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Polycystic ovary syndrome (PCOS) affects about 12% of women of reproductive age. In 2018, the first evidence-based guideline on assessment and management of PCOS was published, and an updated extended guideline was released in August 2023. These guidelines followed best practice and are endorsed by 39 organizations worldwide, making them the most robust source of evidence to guide clinical practice. In the 2023 guideline, diagnostic criteria have been further refined as polycystic ovary morphology can now be assessed with gynecological ultrasound or elevated anti-Müllerian hormone levels. A healthy lifestyle should be at the focus of care for all women with PCOS; however, with no specific diet or physical exercise recommended. The latest evidence on medical treatments and fertility management are reviewed, including special considerations regarding long-term follow-up of metabolic and psychiatric comorbidities and pregnancy in women with PCOS. Here we summarize the recommendations from a Nordic perspective., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

The number of frozen embryo transfer (FET) cycles is increasing rapidly worldwide. Different endometrial preparations for FET result in comparable live birth rates. However, several recent publications have reported higher maternal risks for hypertensive disorders of pregnancy (HDP), pre-eclampsia and postpartum haemorrhage (PPH) in programmed cycles (PC-FET) compared with natural cycles and modified natural cycles with an intact corpus luteum. Nevertheless, PC-FET is frequently used in ovulatory women despite the increased risks for HDP, pre-eclampsia and PPH. Although randomized controlled studies have been suggested, PC-FET raises several methodological problems. Large study populations would be required to investigate the outcomes in question, and the inclusion of ovulatory women, where the intervention may increase the risk of a negative outcome, is ethically troublesome. In the authors' opinion, the existing evidence from large observational studies and systematic reviews is sufficiently strong to recommend an endometrial preparation strategy that aims to maintain or stimulate the corpus luteum to minimize the risk of HDP and pre-eclampsia after FET cycles., (Copyright © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: Current use of combined hormonal contraceptives worsens glucose tolerance and increases the risk of type 2 diabetes mellitus at late fertile age, but the impact of their former use on the risk of glucose metabolism disorders is still controversial., Material and Methods: This was a prospective, longitudinal birth cohort study with long-term follow-up consisting of 5889 women. The cohort population has been followed at birth, and at ages of 1, 14, 31 and 46. In total, 3280 (55.7%) women were clinically examined and 2780 also underwent a 2-h oral glucose tolerance test at age 46. Glucose metabolism indices were analyzed in former combined hormonal contraceptive users (n = 1371) and former progestin-only contraceptive users (n = 52) and in women with no history of hormonal contraceptive use (n = 253)., Results: Compared with women with no history of hormonal contraceptive use, those who formerly used combined hormonal contraceptives for over 10 years had an increased risk of prediabetes (odds ratio [OR] 3.9, 95% confidence interval [CI]: 1.6-9.2) but not of type 2 diabetes mellitus. Former progestin-only contraceptive use was not associated with any glucose metabolism disorders. The results persisted after adjusting for socioeconomic status, smoking, alcohol consumption, parity, body mass index and use of cholesterol-lowering medication., Conclusions: Former long-term use of combined hormonal contraceptives was associated with a significantly increased risk of prediabetes in perimenopausal women, which potentially indicates a need of screening for glucose metabolism disorders in these women., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Study Question: What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature?, Summary Answer: The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI., What Is Known Already: UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation., Study Design, Size, Duration: The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated., Participants/materials, Setting, Methods: Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee., Main Results and the Role of Chance: This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided., Limitations, Reasons for Caution: Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised., Wider Implications of the Findings: The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI., Study Funding/competing Interest(s): The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose., Disclaimer: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.)., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction and Hypothesis: This study was aimed at investigating the long-term effectiveness of minimally invasive mid-urethral sling (MUS) surgery and at comparing the outcomes between retropubic (tension-free vaginal tape, TVT) and transobturator tape (TOT) methods in the treatment of stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) with a predominant stress component in a long-term follow-up of a randomized controlled trial., Methods: This work is a long-term follow-up study of a previous prospective randomized trial conducted in the Department of Obstetrics and Gynecology at Oulu University Hospital between January 2004 and November 2006. The original 100 patients were randomized into the TVT (n=50) or TOT (n=50) group. The median follow-up time was 16 years, and the subjective outcomes were evaluated using internationally standardized and validated questionnaires., Results: Long-term follow-up data were obtained from 34 TVT patients and 38 TOT patients. At 16 years after MUS surgery, the UISS significantly decreased from a preoperative score in the TVT (11.88 vs 5.00, p<0.001) and TOT (11.05 vs 4.95, p<0.001) groups, showing a good long-term success of the MUS surgery in both groups. In comparing the TVT and TOT procedures, the subjective cure rates did not differ significantly between the study groups in long-term follow-up according to validated questionnaires., Conclusion: Midurethral sling surgery had good long-term outcomes in the treatment of SUI and MUI with a predominant stress component. The subjective outcomes of the TVT and TOT procedures were similar after a 16-year follow-up., (© 2023. The Author(s).)

Expressional profiling of the endometrium enables the personalised timing of the window of implantation (WOI). This study presents and evaluates a novel analytical pipeline based on a TAC-seq (Targeted Allele Counting by sequencing) method for endometrial dating. The expressional profiles were clustered, and differential expression analysis was performed on the model development group, using 63 endometrial biopsies spanning over proliferative (PE, n = 18), early-secretory (ESE, n = 18), mid-secretory (MSE, n = 17) and late-secretory (LSE, n = 10) endometrial phases of the natural cycle. A quantitative predictor model was trained on the development group and validated on sequenced samples from healthy women, consisting of 52 paired samples taken from ESE and MSE phases and five LSE phase samples from 31 individuals. Finally, the developed test was applied to 44 MSE phase samples from a study group of patients diagnosed with recurrent implantation failure (RIF). In validation samples (n = 57), we detected displaced WOI in 1.8% of the samples from fertile women. In the RIF study group, we detected a significantly higher proportion of the samples with shifted WOI than in the validation set of samples from fertile women, 15.9% and 1.8% (p = 0.012), respectively. The developed model was evaluated with an average cross-validation accuracy of 98.8% and an accuracy of 98.2% in the validation group. The developed beREADY screening model enables sensitive and dynamic detection of selected transcriptome biomarkers, providing a quantitative and accurate prediction of endometrial receptivity status., (© 2023. Springer Nature Limited.)

Objective: Available evidence has shown that metformin improves insulin sensitivity and weight management in polycystic ovary syndrome (PCOS). Nevertheless, key knowledge gaps remain regarding its efficacy and the specific outcomes in this population. This review evaluates the effectiveness of metformin and lifestyle modification compared with placebo in the management of PCOS and will inform the forthcoming, 2023 evidence-based PCOS guidelines., Design: Systematic review and meta-analysis of the literature., Methods: A search was performed in MEDLINE, EMBASE, PsycINFO, All EBM, and CINAHL. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and included randomized controlled trials published in English through July 2022., Results: Moderate certainty of evidence showed a larger reduction of body mass index (BMI) (mean difference [MD] -0.53, 95% confidence interval [CI] -0.95 to -0.12 kg/m2), homeostatic model assessment for insulin resistance (MD -0.50, 95% CI -0.91 to -0.09) (critical outcomes), and fasting glucose (MD -0.13, 95% CI -0.19 to -0.07 mmol/L) with metformin compared to placebo with increased mild gastrointestinal adverse effects (odds ratio [OR] 7.67, 95% CI 2.74-21.46). Low certainty of evidence showed a larger reduction of waist-hip ratio (MD -0.02, 95% CI -0.03 to -0.00), total cholesterol (MD -0.24, 95% CI -0.43 to -0.05 mmol/L), low-density lipoprotein (MD -0.16, 95% CI -0.30 to -0.01 mmol/L), and triglycerides (MD -0.11, 95% CI -0.20 to -0.02 mmol/L) with metformin than placebo., Conclusions: Metformin should be considered an efficacious adjunct to lifestyle interventions in adults with PCOS, especially for those with a higher BMI, to improve weight loss, insulin resistance, and lipids., Competing Interests: Conflict of interest: J.M. reports a postdoc research grant from Orion Research Foundation. D.R. reports an honorarium from Novo Nordisk for a lecture on PCOS and obesity. T.P. is on the editorial board of the European Journal of Endocrinology but was not involved in the review or editorial process of this paper. The other authors have no conflicts to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Objective: To compare between different combined oral contraceptive pills (COCPs) as part of the update of the International Evidence-Based Guidelines on the Assessment and Management of polycystic ovary syndrome (PCOS)., Design: A systematic review and meta-analysis was performed, Prospero CRD42022345640., Methods: MEDLINE, EMBASE, All EBM, CINAHL, and PsycINFO was searched on July, 8, 2022, for studies including women with PCOS, comparing 2 different COCPs in randomized controlled trials., Results: A total of 1660 studies were identified, and 19 randomized controlled trials (RCTs) were included.Fourth-generation COCP resulted in lower body mass index (BMI) (mean difference [MD] 1.17 kg/m2 [95% confidence interval {CI} 0.33; 2.02]) and testosterone (MD 0.60 nmol/L [95% CI 0.13; 1.07]) compared with third-generation agents, but no difference was seen in hirsutism.Ethinyl estradiol (EE)/cyproterone acetate (CPA) was better in reducing hirsutism as well as biochemical hyperandrogenism (testosterone [MD 0.38 nmol/L {95% CI 0.33-0.43}]) and BMI (MD 0.62 kg/m2 [95% CI 0.05-1.20]) compared with conventional COCPs.There was no difference in hirsutism between high and low EE doses. No evidence regarding natural estrogens in COCP was identified., Conclusion: With current evidence, combined regimens containing an antiandrogen (EE/CPA) may be better compared with conventional COCPs in reducing hyperandrogenism, but EE/CPA will not be recommended as a first-line COCP treatment by the pending PCOS guideline update, due to higher venous thrombotic events (VTE) risk in the general population. Later-generation progestins offer theoretical benefits, but better evidence on clinical outcomes is needed in women with PCOS., Trial Registration: The protocol for the systematic review was registered prospectively in Prospero, CRD42022345640., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Objective: As part of the update of the International Evidence-Based Guidelines for the Assessment and Management of polycystic ovary syndrome (PCOS), a systematic review was performed to inform evidence-based recommendations., Design: Systematic review. Only randomised controlled trial were included., Patients: Women with PCOS; the use of combined oral contraceptive pills (COCP) was compared with no medical treatment., Measurements: Outcomes were designed in collaboration with clinical experts, researchers, and consumers. Critical outcomes included hirsutism, irregular cycles, quality of life, body mass index (BMI), and weight., Results: 1660 publications were identified, but only four studies were included. No studies could be combined for meta-analysis. COCP treatment improved cycle regularity compared with no medical treatment (100% vs. 0%, with low certainty of evidence). COCP showed no difference in improvement of hirsutism or BMI compared with placebo or lifestyle; a lower weight after COCP compared with no treatment (mean difference [MD] -8.0 (95% confidence interval, CI -11.67); -4.33 kg); and improvement in quality of life (MD 1.2 [95% CI 0.96]; 1.44), but these results were all very low certainty of evidence., Conclusion: Results show that COCP benefit cycle regulation, but other benefits or potential adverse effects were only identified with very low certainty of evidence. The COCP is frontline medical treatment in PCOS, but this is still based on established efficacy in the broader general population. Our results show that research in PCOS is seriously lacking and should be prioritised to capture core reproductive, metabolic and psychological outcomes important in PCOS., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This clinical trial aims to compare hormonal and metabolic changes after a 9-week continuous use of oral or vaginal combined hormonal contraceptives (CHCs) in women with polycystic ovary syndrome (PCOS). We recruited 24 women with PCOS and randomized them to use either combined oral (COC, n = 13) or vaginal (CVC, n = 11) contraception. At baseline and 9 weeks, blood samples were collected and a 2 h glucose tolerance test (OGTT) was performed to evaluate hormonal and metabolic outcomes. After treatment, serum sex hormone binding globulin (SHBG) levels increased ( p < 0.001 for both groups) and the free androgen index (FAI) decreased in both study groups (COC p < 0.001; CVC p = 0.007). OGTT glucose levels at 60 min ( p = 0.011) and AUCglucose ( p = 0.018) increased in the CVC group. Fasting insulin levels ( p = 0.037) increased in the COC group, and insulin levels at 120 min increased in both groups (COC p = 0.004; CVC p = 0.042). There was a significant increase in triglyceride ( p < 0.001) and hs-CRP ( p = 0.032) levels in the CVC group. Both oral and vaginal CHCs decreased androgenicity and tended to promote insulin resistance in PCOS women. Larger and longer studies are needed to compare the metabolic effects of different administration routes of CHCs on women with PCOS.

Background: Testosterone levels are linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of genetically determined testosterone on complex diseases in both sexes., Methods: Leveraging genetic and health registry data from the UK Biobank and FinnGen (total N = 625,650), we constructed polygenic scores (PGS) for total testosterone, sex-hormone binding globulin (SHBG) and free testosterone, associating these with 36 endpoints across different disease categories in the FinnGen. These analyses were combined with Mendelian Randomization (MR) and cross-sex PGS analyses to address causality., Results: We show testosterone and SHBG levels are intricately tied to metabolic health, but report lack of causality behind most associations, including type 2 diabetes (T2D). Across other disease domains, including 13 behavioral and neurological diseases, we similarly find little evidence for a substantial contribution from normal variation in testosterone levels. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also illustrate how testosterone levels associate with antagonistic effects on stroke risk and reproductive endpoints between the sexes., Conclusions: Overall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes. Yet the lack of evidence for a causal contribution to most traits beyond sex-specific health underscores the complexity of the mechanisms linking testosterone levels to disease risk and sex differences., (© 2023. The Author(s).)

Objective: To investigate whether there is an association between endometriosis and nongynecological diseases in the general female population by age 50?, Design: A prospective cohort study., Setting: Study participants with and without endometriosis were identified from a general population-based birth cohort. The analyzed data, linking to the national hospital discharge registers, spanned up to the age of 50 years., Patient(s): Endometriosis case identification was based on national register data and self-reported diagnoses, producing a study population of 349 women with endometriosis and 3,499 women without endometriosis., Main Outcome Measure(s): International Classification of Diseases diagnosis codes from 1968 to 2016 were accumulated from the Finnish national Care Register for Health Care, whereas self-reported symptoms and continuous medication usage data were collected from the questionnaires distributed at age 46. The associations between endometriosis and comorbidities were assessed using logistic regression models that included several covariates. The odds ratios and 95% confidence intervals (CIs) were modeled. Endometriosis subtype and temporal analyses were also performed., Result(s): Women with endometriosis were on average twice as likely to have hospital-based nongynecological diagnoses as women without endometriosis (adjusted odds ratio [aOR] 2.32; 95% CI, 1.07-5.02). In more detail, endometriosis was associated with allergies, infectious diseases, pain-causing diseases, and respiratory diseases. Moreover, the affected women presented with nonspecific symptoms and signs (aOR 3.56; 95% CI, 2.73-4.64), especially abdominal and pelvic pain (aOR 4.33; 95% CI, 3.13-4.76) more often compared with nonendometriosis controls. The temporal analysis revealed that diagnoses accumulated at a significantly younger age among women with endometriosis than in nonendometriosis counterparts., Conclusion(s): Women with endometriosis have a high risk for several chronic diseases compared with women without endometriosis, underlying the need for awareness and targeted resources for these women in the health care system. Moreover, endometriosis should be considered in the presence of nonspecific symptoms and abdominal pain, as they may conceal the disease and cause considerable delay in diagnosis and treatment., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials., Study Design: The two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m 2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings., Results: Of 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment., Conclusions: E4/DRSP is associated with a favorable tolerability and safety profile., Implications Statement: Pooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen., Study Design: We pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors., Results: Analyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m 2 . The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI <25 kg/m 2 , 25 to 29.9 kg/m 2 , and ≥30 kg/m 2 of 1.14 (0.64-1.88), 2.19 (1.05-4.03), and 2.27 (0.83-4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] 3.61[1.56-8.38]), Black race (HR 4.61[1.97-10.80]), age 16 to 25 years (HR 2.37[1.09-5.15]) and compliance <99% of expected pills (HR 4.21[2.04-8.66]) with conception., Conclusion: E4/DRSP is an effective oral contraceptive overall and across subgroups stratified by age, contraceptive history, and BMI. Other than compliance, predictors of contraceptive failure are nonmodifiable., Implications Statement: Pooled results from two phase 3 trials demonstrate high contraceptive efficacy of the novel estetrol-drospirenone oral contraceptive. Several non-modifiable risk factors, including prior pregnancy, race, and age, are associated with higher pregnancy risk. Additional research is needed to better understand predictors of combined oral contraceptive failure., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen., Study Design: We pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m 2 . Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes., Results: We included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m 2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event., Conclusion: E4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns., Implications Statement: Most estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive., (Copyright © 2022. Published by Elsevier Inc.)

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting 8%-13% of reproductive-aged women. The aetiology of the syndrome is complex, with genetic susceptibility, androgen exposure in early life and adiposity related dysfunction leading to perturbance in hypothalamic-ovarian function. PCOS clinical features are heterogeneous, with manifestations arising even in early adolescence, developing into multisystem reproductive, metabolic and psychological manifestations in adulthood. In this review, we will discuss challenges in the diagnosis of PCOS and understanding of the natural history of PCOS., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objectives: To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg., Design: Multicenter, open-label, phase 3 trial., Setting: Sixty-nine sites in Europe and Russia., Population: Sexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m 2 ., Methods: E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary., Main Outcome Measures: Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs., Results: A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events., Conclusion: E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile., Tweetable Abstract: A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile., (© 2021 Estetra SRL. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Purpose: Populations living in the Nordic countries are at high risk for vitamin D (VitD) deficiency or insufficiency. To reduce the risk, nationwide interventions based on food fortification and supplementation are being implemented. However, there is limited evidence about the impact of such public health campaigns on target populations., Methods: We studied an unselected sample of 3650 participants (56.2% females) from the longitudinal Northern Finland Birth Cohort 1966 with repeated measures of serum 25-hydroxyvitamin D [25(OH)D] at ages 31 (1997) and 46 (2012-2013). Timepoints corresponded to the period before and during the food fortification. We examined the effect of VitD intake from the diet and supplementation, body mass index and previous 25(OH)D concentration on 25(OH)D concentration at 46 years using a multivariable linear regression analysis. A 25(OH)D z score adjusted for sex, season, latitude and technical effect was used in the analysis., Results: We observed an increase of 10.6 nmol/L in 25(OH)D, when the baseline 25(OH)D was 54.3 nmol/L. The prevalence of serum 25(OH)D below < 50 nmol/L was halved. The changes were found for both sexes and were more pronounced in winter compared to summer months. Regular VitD supplementation had a significant positive effect on 25(OH)D at the age of 46, as well as had the dietary intake of fortified dairy products and fish, and the previous 25(OH)D concentration. However, the intake of fat-spreads albeit VitD-fortified, did not predict 25(OH)D., Conclusion: Our results demonstrated the positive impact of the fortification programme on VitD status in middle-aged population., (© 2021. The Author(s).)

Objectives: Altered intestinal permeability and gut barrier dysfunction have been suggested to play a role in the pathogenetic mechanism of polycystic ovary syndrome (PCOS), the most common endocrine and metabolic condition in reproductive-aged women. However, data on intestinal permeability and dysbiosis of the gut microbiota in PCOS is still limited, with conflicting results. To this end, the concentrations of gastrointestinal permeability and gut dysbiosis markers were analysed in women with PCOS., Design: Case-control study., Setting: General community., Participants: 104 women with PCOS and 203 body mass index (BMI) matched control women at age 46., Primary and Secondary Outcome Measures: Serum levels of zonulin, fatty acid-binding protein 2 (FABP2), urinary levels of indican, and hormonal and metabolic parameters., Results: Serum levels of zonulin (128.0±17.0 vs 130.9±14.0 ng/mL, p=0.13) and FABP2 (1.5±0.9 vs 1.5±0.7 ng/mL, p=0.63) and urinary levels of indican (9.5±5.5 vs 8.4±4.2 mg/dL, p=0.07) were comparable in women with PCOS and controls in the whole study population. Likewise, when the study population was divided into different BMI groups as normal weight, overweight and obese, the levels of the above markers were comparable between the study groups. After BMI adjustment, zonulin levels correlated with the levels of high-sensitivity C reactive protein and homoeostasis model assessment of insulin resistance (p<0.05) both in women with PCOS and controls., Conclusions: Intestinal permeability markers zonulin and FABP2, and the dysbiosis marker indican do not seem to be altered in women with PCOS at age 46 compared with BMI-matched controls. Serum zonulin levels correlated with BMI, insulin resistance and inflammatory marker levels, but did not segregate women with PCOS and controls. This suggests that metabolic factors, but not PCOS per se, is the driving force of dysbiosis in premenopausal women with PCOS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders in women and despite this, diagnostic challenges, delayed diagnosis, and less-than-optimal treatment regimens plague the condition. The International PCOS network, consisting of geographically diverse international experts in PCOS as well as consumers, engaged in a multi-year international evidence-based guideline development process that was jointly sponsored by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM). The guideline was published in 2018 and endorsed by more than 40 international societies involved in PCOS. Translation of this evidence-based guideline to medical practice and consumer groups remains a priority. However, there remain many challenges to both understanding the diagnosis and treatment of PCOS. Evidence suggests that both clinicians and consumers are not satisfied with the timeliness of diagnosis and treatment options. This review summarizes the important findings for diagnosis and treatment from the guidelines and expands on recent developments in the literature since its publication. Special attention to diagnosis at the ends of the reproductive spectrum are discussed and remaining areas of controversy are noted. Additionally, the review highlights some of the remaining challenges in the understanding and management of PCOS to help guide clinicians and investigators in this perplexing condition., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Investing in clinical research and evidence-based medicine has helped to improve the care for women with polycystic ovary syndrome (PCOS). However, several important questions remain unanswered on the optimal prevention and management strategies for PCOS. Addressing this uncertainty is often hindered by suboptimal research conduct leading to inefficient evidence synthesis and research wastage. PCOS research is often practised by varied specialized teams in silo leading to disharmonious and fragmented efforts neglecting the lifelong impact of PCOS on women's wellbeing. Poor engagement among key stakeholders and lay consumers continues to limit the impact and benefits of research to society. Selective reporting on surrogate outcomes with a 'significant' P-value is a common malpractice in PCOS outputs. Effective adoption of the harmonizing research outcomes for PCOS (HARP) core outcome set is needed to minimize heterogeneity in reporting and promote research excellence. Small single-centre studies offer limited value to assess the varied PCOS phenotypes. Efficient large scale data-sharing is needed to address complex research questions and glean the benefits of big data research. We propose a roadmap to address these challenges and remedy future research need by promoting patient and public involvement in PCOS research to guide research efforts and address real patients' needs; engaging all key stakeholder groups to promote a multi-disciplinary lifelong approach to new research; continuously refining research needs and priorities to revise the knowledge gap and allocate resources judiciously; standardizing outcomes definitions and measurement tools to harmonize reporting and promote excellence in research; and by investing in large data-sharing infrastructure to facilitate big data research and govern ethical data sharing., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To compare the effects of two formulations of combined oral contraceptives (COCs), estradiol valerate (EV) and ethinyl estradiol (EE) combined with dienogest (DNG), and DNG-only, on glucose tolerance., Study Design: We performed a randomized, controlled 9-week clinical trial. Inclusion criteria were: age 18-35 years, regular menstrual cycle (28 ± 7 days), no polycystic ovaries, non-smoking, no contraindications for COC use and a 2-month wash-out from hormonal contraceptive use. The women were randomized to EV + DNG (n = 20), EE + DNG (n = 20), and DNG-only (n = 19), and evaluated at baseline, at 4-5 weeks and 8-9 weeks of treatment. Study medications were used continuously for 63 days. Primary outcome measure was change in the whole-body insulin sensitivity index (Matsuda index) derived from the oral glucose tolerance test (OGTT) over the treatment period. Secondary outcome measures were area under curves (AUC) of glucose and insulin, homeostatic model assessment - insulin resistance (HOMA-IR) and Insulin Sensitivity Index (ISI)., Results: Fifty-nine women enrolled, and 56 women completed the study. The Matsuda index changed from baseline as follows (mean percentage change, mean change [95%CI]): DNG-only -12%, -1.45 [95%CI -3.22-0.325] P = 0.10; EV + DNG + 2.7%, -0.10 [-1.34 to 1.14] P = 0.86; EE + DNG -5.5%, -1.02 [-2.51 to 0.46] P = 0.16, comparing the groups P = 0.27. There were no clinically significant differences in glucose tolerance between the COC groups, but the DNG-only group showed an improvement in the 2-h glucose levels (5.5 [95%CI 5.0-6.0] to 4.7 mmol/l [4.2-5.2], P = 0.001)., Conclusion: We found no clinically significant differences between EV and EE combined with DNG and DNG-only on glucose tolerance in healthy, young, normal-weight women, indicating that these preparations appear close to neutral regarding glucose metabolism when used continuously for nine weeks., Implications: Combinations of both ethinyl estradiol and natural estradiol (estradiol valerate) with dienogest (DNG), as well as DNG-only, seem metabolically safe in young and healthy women in short-term continuous use., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial., Design: The study is a prospective longitudinal population-based cohort study., Methods: The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884)., Results: In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3-3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1-9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3-3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5-13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2-3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status., Conclusions: CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

Introduction: The aim of the study was to determine the association of body mass index (BMI), self-reported symptoms or diagnosis of polycystic ovary syndrome (PCOS), and hyperandrogenemia with the occurrence of gestational diabetes mellitus (GDM) through reproductive life., Material and Methods: A cohort of women born in 1966 were investigated at ages 14, 31 and 46. Women with self-reported PCOS symptoms (presence of both oligo-amenorrhea and hirsutism) at age 31 or with formally diagnosed polycystic ovaries (PCO)/PCOS by age 46 formed the group of self-reported PCOS (srPCOS, n = 222) and were compared with women without self-reported PCOS symptoms or diagnosis (n = 1357). We investigated also the association of hyperandrogenism (hirsutism or biochemical hyperandrogenism) at age 31 with the occurrence of GDM throughout reproductive life., Results: Self-reported PCOS alone was not a risk factor for GDM, but combined with overweight at age 31 (odds ratio [OR] 2.43, 95% confidence interval [CI] 1.22-4.86) or 46 (OR 3.04, 95% CI 1.58-5.83) srPCOS was associated with GDM when compared with normal weight controls. The association disappeared when comparing overweight srPCOS women with overweight controls. However, hyperandrogenemia at age 31, but not hirsutism, was associated with GDM even after adjustment for BMI., Conclusions: The increased risk of GDM in women with srPCOS was mostly attributed to overweight or obesity. Importantly, normal weight women with srPCOS did not seem to be at increased risk for developing GDM. However, hyperandrogenemia was associated with GDM even after adjustment for BMI. These findings strengthen the importance of weight management in reproductive-age women and suggest a noteworthy role of hyperandrogenemia in the pathophysiology of GDM., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology.)

Study Question: What are the key core outcomes to be reported in studies on polycystic ovary syndrome (PCOS)?, Summary Answer: We identified 3 generic and 30 specific core outcomes in 6 specialist domains: metabolic (8), reproductive (7), pregnancy (10), oncological (1), psychological (1) and long-term outcomes (1)., What Is Known Already: Research reporting PCOS is heterogeneous with high variation in outcome selection, definition and quality., Study Design, Size, Duration: Evidence synthesis and a modified Delphi method with e-surveys were used as well as a consultation meeting., Participants/materials, Setting, Methods: Overall, 71 health professionals and 123 lay consumers (women with lived experience of PCOS and members of advocacy and peer support groups) from 17 high-, middle- and low-income countries were involved in this analysis., Main Results and the Role of Chance: The final core outcome set included 3 generic outcomes (BMI, quality of life, treatment satisfaction) that are applicable to all studies on women with PCOS and 30 specific outcomes that were categorised into six specialist domains: 8 metabolic outcomes (waist circumference, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypertension, coronary heart disease, lipid profile, venous thromboembolic disease); 7 reproductive outcomes [viable pregnancy (confirmed by ultrasound including singleton, twins and higher multiples), clinical and biochemical hyperandrogenism, menstrual regularity, reproductive hormonal profile, chronic anovulation, ovulation stimulation success including the number of stimulated follicles ≥ 12 mm, incidence and severity of ovarian hyperstimulation syndrome]; 10 pregnancy outcomes (live birth, miscarriage, stillbirth, neonatal mortality, gestational weight gain, gestational diabetes, preterm birth, hypertensive disease in pregnancy, baby birth weight, major congenital abnormalities); 3 psychological outcomes (depression, anxiety, eating disorders); 1 oncological (abnormal endometrial proliferation including atypical endometrial hyperplasia and endometrial cancer); and 1 outcome in the long-term domain (long-term offspring metabolic and developmental outcomes)., Limitations, Reasons for Caution: We involved lay consumers in all stages of study through e-surveys but not through focus groups, thereby limiting our understanding of their choices. We did not address the variations in the definitions and measurement tools for some of the core outcomes., Wider Implications of the Findings: Implementing this core outcome set in future studies on women with PCOS will improve the quality of reporting and aid evidence synthesis., Study Funding/competing Interest(s): Evidence synthesis was funded through the Australian government, National Health and Medical Research Council (NHMRC) Centre for Research Excellence in PCOS, and H.T. is funded through an NHMRC fellowship. B.H.A. is funded through an NIHR lectureship. All authors have no competing interest to declare., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objectives: Previous studies of women in their 20s and 30s have reported impaired autonomic function in women with polycystic ovary syndrome (PCOS). We aimed to study, for the first time, whether PCOS is associated with impaired cardiac autonomic function independent of metabolic and hormonal status in their late reproductive years., Design: A prospective Northern Finland Birth Cohort 1966 (NFBC1966) study including 5889 women born in 1966 and followed through the age of 46. At that age, n=3706/5123 women (72%) answered the postal questionnaires and n=3280/5123 women (64%) participated in the clinical examination., Setting: General community., Participants: The sample included women presenting both irregular menses (oligomenorrhoea or amenorrhoea) and hirsutism at age 31 (n=125) or with formally diagnosed PCOS by age 46 (n=181) and women without PCOS symptoms or diagnosis (n=1577)., Primary and Secondary Outcome Measures: Heart rate variability parameters: the root mean square of successive R-R differences (rMSSD), spectral power densities (LF: low frequency and HF: high frequency) and baroreflex sensitivity (BRS)., Results: We found that parasympathetic activity (assessed by rMSSD: 19.5 (12.4; 31.9) vs 24.3 (16.1; 34.8) ms, p=0.004 and HF: 172 (75; 399) vs 261 (112; 565) ms 2 , p=0.002) and BRS (6.13±3.12 vs 6.99±3.52 ms/mm Hg, p=0.036) were lower in women with PCOS compared with the controls. However, in the multivariate regression analysis, PCOS, body mass index and the free androgen index did not significantly associate with rMSSD, whereas blood pressure, insulin resistance and triglycerides did., Conclusions: We report here for the first time that late reproductive-aged women with PCOS display impaired cardiac autonomic function manifested as decreased vagal activity. Metabolic status, rather than hyperandrogenaemia and PCOS per se, was the strongest contributing factor. Given the link between cardiac morbidity and impaired autonomic function, the findings underline the importance of screening and treating metabolic abnormalities early on in women with PCOS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Conflicting evidence supports a role for vitamin D in women with reproductive disorders such as polycystic ovary syndrome (PCOS) but studies on large, unselected populations have been lacking., Methods: We conducted a general population-based study from the prospective Northern Finland Birth Cohort 1966 (NFBC1966). Serum 25-hydroksyvitamin D (25(OH)D) levels were evaluated in women with self-reported PCOS ( n = 280) versus non-symptomatic controls ( n = 1573) at the age of 31 with wide range of endocrine and metabolic confounders., Results: The levels of 25(OH)D were similar among women with and without self-reported PCOS (50.35 vs. 48.30 nmol/L, p = 0.051). Women with self-reported PCOS presented with a higher body mass index (BMI), increased insulin resistance, and low-grade inflammation and testosterone levels compared to controls. The adjusted linear regression model showed a positive association between total 25(OH)D levels in self-reported PCOS (β = 2.46, 95% confidence interval (CI) 0.84 to 4.08, p = 0.003). The result remained after adjustment for BMI, testosterone, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hs-CRP) levels., Conclusion: In this population-based setting, PCOS was associated with higher vitamin D levels when adjusting for confounding factors, without distinct beneficial effects on metabolic derangements.

Background: Polycystic ovary syndrome (PCOS) has a prevalence of 8%-13%. Given the prevalence, diverse health impacts and variation in care, rigorous evidence-based guidelines are needed in PCOS management. This systematic review with meta-analyses aimed to investigate the effect of the combined oral contraceptive pill (COCP) and/or metformin in the management of hormonal and clinical features of PCOS, to inform international guidelines., Methods: Electronic databases were searched systematically from inception until 11 January 2017 to inform the guideline process. Eligible studies were randomized controlled trials which investigated the effect of COCPs and/or metformin alone or combined on hormonal and clinical features in women with PCOS. Outcomes were prioritized as critical for informing a decision about an intervention or important or not important, according to GRADE. Articles were assessed by one author against selection criteria, in consultation with a second author. Data were double extracted independently by four authors, and data quality appraisal was completed. Meta-analyses were conducted, where appropriate., Results: Fifty-six studies were eligible for inclusion. Outcomes prioritized by women and health professionals included the following: irregular cycles, insulin resistance, weight, BMI, thromboembolic events and gastrointestinal effects. In low-quality evidence in adolescents, meta-analyses demonstrated that metformin was better than COCP for BMI (mean difference [MD] -4.02 [-5.23, -2.81], P < 0.001); COCP was better than metformin for menstrual regulation (MD -0.19 [-0.25, -0.13], P < 0.00001). In low-quality evidence in adults, meta-analyses demonstrated that metformin was better than placebo for BMI (MD -0.48 [-0.94, -0.02], P = 0.04); metformin was better than COCP for fasting insulin (MD 4.00 [2.59, 5.41], P = 0.00001), whereas COCP was better than metformin for irregular cycles (MD 12.49 [1.34, 116.62], P = 0.03). Combined oral contraceptive pill alone was better than the combination with an anti-androgen for BMI (MD -3.04 [-5.45, -0.64], P = 0.01). Metformin was associated with generally mild gastrointestinal adverse events. Differences in statistical significance were observed when outcomes were subgrouped by BMI., Conclusions: This review identified that COCP therapy has benefits for management of hyperandrogenism and menstrual regulation. Metformin combined with the COCP may be useful for management of metabolic features. There is minimal evidence of benefits of adding an anti-androgen to COCP therapy. Metformin alone has benefits for adult women for management of weight, hormonal and metabolic outcomes, especially for women with BMI ≥ 25 kg/m 2 . There is inadequate evidence to suggest the optimal COCP formulation, or dosing regimen and formulation of metformin., (© 2019 John Wiley & Sons Ltd.)

Objective was to evaluate serum anti-Müllerian hormone (AMH) levels in polycystic ovary syndrome (PCOS) and in its different phenotypes in relation to clinical, endocrine and metabolic parameters using a new automated VIDAS ® method and to compare it with the Gen II method. Study design was multi-center study including 319 PCOS women and 109 healthy controls. Serum AMH levels measured using VIDAS ® were significantly higher in PCOS women than controls ( p  < .001), and they correlated with those measured using the AMH Gen II method. An AMH cutoff value of 42.1 pmol/L distinguished PCOS women from controls with 67% sensitivity and 83% specificity. The PCOS women with three Rotterdam criteria or hyperandrogenism displayed significantly higher AMH levels compared with those with two Rotterdam criteria or normoandrogenism. In PCOS, AMH levels correlated positively with luteinizing hormone (LH), androgen and sex hormone-binding globulin (SHBG) levels and negatively with BMI, abdominal obesity, follicle-stimulating hormone (FSH), fasting glucose and insulin, and insulin resistance. In conclusion, AMH evaluated using the VIDAS ® method distinguished PCOS patients from healthy controls relatively well, especially in those with more severe phenotypes. Further studies are needed to establish whether AMH measurements can distinguish PCOS patients with different metabolic risk factors.

Polycystic ovary syndrome (PCOS) is associated with worsened pregnancy and infant outcomes, higher body mass index (BMI), and longitudinal weight gain. Despite most of the clinical features of PCOS being risk factors for worsened infant outcomes in the general population, their impact on infant outcomes in PCOS is unknown. We aimed to investigate the association of PCOS with infant outcomes considering maternal adiposity, other known risk factors, and potential confounders. The meta-analyses included 42 studies in 7041 women with PCOS and 63 722 women without PCOS. PCOS was associated with higher gestational weight gain (GWG) and with higher preterm birth and large for gestational age and with lower birth weight with this association varying by geographic continent, PCOS phenotypes, and study quality. However, PCOS was associated with none of these outcomes on BMI-matched studies. Gestational diabetes was significantly associated with an increased preterm birth on meta-regression. We report for the first time that GWG is higher in PCOS. Infant outcomes vary by geographic continent and study quality but are similar in BMI-matched women with and without PCOS. This suggests that infant outcomes in PCOS may be related to maternal obesity. These novel findings warrant future studies in PCOS investigating screening and management of infant outcomes with consideration of maternal obesity., (© 2019 World Obesity Federation.)

Objective: Serum levels of retinol-binding protein 4 (RBP4), an adipokine thought to affect systemic insulin sensitivity, were compared between women with polycystic ovary syndrome (PCOS) and non-PCOS controls to evaluate the association of RBP4 with clinical, hormonal and metabolic parameters of PCOS., Subjects and Methods: Serum RBP4 levels were analysed in 278 women with PCOS (age range 18-57 years) and 191 non-PCOS controls (age 20-53 years) by enzyme-linked immunosorbent assay., Results: Serum levels of RBP4 were increased in women with PCOS compared with control women in the whole population (45.1 ± 24.0 (s.d.) vs 33.5 ± 18.3 mg/L, P < 0.001). Age-stratified analysis showed that serum RBP4 levels were increased in women with PCOS aged ≤30 years compared with controls (47.7 ± 23.5 vs 27.1 ± 10.4 mg/L, P < 0.001), whereas no significant differences were seen in the other age groups. No significant correlations of RBP4 were seen with either steroids or indices of insulin resistance., Conclusions: Although serum RBP4 levels were increased in younger women with PCOS compared with age-matched non-PCOS controls, RBP4 does not seem to be a good marker of insulin resistance or other metabolic derangements in women with PCOS.

Polycystic ovary syndrome (PCOS) is associated with an increased risk of maternal pregnancy and delivery complications. However, the impact of clinical features of PCOS and other potential risk factors in PCOS is still unknown. We aimed to investigate the association of PCOS with maternal pregnancy and delivery complications with consideration of risk factors and potential confounders. The meta-analysis included 63 studies. PCOS was associated with higher miscarriage, gestational diabetes mellitus, gestational hypertension, pre-eclampsia, induction of labour, and caesarean section. The association of PCOS with these outcomes varied by geographic continent, PCOS phenotypes, and study quality. Pre-eclampsia and induction of labour were not associated with PCOS on body mass index-matched studies. No outcome was associated with PCOS on assisted pregnancies. Age was significantly associated with higher miscarriage on meta-regression. There were no studies assessing perinatal depression. We confirm that PCOS is associated with an increased risk of maternal pregnancy and delivery complications. The association of PCOS with the outcomes is worsened in hyperandrogenic PCOS phenotypes, in specific geographic continents, and in the highest quality studies but disappears in assisted pregnancies. Future studies in PCOS are warranted to investigate proper timing for screening and prevention of maternal pregnancy and delivery complications with consideration of clinical features of PCOS., (© 2019 World Obesity Federation.)

Background: Copper is an abundant trace element in humans where alterations in the circulating concentration could inform on chronic disease aetiology. To date, data are lacking to study how copper may associate with cardiovascular disease (CVD) risk factors in young and healthy population. Molecular evidence suggests an important role of copper in liver metabolism, an essential organ in maintaining cardiovascular health and inflammation, therefore supporting copper as an associated biomarker of the risk., Objective: We performed a cross-sectional analysis to examine the possible associations between blood copper levels and risk factors for CVD and pre-inflammatory process., Design: The data has been collected from a sub-sample set of the Northern Finland Birth Cohort 1966 (NFBC1966) at 31 years., Participants: The study included 206 individuals, 116 men and 90 women. To reduce environmental individual variations affecting both copper and the metabolic profile in the study sample, the participants were selected as: i) being born in Finnish Lapland and ii) living in their birth place for the last five years preceding blood sampling., Main Outcome Measures: Fasting blood copper concentration was measured by inductively coupled plasma mass spectrometer. The CVD risk factors included 6 metabolic clusters (30 cardiovascular and pro-inflammatory factors) assessed by nuclear magnetic resonance. Multivariate linear regression analysis was performed to test the linear association between blood copper and 6 metabolic clusters for CVD risk. Associations were assessed under correction for multiple testing., Results: Copper (Cu) levels were comparable in men and women, with no difference between sexes (p-value <0.60). In multiple regression models, sex adjusted, copper was associated with 9 metabolites from 4 metabolic clusters. After adjustment with BMI, copper was associated with 4 metabolites from 3 metabolic clusters: glutamine, beta-hydroxybutyrate, alpha-1-acid glycoprotein (AGP) and high-sensitive C-reactive protein (hs-CRP). After correction for multiple testing, Cu was found positively associated with only 2 biomarkers of inflammation including AGP [p = 0.04] and hs-CRP [p = 0.0001]., Conclusions: Considering the strength and limitation of the study design, the present study does not support evidence for an independent role of copper on biomarkers for CVD risk. Nevertheless, we are reporting a robust association of copper with the inflammatory load that is important to consider in light with the inflammatory component of chronic health. In addition, the association of copper with metabolites may be attributable to BMI or environmental factors associated to it, and warrants further research in large population samples., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Introduction: We have developed the first international evidence-based guideline for the diagnosis and management of polycystic ovary syndrome (PCOS), with an integrated translation program incorporating resources for health professionals and consumers. The development process involved an extensive Australian-led international and multidisciplinary collaboration of health professionals and consumers over 2 years. The guideline is approved by the National Health and Medical Research Council and aims to support both health professionals and women with PCOS in improving care, health outcomes and quality of life. A robust evaluation process will enable practice benchmarking and feedback to further inform evidence-based practice. We propose that this methodology could be used in developing and implementing guidelines for other women's health conditions and beyond. Main recommendations: The recommendations cover the following broad areas: diagnosis, screening and risk assessment depending on life stage; emotional wellbeing; healthy lifestyle; pharmacological treatment for non-fertility indications; and assessment and treatment of infertility. Changes in management as a result of this guideline: •Diagnosis:▪when the combination of hyperandrogenism and ovulatory dysfunction is present, ultrasound examination of the ovaries is not necessary for diagnosis of PCOS in adult women;▪requires the combination of hyperandrogenism and ovulatory dysfunction in young women within 8 years of menarche, with ultrasound examination of the ovaries not recommended, owing to the overlap with normal ovarian physiology; and▪adolescents with some clinical features of PCOS, but without a clear diagnosis, should be regarded as "at risk" and receive follow-up assessment.•Screening for metabolic complications has been refined and incorporates both PCOS status and additional metabolic risk factors.•Treatment of infertility: letrozole is now first line treatment for infertility as it improves live birth rates while reducing multiple pregnancies compared with clomiphene citrate.

Study Question: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference?, Summary Answer: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS., What Is Known Already: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist., Study Design, Size, Duration: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength., Participants/materials, Setting, Methods: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels., Main Results and the Role of Chance: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management., Limitations, Reasons for Caution: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided., Wider Implications of the Findings: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program., Study Funding/competing Interest(s): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

Background: To inform knowledge translation by identifying evidence-practice gaps in polycystic ovary syndrome (PCOS) care and variations between disciplines and across world regions via an online, anonymous, devised questionnaire distributed via professional societies and completed by 1,495 physicians (2015-2016)., Methods: Multivariable logistic regression analyses generated adjusted odds ratios (OR) and 95% confidence intervals (CI) for associations between outcome measures and world region, specialty, annual patients with PCOS, age, and sex., Results: Features corresponding to Rotterdam diagnostic criteria were well recognized (e.g., irregular menstrual cycles by 99% of physicians), but psychological implications were recognized only by 29 to 64%. Reproductive endocrinologists were more likely to use Rotterdam diagnostic criteria (OR: 3.1; 95% CI: 2.3-4.3; p  < 0.007) than obstetrician-gynecologists. Reproductive (OR: 2.0; 95% CI: 1.5-2.8; p  < 0.007) and medical endocrinologists (OR: 3.1; 95% CI: 1.7-5.7; p  < 0.007) were more likely to recommend lifestyle management than obstetrician-gynecologists. Physicians in Europe (OR: 4.7; 95% CI: 3.5-6.1; p  < 0.007) and other regions (OR: 4.0; 95% CI: 2.8-5.9; p  < 0.007) were more likely to use Rotterdam diagnostic criteria than physicians in North America., Conclusion: Knowledge gaps in PCOS care to be addressed internationally include physician awareness of the breadth of PCOS features, application of diagnostic criteria, and recommending lifestyle management effectively., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: Hyperandrogenism, hyperinsulinaemia and obesity, known characteristics of polycystic ovary syndrome (PCOS), may influence bone mineral density and biochemical markers of bone turnover (BTMs) can provide a noninvasive assessment of bone turnover. To this end, the serum concentrations of BTMs and 25-hydroxyvitamin D (25OHD) were analysed in women with PCOS, and their possible associations with metabolic parameters of PCOS were determined., Subjects and Methods: Bone formation markers procollagen type I amino-terminal propeptide (PINP) and osteocalcin (OC), and bone resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX), along with 25OHD, were measured in 298 women with PCOS and 194 healthy controls., Results: Serum levels of PINP (47.0 ± 20.2 vs 58.1 ± 28.6 μg/L, P < .001) and OC (18.2 ± 7.5 vs 20.6 ± 9.8 μg/L, P < .001) were decreased in women with PCOS compared with controls, whereas no significant differences were found in CTX and 25OHD levels. Age-stratified analyses suggested that PINP (50.5 ± 21.7 vs 68.2 ± 26.6 μg/L, P < .001) and OC levels (20.4 ± 7.6 vs 25.5 ± 9.6 μg/L, P < .001) were decreased only in the younger age group (≤30 years) women with PCOS compared with controls. The formation markers and resorption marker decreased with age in both study groups., Conclusions: Bone formation markers were decreased in younger women with PCOS when compared with healthy women, which may affect bone mass in these women., (© 2017 John Wiley & Sons Ltd.)

Study Question: Is oral glucose tolerance test (OGTT) needed in all women with polycystic ovary syndrome (PCOS)?, Summary Qnswer: OGTT is not routinely needed in women with PCOS and BMI < 25 kg/m2., What Is Known Already: PCOS is associated with insulin resistance and increased prevalence of prediabetes and Type 2 diabetes (T2D) which is closely linked to obesity and possibly age, ethnicity and PCOS phenotype. Several guidelines recommend OGTT upon diagnosis of PCOS and during follow-up., Study Design, Size, Duration: A Nordic cross-sectional study including 876 women., Participants/materials, Setting, Methods: The 876 Nordic women with PCOS, aged 14-57 years, were examined for T2D and prediabetes (impaired glucose tolerance [IGT] or impaired fasting glucose (IFG) by OGTT., Main Result and the Role of Chance: Of all study subjects 3% (23/876) had T2D, 23% (204/876) prediabetes and 74% (649/876) had normal glucose tolerance (NGT). Increased BMI and waist circumference were significantly (P < 0.001) associated with prevalence of prediabetes and T2D. No normal-weight woman (BMI < 25 kg/m2) was diagnosed with T2D. The prevalence of BMI ≥ 25 kg/m2 was 66% (578/ 876). 91% of women (21/23) with T2D had BMI ≥ 30 kg/m2. Testosterone levels and PCOS phenotype did not predict 2-h glucose levels during OGTT after adjustment for BMI and age., Limitations, Reasons for Caution: The present study included cross-sectional data and prospective studies are needed to confirm our results. These results may not apply to populations of other ethnic origin., Wider Implications of the Findings: Routine OGTT may not be indicated in normal-weight women with PCOS., Study Funding/competing Interest(s): None., Trial Registration Number: N/A., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Background: Polycystic ovary syndrome is a heterogeneous disorder and its presentation varies with race and ethnicity. Reproductive-age women with polycystic ovary syndrome are at increased risk of metabolic syndrome; however, it is not clear if prevalence of metabolic syndrome and clustering of its components differs based on race and ethnicity. Moreover, the majority of these women do not undergo routine screening for metabolic syndrome., Objective: We sought to compare the prevalence of metabolic syndrome and clustering of its components in women with polycystic ovary syndrome in the United States with women in India, Brazil, Finland, and Norway., Study Design: This is a cross-sectional study performed in 1089 women with polycystic ovary syndrome from 1999 through 2016 in 5 outpatient clinics in the United States, India, Brazil, Finland, and Norway. Polycystic ovary syndrome was defined by the Rotterdam criteria. Main outcome measures were: metabolic syndrome prevalence, blood pressure, body mass index, fasting high-density lipoprotein cholesterol, fasting triglycerides, and fasting glucose. Data from all sites were reevaluated for appropriate application of diagnostic criteria for polycystic ovary syndrome, identification of polycystic ovary syndrome phenotype, and complete metabolic workup. The US White women with polycystic ovary syndrome were used as the referent group. Logistic regression models were used to evaluate associations between race and metabolic syndrome prevalence and its components and to adjust for potential confounders, including age and body mass index., Results: The median age of the entire cohort was 28 years. Women from India had the highest mean Ferriman-Gallwey score for clinical hyperandrogenism (15.6 ± 6.5, P < .001). The age-adjusted odds ratio for metabolic syndrome was highest in US Black women at 4.52 (95% confidence interval, 2.46-8.35) compared with US White women. When adjusted for age and body mass index, the prevalence was similar in the 2 groups. Significantly more Black women met body mass index and blood pressure criteria (P < .001), and fewer met fasting triglycerides criteria (P < .05). The age- and body mass index-adjusted prevalence of metabolic syndrome was highest in Indian women (odds ratio, 6.53; 95% confidence interval, 3.47-12.30) with abnormalities in glucose and fasting high-density lipoprotein cholesterol criterion and in Norwegian women (odds ratio, 2.16; 95% confidence interval, 1.17-3.98) with abnormalities in blood pressure, glucose, and fasting high-density lipoprotein cholesterol criterion. The Brazilian and Finnish cohorts had similar prevalence of metabolic syndrome and its components compared to US White women., Conclusion: Despite a unifying diagnosis of polycystic ovary syndrome, there are significant differences in the prevalence of metabolic syndrome and clustering of its components based on race and ethnicity, which may reflect contributions from both racial and environmental factors. Our findings indicate the prevalence of metabolic syndrome components varies in women with polycystic ovary syndrome, such that compared to White women from the United States, Black US women had the highest prevalence, whereas women from India and Norway had a higher prevalence of metabolic syndrome independent of obesity. The differences in clustering of components of metabolic syndrome based on ethnicity highlight the need to routinely perform complete metabolic screening to identify specific targets for cardiovascular risk reduction strategies in these reproductive-age women., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Study Question: Is it necessary to monitor lipid profiles in all young women with polycystic ovary syndrome (PCOS)?, Summary Answer: Lipid profiling is required when women with PCOS develop type 2 diabetes (T2D) or hypertension, but rarely changes clinical care before the age of 35 years., What Is Known Already: PCOS consensus statements and guidelines recommend that women with PCOS should be screened for dyslipidaemia every second year or annually., Study Design, Size, Duration: Women from Denmark, Norway, Finland and Sweden, who had participated in research projects or clinical trials or in whom lipid profiles had been determined routinely as part of clinical care since 2000 were included., Participants/materials, Setting, Methods: One thousand three hundred and twenty-seven women with PCOS (Rotterdam criteria) were included. Based on individual cardiovascular risk score and lipid levels, treatment level was guided by the European Society of Cardiology and the European Atherosclerosis Society Task Force for the management of dyslipidaemias. Change in clinical care was defined as need to (i) immediately start statin treatment or (ii) consider statin treatment if life-style intervention fails., Main Results and the Role of Chance: All in all, 74 (5.6%) women with PCOS should immediately start statin treatment, and statin treatment should be considered in 33 women (2.5%). Among women with T2D, 27/28 (96.4%) should initiate statin treatment and the corresponding number for women with hypertension was 42/57 (73.7%). In PCOS women who had not yet developed T2D or hypertension, lipid profiling only changed clinical care in 28 (2.3%). This number was further reduced to 12 (1.2%) in women below the age of 35 years, and to zero in normal-weight women below the age of 35 years., Limitations, Reasons for Caution: Findings can only be generalized to countries with low cardiovascular mortality rates., Wider Implications of the Findings: Lipid profiling is required when women with PCOS develop T2D or hypertension. However, lipid profiling rarely changes the clinical care of low risk PCOS patients before the age of 35, especially in the normal-weight women., Study Funding/competing Interests: The Academy of Finland, Sigrid Juselius Foundation and the Nordic Federation of Obstetrics and Gynecology. There are no conflicts of interest to be declared., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: Are uterine fibroids associated with increased cardiovascular risk?, Summary Answer: This study reports an association between increased serum lipids and metabolic syndrome with an increased risk of uterine fibroids., What Is Known Already: Recent studies suggest similarities in biological disease mechanisms and risk factors for fibroids and atherosclerosis: obesity, hypertension and abnormal serum lipids. These findings are awaiting confirmation that a population-based follow-up study could offer with extensive health examination data collection linked with a national hospital discharge register., Study Design, Size, Duration: The Northern Finland Birth Cohort (NFBC1966) is a population-based long-term follow-up study including all children with estimated date of delivery in 1966 in the Northern Finland area. The data were collected from national registries, postal questionnaires and clinical health examinations. The study population for this study comprised all females included in the NFBC1966 that underwent an extensive clinical health examination at age 46 years (n = 3635)., Participants/materials, Setting, Methods: All females included in the NFBC1966 who were alive and traceable (n = 5118) were invited for the 46-year follow-up study; 3268 (63.9%) responded, returned the postal questionnaire and attended the clinical examination. Uterine fibroid cases were identified through the national hospital discharge register that has data on disease diagnoses based on WHO ICD-codes. Uterine fibroid codes, ICD-9: 218 and ICD-10: D25 were used for case identification. Self-reported fibroid cases were identified through the postal questionnaire., Main Results and the Role of Chance: A total of 729 fibroid cases were identified, including 293 based on hospital discharge registries. With adjustment for BMI, parity, education and current use of exogenous hormones the risk of prevalent fibroids rose significantly for every 1 mmol/l increase in LDL (OR = 1.13, 95% CI: 1.02-1.26 for all cases) and triglycerides (OR = 1.27, 95% CI: 1.09-1.49 for all cases). Metabolic syndrome associated with hospital discharge-based fibroid diagnosis (OR = 1.48, 95% CI: 1.09-2.01). Additionally every 1 unit increase in waist-hip ratio associated with fibroids (OR = 1.32, 95% CI: 1.10-1.57)., Limitations, Reasons for Caution: The case ascertainment may present some limitations. There was likely an under-identification of cases and misclassification of some cases as controls; this would have diluted the effects of reported associations. The data analysed were cross-sectional and therefore cause and effect for the associations observed cannot be distinguished., Wider Implications of the Findings: Increased serum lipids and metabolic syndrome are associated with increased risk of uterine fibroids. Along with central obesity these findings add to an increased risk for cardiovascular disease among women with fibroids. These observations may suggest that there are shared predisposing factors underlying both uterine fibroids and adverse metabolic and cardiac disease risk, or that metabolic factors have a role in biological mechanisms underlying fibroid development., Study Funding/competing Interests: This study was supported by the Academy of Finland, University Hospital Oulu, University of Oulu, Finland, Northern Finland Health Care Foundation, Duodecim Foundation, ERDF European Regional Development Fund-Well-being and health: Research in the Northern Finland Birth Cohort 1966. The authors declare no conflict of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Obesity affects the majority of women with polycystic ovary syndrome (PCOS), but previous studies are inconsistent about the prevalence of obesity and the importance of weight gain in the development of the syndrome., Objective: Our objective was to explore the association between weight, weight gain, hyperandrogenism, and PCOS from adolescence to late adulthood., Design: The study includes a prospective Northern Finland Birth Cohort 1966 study including 5889 females born in 1966 and followed at the ages of 14, 31, and 46 years., Setting: The setting was the general community., Participants: Women presenting both oligo/amenorrhea (OA) and hirsutism (H) at age 31 (N = 125) or with formally diagnosed PCOS by age 46 (N = 181) were compared with women without PCOS symptoms or diagnosis (n = 1577)., Interventions: None., Main Outcome Measures: Body mass index (BMI), weight change through life, waist circumference, Free Androgen Index, lipids, glucose, insulin, high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance, and PCOS., Results: Women with OA+H at age 31 or diagnosis of PCOS by age 46 had the highest BMI at all ages compared with the controls. Increase of BMI between ages 14 and 31, but not between 31 and 46, was greater in women with isolated OA (P = .006), OA+H (P = .001), and diagnosis of PCOS (P = .001) compared with controls. In the multivariate analysis, PCOS was significantly associated with BMI at all ages (BMI at age 31: odds ratio [OR] = 1.05 [95% confidence interval (CI), 1.00-1.10], Free Androgen Index (OR = 1.08 [95% CI, 1.03-1.14]), serum levels of insulin (OR = 1.05 [95% CI, 1.00-1.09]), and triglycerides (OR = 1.48 [95% CI, 1.08-2.03])., Conclusions: Symptoms or diagnosis of PCOS are associated with dyslipidemia, hyperandrogenemia, and significantly increased weight gain, especially in early adulthood. This observation is important because it may identify a sensitive time period when weight gain plays a crucial role in the emergence of PCOS and when preventive actions against metabolic and cardiovascular diseases should be implemented.

There are no age limits for the start or use of contraception. Prior gynecological examination or cervical smear is not needed. Condom is the only method that protects from sexually transmitted diseases. An increase in the risk of venous thromboembolism (VTE) is associated only with combined contraceptives. However, the risk is remarkably higher with pregnancy, puerperium or with smoking. The most effective reversible methods are intrauterine devices (IUD) and implants, as these do not depend on daily memory. Natural family planning methods are not reliable, and effective contraception should be easily available for all at all times.

Aims: Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C)., Methods: In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20 mg day(-1) (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α-epoxycholesterol ratios were used as negative controls., Results: Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference -0.0595, -0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin -0.032, placebo 0.0055, P = 0.020, 95% CI of the difference -0.069, -0.0067). The ratios of 25-hydroxycholesterol and 5α,6α-epoxycholesterol to cholesterol did not change., Conclusions: The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations., (© 2015 The British Pharmacological Society.)

Context: Statins have been shown to improve hyperandrogenism in women with polycystic ovary syndrome (PCOS). However, their use has also been associated with impairment of glucose metabolism and an increased risk of type 2 diabetes mellitus. Because women with PCOS are prone to disturbances in glucose metabolism, statin therapy could also have negative effects., Objective: Our objective was to explore the effects of atorvastatin therapy on hormonal and metabolic parameters in women with PCOS., Design and Setting: We conducted a randomized, double-blind, placebo-controlled 6-month follow-up study conducted at Oulu University Hospital, Finland., Patients: Women with PCOS (Rotterdam criteria) were treated with atorvastatin (20 mg/d, n = 15) or placebo (n = 13) for 6 months., Interventions: Fasting serum samples were collected at baseline and at 3 and 6 months. Oral and iv glucose tolerance tests were performed at 0 and 6 months., Main Outcome Measures: Androgen secretion and glucose metabolism were measured., Results: Fasting levels and area under the curve of insulin increased significantly and insulin sensitivity (insulinogenic and Matsuda indexes) decreased during 6 months of atorvastatin therapy. Serum levels of dehydroepiandrosterone sulfate decreased in the atorvastatin group, whereas no change was observed in serum testosterone levels. Levels of C-reactive protein, total and low-density lipoprotein-cholesterol, and triglycerides decreased significantly during statin therapy., Conclusions: Atorvastatin therapy improves chronic inflammation and lipid profile, but it impairs insulin sensitivity in women with PCOS. Because women with PCOS have an increased risk of developing type 2 diabetes mellitus, the results suggest that statin therapy should be initiated on the basis of generally accepted criteria and individual risk assessment of cardiovascular disease, and not only because of PCOS.