Alessia Prati

Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients

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.

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.

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.

Effects of a Combination of Alpha Lipoic Acid and Myo-Inositol on Insulin Dynamics in Overweight/Obese Patients with PCOS

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

Short-term estriol administration modulates hypothalamo-pituitary function in patients with functional hypothalamic amenorrhea (FHA)

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

PCOS from Lifestyle to the Use of Inositol and Insulin Sensitizers

PCOS patients are typically characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries, and these aspects are frequent in a high percentage of women during the reproductive life. PCOS frequently show overweight and/or obesity and are characterized by a higher production of androgens and reduced sensitivity to insulin. In fact it is of great importance to note that more than 40–45% of all PCOS patients show overweight up to obesity and that these patients have a modest up to an exaggerated hyperinsulinism in response to the standard oral glucose tolerance test (OGTT). What is relevant to point out is that such reduced insulin sensitivity can be observed also in 10–15% of the normal weight PCOS, thus confirming that hyperinsulinism can show up not only in relation to obesity or to excess of fat tissue but also as an intrinsic abnormal ability to control glucose metabolism.

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.

Functional Hypothalamic Amenorrhea as Stress Induced Defensive System

Since the activity of the reproductive axis is quite complex and modulated and/or affected by several neurotransmitters, neuromodulators and hormones, it is easy to understand that minimal changes of the equilibrium of few of these substances might induce changes of the reproductive axis leading to the amenorrheic condition.

Medical Treatment of Myomas

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

Pharmacological and Integrative Treatment of Stress-Induced Hypothalamic Amenorrhea

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.