Inositols and female reproduction disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-Women's Endocrinology.

PURPOSE: To provide the latest scientific knowledge on the efficacy of inositols for improving reproductive disorders in women with and without polycystic ovary syndrome (PCOS) and to reach a consensus on their potential use through a Delphi-like process. METHODS: A panel of 17 endocrinologists and 1 gynecologist discussed 4 key domains: menses irregularity and anovulation, fertility, pregnancy outcomes, and neonatal outcomes. RESULTS: A total of eight consensus statements were drafted. Myo-inositol (Myo) supplementation can be used to improve menses irregularities and anovulation in PCOS. Myo supplementation can be used in subfertile women with or without PCOS to reduce the dose of r-FSH for ovarian stimulation during IVF, but it should not be used to increase the clinical pregnancy rate or live birth rate. Myo supplementation can be used in the primary prevention of gestational diabetes mellitus (GDM), but should not be used to improve pregnancy outcomes in women with GDM. Myo can be preconceptionally added to folic acid in women with a previous neural tube defects (NTD)-complicated pregnancy to reduce the risk of NTDs in newborns. Myo can be used during pregnancy to reduce the risk of macrosomia and neonatal hypoglycemia in mothers at risk of GDM. CONCLUSION: This consensus statement provides recommendations aimed at guiding healthcare practitioners in the use of inositols for the treatment or prevention of female reproductive disorders. More evidence-based data are needed to definitively establish the usefulness of Myo, the appropriate dosage, and to support the use of D-chiro-inositol (DCI) or a definitive Myo/DCI ratio.

The Translational Role of miRNA in Polycystic Ovary Syndrome: From Bench to Bedside-A Systematic Literature Review.

MicroRNAs (miRNAs) are small, non-coding RNAs that are essential for the regulation of post-transcriptional gene expression during tissue development and differentiation. They are involved in the regulation of manifold metabolic and hormonal processes and, within the female reproductive tract, in oocyte maturation and folliculogenesis. Altered miRNA levels have been observed in oncological and inflammatory diseases, diabetes or polycystic ovary syndrome (PCOS). Therefore, miRNAs are proving to be promising potential biomarkers. In women with PCOS, circulating miRNAs can be obtained from whole blood, serum, plasma, urine, and follicular fluid. Our systematic review summarizes data from 2010-2021 on miRNA expression in granulosa and theca cells; the relationship between miRNAs, hormonal changes, glucose and lipid metabolism in women with PCOS; and the potential role of altered miRNAs in fertility (oocyte quality) in PCOS. Furthermore, we discuss miRNAs as a potential therapeutic target in PCOS and as a diagnostic marker for PCOS.

Urinary Metabolites Reveal Hyperinsulinemia and Insulin Resistance in Polycystic Ovarian Syndrome (PCOS).

The identification of insulin resistance and hyperinsulinemia in polycystic ovary syndrome (PCOS) is not a minor issue. The homeostasis model assessment of insulin resistance index (HOMA) is the most used index of IR (Insulin Resistance), validated in overweight and obese patients but not in normal-weight PCOS subjects, who can still present with increased insulin secretion by an oral glucose tolerance test (OGTT). The evaluation of insulin secretion and resistance represents a still unresolved problem. The aim of this study is to identify a possible yet noninvasive method to properly evaluate the insulin metabolism in young non-diabetic subjects. Girls aged 14-22 years, afferent to the center of Gynecological Diseases in Childhood and Adolescence of Cagliari (Italy), were screened for PCOS. A total of 42 subjects comprised the study group. Hormonal assays, OGTT, transabdominal (TA) or transvaginal (TV) US, and urine collection for 1H-NMR analysis were assayed in the early follicular phase. A 1H-NMR coupled multivariate statistical analysis was performed. The OPLS model indicated that the NMR profile of urine had a good fit and prediction ability for the AUC OGTT with R2 = 0.813. Metabolomics can be a promising tool to the potential identification of biomarkers of an exaggerated insulin response to OGTT and can encourage substantial progress for a more accurate and early diagnosis in PCOS.

Polycystic Ovarian Morphology in Normocyclic Non-hyperandrogenic Adolescents.

OBJECTIVE: To understand whether polycystic ovarian morphology (PCOM) represents a transient phase, and whether an increased stroma could help to characterize the phenotype of the ovary in adolescence. METHODS: Cross-sectional population-based study on high-school students in Cagliari, Italy. The study population consisted of 257 normocyclic non-hyperandrogenic girls selected from a sample of 600 healthy volunteers recruited from 2012 to 2016. Clinical examination, medical history, blood sampling, and pelvic ultrasound (US) were performed. Postmenarchal years and body mass index (BMI) were estimated. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17ß estradiol (E2), total testosterone (tT), delta-4-androstenedione (A), and 17-hydroxyprogesterone (17-OHP) were measured. Ovarian volume, follicular number per section (FNPS), and S/A ratio were measured by pelvic US. RESULTS: Following the Rotterdam guidelines for US PCOS diagnosis and setting the normal S/A ratio at ≤0.3, subjects were categorized into 3 groups: (1) normal ovarian morphology (NOM; n = 154, 60%); (2) polycystic ovarian morphology (PCOM) with normal S/A ratio (PCOM-NS; n = 70, 27%); and (3) PCOM with increased S/A ratio (PCOM-IS; n = 33, 13%). The NOM group had more postmenarchal years and a lower LH than both the PCOM groups, and lower A and tT than the PCOM-IS group. The PCOM-NS group had fewer postmenarchal years and lower A than the PCOM-IS group. Interestingly, unlike NOM and PCOM-NS, the prevalence of PCOM-IS remained constant among the 3 phases of postmenarchal age (10% vs 16% vs 15%, P = not significant). CONCLUSION: This study demonstrates that PCOM can be a transient condition, whereas a high S/A ratio is a stable US alteration present from early postmenarchal years.

HMGB1 is increased in adolescents with polycystic ovary syndrome (PCOS) and decreases after treatment with myo-inositol (MYO) in combination with alpha-lipoic acid (ALA).

PCOS treatment should be based on pathophysiology. High-mobility-group-box-1 (HMGB1) was shown to increase in PCOS patients as a consequence of reduced cystic-fibrosis-transmembrane-conductance-regulator (CFTR) expression in the ovary, and was associated with insulin resistance and inflammation, both features of PCOS. Inositols and ALA derivatives could have positive effects on insulin sensitivity, reduce androgens, and improve ovulation rhythm. The aim of this study was to verify changes in HMGB1, in metabolic and endocrine parameters in adolescents with PCOS compared with controls and after treatment with a combination of MYO + ALA. Twenty-three PCOS adolescents and 21 controls matched for age and BMI were enrolled. In all subjects, metabolic and hormonal parameters were assayed. Homeostatic index (HOMA-IR) and the triglyceride/HDL-cholesterol ratio were calculated. Ovarian volumes were evaluated. Patients were treated with MYO + ALA for 6 months. HMGB1 was measured using a specific ELISA assay. HMGB1 was increased in PCOS compared with controls (19.76 ± 5.99 versus 5.65 ± 1.88 ng/ml; p < .05) and normalized after treatment (2.27 ± 0.36 ng/ml, p < .05). Treatment significantly reduced insulin (24.0 ± 4.11 versus 12.13 ± 2.13 uU/ml), HOMA-IR (3.91 ± 0.41 versus 2.42 ± 0.45), and 17-hydroxyprogesterone (1.20 ± 0.15 versus 0.78 ± 0.11 ng/ml). Cholesterol, luteinizing hormone, 17-ß-estradiol, delta 4-androstenedione, and testosterone were unchanged. Circulating HMGB1 was increased in PCOS adolescents, and treatment was effective in normalizing HMGB1.

Very low dose of flutamide in the treatment of hyperandrogenism.

Hyperandrogenism is a condition affecting 5-10% of adolescents. The aim of this study was to evaluate the efficacy of very low dose of flutamide in the treatment of hyperandrogenism in adolescence. One hundred and fifty-eight patients, presenting severe acne and/or hirsutism, received 62.5 mg/day of flutamide + ethinylestradiol + gestodene for 18 months. The patients were subjected to assessments of hepatic enzymes levels. Thirty subjects treated with drospirenone + ethinylestradiol represented the control group. After 18 months of treatment, it was obtained a decrease of hirsutism (-39.9%), an almost recovery of acne (98% of patients) with better results of those obtained in control group. Only one case of light hypertransaminasemia was recorded, regressed spontaneously. Very low dose of flutamide was successful and safe and in the treatment of hyperandrogenism in adolescence.

Insulin resistance and hyperandrogenism have no substantive association with birth weight in adolescents with polycystic ovary syndrome.

OBJECTIVE: To assess whether birth weight influences the metabolic and hormonal profile of adolescents with polycystic ovary syndrome (PCOS). DESIGN: Retrospective study. SETTING: University outpatient clinic. PATIENT(S): One hundred seventy consecutive adolescents 12 to 19 years of age with PCOS, 15 of whom were small for gestational age (SGA), and 75 healthy female aged-matched adolescents as controls. INTERVENTION(S): Physical evaluations, fasting blood samples for measuring endocrine and metabolic parameters, and an oral glucose tolerance test. MAIN OUTCOMES MEASURE(S): Physical, endocrine, and metabolic features. RESULT(S): The birth weights of adolescents with PCOS as well as those with hyperinsulinemic or insulin resistance were similar to those of the control group. The PCOS SGA adolescents had basal insulin (15.93 ± 7.16 µU/mL vs. 10.97 ± 5.79 µU/mL) and homeostasis model assessment of insulin resistance values (3.2 ± 1.54 vs. 2.19 ± 1.28) that were statistically significantly higher than in the control group. The mean levels of total testosterone in the SGA adolescents with PCOS were above the upper limit of the normal range (0.80 ng/mL). CONCLUSION(S): Low birth weight may influence the appearance of hyperandrogenism and insulin resistance in a portion of adolescents with PCOS, but only 9% of the adolescents with PCOS in this study were SGA. In the majority of adolescents with PCOS, hyperinsulinemia and hyperandrogenism are related to factors other than birth weight alone.

Ovulation induction in young girls with menometrorragia: a safe and effective treatment.

UNLABELLED: The prevalence of menometrorrhagia in fertile women is 11.4-13.2% and increases with aging. The presence of metrorrhagia is a relatively common cause of concern among adolescents and their parents, as well as a frequent cause of visits to emergency departments, gynaecologists, and pediatricians. Clomiphene is a selective estrogen receptor modulator (SERM) that increases the production of gonadotropins by inhibiting negative feedback on the hypothalamus. Clomiphene is primarily used in the treatment of female infertility for ovulation induction to reverse oligoovulation or anovulation, as occurs in polycystic ovary syndrome. OBJECTIVE: The aim of our study was to evaluate the use of clomiphene citrate in ovulation induction, and therefore, in the cessation of bleeding in adolescents with menometrorrhagia in the absence of uterine, ovarian, or systemic pathologies. DESIGN: Cohort study. MATERIALS AND METHODS: The study group was comprised of 50 subjects (age range, 13-16 years) with menometrorrhagia (bleeding >7 days in length with an average blood loss >80 ml). The treatment with clomiphene citrate at a dose of 50 mg/day for 5 days during the attack cycle, and from days 3 to 7 of three subsequent cycles, was offered to the patients. RESULTS: After three cycles of therapy, all patients had resolution of the menometrorrhagia and resumption of ovulatory cycles. No patient reported unwanted side effects. CONCLUSION: We propose that low-dose clomiphene should be the first step in the treatment of adolescent dysfunctional bleeding (DUB).

The quantitative insulin sensitivity check index is not able to detect early metabolic alterations in young patients with polycystic ovarian syndrome.

OBJECTIVE: To verify whether QUICKY is a suitable method for the identification of metabolic deterioration in normal weight patients affected by polycystic ovarian syndrome (PCOS). DESIGN: Prospective clinical study. PATIENT(S): Seventy-nine PCOS normal weight adolescent subjects, 50 eumenorrheic, normal weight, non-hirsute controls matched for age and BMI. METHOD(S): Quantitative insulin sensitivity check index (QUICKY) and integrated secretory area under the curve of insulin values (I-AUC) during oral glucose tolerance test were calculated. RESULT(S): Seventy-nine PCOS and 50 controls were studied. Normal insulin sensitivity was defined as upper control 95th percentile by QUICKY values <0.31, I-AUC at 180 min < 16,645. When applying the calculated I-AUC cut-off, 41 PCOS were classified as normoinsulinemic and 38 as hyperinsulinemic, whereas using the calculated QUICKY cut-off, only 19 PCOS could be classified as insulin resistant (IR). Fifteen out of the 60 non-IR PCOS presented hyperinsulinemia; fasting glucose and insulin levels and QUICKY were not sufficient to identify these subjects. Thus, QUICKY displayed a low sensitivity (44%) and specificity (91%) in the diagnosis of the metabolic disorder disclosed by I-AUC. CONCLUSIONS.: In young normal weight patients with PCOS the prevalence of early alterations of insulin metabolism are not detectable by QUICKY studies.

Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome.

CONTEXT: The determinants of the variability in the clinical response to metformin in women with the polycystic ovary syndrome (PCOS) are enigmatic. Organic cation transporter 1 (OCT1) plays a trigger role in the hepatic uptake of metformin. In cellular studies, it was recently shown that seven polymorphisms of OCT1 exhibit reduced transport of metformin. It is noteworthy that four of the seven variants, R61C (C>T), G401S (G>A), G465R (G>A), and 420del, are present in individuals of European descent. OBJECTIVE: The aim was testing the hypothesis that polymorphisms in OCT1 may contribute to the variability in the response to metformin in PCOS. DESIGN AND SETTING: We conducted a prospective study at an academic hospital. PATIENTS: We studied 150 Italian PCOS patients aged 18-45 yr. INTERVENTIONS: We administered two oral doses of metformin per day for 6 months. MAIN OUTCOME MEASURES: We measured the genotype distribution of R61C, G401S, G465R, and 420del and the influence of genotypes on response to metformin. RESULTS: Eighty-four PCOS women had the reference allele at all four positions and were classified as "References," whereas 66 PCOS women carried at least one copy of the four polymorphisms (52 carried one polymorphism, 13 carried two polymorphisms, and one carried three polymorphisms) and were classified as "Variants." Only the References reduced their total cholesterol [-14 mg/dl (-22 to -5); P = 0.002] and triglycerides [-17 mg/dl (-29 to -5); P = 0.008]. Insulin(AUC) decreased in References and in Variants carrying one polymorphism, but it did not change in Variants carrying two or more polymorphisms. CONCLUSIONS: Genetic variation in OCT1 may be associated with heterogeneity in the metabolic response to metformin in women with PCOS.

Metformin effects on ovarian ultrasound appearance and steroidogenic function in normal-weight normoinsulinemic women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial.

OBJECTIVE: To investigate metformin effects on the endocrine-metabolic parameters and ovarian morphology in normoinsulinemic women with polycystic ovary syndrome (PCOS). DESIGN: Randomized double-blind study. SETTING: Operative Division of Endocrinological Gynecology, Università Cattolica del Sacro Cuore. PATIENT(S): Twenty-eight normal-weight normoinsulinemic PCOS women. INTERVENTION(S): Patients were randomized to receive metformin 500 mg twice a day (group A, 15 subjects) or placebo (group B, 13 subjects) for 6 months. Ultrasonographic pelvic exams, hormonal and lipid features, and oral glucose tolerance test were performed at baseline and after 3 and 6 months of treatment. MAIN OUTCOME MEASURE(S): Hormonal and glycoinsulinemic assessment, ovarian ultrasound appearance. RESULT(S): Glycoinsulinemic assessment remained unvaried in both groups. About 70% of patients in group A experienced a restoration of menstrual cyclicity. Metformin significantly decreased testosterone levels at 3 and 6 months) and 17-hydroxyprogesterone levels at 6 months, and improved hirsutism score at 6 months. No clinical or hormonal modifications occurred in group B. Metformin, but not placebo, reduced ovarian volume and stromal/total area ratio at 3 and 6 months. CONCLUSION(S): Metformin seems to improve the menstrual pattern and ultrasonographic ovarian features in normoinsulinemic PCOS women. These effects seem to be, at least in part, independent of the insulin-lowering properties of the drug.

Diagnosis of metabolic disorders in women with polycystic ovary syndrome.

UNLABELLED: Although there is a widespread on-going debate throughout the scientific community with regard to the pathogenesis of polycystic ovary syndrome, the association between this frequently observed endocrine disorder and insulin resistance has been universally acknowledged. Numerous tests have been proposed for use in assessing reduced sensitivity to insulin in women with polycystic ovary syndrome. The gold standard is represented by the euglycemic hyperinsulinemic clamp, although not yet available for application in routine clinical practice in view of its complexity and high cost. Measurement of oral glucose load and the use of several fasting tests feature a good degree of reliability and can be easily repeated. It remains to be ascertained, however, which therapeutic procedures, if any, are best suited for use in women affected by hyperinsulemia. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After reading this article, the reader should be able to outline metabolic consequences of polycystic ovarian syndrome (PCOS), conclude that testing insulin resistance is an important step in the care of women with PCOS, and recall the indications and limits of testing strategies for insulin resistance.

Hirsutism and hyperandrogenism associated with hyperreactio luteinalis in a singleton pregnancy: a case report.

The incidence of hyperandrogenism during pregnancy is low, although the incidence of some of the ovarian diseases that can cause it is higher. Hyperreactio luteinalis is a rare benign condition that may mimic ovarian and trophoblastic malignancies. A 23-year-old woman at 20 weeks' gestational age presenting with severe hirsutism and ovarian masses was treated conservatively and subsequently gave birth to a healthy female neonate. Final diagnosis was hyperreactio luteinalis. Conservative management with close monitoring of patients with hyperreactio luteinalis represents the best approach in such rare cases. Counseling should be provided to reassure the patient as to the transient effects of hyperandrogenism on the mother and the fetus.

Failure of the homeostatic model assessment calculation score for detecting metabolic deterioration in young patients with polycystic ovary syndrome.

OBJECTIVE: To verify whether the homeostatic model assessment (HOMA) test is a suitable method for the identification of metabolic deterioration in normal-weight patients affected by polycystic ovary syndrome (PCOS). DESIGN: Prospective clinical study. SETTING: Academic clinic and research environment in Cagliari, Italy. PATIENT(S): Forty-nine PCOS normal-weight adolescent subjects, and 50 eumenorrheic, normal-weight, nonhirsute controls matched for age and body mass index (BMI). INTERVENTION(S): History and physical examination, oral glucose tolerance test (OGTT) and blood sampling, ultrasound. MAIN OUTCOME MEASURE(S): The HOMA score and integrated secretory area under the curve of insulin values (I-AUC) during the OGTT were calculated. RESULT(S): Normal insulin sensitivity was defined as upper control 95th percentile by HOMA values <65.6, I-AUC at 180 minutes <16,921, and I-AUC at 120 minutes <11,817. When applying the calculated I-AUC cutoff, 27 PCOS patients were classified as normoinsulinemic and 22 as hyperinsulinemic, whereas using the calculated HOMA cutoff, only 9 PCOS patients could be classified as insulin resistant (IR). Thirteen of the 40 non-IR PCOS patients presented with hyperinsulinemia; fasting glucose and insulin levels and HOMA scores were not sufficient to identify these subjects. Thus, the HOMA test displayed a low sensitivity (41%) and specificity (100%) in the diagnosis of the metabolic disorder disclosed by I-AUC. Moreover, analysis of I-AUC after 120 and 180 minutes revealed how the shorter evaluation period did not suffice for identification of all hyperinsulinemic subjects, implying an unrecognized condition in 11 of 22 subjects. CONCLUSION(S): In young, normal-weight patients with PCOS, the prevalence of hyperinsulinemia is not detectable by HOMA studies. The prevalence of IR was 18% according to HOMA evaluation, whereas hyperinsulinemia was found in 44% of subjects examined by I-AUC. Normal-weight, young PCOS patients should undergo a 3-hour OGTT to detect early metabolic abnormalities.

N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of N-acetyl-cysteine (NAC) on insulin secretion and peripheral insulin resistance in subjects with polycystic ovary syndrome (PCOS). DESIGN: Prospective data analysis. SETTING: Volunteer women in an academic research environment. PATIENT(S): Six lean and 31 obese subjects, aged 19-33 years. INTERVENTION(S): Patients were treated for 5-6 weeks with NAC at a dose of 1.8 g/day orally. A dose of 3 g/day was arbitrarily chosen for massively obese subjects. Six of 31 obese patients with PCOS were treated with placebo and served as controls. MAIN OUTCOME MEASURE(S): Before and after the treatment period, the hormonal and lipid blood profile and insulin sensitivity, assessed by an hyperinsulinemic euglycemic clamp, were evaluated and an oral glucose tolerance test (OGTT) was performed. RESULT(S): Fasting glucose, fasting insulin, and glucose area under curve (AUC) were unchanged after treatment. Insulin AUC after OGTT was significantly reduced, and the peripheral insulin sensitivity increased after NAC administration, whereas the hepatic insulin extraction was unaffected. The NAC treatment induced a significant fall in T levels and in free androgen index values (P<.05). In analyzing patients according to their insulinemic response to OGTT, normoinsulinemic subjects and placebo-treated patients did not show any modification of the above parameters, whereas a significant improvement was observed in hyperinsulinemic subjects. CONCLUSION(S): NAC may be a new treatment for the improvement of insulin circulating levels and insulin sensitivity in hyperinsulinemic patients with polycystic ovary syndrome.