Hyperandrogenism and menstrual imbalance are the best predictors of metformin response in PCOS patients

Background Moving from the correlation between insulin-resistance and PCOS, metformin has been administered in some PCOS women improving ovulatory and metabolic functions and decreasing androgen levels. Inconsistency and unpredictability of response to metformin limit its extensive use. Aim of this study was to identify reliable predictors of response to metformin therapy for weight loss and reduction in plasma androgen levels using ANNs (artificial neural networks). Methods One hundred eight consecutive women with PCOS (ESHRE/ASRM 2003 Rotterdam criteria) treated with metformin 1500 mg/day, at inclusion and every 6 months underwent to a complete clinical, endocrine/metabolic assessment and ultrasonographic evaluation. Therapy outcomes were BMI reduction (≥1 kg/m2) in overweight/obese and free-androgen-index (FAI) decrease (≥1%) in hyperandrogenemic women. Semantic connectivity maps (SCMs) were obtained through Auto-CM, a fourth generation ANN, to compare patients’ baseline clinical features to the treatment outcomes. Multivariate logistic regression analysis was used to assess the major predictor in drop-out patients and the associated risk. Results At 6 months 54 out of 103 (52,4%) obese patients showed BMI reduction and 45 out of 89 (50,6%) hyperandrogenemic women showed FAI decrease. The further response rates at 12 months were 30,6 and 47%, respectively. SCMs showed a clear polarization for both the outcomes with elevated accuracy. Treatment responsiveness resulted strictly related to oligo-amenorrhea and hyperandrogenemia at baseline. In addition, lower serum testosterone levels at baseline were found to be the major predictor of treatment discontinuation. Conclusions In women with PCOS, menstrual pattern imbalance and ovarian androgens excess are the best predictors of metformin response. They may pave the way for a rethinking of the criteria for evaluating hyperandrogenism in order to better define the large population included in the diagnosis of PCOS. Baseline plasma testosterone level can serve as a sensitive marker to predict treatment compliance.

Hyperandrogenemia in Early Adulthood Is an Independent Risk Factor for Abnormal Glucose Metabolism in Middle Age

Context The role of androgen excess as a contributing factor to abnormal glucose metabolism (AGM) and insulin resistance in women remains controversial. Objective To investigate whether hyperandrogenemia (HA) estimated by serum testosterone (T) level and free androgen index (FAI) at ages 31 and 46 is associated with insulin resistance, insulin secretion and AGM by age 46. Design Prospective study including 5,889 females followed at ages 31 and 46. Setting General community. Participants Women with HA were compared with normoandrogenic women at ages 31 and 46. Intervention None. Main outcome measurements AGM, including pre-diabetes and T2DM, homeostatic model assessments of insulin resistance (HOMA–IR) and of pancreatic β-cell function (HOMA–B). Results At age 31, HA women displayed increased HOMA–IR P=0.05), HOMA–B (P=0.006), and higher fasting insulin (P=0.034) than normoandrogenic women after adjusting for body mass index (BMI). At age 46, there was a nonsignificant trend towards higher fasting glucose (P=0.07) and glycated hemoglobin A1 (P=0.067) levels in HA women. Women in the highest T quartile (odds ratio [OR]= 1.80;95%CI, 1.15–2.82) at age 31 and in the two highest FAI quartiles at ages 31 (Q4:OR=3.76;95%CI, 2.24–6.32) and 46 (Q4:OR=2.79;95%CI, 1.74–4.46) had increased risk for AGM, independently of BMI, when compared with women in Q1. Sex hormone-binding globulin (SHBG) was inversely associated with AGM (at age 31:Q4:OR=0.37;95%CI, 0.23–0.60, at age 46:Q4:OR=0.28;95%CI, 0.17–0.44). Conclusion Hyperandrogenemia and low SHBG in early and middle age associates with AGM independently of BMI.

Exenatide, dapagliflozin or phentermine/topiramate differentially affect metabolic profiles in polycystic ovary syndrome

Context Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors reduce weight and improve insulin sensitivity via different mechanisms. Objective The efficacy of once-weekly exenatide (EQW) and dapagliflozin (DAPA) alone and co-administered (EQW/DAPA), DAPA/extended release metformin (DAPA/MET), and phentermine topiramate extended release (PHEN/TPM) on metabolic parameters, body composition, and sex hormones were examined in obese women with PCOS. Research Design and Methods Non-diabetic women (n=119; 18-45y) with BMI>30 <45 and PCOS (NIH criteria) were randomized in a single-blind fashion to EQW (2 mg weekly); DAPA (10 mg daily), EQW/DAPA (2 mg weekly/10 mg daily), DAPA (10 mg)/MET (2000mg XR daily) or PHEN (7.5 mg)/TPM (46mg ER daily) treatment for 24 weeks. Study visits at baseline and 24 weeks included weight, blood pressure (BP), waist (WC) measures and body composition evaluated by dual-energy X-ray absorptiometry (DXA). Oral glucose tolerance tests (OGTT) were done to assess glycemia, mean blood glucose (MBG), and compute insulin sensitivity (SI) and secretion (IS) measures. Sex steroids, free androgen index (FAI) and lipid profiles were measured in the fasting sample. Results EQW/DAPA and PHEN/TPM resulted in the most loss of weight, total body fat by DXA, and WC. Despite equivalent reductions in BMI and WC with PHEN/TPM, only EQW/DAPA and EQW resulted in significant improvements in MBG, SI and IS. Reductions in fasting glucose, testosterone, FAI and BP were seen with all drugs. Conclusion Dual therapy with EQW/DAPA was superior to either alone, DAPA/MET and PHEN/TPM in terms of clinical and metabolic benefits in this patient population.

Effect of aging on clinical features and metabolic complications of women with polycystic ovary syndrome

Purpose To assess the distribution of clinical features and metabolic abnormalities of polycystic ovary syndrome (PCOS) women according to their age. Methods Retrospective study on 602 women (mean age 23.9 ± 6.2 years), diagnosed according to International PCOS Network Guidelines criteria as having PCOS in a University-based Hospital. Anthropometric features, hormonal and metabolic parameters were measured and compared between the different age groups (group A ≤ 20 years; group B 21–30 years; group C > 30 years). Results Patients in group A were more often hyperandrogenic, while in group C hypertension, dyslipidemia, obesity, impaired fasting glucose, and insulin resistance (IR) were more prevalent. After adjusting for BMI, age correlated positively with sex hormone-binding globulin (SHBG), IR, total- and LDL-cholesterol, and negatively with DHEAS, insulin, and free androgen index (FAI). SHBG was significantly associated with IR and atherogenic dyslipidemia, while FAI levels were linked to hypertension, independently of other factors considered. Furthermore, the regression analysis showed a stronger relationship between BMI and metabolic outcomes, regardless of age. Conclusion Polycystic ovarian syndrome (PCOS) phenotype changes with age. Clinical and biochemical hyperandrogenism are a major concern in young PCOS women, while metabolic burden tends to increase with aging. Some of the cardiovascular risk factors are dependent on FAI and SHBG levels, whereas BMI confirms its key role in the genesis of most of the metabolic sequelae in PCOS, independently of age.

Clinical and Biochemical Signs of Polycystic Ovary Syndrome in Young Women Born Preterm

Objective: It has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term. Design: The ESTER Preterm Birth Study participants were born in Northern Finland, and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm (<34 gestational weeks, VMPT), 127 born late preterm (at 34–36 weeks, LPT), and 184 born full term (≥37 weeks, controls) were included in the analysis (mean age 23.2y). Methods: We measured serum total testosterone and sex hormone binding globulin (SHBG) and calculated free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire), or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/l). Results: Women born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (-2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/ 42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject’s birth weight SD. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70). Conclusions: Women born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.

The Effect of Free Androgen Index on the Quality of Life of Women With Polycystic Ovary Syndrome: A Cross-Sectional Study

Purpose: Free androgen index (FAI) and anti-Mullerian hormone (AMH) are independently associated with polycystic ovary syndrome (PCOS). This study aimed to describe the relationship between these two markers and health-related quality of life (HR-QoL) in women with PCOS.Methods: This cross-sectional study consisted of 81 women in the Hull PCOS biobank, who fulfilled the Rotterdam consensus criteria for the diagnosis of PCOS. The primary outcome was to measure the various domains of the QoL in the modified polycystic ovary syndrome questionnaire (MPCOSQ).Results: Mean age of the study participants was 28 ± 6.0 years, mean body mass index (BMI) 33.5 ± 7.8 kg/m2, mean FAI (6 ± 5.5), free testosterone (2.99 ± 0.75) and mean AMH (3.5 ± 0.8 units). In linear regression analysis, the FAI was associated with overall mean MPCOSQ score (Beta = 0.53, P-value = 0.0002), and with depression (Beta = 0.45, P-value = 0.01), hirsutism (Beta = 0.99, P-value = 0.0002) and menstrual irregularity (Beta = 0.31, P-value = 0.04). However, with adjustment for age and BMI, FAI was only associated with the hirsutism domain (Beta = 0.94, P-value = 0.001) of the MPCOSQ. FAI was also associated with the weight domain (Beta = 0.63 P-value = 0.005) of MPCOSQ. However, AMH was not associated with the overall mean MPCOSQ score or with any of its domains.Conclusion: FAI but not AMH was associated with QoL in women with PCOS, and this effect was mediated by BMI.

Wet-cupping on calf muscles in polycystic ovary syndrome: a quasi-experimental study

Objectives Current modalities for treating polycystic ovary syndrome (PCOS) are not curative and using them for a long period is associated with adverse effects. According to Persian Medicine recommendations, wet cupping on calf muscles can induce menstrual bleeding. In the present study, the effect of wet-cupping (traditional bleeding from capillary vessels) was assessed on menstrual cycles (as primary outcome), hirsutism, and laboratory manifestation of PCOS. Methods A quasi-experimental study was conducted from 2016/5/21 until 2017/5/20 on 66 PCOS women within the age range of 20–40 years and a menstrual interval of at least 60 days during the last year. Participants’ calf muscles were cupped on day 26 of their last menstruation cycle following the Persian Medicine recommendations. They were followed for 12 weeks and a menstruation history and physical examination was done twice (4 and 12 weeks after wet cupping). Insulin Resistance (IR) and Free Androgen Index (FAI) were evaluated at baseline and end of the study. Results Wet-cupping on calf muscles significantly improved menstrual cycles’ frequency 0.37(95% CI: 0.13, 0.51), p-value=0.001 and hirsutism after 4 and 12 weeks of intervention were −1.9 (95% CI: −2.5, −0.5), p-value<0.001 and −1.4(95% CI: −2.1, −0.8), p-value<0.001, respectively. While it was not significant in changing the IR and FAI. About 33% of participants suffered from mild temporary discomforts (which were resolved within a few minutes of rest) and 9% reported mild long-term side effects. Conclusions It is considered that wet-cupping on calf muscles can be propounded as an optional treatment of PCOS for those not willing to use chemical medication.