Alpha lipoic acid administration improved both peripheral sensitivity to insulin and liver clearance of insulin reducing potential risk of diabetes and nonalcoholic fatty liver disease in overweight/obese PCOS patients.

OBJECTIVE: To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients. METHODS: This was a retrospective study in which thirty-two overweight/obese patients with PCOS (n = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated. RESULTS: ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease. CONCLUSION: ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients.

Low-Dose Estrogens as Neuroendocrine Modulators in Functional Hypothalamic Amenorrhea (FHA): The Putative Triggering of the Positive Feedback Mechanism(s).

Functional hypothalamic amenorrhea (FHA) is a non-organic reversible chronic endocrine disorder characterized by an impaired pulsatile secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus. This impaired secretion, triggered by psychosocial and metabolic stressors, leads to an abnormal pituitary production of gonadotropins. As LH and FSH release is defective, the ovarian function is steadily reduced, inducing a systemic hypoestrogenic condition characterized by amenorrhea, vaginal atrophy, mood changes and increased risk of osteoporosis and cardiovascular disease. Diagnosis of FHA is made excluding other possible causes for secondary amenorrhea, and it is based upon the findings of low serum gonadotropins and estradiol (E2) with evidence of precipitating factors (excessive exercise, low weight, stress). Treatments of women with FHA include weight gain through an appropriate diet and physical activity reduction, psychological support, and integrative approach up to estrogen replacement therapy. If no spontaneous ovarian function is restored, assisted reproductive technologies may be used when pregnancy is desired. Because subjects with FHA are hypoestrogenic, the use of low-dose estrogens has been proposed as a putative treatment to positively modulate the spontaneous restart of gonadotropin secretion, counteracting the blockade of the reproductive axis triggered by stress acting through the neuroendocrine pathways at the basis of positive feedback of estrogens. The mechanism through which low-dose estrogens acts is still unknown, but kisspeptin-secreting neurons may be involved.

Putative Complementary Compounds to Counteract Insulin-Resistance in PCOS Patients.

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

Familial diabetes predisposes PCOS patients to insulin resistance (IR), reproductive impairment and hepatic dysfunction: effects of d-chiro inositol (DCI) and alpha lipoic acid (ALA) administration on hepatic insulin extraction (HIE) index.

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

Neuroendocrine Effects of Carnitines on Reproductive Impairments.

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

Differential insulin response to oral glucose tolerance test (OGTT) in overweight/obese polycystic ovary syndrome patients undergoing to myo-inositol (MYO), alpha lipoic acid (ALA), or combination of both.

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.