Soulmaz Shorakae

Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis

BACKGROUND Polycystic ovary syndrome (PCOS) is a common endocrine disorder with diverse reproductive and metabolic features. It is underpinned by insulin resistance that is exacerbated by obesity. Lifestyle modification is the first line treatment in PCOS, but it is associated with low adherence and sustainability. In small studies, metformin improves outcomes such as hyperinsulinaemia, ovulation and menstrual cyclicity. We conducted a systematic review and meta-analysis to compare the effect of lifestyle modification + metformin with lifestyle modification ± placebo, and of metformin alone with lifestyle modification ± placebo in PCOS on anthropometric, metabolic, reproductive and psychological outcomes. METHODS Databases including MEDLINE, EMBASE, Pubmed, Scopus, Cochrane, PsycINFO, CINAHL, Clinical Trials registry and ANZCTR were searched for RCTs conducted on humans and published in English up to August 2014. Inclusion criteria were diagnosis of PCOS based on Rotterdam criteria (inclusive of National Institutes of Health criteria) at any age and with any BMI. Interventions of interest included lifestyle + metformin (with any dose and any duration) or metformin alone compared with lifestyle ± placebo. RESULTS Of 2372 identified studies, 12 RCTs were included for analysis comprising 608 women with PCOS. Lifestyle + metformin were associated with lower BMI (mean difference (MD) -0.73 kg/m(2), 95% confidence intervals (CI) -1.14, -0.32, P = 0.0005) and subcutaneous adipose tissue (MD -92.49 cm(2), 95% CI -164.14, -20.84, P = 0.01) and increased number of menstrual cycles (MD 1.06, 95% CI 0.30, 1.82, P = 0.006) after 6 months compared with lifestyle ± placebo. There were no differences in other anthropometric, metabolic (surrogate markers of insulin resistance, fasting and area under the curve glucose, lipids and blood pressure), reproductive (clinical and biochemical hyperandrogenism), and psychological (quality of life) outcomes after 6 months between lifestyle + metformin compared with lifestyle ± placebo. With metformin alone compared with lifestyle ± placebo, weight and BMI were similar after 6 months, but testosterone was lower with metformin. CONCLUSIONS Lifestyle + metformin is associated with lower BMI and subcutaneous adipose tissue and improved menstruation in women with PCOS compared with lifestyle ± placebo over 6 months. Metformin alone compared with lifestyle showed similar BMI at 6 months. These results suggest the combination of lifestyle with metformin has a role to play in weight management: a key concern for women with PCOS. Existing study limitations include small sample sizes, short durations and risk of bias. With international guidelines now acknowledging that lifestyle and pharmacotherapy are required for weight loss and maintenance in obesity, future studies of appropriate size and duration are vital to clarify the role of metformin in PCOS management.

The Emerging Role of Chronic Low-Grade Inflammation in the Pathophysiology of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) has become increasingly common over recent years and is associated with reproductive features as well as cardiometabolic risk factors, including visceral obesity, dyslipidemia and impaired glucose homeostasis, and potentially cardiovascular disease. Emerging evidence suggests that these long-term metabolic effects are linked to a low-grade chronic inflammatory state with the triad of hyperinsulinemia, hyperandrogenism, and low-grade inflammation acting together in a vicious cycle in the pathophysiology of PCOS. Dysregulation of the sympathetic nervous system may also act as an important component, potentially creating a tetrad in the pathophysiology of PCOS. The aim of this review is to examine the role of chronic inflammation and the sympathetic nervous system in the development of obesity and PCOS and review potential therapeutic options to alleviate low-grade inflammation in this setting.

Sympathetic activation and endothelial dysfunction in polycystic ovary syndrome are not explained by either obesity or insulin resistance.

Polycystic ovary syndrome (PCOS) is a common endocrine condition underpinned by insulin resistance and associated with increased risk of obesity, type 2 diabetes and adverse cardiovascular risk profile. Previous data suggest autonomic imbalance [elevated sympathetic nervous system (SNS) activity and decreased heart rate variability (HRV)] as well as endothelial dysfunction in PCOS. However, it is not clear whether these abnormalities are driven by obesity and metabolic disturbance or whether they are independently related to PCOS.

Polycystic ovary syndrome: a common hormonal condition with major metabolic sequelae that physicians should know about.

Polycystic ovary syndrome (PCOS) is a prevalent, chronic and heterogeneous endocrine condition, with reproductive, metabolic and psychological features. Insulin resistance and hyperandrogenaemia are the key pathophysiological hormonal abnormalities. Insulin resistance is a significant contributor to the reproductive and metabolic complications of PCOS, both independently and in the setting of excess bodyweight. While the diagnostic criteria are now internationally uniformly accepted, individual components of the criteria are ill‐defined, making diagnosis challenging. This, along with low awareness of PCOS, has resulted in a significant proportion of women remaining undiagnosed. While reproductive features are best recognised in PCOS and form the basis of the diagnostic criteria, awareness of psychological and metabolic features, recommended screening protocols, and management strategies to prevent metabolic complications are important. In this review, we focus on diagnostic criteria, and reproductive, metabolic and psychological features of PCOS, as well as recommended screening and management strategies suggested by national and international evidence‐based guidelines.

Relationship between vitamin D and gestational diabetes in overweight or obese pregnant women may be mediated by adiponectin

SCOPE Maternal vitamin D deficiency has been implicated in adverse pregnancy outcomes. However, the association between vitamin D and inflammation, particularly adipokines, remains unexplored in pregnancy. METHODS AND RESULTS In 102 overweight or obese pregnant women at high-risk of gestational diabetes mellitus (GDM), we investigated relationships between maternal 25-hydroxyvitamin D (25(OH)D) concentrations at 12-15 wk gestation (baseline) and serum lipids, inflammatory markers, novel adipokines (omentin-1, visfatin, high molecular weight (HMW) adiponectin), and subsequent pregnancy outcomes (GDM, preeclampsia, preterm birth [PTB]). After adjustment for maternal factors (age, BMI, parity, ethnicity, and smoking status), baseline 25(OH)D concentrations were inversely associated with total cholesterol and triglycerides, and positively associated with HMW-adiponectin. Higher baseline 25(OH)D concentrations were associated with decreased fasting and 1-h post-OGTT glucose and reduced risk of GDM at 26-28 wk, as well as with longer gestation and reduced risk of PTB upon additional adjustment for caesarean section. Adding HMW-adiponectin to the multivariable models attenuated most associations, and HMW-adiponectin was a significant predictor in the models. CONCLUSION Our findings suggest that lower maternal 25(OH)D concentrations in overweight/obese pregnant women at high-risk of GDM are associated with increased cardiometabolic risks during pregnancy and adverse pregnancy outcomes, and that these associations may be mediated by HMW-adiponectin.

Bioavailable and free 25-hydroxyvitamin D and vitamin D binding protein in polycystic ovary syndrome: Relationships with obesity and insulin resistance

Polycystic ovary syndrome (PCOS) is a common condition characterised by both reproductive and metabolic features (obesity, insulin resistance, diabetes risk). Some evidence suggests that women with PCOS have lower vitamin D levels compared to healthy controls. Vitamin D binding protein (DBP) is the main carrier of vitamin D in circulation and plays an important role in regulating vitamin D concentration and bioavailability for target tissues. To our knowledge, no previous studies have examined DBP, bioavailable and free 25-hydroxyvitamin D (25(OH)D) in women with PCOS. The primary aim of this study was to compare DBP, bioavailable and free 25(OH)D concentrations in women with PCOS and controls. The secondary aim was to investigate relationships between DBP, bioavailable and free 25(OH)D and metabolic features (anthropometric measures, insulin resistance, and lipid profile). In a cross sectional study using bio-banked samples, we measured 25(OH)D, DBP and albumin. Bioavailable and free 25(OH)D were calculated using previously validated formula. BMI, body composition (dual X-ray absorptiometry, DXA), insulin resistance (homeostatic model assessment of insulin resistance (HOMA-IR)) and glucose infusion rate (GIR) from hyperinsulinaemic euglycaemic clamp and serum lipids (ELISA) were also measured in a physically and biochemically well-characterised cohort of women with and without PCOS. We studied 90 women with PCOS and 59 controls aged 18-48 years. DBP concentrations were lower in PCOS compared to controls (median [IQR]: 443.40 [314.4] vs 482.4 [156.8] μg/ml, p=0.02). No significant differences were found in bioavailable or free 25(OH)D concentrations between groups. DBP was not associated with BMI, percent body fat or markers of insulin resistance (all p>0.2). High-density lipoprotein (HDL) was the main determinant of DBP in the overall cohort (β=-0.12, p=0.02), after adjusting for covariates including PCOS/control status, age, BMI, total 25(OH)D and HOMA-IR. In PCOS, total and free 25(OH)D were related to markers of insulin resistance and lipids. Only the associations between free 25(OH)D and triglycerides (p=0.02), and HDL (p=0.03) remained significant after adjusting for age and BMI. In conclusion, women with PCOS had lower DBP, but similar bioavailable or free 25(OH)D concentrations compared to controls, independent of BMI and age. DBP was not associated with insulin resistance or BMI in PCOS. Further studies are needed to investigate the pathophysiology and clinical implications of reduced DBP in PCOS.

The association between dysregulated adipocytokines in early pregnancy and development of gestational diabetes

To investigate the association of adipocytokines and other inflammatory markers with development of GDM.

High-molecular-weight adiponectin is inversely associated with sympathetic activity in polycystic ovary syndrome

OBJECTIVE To examine the role of high-molecular-weight (HMW) adiponectin and its relationship to sympathetic activity in women with polycystic ovary syndrome (PCOS). DESIGN Cross sectional study using biobanked samples. SETTING Not applicable. PATIENT(S) Premenopausal women with PCOS (n = 46, Rotterdam diagnostic criteria) and without PCOS (n = 22). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) High-molecular-weight adiponectin levels with secondary outcomes of sympathetic activity and leptin levels. RESULT(S) The high-molecular-weight adiponectin level was lower in women with PCOS (median 2.2 [interquartile range (IQR)2.3] μg/mL) than in controls (median 3 [IQR2.5] μg/mL) (age and BMI adjusted), and it correlated inversely with the values measured for homeostatic model of assessment of insulin resistance (HOMA-IR), fasting insulin, triglycerides, and free androgen index and positively with sex hormone-binding globulin (SHBG) and high-density lipoprotein cholesterol in all participants and in the PCOS group. In the PCOS group, sympathetic activity (burst frequency) was statistically significantly higher than in controls (median 26 [IQR11] vs. median 22 [IQR14], respectively) and correlated inversely with HMW adiponectin (r = -0.230). The leptin levels were similar between the women with PCOS and controls and did not statistically significantly correlate with HMW adiponectin or sympathetic activity. On multiple regression analysis, burst frequency and SHBG explained 40% of the HMW adiponectin variability (B = -0.7; 95% CI -1.2 to -0.2; and B = 0.01; 95% CI 0.004-0.01) in PCOS. CONCLUSION(S) Alongside insulin resistance, increased sympathetic activity is associated with and may modulate HMW adiponectin levels in women with PCOS.

Effect of Central Sympathoinhibition With Moxonidine on Sympathetic Nervous Activity in Polycystic Ovary Syndrome—A Randomized Controlled Trial

Sympathetic nervous system (SNS) activity is increased in polycystic ovary syndrome (PCOS). Moxonidine is a centrally acting sympatholytic drug with known beneficial effects on hypertension, insulin sensitivity, dyslipidemia and inflammation. In this double-blind placebo controlled randomized clinical trial we examined the effect of moxonidine on modulating sympathetic activity and downstream metabolic abnormalities in 48 pre-menopausal women with PCOS (Rotterdam diagnostic criteria), recruited from the community (January 2013–August 2015). Participants received moxonidine (0.2 mg daily initially, up titrated to 0.4 mg daily in 2 weeks) (n = 23) or placebo (n = 25) for 12 weeks. Multiunit muscle sympathetic activity (by microneurography) and plasma noradrenaline levels were measured (primary outcomes). Fasting lipids, insulin resistance, serum androgens, and inflammatory markers were measured as secondary outcomes. Forty three women completed the trial (19 moxonidine, 24 placebo). Mean change in burst frequency (−3 ± 7 vs. −3 ± 8 per minute) and burst incidence (−3 ± 10 vs. −4 ± 12 per 100 heartbeat) did not differ significantly between moxonidine and placebo groups. Women on moxonidine had a significant reduction in hs-CRP compared to placebo group (−0.92 ± 2.3 vs. −0.04 ± 1.5) which did not persist post Bonferroni correction. There was a significant association between markers of insulin resistance at baseline and reduction in sympathetic activity with moxonidine. Moxonidine was not effective in modulating sympathetic activity in PCOS. Anti-inflammatory effects of moxonidine and a relationship between insulin resistance and sympathetic response to moxonidine are suggested which need to be further explored. Clinical Trial Registration Number: (NCT01504321)

Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic inflammation in PCOS

Insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic low‐grade inflammation may act together in a vicious cycle in the pathophysiology of PCOS. However, the inter‐relationships of these components are not fully understood. We aimed to study these mechanisms in the pathophysiology of PCOS.