Chiara Lanzoni

Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome.

Objective. To evaluate the effects the administration of myo-inositol (MYO) on hormonal parameters in a group of PCOS patients. Design. Controlled clinical study. Setting. PCOS patients in a clinical research environment. Patients. 20 overweight PCOS patients were enrolled after informed consent. Interventions. 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 μg every day; Group B (n = 10): folic acid 200 μg 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-inositol administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.

Metformin administration is more effective when non-obese patients with polycystic ovary syndrome show both hyperandrogenism and hyperinsulinemia

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.

Might DHEA be considered a beneficial replacement therapy in the elderly

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.

Diagnostic and therapeutic approach to hypothalamic amenorrhea.

Abstract:  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 stressant 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 stressant 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.

Metformin administration modulates neurosteroids secretion in non-obese amenorrhoic patients with polycystic ovary syndrome.

Background. 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. 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 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. Method. 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. Results. 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. Conclusions. 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.

Hypothalamic amenorrhea: From diagnosis to therapeutical approach

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.

Acetyl-L-carnitine (ALC) administration positively affects reproductive axis in hypogonadotropic women with functional hypothalamic amenorrhea

Background: Hypothalamic amenorrhea (HA) is characterized by neuroendocrine impairment that, in turn, negatively modulates endocrine function, mainly within the reproductive axis. HA presents with hypo-LH, 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: Twenty-four patients affected by stress-induced HA were divided into two groups according to LH plasma levels: group A, hypo-LH (LH≤3 mIU/ml; no.=16), and group B, normo-LH (LH>3 mIU/ml; no.=8), were treated with 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 mIU/ml, p<0.01 ) and in LH pulse amplitude (p<0.001). No changes were observed in the normo-LH group. LH response to naloxone was restored under ALC therapy. Maximal LH response and area under the curve 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 stress-induced abnormalities in hypo-LH patients affected by hypothalamic amenorrhea.