Erika Rattighieri

Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients

Abstract 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.

Metformin administration restores allopregnanolone response to adrenocorticotropic hormone (ACTH) stimulation in overweight hyperinsulinemic patients with PCOS

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.

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.

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

Background and aim. 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 algaes natural neuromodulators (phenylethylamine as well as natural selective MAO-B inhibitors). Conclusions. 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.

Myo-inositol modulates insulin and luteinizing hormone secretion in normal weight patients with polycystic ovary syndrome

To investigate hormonal dynamics in a group of non‐obese polycystic ovary syndrome (PCOS) patients under myo‐inositol (MYO) administration.

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.

Estimation of instantaneous secretory rates and intrinsic characteristics of luteinizing hormone secretion in women with Kallmann syndrome before and after estriol administration

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.

Obesity and Metabolic Syndrome: Impact and Relationship with Menopausal Transition

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.

PCOS and Insulin Resistance (IR): From Lifestyle to Insulin Sensitizers

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.

Pathophysiology and Clinical Assessment of Hyperandrogenic States

Human reproduction has been demonstrated to be complex and more fragile than expected since a very complicated network is at the basis of its control. Such network is mainly based on specific endocrine and neuroendocrine pathways that control or modulate the hypothalamic–pituitary–ovarian axis.