulinism, allopregnanolone secretion is impaired and metformin administration restored normal allopregnanolone concentrations modulating both steroid syntheses from the ovaries and from adrenal gland.

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.

Metformin is quite an old drug, but it is optimal for the control of glycemia in Type 2 diabetes. It was reported, 15 years ago, that insulin resistance was abnormally high in most polycystic ovary syndrome (PCOS) patients. Starting from that moment, increasing numbers of studies were performed to demonstrate the efficacy of metformin in controlling and/or modulating several aspects of PCOS, which is the most common cause of menstrual irregularity, inesthetisms and infertility. Metformin induces higher glucose uptake, thus inducing a lower synthesis/secretion of insulin. Such an effect permits the possible restoration of the normal biological functions that are severely affected by the compensatory hyperinsulinemia reactive to the increased peripheral insulin resistance. These are the basis of the many positive effects of this drug, such as the restoration of menstrual cyclicity, ovulatory cycles and fertility, because abnormal insulin levels affect the hypothalamus-pituitary-ovarian function, as well as the use of glucose in peripheral tissues. Metformin improves the impairments typically observed in hyperinsulinemic PCOS patients, reducing the possible evolution towards metabolic syndrome and Type 2 diabetes; and when pregnancy occurs, it consistently reduces the risk of gestational diabetes, eclampsia and hypertension. PCOS seems to be the perfect physiopathological condition that might have higher benefits from metformin administration, obviously after Type 2 diabetes. This review focuses on the many aspects of PCOS and on the possible issues of this disease for which metformin might be a putative optimal treatment.

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.

Because of a growing demand for alternative treatments of the psychological and somatic/vasomotor symptoms related to menopausal transition, in this study we aimed to investigate the effect of a 2-month supplementation period with the Klamath algae extract (Klamin, Nutratec Srl, Urbino, Italy) on the general and psychological well-being of a group of 21 menopausal women not treated with hormonal therapy, as well as on their oxidative stress status and level of antioxidants. Klamin is an extract naturally rich in powerful algal antioxidant molecules (AFA-phycocyanins) and concentrated with Klamath algae's natural neuromodulators (phenylethylamine as well as natural selective MAO-B inhibitors).At the end of the Klamin supplementation period, plasma lipid peroxidation significantly decreased (as proven by a significant lowering of plasma MDA levels), while the overall antioxidant system improved thanks to the significant increase in the plasma levels of carotenoids, tocopherols and retinol. Furthermore, the average Green Scale score, which evaluates menopausal symptoms and thus by contrast the overall and psychological well-being of menopausal women, was significantly reduced. As it did not show the steroid-like effects on the hormonal parameters, Klamin could be proposed both as a valid natural remedy for women seeking an alternative to hormonal therapy, as well as as a complementary treatment for many climacteric symptoms.

We investigated the prevalences of human papillomavirus (HPV) of type 6, 11, 16, 18, 31, 33, 35 and 42 in 276 cervical tissue samples biopsied from a group of North-Italian women in which a HPV infection of the cervix had been suspected. The specimens were evaluated by conventional histological examination and by HPV typing, using Southern blot hybridization on the extracted DNA. We related different degrees of squamous cervical dysplasia, showing or not viral cytopathic effects, with the HPV types harboured in the lesions. Significant rising of HPV 16 prevalences was observed proceeding from mild to moderate and to severe dysplasias both in presence (r = 0.9623, P less than 0.01) and in absence (r = 0.879, P less than 0.05) of koilocytosis, while an opposite trend was detected for HPV 6 and 11. In our sampling we did not find HPV 35 DNA sequences; in all occasions HPV 31 was associated with mild dysplasias. The absolute prevalences of types 18, 33 and 42 were generally low (from 2 to 3%); they did not show any association with specific histological damage of the cervix or with significant patterns related with the progression of cervical dysplasia.

To evaluate the effects the administration of myo-inositol (MYO) on hormonal parameters in a group of PCOS patients.Controlled clinical study.PCOS patients in a clinical research environment.20 overweight PCOS patients were enrolled after informed consent.All patients underwent hormonal evaluations and an oral glucose tollerance test (OGTT) before and after 12 weeks of therapy (Group A (n = 10): myo-inositol 2 gr. plus folic acid 200 mug every day; Group B (n = 10): folic acid 200 mug every day). Ultrasound examinations and Ferriman-Gallwey score were also performed.Plasma LH, FSH, PRL, E2, 17OHP, A, T, glucose, insulin, C peptide concentrations, BMI, HOMA index and glucose-to-insulin ratio.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.Myo-inositol administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.

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.