Systematic review and meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome.

Screening for polycystic ovary syndrome (PCOS) in antenatal care is inadequate, largely owing to the lack of clarity around whether PCOS is an independent risk factor for pregnancy complications. This systematic review and meta-analysis include 104 studies and 106,690 pregnancies in women with and without PCOS from inception until 13th July 2022. We report that women with PCOS are younger and have higher body mass index (BMI) around conception and have greater gestational weight gain. The odds of miscarriage, gestational diabetes mellitus, gestational hypertension, pre-eclampsia and cesarean section are higher in women with PCOS. The increased odds of adverse outcomes in PCOS remain significant when age and BMI are matched and when analyses are restricted to high-quality studies. This work informed the recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome, emphasizing that PCOS status should be captured in all women who are planning to, or have recently become pregnant to facilitate prevention of adverse outcomes and improve pregnancy outcomes.

Systematic review and meta-analysis of birth outcomes in women with polycystic ovary syndrome.

It is unclear whether polycystic ovary syndrome (PCOS) is an independent risk factor for adverse birth outcomes in the offspring of affected women. Here, we investigate the association of PCOS with birth outcomes in the offspring of women with PCOS overall and by potential confounders. This systematic review and meta-analysis included 73 studies and 92,881 offspring of women with and without PCOS from inception until 13th July 2022. We report that mothers with PCOS are younger and have higher body mass index (BMI) around conception and have greater gestational weight gain. The odds of preterm birth, fetal growth restriction and low birth weight are higher and mean birthweight is lower in PCOS of which a lower mean birthweight and a higher small for gestational age are probably independent of BMI. This work informed the recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome, emphasizing that PCOS status should be captured at pregnancy to identify risk and improve birth outcomes in the offspring.

High-intensity training elicits greater improvements in cardio-metabolic and reproductive outcomes than moderate-intensity training in women with polycystic ovary syndrome: a randomized clinical trial.

STUDY QUESTION: Does 12 weeks of high-intensity interval training (HIIT) result in greater improvements in cardio-metabolic and reproductive outcomes compared to standard moderate-intensity continuous training (MICT) in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: HIIT offers greater improvements in aerobic capacity, insulin sensitivity and menstrual cyclicity, and larger reductions in hyperandrogenism compared to MICT. WHAT IS KNOWN ALREADY: Exercise training is recognized to improve clinical outcomes in women with PCOS, but little is known about whether HIIT results in greater health outcomes compared to standard MICT. STUDY DESIGN, SIZE, DURATION: This was a two-armed randomized clinical trial enrolling a total of 29 overweight women with PCOS between May 2016 and November 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS aged 18-45 years were randomly assigned to 12 weeks of either MICT (60-75% peak heart rate, N = 14) or HIIT (>90% peak heart rate, N = 15), each completed three times per week. The primary clinical outcomes were aerobic capacity (VO2peak) and insulin sensitivity (euglycaemic-hyperinsulinaemic clamp). Secondary outcomes included hormonal profiles, menstrual cyclicity and body composition. MAIN RESULTS AND THE ROLE OF CHANCE: Both HIIT and MICT improved VO2peak (HIIT; Δ 5.8 ± 2.6 ml/kg/min, P < 0.001 and MICT; Δ 3.2 ± 2 ml/kg/min, P < 0.001), however, the HIIT group had a greater improvement in aerobic capacity compared to MICT (ß = 2.73 ml/kg/min, P = 0.015). HIIT increased the insulin sensitivity index compared to baseline (Δ 2.3 ± 4.4 AU, P = 0.007) and MICT (ß = 0.36 AU, P = 0.030), and caused higher increases in sex hormone-binding globulin compared to MICT (ß = 0.25 nmol/l, P = 0.002). HIIT participants were 7.8 times more likely to report improved menstrual cyclicity than those in the MICT group (odds ratio 7.8, P = 0.04). LIMITATIONS, REASONS FOR CAUTION: This study has a small sample size and the findings of the effect of the exercise interventions are limited to overweight reproductive-aged women, who do not have any co-existing co-morbidities that require medication. WIDER IMPLICATIONS OF THE FINDINGS: Exercise, regardless of intensity, has clear health benefits for women with PCOS. HIIT appears to be a more beneficial strategy and should be considered for promoting health and reducing cardio-metabolic risk in overweight women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a Project Support Grant from the Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence in PCOS. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: ACTRN12615000242527. TRIAL REGISTRATION DATE: 19 February 2015. DATE OF FIRST PATIENT'S ENROLMENT: 27 May 2016.

Does moxonidine reduce Achilles tendon or musculoskeletal pain in women with polycystic ovarian syndrome? A secondary analysis of a randomised controlled trial.

BACKGROUND: Sympathetic activity and insulin resistance have recently been linked with chronic tendon and musculoskeletal pain. Polycystic ovarian syndrome is linked with insulin resistance and increased sympathetic drive and was therefore an appropriate condition to study the effects of modulating sympathetic activity on Achilles tendon and musculoskeletal symptoms. METHODS: A secondary analysis of a double-blinded, randomised controlled trial on women with polycystic ovarian syndrome was conducted. Participants received 12 weeks of moxonidine (n = 14) or placebo (n = 18). Musculoskeletal symptom and Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaires were distributed, and ultrasound tissue characterisation quantified tendon structure at 0 and 12 weeks. 2-way ANOVA was used for multiple comparisons. RESULTS: There was no difference in mean change in musculoskeletal symptoms (- 0.6 ± 1.7 vs - 0.4 ± 1.8, p = 0.69) or VISA-A (moxonidine - 0.2 ± 8.8 vs placebo + 4.2 ± 14.6, p = 0.24) attributable to the intervention. There was no difference in any measures of Achilles structure. Moxonidine did not reduce sympathetic drive when compared to placebo. CONCLUSIONS: This was the first study to investigate the effects of blocking sympathetic drive on musculoskeletal and Achilles tendon symptoms in a metabolically diverse population. While the study was limited by small sample size and lack of sympathetic modulation, moxonidine did not change tendon pain/structure or musculoskeletal symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01504321 . Registered 5 January 2012.

The Relationship between Vitamin D Metabolites and Androgens in Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, with hyperandrogenism present in up to 90% of affected women. Some evidence suggests a link between vitamin D deficiency and PCOS features via insulin resistance and inflammation. Our aim was to explore the relationship between biochemical markers of vitamin D status and androgens in women with PCOS. This cross-sectional study used bio-banked samples from 46 pre-menopausal women with PCOS (mean ± SD: age 30 ± 6 years; BMI 29 ± 6 kg/m2). We measured 25-hydroxyvitamin D (25[OH]D), vitamin D-binding protein (DBP), total testosterone, sex hormone-binding globulin (SHBG), and calculated the free androgen index (FAI) and bioavailable and free 25(OH)D. Fasting glucose and insulin were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) and body fat percentage was determined via dual energy x-ray absorptiometry. High-sensitivity C-reactive protein (hs-CRP) was measured as a marker of inflammation. DBP was positively associated with total 25(OH)D and expectedly, negatively associated with free 25(OH)D. There were no associations between vitamin D metabolites and total testosterone, SHBG or FAI, even after adjusting for age, body fat percentage, HOMA-IR and hs-CRP. We found no associations between vitamin D metabolites and androgens in women with PCOS. Studies that have identified a vitamin D-androgen link have largely relied on methodology with numerous pitfalls; future studies should exclusively use gold-standard measures to confirm these findings in this population.

The Role of Lifestyle Intervention in the Prevention and Treatment of Gestational Diabetes.

Obesity during pregnancy is associated with the development of adverse outcomes, including gestational diabetes mellitus (GDM). GDM is highly associated with obesity and independently increases the risk of both complications during pregnancy and future impaired glycemic control and risk factors for cardiovascular disease for both the mother and child. Despite extensive research evaluating the effectiveness of lifestyle interventions incorporating diet and/or exercise, there remains a lack of definitive consensus on their overall efficacy alone or in combination for both the prevention and treatment of GDM. Combination of diet and physical activity/exercise interventions for GDM prevention demonstrates limited success, whereas exercise-only interventions report of risk reductions ranging from 3 to 49%. Similarly, combination therapy of diet and exercise is the first-line treatment of GDM, with positive effects on maternal weight gain and the prevalence of infants born large-for-gestational age. Yet, there is inconclusive evidence on the effects of diet or exercise as standalone therapies for GDM treatment. In clinical care, women with GDM should be treated with a multidisciplinary approach, starting with lifestyle modification and escalating to pharmacotherapy if needed. Several key knowledge gaps remain, including how lifestyle interventions can be optimized during pregnancy, and whether intervention during preconception is effective for preventing the rising prevalence of GDM.

The effectiveness of high intensity intermittent training on metabolic, reproductive and mental health in women with polycystic ovary syndrome: study protocol for the iHIT- randomised controlled trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive-metabolic condition. Insulin resistance is a hallmark of PCOS and is related to increased hyperandrogenism that drives inherent metabolic, reproductive and psychological features of the syndrome. Insulin resistance in women with PCOS is managed by weight loss, lifestyle interventions (i.e. exercise, diet) and insulin-sensitising medications. This manuscript describes the protocol of our study evaluating the effectiveness of high intensity intermittent training (HIIT) or moderate intensity exercise on cardiometabolic, reproductive and mental health in overweight women with PCOS. METHODS/DESIGN: We will employ a three arm, parallel-group, randomised controlled trial recruiting 60 women diagnosed with PCOS, aged between 18 and 45 years and with a body mass index (BMI) greater than 25 kg/m2. Following screening and baseline testing, women will be randomised by simple randomisation procedure using computer generated sequence allocation to undergo one of two 12-week supervised interventions: either HIIT or moderate intensity exercise (standard supervised exercise), or to standard care [Con] (unsupervised lifestyle advice) at a 1:1:1 allocation ratio. The primary outcome for this trial is to measure the improvements in metabolic health; specifically changes in insulin sensitivity in response to different exercise intensities. Baseline and post-intervention testing include anthropometric measurements, cardiorespiratory fitness testing, reproductive hormone profiles (anti-müllerian hormone and steroid profiles), metabolic health, health-related quality of life and mental health questionnaires and objective and subjective lifestyle monitoring. Reporting of the study will follow the CONSORT statement. DISCUSSION: This trial aims to demonstrate the comparative efficacy and maintenance of different exercise intensities to advance the understanding of PCOS management and provide insight into the optimal exercise intensity for improved cardiometabolic outcomes. Secondary outcomes will include the impact of different exercise protocols on reproductive hormone profiles, mental health and health-related quality of life. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000242527 . Registered on 17 March 2015.

Role of serum biomarkers to optimise a validated clinical risk prediction tool for gestational diabetes.

BACKGROUND: Clinical risk prediction tools for gestational diabetes (GDM) may be enhanced by measuring biomarkers in early pregnancy. AIM: To evaluate a two-step GDM risk prediction tool incorporating fasting glucose (FG) and serum biomarkers in early pregnancy. MATERIALS AND METHODS: High molecular weight (HMW) adiponectin, omentin-1 and interleukin-6 (IL-6) were measured at 12-15 weeks gestation in women with high risk of GDM from a randomised trial using a clinical risk prediction tool. GDM diagnosis (24-28 weeks) was evaluated using 1998 Australian Diabetes in Pregnancy (ADIPS) criteria and newer International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria. Associations between biomarkers and development of GDM were examined using multivariable regression analysis. Area under the receiver-operator curve (AUC), sensitivity and specificity were calculated to determine classification ability of each model compared to FG and maternal characteristics. RESULTS: HMW adiponectin improved prediction of ADIPS GDM (AUC 0.85, sensitivity 50%, specificity 96.2%, P = 0.04), compared to FG and maternal factors (0.78, 35% and, 98.1%, respectively). HMW adiponectin <1.53 µg/mL further improved the model (AUC 0.87, sensitivity 75%, specificity 88.2%, P = 0.01). HMW adiponectin did not improve prediction of IADPSG GDM (AUC 0.84, sensitivity 64%, specificity 97.9%, P = 0.22) compared to FG and maternal factors (0.79, 56%, 93.8%). Omentin-1 and IL-6 did not significantly improve classification ability for GDM. CONCLUSIONS: A two-step approach combining FG and HMW adiponectin to a validated clinical risk prediction tool improved sensitivity and predictive ability for ADIPS GDM. Further research is required to enhance GDM prediction using IADPSG criteria for application in clinical practice.

Brown adipose tissue thermogenesis in polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with increased obesity with a greater propensity to weight gain and a lack of sustainable lifestyle interventions. Altered brown adipose tissue (BAT) thermogenesis is a potential contributor to obesity in PCOS. BAT activity and modulation have not been studied in PCOS. This observational study explored BAT thermogenesis and its associations in women with and without PCOS. PARTICIPANTS AND METHODS: Cutaneous temperature was recorded from supraclavicular (indicator of BAT activity) and upper arm regions using dataloggers (SubCue, Calgary, Canada) in a cross-sectional substudy, nested within a randomized control trial, of community-recruited premenopausal women with (n = 47, Rotterdam diagnostic criteria) and without (n = 11) PCOS. RESULTS: Complete temperature data were available in 44 PCOS (mean age: 30.0 ± 6.2, mean BMI: 29.3 ± 5.5) and 11 non-PCOS (mean age: 33.0 ± 7.0, mean BMI: 25 ± 3) women. Women with PCOS had lower supraclavicular skin temperature compared to controls overall (33.9 ± 0.7 vs 34.5 ± 1, P < 0.05) and during sleep (34.5 ± 0.6 vs 35.2 ± 0.9, P < 0.001). In the PCOS group, supraclavicular skin temperature overall and over sleep and waking hours correlated inversely with testosterone (r = -0.41 P < 0.05, r = -0.485 P < 0.01 and r = -0.450 P < 0.01 respectively). Testosterone levels explained approximately 15%, 30% and 20% of the variability in supraclavicular skin temperature overall and over sleep and waking hours in women with PCOS, respectively. CONCLUSION: Women with PCOS have lower BAT activity compared to controls. BAT thermogenesis is negatively associated with androgen levels in 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.

OBJECTIVE: 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. PARTICIPANTS AND METHODS: Premenopausal women with PCOS (Rotterdam diagnostic criteria) and without PCOS were recruited from a community setting into a cross-sectional substudy within a randomized control trial. Insulin resistance (fasting insulin and glucose), hyperandrogenism (testosterone, sex hormone-binding globulin [SHBG] and Free Androgen Index [FAI]), muscle sympathetic nerve activity (MSNA) and markers of chronic low-grade inflammation (high sensitivity C-reactive protein [hs-CRP] and high molecular weight adiponectin [HMW-adiponectin]) were measured. RESULTS: Forty-nine women with PCOS (mean age 30 ± 6 mean BMI 29 ± 5) and 23 controls (mean age 29 ± 8 mean BMI 33 ± 7) with included in this analysis. MSNA and testosterone level were most significantly associated with PCOS status, after adjustment for age and BMI. In women with PCOS, markers of sympathetic activity correlated inversely with HMW-adiponectin and HMW-adiponectin correlated inversely with FAI. Testosterone and FAI both correlated positively with insulin resistance in women PCOS. CONCLUSION: Sympathetic dysfunction and hyperandrogenism are significantly associated with PCOS. Chronic low-grade inflammation potentially mediates the effect of sympathetic dysfunction on hyperandrogenism and insulin resistance.

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.

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 (ß=-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.

Efficacy of predictive models for polycystic ovary syndrome using serum levels of two antimüllerian hormone isoforms (proAMH and AMHN,C).

OBJECTIVE: To compare total antimüllerian hormone (AMH), proAMH, AMHN,C, and the ratio of the two forms in predictive models for polycystic ovary syndrome (PCOS) diagnosis. Total AMH consists of proAMH (inactive precursor) and AMHN,C (receptor-competent), but neither isoform has been tested individually for their ability to predict PCOS diagnosis. DESIGN: Cross-sectional study using biobanked samples collected between July 2008 and January 2010. SETTING: Not applicable. PATIENT(S): Overweight, premenopausal women aged 18-45 years with PCOS (n = 45, with 21 fulfilling National Institutes of Health diagnostic criteria and 24 fulfilling European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE) criteria, but not National Institutes of Health criteria) and without PCOS (n = 23 controls). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum concentrations of proAMH and total AMH (proAMH and AMHN,C combined) were determined by immunoassay. The AMHN,C concentrations were calculated by subtraction ([AMHN,C] = [total AMH] - [proAMH]). Relative levels of proAMH were expressed as the AMH prohormone index (API = [ProAMH]/[Total AMH] × 100). RESULT(S): In women with PCOS, total AMH, proAMH, and AMHN,C levels were higher, and the API was lower (P=.010), than in controls indicating increased conversion of proAMH to AMHN,C. Receiver-operating characteristic analysis for proAMH (area under the curve [AUC] = 0.82), AMHN,C (AUC = 0.86), and API (AUC = 0.70) did not improve the prediction for PCOS when compared with total AMH (AUC = 0.86). CONCLUSION(S): The proAMH and AMHN,C do not appear to improve the ability to predict a diagnosis of PCOS beyond total AMH assays. However, the ratio of inactive proAMH precursor to receptor-competent AMHN,C (API) differs in women with PCOS relative to unaffected controls indicating that AMH signaling mechanisms may be altered in women with PCOS.

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

BACKGROUND: To investigate the association of adipocytokines and other inflammatory markers with development of GDM. METHODS: Serum adipocytokines and inflammatory markers were studied at 12 to 15 weeks gestation using biobanked control samples from a randomised trial. Study participants were identified as high risk for GDM using a validated clinical risk prediction tool. Markers were tested using commercial ELISA kits for high molecular weight (HMW) adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1, visfatin, omentin-1, sex-hormone binding globulin, monocyte chemoattractant protein, and asymmetrical dimethylarginine. The association between each biomarker and development of GDM at 24 to 28 weeks was evaluated using multivariable logistic regression analysis adjusted for maternal factors. RESULTS: There were no differences in age, parity, country of birth, smoking, body mass index, or family history of diabetes in women with normal glucose tolerance (n = 78) and women who developed GDM (n = 25). Women with GDM were more likely to have a past history of GDM (P = 0.004). HMW adiponectin (odds ratio OR 0.37 [95% confidence interval 0.19-0.74]), omentin-1 (0.97 [0.94-0.99]), and IL-6 (1.87[1.03-3.37]) were associated with development of GDM, after adjustment for maternal age, body mass index, and past history of GDM. The other markers were not associated with GDM development. CONCLUSIONS: Decreased high molecular weight adiponectin and omentin-1 and increased IL-6 may enhance sensitivity of early risk prediction tools for women at high risk of GDM. This may allow early identification and opportunities for prevention of GDM and adverse outcomes. Further research is required in large validation studies to confirm these results.

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.

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.

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.