Search

The 2023 international evidence-based guideline update for the assessment and management of polycystic ovary syndrome (PCOS) recommends using the Rotterdam criteria for the diagnosis of PCOS. The updated guideline has evidence-based recommendation for the diagnosis, and it now also includes serum anti-Müllerian hormone (AMH) measurement as an alternative tool for gynecological ultrasound to diagnose polycystic ovary morphology (PCOM). The aim of this new recommendation was to facilitate PCOS diagnostic workup in primary care and other disciplines, as currently most diagnosing is done in gynecology and infertility clinics. Here, we review factors affecting AMH levels as well as the utility of AMH in PCOS diagnosis. We identified relevant studies that report different cut-offs for AMH to diagnose PCOM as part of PCOS diagnosis. There are, however, some limitations when using AMH that should be acknowledged. These include physiological aspects like age, ethnicity, and obesity and iatrogenic causes like hormonal medication and ovarian surgery. Also reference ranges are different depending on AMH assay used. As a summary, we conclude that AMH is a usable tool in PCOM diagnostics, but it does not have a single cut-off. Therefore, further studies are needed to establish age and assay-based reference ranges. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies have shown good correlation between polycystic ovarian morphology (PCOM) and serum anti-Müllerian hormone (AMH) levels. We evaluated the utility of AMH as a surrogate for PCOM as a part of the polycystic ovary syndrome (PCOS) diagnosis by describing how the use of different AMH cut-off values would change the prevalence of PCOS. Methods: A general population-based birth cohort study. Anti-Müllerian hormone concentrations were measured from serum samples taken at age 31 years (n = 2917) using the electrochemiluminescence immunoassay (Elecsys). Anti-Müllerian hormone data were combined with data on oligo/amenorrhoea and hyperandrogenism to identify women with PCOS. Results: The addition of AMH as a surrogate marker for PCOM increased the number of women fulfilling at least two PCOS features in accordance with the Rotterdam criteria. The prevalence of PCOS was 5.9% when using the AMH cut-off based on the 97.5% quartile (10.35 ng/mL) and 13.6% when using the recently proposed cut-off of 3.2 ng/mL. When using the latter cut-off value, the distribution of PCOS phenotypes A, B, C, and D was 23.9%, 4.7%, 36.6%, and 34.8%, respectively. Compared with the controls, all PCOS groups with different AMH concentration cut-offs showed significantly elevated testosterone (T), free androgen index (FAI), luteinizing hormone (LH), LH/ follicle-stimulating hormone (FSH) ratio, body mass index (BMI), waist circumference, and homoeostatic model assessment of insulin resistance (HOMA-IR) values, as well as significantly decreased sex hormone-binding globulin (SHBG) values. Conclusions: Anti-Müllerian hormone could be useful surrogate for PCOM in large data sets, where transvaginal ultrasound is not feasible, to aid the capturing of women with typical PCOS characteristics. Anti-Müllerian hormone measurement from archived samples enables retrospective PCOS diagnosis when combined with oligo/amenorrhoea or hyperandrogenism. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This document is a journal article titled "AMH in Reproductive Medicine" from the journal Seminars in Reproductive Medicine. The article is edited by Dr. Paolo Giacobini, a research director at the French National Institute of Health and Medical Research (INSERM) in Lille, France. Dr. Giacobini's research focuses on the neuroendocrine regulation of the reproductive axis in physiological and pathological processes, particularly the development and function of gonadotropin-releasing hormone (GnRH) neurons. He has made significant contributions to the field and has been published in prestigious journals. Dr. Giacobini has also received grants and awards for his work, and he holds various institutional responsibilities in neuroscience and neuroendocrinology societies. The article is authored by Kathleen M. Hoeger and Terhi T. Piltonen. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Pericytes are versatile cells integral to the blood vessel walls of the microcirculation, where they exhibit specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, and maintaining homeostasis and are involved in the tissue repair process. The human endometrium is a unique and complex tissue that serves as a natural scar-free healing model with its cyclical repair and regeneration process every month. The regulation of pericytes has gained increasing attention due to their involvement in various physiological and pathological processes. However, endometrial pericytes are less well studied compared to the pericytes in other organs. This review aims to provide a comprehensive overview of endometrial pericytes, with a focus on elucidating their physiological function and potential implications in uterine disorders. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 15% of the female population. The natural history of the syndrome is complex, including both androgen exposure in early life and adiposity-driven dysfunction involving also dysregulated, also involving altered hypothalamus–ovarian crosstalk. The manifestations can arise as early as childhood or puberty onward, suggesting that genetic susceptibility is an important etiological factor. In adulthood, women with PCOS present with reproductive, metabolic, and psychological health issues at a population-based level. Epidemiological studies on large datasets offer an excellent opportunity to evaluate health effects and costs related to the syndrome. Hospital or insurance-based datasets are also available; however, the results are not representative of the female population in the community. More longitudinal studies spanning from early childhood to late adulthood are needed to assess the long-term health impact and early manifestations of PCOS. Moreover, the identification of women with PCOS from large datasets can be expensive. Self-reported symptoms or PCOS diagnosis may offer a feasible approach. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. An endometrial component has been suggested to contribute to subfertility and poor reproductive outcomes in affected women.Objective and Rationale: The aim of this review was to determine whether there is sufficient evidence to support that endometrial function is altered in women with PCOS, whether clinical features of PCOS affect the endometrium, and whether there are evidence-based interventions to improve endometrial dysfunction in PCOS women.Search Methods: An extensive literature search was performed from 1970 up to July 2020 using PubMed and Web of Science without language restriction. The search included all titles and abstracts assessing a relationship between PCOS and endometrial function, the role played by clinical and biochemical/hormonal factors related to PCOS and endometrial function, and the potential interventions aimed to improve endometrial function in women with PCOS. All published papers were included if considered relevant. Studies having a specific topic/hypothesis regarding endometrial cancer/hyperplasia in women with PCOS were excluded from the analysis.Outcomes: Experimental and clinical data suggest that the endometrium differs in women with PCOS when compared to healthy controls. Clinical characteristics related to the syndrome, alone and/or in combination, may contribute to dysregulation of endometrial expression of sex hormone receptors and co-receptors, increase endometrial insulin-resistance with impaired glucose transport and utilization, and result in chronic low-grade inflammation, immune dysfunction, altered uterine vascularity, abnormal endometrial gene expression and cellular abnormalities in women with PCOS. Among several interventions to improve endometrial function in women with PCOS, to date, only lifestyle modification, metformin and bariatric surgery have the highest scientific evidence for clinical benefit.Wider Implications: Endometrial dysfunction and abnormal trophoblast invasion and placentation in PCOS women can predispose to miscarriage and pregnancy complications. Thus, patients and their health care providers should advise about these risks. Although currently no intervention can be universally recommended to reverse endometrial dysfunction in PCOS women, lifestyle modifications and metformin may improve underlying endometrial dysfunction and pregnancy outcomes in obese and/or insulin resistant patients. Bariatric surgery has shown its efficacy in severely obese PCOS patients, but a careful evaluation of the benefit/risk ratio is warranted. Large scale randomized controlled clinical trials should address these possibilities. [ABSTRACT FROM AUTHOR]

Dr. Antti Perheentupa, a specialist in obstetrics and gynecology with expertise in reproductive endocrinology and andrology, has been selected as the guest editor for this issue of Seminars in Reproductive Medicine. He is recognized as the top andrology expert in Finland and currently holds positions at the Turku University Hospital. Dr. Perheentupa has a strong international network and has published numerous peer-reviewed articles on male fertility and other related topics. This issue of the journal focuses on current hot topics in andrology, including male infertility and male contraception. [Extracted from the article]

This article, titled "Microbiome in Reproduction," is a special issue of Seminars in Reproductive Medicine. The guest editor for this issue is Dr. Signe Altmäe, an associate professor at the University of Granada and a visiting researcher at the Karolinska Institute. Dr. Altmäe's research focuses on the molecular aspects of endometrial receptivity and the impact of molecular dysregulation on embryo implantation and fertility. She is also studying the composition of microorganisms in the human reproductive tract and their associations with reproductive parameters, fertility, and infertility in both women and men. The article aims to provide a comprehensive review of the methods used in microbiome studies and the challenges and solutions in assessing the microbiome in the human reproductive tract. [Extracted from the article]

Dr. Wendy Vitek has been selected as the guest editor for the latest issue of Seminars in Reproductive Medicine, focusing on the intersection of obesity and reproductive dysfunction. Dr. Vitek is board certified in obstetrics and gynecology, reproductive endocrinology, and obesity medicine, providing her with a unique perspective on the challenges faced by clinicians in this area. She has curated a comprehensive review of the topic, featuring expert authors to delve into the issues. Dr. Vitek is an academic reproductive endocrinologist at the University of Rochester Medical Center and conducts research on weight and infertility. The issue aims to provide a thorough examination of the assessment and treatment of reproductive concerns in the context of obesity. [Extracted from the article]

Seminars in Reproductive Medicine is a peer-reviewed journal that publishes in-depth reviews on relevant and timely clinical themes in the field of reproductive medicine. The journal was established in 1983 as Seminars in Reproductive Endocrinology and changed its name in 2000 to reflect the broader scope of reproductive medicine. Professor Helena Teede recently stepped down as the Editor-in-Chief, and in January 2023, professors Kathleen Hoeger and Terhi Piltonen were appointed as the new co-Editors-in-Chief. The journal aims to capture perspectives from a worldwide viewpoint and has developed an editorial board that represents the diversity of experiences in reproductive medicine. The first issue under the new editors focuses on the updated international guidelines for the diagnosis and management of polycystic ovary syndrome (PCOS). The journal plans to publish four issues per year and welcomes input from readers on topics they would like to see reviewed. The goal is to provide a platform for high-level reviews that are timely and helpful to the reproductive medicine community. [Extracted from the article]

In conclusion, we would like to emphasize the importance of the previous and future work that is based on self-reported PCOS symptoms, in understanding the natural history of PCOS. Sir, We have read with great interest the article 'Where are we in understanding the natural history of polycystic ovary syndrome?. [Extracted from the article]

Objective:To study the associations between androgens, glucose homeostasis, inflammation and statin treatment in women with polycystic ovary syndrome (PCOS). Design and methods:Oral glucose tolerance tests, androgens, hs-CRP and interleukin-1 receptor antagonist (IL-1Ra) were analyzed at baseline and after 6 months of atorvastatin (20 mg/d) or placebo treatment in 27 women with PCOS. Results:Testosterone associated with insulin resistance measured with ISIMatsudaindependently of BMI, age and SHBG concentrations and the full model, including IL-1Ra, hs-CRP and HDL-C, also showed independency of BMI and waist circumference (p ≤ .042). Free androgen index (FAI) associated with ISIMatsudaindependently of adiposity (p ≤ .025) but in the full model with waist circumference the association was insignificant. ISIMatsudadecreased with testosterone >1.2 nmol/l compared with lower levels at baseline (p = .043) and at six months (p = .003). Accordingly, 30-minute insulin levels were increased with moderately elevated testosterone independently of adiposity (p ≤ .046). Increased fasting glucose and AUC insulin associated with statin treatment independently of adiposity and the associations attenuated after adjusting for testosterone. Conclusions:Moderately elevated testosterone concentrations together with obesity-related inflammatory factors modify glucose homeostasis by increasing insulin resistance and early insulin secretion. [ABSTRACT FROM AUTHOR]

Objective To investigate serum interleukin-1 receptor antagonist ( IL-1Ra) levels in women with polycystic ovary syndrome ( PCOS). Subjects and methods Serum IL-1Ra levels were measured at baseline in 73 women with PCOS and 45 control subjects (18-47 years), and in 27 women with PCOS who underwent oral and intravenous glucose tolerance tests ( OGTTs and IVGTTs). Results IL-1Ra concentrations predicted OGTT 2-h glucose levels independently of BMI and insulin resistance ( P ≤ 0·001) in women with PCOS. Serum IL-1Ra concentration was elevated in women with PCOS compared with controls [mean ( SD): 309·5 (208·8) vs 199·1 (81·4) ng/l, P < 0·001], but the difference disappeared after adjusting for BMI. An increment of five BMI units raised IL-1Ra levels by 108·5 ng/l [95% confidence interval ( CI): 85·5-131·5, r2 = 0·603] in women with PCOS and only by 77·0 ng/l (95% CI: 50·5-103·5, r2 = 0·512) in controls when adjusted for BMI and age. Levels of IL-1Ra in obese women with PCOS reflected decreasing OGTT-derived insulinogenic index ( P = 0·032) and disposition index ( P = 0·046) independently of BMI. Increased levels of IL-1Ra correlated with indices showing increasing insulin resistance and AUC insulin ( P ≤ 0·002). Conclusions Increased IL-1Ra levels in women with PCOS were largely explained by increasing adiposity. However, serum IL-1Ra concentrations predicted 2-h glucose levels independently of BMI suggesting that increased IL-1Ra may be associated with disturbed glucose metabolism. [ABSTRACT FROM AUTHOR]

(1) Background: Endometriosis is a highly prevalent gynecological disease affecting 10% of women of reproductive age worldwide. miRNAs may play a role in endometriosis, though their exact function remains unclear. This study aimed to identify differentially expressed miRNAs in endometriosis and study their functions in the disease. (2) Methods: Endometrial tissue was collected from women with endometriosis (n = 15) and non-endometriosis controls (n = 17). Dysregulated miRNAs were identified through small RNA-sequencing, and their biological significance was explored by target gene prediction and pathway analysis. Selected miRNAs were examined in paired ectopic endometriomas and eutopic endometrium (n = 10) using qRT-PCR. Their roles in cell migration and proliferation were further examined in vitro using functional assays. To identify potential target genes, we performed mRNA sequencing on transfected cells and the endometrioma cohort. (3) Results: We identified 14 dysregulated miRNAs in the eutopic endometrium of women with endometriosis compared to endometrial tissue from women without endometriosis. Pathway analysis indicated enrichment in cell migration and proliferation-associated pathways. Further ex vivo studies of miR-193b-5p and miR-374b-5p showed that both miRNAs were upregulated in endometrioma. Overexpression of these two miRNAs in vitro inhibited cell migration, and mRNA sequencing revealed several migration-related genes that are targeted by these miRNAs. (4) Conclusions: Our study identified two key endometrial miRNAs that may be involved in the pathogenesis of endometriosis by regulating cell migration. [ABSTRACT FROM AUTHOR]

It is not controversial to state that parental age is increasing in several countries. But how to deal with this increase might be. Some Nordic countries have set an upper age limit for females seeking assisted reproduction in their national legislation, but none have done so for males. There are also recommendations in place that restrict access to publicly funded assisted reproduction for both females and males of advanced age in some Nordic countries. As recent data now show somatic and psychiatric health risks related to advanced paternal age, we ask if the time has come for countries to set an upper age limit for males seeking assisted reproduction like there already is for females, and summarize some of the risks and rewards involved in treating couples with advanced age in fertility clinics. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions Circadian rhythm disruption has been associated with the risk of polycystic ovary syndrome (PCOS), as the evening chronotype (EC) shares several traits with PCOS, including metabolic disorders, cardiovascular diseases, and psychiatric disorders. It has been suggested that the biological clock could be targeted with new, preventive, and therapeutic strategies for PCOS in women with biorhythm disorders. We evaluated inner circadian rhythmicity in middle‐aged women with PCOS in a population‐based setting, focusing on whether women with PCOS and an EC have a specific subtype in relation to their clinical characteristics.The data derived from the Northern Finland Birth Cohort, a population‐based longitudinal birth cohort of 12 058 individuals born in 1966. We compared the circadian phenotype between 314 women with PCOS (according to the Rotterdam criteria) and 1248 women without PCOS at age 46 years using the validated Finnish shortened 6‐item Morningness‐Eveningness Questionnaire (sMEQ) and the single‐item self‐assessed morningness‐eveningness question.PCOS was not associated with the EC by the sMEQ (p = 0.495) or self‐assessment (p = 0.303). The self‐assessed morningness‐eveningness values differed from the sMEQ chronotype distribution (p < 0.001), nevertheless, the most frequent chronotype was the intermediate chronotype (IC) determined by both chronotyping methods (sMEQ PCOS 47.7% vs. 45.2% non‐PCOS; self‐assessment PCOS 66.5% vs. 68.4% non‐PCOS). The hyperandrogenic PCOS phenotypes A–C did not differ from the non‐hyperandrogenic phenotype D as for the chronotype (p = 0.271). The EC was associated in both groups with depressive and anxiety symptoms (PCOS p = 0.012, non‐PCOS p < 0.001) and the use of sleep medication (PCOS p = 0.017, non‐PCOS p < 0.001).The EC was not over‐represented in middle‐aged women with PCOS or in the hyperandrogenic PCOS phenotypes A–C in our study. This does not support the need for chronotyping in the comprehensive assessment of women with PCOS. However, as chronotypes tend to change with aging, cross‐sectional studies in different age groups are warranted to draw conclusions on the role of chronotypes in PCOS and the associated metabolic risks. [ABSTRACT FROM AUTHOR]

Objective The present study aimed to clarify the conflicting association of premenopausal hyperandrogenaemia (HA) with the development of hypertension and cardiovascular disease (CVDs) in women. Design A population-based cohort study including 5889 women. Methods The association of serum testosterone (T), sex hormone-binding globulin (SHBG), and free androgen index (FAI) at age 31 with blood pressure (BP) and hypertension (BP ≥ 140/90 mmHg and/or use of antihypertensive medication) at ages 31 and 46 and with CVDs (angina pectoris [AP] and/or acute myocardial infarction [AMI] n = 74, transitory cerebral ischaemia and/or stroke n = 150) and combined CVD events (AP, AMI, stroke, heart failure, or CVD mortality n = 160) by age 53 was investigated. Results T and FAI were positively associated with systolic and diastolic BP at ages 31 and 46 in the multivariable model. Compared to their lowest quartile, the highest quartiles of T and FAI were positively associated with hypertension at age 31 in the multivariable model. During the 22-year follow-up, FAI was positively associated with increased risk of AP/AMI (hazard ratio [HR]: 2.02, 95% CI: 1.06 - 3.85) and overall CVD events or mortality (HR: 1.54, 95% CI: 1.02 - 2.33) in the unadjusted models. However, the significance disappeared after adjusting for body mass index (BMI). Conclusions Women with HA at premenopausal age had an elevated risk of hypertension, and together with BMI, increased risk of CVD events and CVD mortality during the 22-year follow-up. However, because of several study limitations regarding ethnicity and BMI characteristics, a longer follow-up of this cohort and future studies in ethnically diverse populations are needed to verify the results. [ABSTRACT FROM AUTHOR]

Objective: To date, little is known about differences in the knowledge, diagnosis making and treatment strategies of health care providers regarding polycystic ovary syndrome (PCOS) across different disciplines in countries with similar health care systems. To inform guideline translation, we aimed to study physician reported awareness, diagnosis and management of PCOS and to explore differences between medical disciplines in the Nordic countries and Estonia. Methods: This cross-sectional survey was conducted among 382 endocrinologists and obstetrician-gynaecologists in the Nordic countries and Estonia in 2015–2016. Of the participating physicians, 43% resided in Finland, 18% in Denmark, 16% in Norway, 13% in Estonia, and 10% in Sweden or Iceland, and 75% were obstetrician-gynaecologists. Multivariable logistic regression models were run to identify health care provider characteristics for awareness, diagnosis and treatment of PCOS. Results: Clinical features, lifestyle management and comorbidity were commonly recognized in women with PCOS, while impairment in psychosocial wellbeing was not well acknowledged. Over two-thirds of the physicians used the Rotterdam diagnostic criteria for PCOS. Medical endocrinologists more often recommended lifestyle management (OR = 3.6, CI 1.6–8.1) or metformin (OR = 5.0, CI 2.5–10.2), but less frequently OCP (OR = 0.5, CI 0.2–0.9) for non-fertility concerns than general obstetrician-gynaecologists. The physicians aged <35 years were 2.2 times (95% CI 1.1–4.3) more likely than older physicians to recommend lifestyle management for patients with PCOS for fertility concerns. Physicians aged 46–55 years were less likely to recommend oral contraceptive pills (OCP) for patients with PCOS than physicians aged >56 (adjusted odds ratio (OR) = 0.4, 95% CI 0.2–0.8). Conclusion: Despite well-organized healthcare, awareness, diagnosis and management of PCOS is suboptimal, especially in relation to psychosocial comorbidities, among physicians in the Nordic countries and Estonia. Physicians need more education on PCOS and evidence-based information on Rotterdam diagnostic criteria, psychosocial features and treatment of PCOS, with the recently published international PCOS guideline well needed and welcomed. [ABSTRACT FROM AUTHOR]

This article is a response to a critique of a previous article on the treatment of polycystic ovary syndrome (PCOS). The authors clarify that their focus was on presenting updated guidelines and evidence-based treatments, rather than exploring the syndrome's pathogenesis. They acknowledge the role of insulin resistance in PCOS but note that not all women with PCOS are insulin resistant. The authors also mention that the treatment options proposed by the critics were not included in their article due to insufficient evidence. They emphasize that their article aimed to summarize the updated guidelines from a Nordic perspective. [Extracted from the article]

To describe the effects of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg on physical and emotional premenstrual and menstrual symptoms. We used Menstrual Distress Questionnaire (MDQ) data from a phase-3 trial (NCT02817828) in Europe and Russia with participants (18 − 50 years) using E4/DRSP for up to 13 cycles. We assessed mean changes in MDQ-t-scores from baseline to end of treatment in premenstrual (4 days before most recent flow) and menstrual (most recent flow) scores for 4 MDQ domains in starters and switchers (use of hormonal contraception in prior 3 months) and performed a shift analysis on individual symptoms within each domain. Of 1,553 treated participants, 1,398(90.0%), including 531(38%) starters, completed both MDQs. Starters reported improvements for premenstrual Pain (−1.4), Water Retention (−3.3) and Negative Affect (−2.5); and for menstrual Pain (−3.5), Water Retention (−3.4), and Negative Affect (−2.7) (all p < 0.01). For switchers, no changes were significant except an increase in premenstrual (+1.0, p = 0.02) and menstrual (+1.5, p = 0.003) Water Retention. We observed a change in symptom intensity in >40% of participants for Cramps, Backache and Fatigue (domain Pain), Painful or Tender Breast and Swelling (domain Water Retention) and Mood Swings and Irritability (domain Negative Affect). E4/DRSP starters experienced significant improvements in the domains Pain, Water Retention and Negative Affect particularly benefiting those with more severe baseline symptoms. Switchers showed minimal changes. A phase 3 study in Europe and Russia showed that Estetrol/Drospirenone, a new combined oral contraceptive, significantly improved the MDQ scores for domains Pain, Water Retention and Negative Affect in women starting COC use, while switchers showed minimal changes. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the prospective risk of Type 2 diabetes (T2D) in Nordic women with polycystic ovary syndrome (PCOS) compared to controls? SUMMARY ANSWER A diagnosis of PCOS and BMI ≥30 kg/m2 is a high-risk phenotype for a prospective risk of T2D diagnosis across Nordic countries. WHAT IS KNOWN ALREADY The risk of T2D in women with PCOS is increased. The risk of T2D is related to BMI and the magnitude of risk in normal weight women with PCOS has been discussed. However, prospective data regarding risk of T2D in population-based cohorts of women with PCOS are limited. STUDY DESIGN, SIZE, DURATION This national register-based study included women with PCOS and age-matched controls. The main study outcome was T2D diagnosis occurring after PCOS diagnosis. T2D was defined according to ICD-10 diagnosis codes and/or filled medicine prescriptions of anti-diabetic medication excluding metformin. PARTICIPANTS/MATERIALS, SETTING, METHODS The study cohort included women originating from Denmark (PCOS Denmark, N = 27 016; controls, N = 133 994), Finland (PCOS Finland, N = 20 467; controls, N = 58 051), and Sweden (PCOS Sweden, N = 52 409; controls, N = 254 010). The median age at cohort entry was 28 years in PCOS Denmark, Finland, and Sweden with a median follow-up time (interquartile range) in women with PCOS of 8.5 (4.0–14.8), 9.8 (5.1–15.1), and 6.0 (2.0–10.0) years, respectively. Cox regression analyses were adjusted for BMI and length of education. MAIN RESULTS AND THE ROLE OF CHANCE The crude hazard ratio (HR, 95% CI) for T2D diagnosis in women with PCOS was 4.28 (3.98–4.60) in Denmark, 3.40 (3.11–3.74) in Finland, and 5.68 (5.20–6.21) in Sweden. In adjusted regression analyses, BMI ≥30 vs <25 kg/m2 was associated with a 7.6- to 11.3-fold risk of T2D. In a combined meta-analysis (PCOS, N = 99 892; controls, N = 446 055), the crude HR for T2D in PCOS was 4.64 (3.40–5.87) and, after adjustment for BMI and education level, the HR was 2.92 (2.32–3.51). LIMITATIONS, REASONS FOR CAUTION Inclusion of more severe cases of PCOS in the present study design could have lead to an overestimation of risk estimates in our exposed population. However, some women in the control group would have undiagnosed PCOS, which would lead to an underestimation of T2D risk in women with PCOS. BMI data were not available for all participants. The present study should be repeated in study cohorts with higher background risks of T2D, particularly in populations of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS The prospective risk for diagnosis of T2D is increased in women with PCOS, and the risk is aggravated in women with BMI ≥30 kg/m2. STUDY FUNDING/COMPETING INTEREST(S) Funding in Denmark was from the Region of Southern Denmark, Overlægerådet, Odense University Hospital. Funding in Finland was from Novo Nordisk Foundation, Finnish Research Council and Sigrid Juselius Foundation, the National Regional Fund, Sakari Alhopuro Foundation and Finnish Diabetes Research Foundation. E.E. has received a research grant from Ferring Pharmaceuticals (payment to institution) and serves as medical advisor for Tilly AB, not related to this manuscript. The remaining authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

The beneficial effects of physical activity (PA) on gut microbiome have been reported, nevertheless the findings are inconsistent, with the main limitation of subjective methods for assessing PA. It is well accepted that using an objective assessment of PA reduces the measurement error and also allows objective assessment of sedentary behavior (SB). We aimed to study the associations between accelerometer‐assessed behaviors (i.e., SB, light‐intensity physical activity [LPA] and moderate‐to‐vigorous physical activity [MVPA]) with the gut microbiome using compositional data analysis, a novel approach that enables to study these behaviors accounting for their inter‐dependency. This cross‐sectional study included 289 women from the Northern Finland Birth Cohort 1966. Physical activity was measured during 14 days by wrist‐worn accelerometers. Analyses based on the combined effect of MVPA and SB, and compositional data analyses in association with the gut microbiome data were performed. The microbial alpha‐ and beta‐diversity were not significantly different between the MVPA‐SB groups, and no differentially abundant microorganisms were detected. Compositional data analysis did not show any significant associations between any movement behavior (relative to the others) on microbial alpha‐diversity. Butyrate‐producing bacteria such as Agathobacter and Lachnospiraceae CAG56 were significantly more abundant when reallocating time from LPA or SB to MVPA (γ = 0.609 and 0.113, both p‐values = 0.007). While PA and SB were not associated with microbial diversity, we found associations of these behaviors with specific gut bacteria, suggesting that PA of at least moderate intensity (i.e., MVPA) could increase the abundance of short‐chain fatty acid–producing microbes. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of gestational diabetes mellitus (GDM) is globally increasing, and it has been associated with later type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease (CVD). However, long‐term population‐based studies investigating common CVD risk factors years after pregnancy are lacking. To evaluate the future mortality and morbidity in cardiovascular and metabolic diseases, we conducted a thorough investigation of midlife risk factors in women with and without previous GDM. Material and Methods: A prospective population‐based cohort study was conducted of 3173 parous women from the Northern Finland Birth Cohort, 1966. Study participants were obtained from the national register or patient records. Those with a GDM diagnosis formed the GDM cohort (n = 271), and those without a previous GDM diagnosis formed the control cohort (n = 2902). Clinical examinations were performed on participants at the age of 46 and included anthropometric measurements, oral glucose tolerance test (OGTT), biochemical measurements, and cardiovascular assessment. Results: At the age of 46, women in the GDM cohort had a higher body mass index (BMI, 29.0 kg/m2 vs 26.3 kg/m2, p < 0.001) and greater waist circumference (94.1 cm vs 86.5 cm, p < 0.001) than the control cohort. In the GDM cohort, a higher incidence of impaired glucose tolerance (12.6% vs 7.3%, p = 0.002), more previously diagnosed and OGTT‐detected type 2 diabetes (23.3% vs 3.9%, p < 0.001), lower high‐density lipoprotein (1.53 mmol/L vs 1.67 mmol/L, p = 0.011), higher triglycerides (1.26 mmol/L vs 1.05 mmol/L, p = 0.002) and a higher fatty liver index (6.82 vs 2.47, p < 0.001), were observed even after adjusting for BMI, polycystic ovary syndrome, parity, level of education, physical activity, smoking, and alcohol consumption. The women in the GDM cohort also had more MetS (42.6% vs 21.9%, p < 0.001) and higher risk scores for CVD and fatal events (Framingham 4.95 vs 3.60, p < 0.001; FINRISK 1.71 vs 1.08, p < 0.001). Conclusions: Women with a previous diagnosis of GDM exhibit more risk factors for CVD in midlife and are at a higher risk for cardiovascular events later in life. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can a genome-wide association study (GWAS) meta-analysis, including a large sample of young premenopausal women from a founder population from Northern Finland, identify novel genetic variants for circulating anti-Müllerian hormone (AMH) levels and provide insights into single-nucleotide polymorphism enrichment in different biological pathways and tissues involved in AMH regulation? SUMMARY ANSWER The meta-analysis identified a total of six loci associated with AMH levels at P  <   5 × 10−8, three of which were novel in or near CHEK2 , BMP4 , and EIF4EBP1 , as well as highlighted significant enrichment in renal system vasculature morphogenesis, and the pituitary gland as the top associated tissue in tissue enrichment analysis. WHAT IS KNOWN ALREADY AMH is expressed by preantral and small antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with several health conditions. However, the biological mechanisms underlying the association between health conditions and AMH levels are not yet fully understood. Previous GWAS have identified loci associated with AMH levels in pre-menopausal women, in or near MCM8 , AMH , TEX41 , and CDCA7. STUDY DESIGN, SIZE, DURATION We performed a GWAS meta-analysis for circulating AMH level measurements in 9668 pre-menopausal women. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a GWAS meta-analysis in which we combined 2619 AMH measurements (at age 31 years) from a prospective founder population cohort (Northern Finland Birth Cohort 1966, NFBC1966) with a previous GWAS meta-analysis that included 7049 pre-menopausal women (age range 15–48 years) (N = 9668). NFBC1966 AMH measurements were quantified using an automated assay. We annotated the genetic variants, combined different data layers to prioritize potential candidate genes, described significant pathways and tissues enriched by the GWAS signals, identified plausible regulatory roles using colocalization analysis, and leveraged publicly available summary statistics to assess genetic and phenotypic correlations with multiple traits. MAIN RESULTS AND THE ROLE OF CHANCE Three novel genome-wide significant loci were identified. One of these is in complete linkage disequilibrium with c.1100delC in CHEK2 , which is found to be 4-fold enriched in the Finnish population compared to other European populations. We propose a plausible regulatory effect of some of the GWAS variants linked to AMH, as they colocalize with GWAS signals associated with gene expression levels of BMP4 , TEX41 , and EIFBP41. Gene set analysis highlighted significant enrichment in renal system vasculature morphogenesis, and tissue enrichment analysis ranked the pituitary gland as the top association. LARGE SCALE DATA The GWAS meta-analysis summary statistics are available for download from the GWAS Catalogue with accession number GCST90428625. LIMITATIONS, REASONS FOR CAUTION This study only included women of European ancestry and the lack of sufficiently sized relevant tissue data in gene expression datasets hinders the assessment of potential regulatory effects in reproductive tissues. WIDER IMPLICATIONS OF THE FINDINGS Our results highlight the increased power of founder populations and larger sample sizes to boost the discovery of novel trait-associated variants underlying variation in AMH levels, which aided the characterization of GWAS signals enrichment in different biological pathways and plausible genetic regulatory effects linked with AMH level variation for the first time. STUDY FUNDING/COMPETING INTEREST(S) This work has received funding from the European Union's Horizon 2020 Research and Innovation Programme under the MATER Marie Sklodowska-Curie Grant Agreement No. 813707 and Oulu University Scholarship Foundation and Paulon Säätiö Foundation. (N.P.-G.), Academy of Finland, Sigrid Jusélius Foundation, Novo Nordisk, University of Oulu, Roche Diagnostics (T.T.P.). This work was supported by the Estonian Research Council Grant 1911 (R.M.). J.R. was supported by the European Union's Horizon 2020 Research and Innovation Program under Grant Agreements No. 874739 (LongITools), 824989 (EUCAN-Connect), 848158 (EarlyCause), and 733206 (LifeCycle). U.V. was supported by the Estonian Research Council grant PRG (PRG1291). The NFBC1966 received financial support from University of Oulu Grant No. 24000692, Oulu University Hospital Grant No. 24301140, and ERDF European Regional Development Fund Grant No. 539/2010 A31592. T.T.P. has received grants from Roche, Perkin Elmer, and honoraria for scientific presentations from Gedeon Richter, Exeltis, Astellas, Roche, Stragen, Astra Zeneca, Merck, MSD, Ferring, Duodecim, and Ajaton Terveys. For all other authors, there are no competing interests. [ABSTRACT FROM AUTHOR]

Summary: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in females. Modest weight loss improves reproductive and metabolic PCOS features. While lifestyle modifications and pharmacotherapies remain first‐line weight loss strategies, bariatric surgery is emerging as a potentially effective treatment. We performed a systematic review and meta‐analysis of published literature to examine the impact of bariatric surgery in PCOS to inform the 2023 International PCOS Evidence‐based Guidelines. Electronic databases were searched for observational studies and trials comparing pharmacologic or lifestyle treatments to bariatric surgery in women with PCOS or bariatric surgery in women with or without PCOS. Anthropometric, reproductive, hormonal, and metabolic outcomes were included and, where possible, meta‐analyzed using random‐effects models. Risk of bias and evidence quality were assessed. Ten studies were included involving 432 women with and 590 women without PCOS. Comparisons between bariatric surgery and pharmacologic or lifestyle treatments were only reported in one study each, and most reproductive outcomes were limited to a single study; therefore, meta‐analyses could not be performed. Meta‐analysis found that women with PCOS experience similar improvements in anthropometric, hormonal, and metabolic outcomes after bariatric surgery compared to those without PCOS. Existing research is limited and of low quality with high risk of bias, especially in comparison to existing PCOS treatments and with respect to reproductive outcomes including pregnancy, highlighting the need for additional studies to inform clinical recommendations. [ABSTRACT FROM AUTHOR]

Objective This population-based follow-up study investigated register-based disease diagnoses and medication use up till age of 50 years among women with polycystic ovary syndrome (PCOS) that were identified from a population-based birth cohort. Design Population-based longitudinal cohort study. Patients Women reporting oligo/amenorrhea and hirsutism at age 31 and/or who were diagnosed with PCOS by a physician by age 46 (n = 244) and women without PCOS symptoms or diagnosis (n = 1556) in the Northern Finland Birth Cohort 1966. Main Outcome Measures National register data on diagnosed diseases (International Statistical Classification of Diseases [ICD]-8-10) and medication use (Anatomical Therapeutic Chemical) until the age of 50. Results Women with PCOS had a 26% higher risk for any registered diagnosis (risk ratio [RR]: 1.26 [1.09-1.46]) and a 24% higher risk for medication use (RR: 1.24 [1.05-1.46]) compared with non-PCOS women, even after adjusting for several confounders. Several main ICD categories were more prevalent among women with PCOS versus non-PCOS controls, eg, endocrine, metabolic, nervous system, musculoskeletal, and genitourinary diseases in addition with different symptoms and injuries. Surprisingly, even though the overall morbidity was only increased in women with PCOS with a body mass index (BMI) ≥ 25 kg/m2, there were several ICD main categories that showed higher comorbidity risk especially in women with PCOS with a BMI < 25 kg/m2. Several medications were prescribed more often to women with PCOS versus non-PCOS controls, eg, medications related to the alimentary tract and metabolism, the cardiovascular system, genitourinary system drugs and sex hormones, dermatologic and hormonal preparations, and medications to treat the musculoskeletal, nervous, and respiratory systems. Conclusion Women with PCOS are burdened with multimorbidity and higher medication use, independent of BMI and other confounders. Accordingly, preventive strategies are needed to alleviate the disease burden and improve the health outcomes of women with PCOS. [ABSTRACT FROM AUTHOR]

Objective: To investigate plasma antimüllerian hormone (AMH) concentration and its relation to steroid hormone levels in pregnant women with polycystic ovary syndrome (PCOS) and controls at term.Design: Case-control study.Setting: University-affiliated hospital.Patient(s): A total of 74 pregnant women at term: 25 women with PCOS (aged 31.6 ± 3.9 years [mean ± standard deviation], body mass index 24.0 ± 3.9 kg/m2, mean gestational length 279 ± 9 days) and 49 controls (aged 31.7 ± 3.3 years, body mass index 24.0 ± 3.3 kg/m2, mean gestational length 281 ± 9 days).Intervention(s): None.Main Outcome Measure(s): Plasma AMH and steroid hormone levels.Result(s): Antimüllerian hormone, T, and androstenedione levels were higher in women with PCOS at term compared with controls, whereas estrogen and P levels were similar. The differences were pronounced in women carrying a female fetus. Testosterone and AMH levels correlated positively in both groups, but E2 levels only in women with PCOS.Conclusion(s): Pregnant women with PCOS present with elevated AMH and androgen levels even at term, suggesting a hormonal imbalance during PCOS pregnancy. Differences were detected especially in pregnancies with a female fetus, raising the question of whether female pregnancies are more susceptible to AMH and steroid hormone actions. [ABSTRACT FROM AUTHOR]

Study Question: Are children of mothers with polycystic ovary syndrome (PCOS) or anovulatory infertility at increased risks of obesity or diabetes?Summary Answer: Maternal PCOS/anovulatory infertility is associated with an increased risk of offspring obesity from early age and diabetes in female offspring from late adolescence.What Is Known Already: Women with PCOS often have comorbid metabolic disorders such as obesity and diabetes, and children of mothers with PCOS have an increased risk of subtle signs of cardiometabolic alterations.Study Design, Size, Duration: This was a nationwide cohort study of all live births (n = 1 105 997) during 1996-2014 in Finland, excluding those with maternal diagnoses sharing signs and symptoms with PCOS (n = 8244). A total of 1 097 753 births were included and followed up until 31 December 2018.Participants/materials, Setting, Methods: National registries were linked to identify births with maternal PCOS or anovulatory infertility (n = 24 682). The primary outcomes were diagnoses of obesity (ICD-10: E65, E66) and diabetes (ICD-10: E10-E14) in offspring recorded in the Finnish Care Register for Health Care. Cox proportional hazards regression was modeled to analyze the risk of offspring obesity and diabetes in relation to prenatal exposure to maternal PCOS/anovulatory infertility. Differently adjusted models and stratified analyses were used to assess whether the risk was modified by maternal obesity or diabetes diagnoses, pre-pregnancy BMI, fertility treatment or perinatal problems.Main Results and the Role Of Chance: Exposure to maternal PCOS/anovulatory infertility was associated with a higher cumulative incidence of obesity in the children (exposed: 1.83%; 95% CI 1.66-2.00% vs unexposed: 1.24%; 95% CI 1.22-1.26%). Accounting for birth factors and maternal characteristics such as obesity and diabetes diagnoses, the hazard ratio (HR) for obesity was increased in offspring below 9 years of age (HR 1.58; 95% CI 1.30-1.81), and in those 10-16 years of age (HR 1.37; 95% CI 1.19-1.57), but not in those aged 17-22 years (HR 1.24; 95% CI 0.73-2.11). Sex-stratified analyses revealed similar risk estimates for boys (HR 1.48; 95% CI 1.31-1.68) and girls (HR 1.45; 95% CI 1.26-1.68). Notably, the joint effect of PCOS/anovulatory infertility and BMI-based pre-pregnancy obesity on offspring obesity (HR 8.89; 95% CI 7.06-11.20) was larger than that of either PCOS/anovulatory infertility or obesity alone. Furthermore, PCOS/anovulatory infertility was associated with offspring obesity in children without perinatal problems (HR 1.27; 95% CI 1.17-1.39), with larger effect size for maternal PCOS/anovulatory infertility and joint perinatal problems (HR 1.61; 95% CI 1.35-1.91). However, the risk estimates were comparable between maternal PCOS/anovulatory infertility with (HR 1.54; 95% CI 1.17-2.03) and without fertility treatment (HR 1.46; 95% CI 1.32-1.61). For offspring diabetes, the HR was increased only between 17 and 22 years of age (HR 2.06; 95% CI 1.23-3.46), and specifically for Type 1 diabetes in females (HR 3.23; 95% CI 1.41-7.40).Limitations, Reasons For Caution: The prevalence of PCOS/anovulatory infertility in this study was 2.2%, lower than that reported in previous studies. In addition, the incidence of obesity in offspring was lower than that reported in studies based on measured or self-reported weight and height and may include mainly moderate and severe obesity cases who needed and/or actively sought medical care. Moreover, mothers with PCOS/anovulatory infertility were identified based on ICD codes, with no information on PCOS phenotypes. Furthermore, maternal pre-pregnancy BMI was available only from 2004. The PCOS/anovulatory infertility association with female offspring diabetes was based on only a few cases. Mothers' weight gain during pregnancy, use of fertility treatment other than fresh or frozen IVF/ICSI, offspring lifestyle, as well as fathers' age, medical disorders or medication prescriptions were not available for this study.Wider Implications Of the Findings: These findings support that prenatal PCOS/anovulatory infertility exposure influences metabolic health in the offspring from early age.Study Funding/competing Interest(s): This study was supported by Shandong Provincial Natural Science Foundation, China [ZR2020MH064 to X.C.], Shandong Province Medical and Health Technology Development Plan [2018WS338 to X.C.], the joint research funding of Shandong University and Karolinska Institute [SDU-KI-2019-08 to X.C. and C.L.], the Finnish Institute for Health and Welfare: Drug and Pregnancy Project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 and SLL20190589 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. received grants from the China Scholarship Council at the beginning of the study. The authors have no competing interests to disclose.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Introduction: Urinary incontinence is a common ailment in women and is likely to affect their work ability. We investigated the associations between the different subtypes of urinary incontinence and several dimensions of perceived work ability in middle‐aged general population. Material and methods: Cross‐sectional survey at age 46 among participants of the Northern Finland Birth Cohort 1966 study (n = 3706, response rate 72%). Urinary incontinence symptoms and several items of Work Ability Index were collected by postal questionnaire. Work ability was dichotomized as good or poor work ability in general, in relation to physical job demands, to diseases and own 2‐year prospect of work ability. The associations between urinary incontinence and work ability measures were assessed using logistic regression models, with further adjustments for biological, behavioral and work‐related factors as well as general health. Results: The odds ratio (OR), from lowest to highest, for poor work ability were 1.4‐fold among women with stress urinary incontinence (OR 1.37, 95% confidence interval [CI] 1.09–1.72), 2.5‐fold with mixed urinary incontinence (OR 2.51, 95% CI 1.68–3.74) and 3.3‐fold with urgency urinary incontinence (OR 3.34, 95% CI 1.95–5.70). We note that our results reflect work ability in a Nordic society. Conclusions: Especially urgency and mixed types of urinary incontinence are associated with poor work ability among middle‐aged women. [ABSTRACT FROM AUTHOR]

Study Question: Is maternal polycystic ovary syndrome (PCOS) associated with increased risks for a broad spectrum of psychiatric and mild neurodevelopmental disorders in offspring?Summary Answer: Maternal PCOS and/or anovulatory infertility is independently, and jointly with maternal obesity, perinatal problems, cesarean delivery and gestational diabetes, associated with increased risks in offspring for almost all groups of psychiatric and mild neurodevelopmental disorders with onset in childhood or adolescence.What Is Known Already: Maternal PCOS was previously associated with autism spectrum disorder, attention-deficit/hyperactivity disorders and possibly developmental delay in offspring. Few studies have investigated the association between maternal PCOS and other psychiatric and neurodevelopmental disorders in offspring.Study Design, Size, Duration: This was a population-based cohort study in Finland including all live births between 1996 and 2014 (n = 1 105 997). After excluding births to mothers with symptoms similar to PCOS, a total of 1 097 753 births by 590 939 mothers remained. Children were followed up until 31 December 2018, i.e. up to the age of 22 years.Participants/materials, Setting, Methods: National registries were used to link data of the included births and their mothers. Data from 24 682 (2.2%) children born to mothers with PCOS were compared with 1 073 071 (97.8%) children born to mothers without PCOS. Cox proportional hazards modeling was used to evaluate the hazard ratio (HR) and 95% CI for the risk of neuropsychiatric disorders in relation to maternal PCOS. Stratified analyses were performed to test the independent role of PCOS and the joint effects of PCOS with maternal obesity, perinatal problems, cesarean delivery, gestational diabetes and use of fertility treatment. The analysis was adjusted for maternal age, country of birth, marriage status at birth, smoking, parity, psychiatric disorders, prescription of psychotropic N05/N06 during pregnancy and systemic inflammatory diseases when applicable.Main Results and the Role Of Chance: A total of 105 409 (9.8%) children were diagnosed with a neurodevelopmental or psychiatric disorder. Firstly, maternal PCOS was associated with any psychiatric diagnosis (HR 1.32; 95% CI 1.27-1.38) in offspring. Particularly, the risk was increased for sleeping disorders (HR 1.46; 95% CI 1.27-1.67), attention-deficit/hyperactivity disorders and conduct disorders (HR 1.42; 95% CI 1.33-1.52), tic disorders (HR 1.42; 95% CI 1.21-1.68), intellectual disabilities (HR 1.41; 95% CI 1.24-1.60), autism spectrum disorder (HR 1.40; 95% CI 1.26-1.57), specific developmental disorders (HR 1.37; 95% CI 1.30-1.43), eating disorders (HR 1.36; 95% CI 1.15-1.61), anxiety disorders (HR 1.33; 95% CI 1.26-1.41), mood disorders (HR 1.27; 95% CI 1.18-1.35) and other behavioral and emotional disorders (ICD-10 F98, HR 1.49; 95% CI 1.39-1.59). In short, there was no significant difference between sexes. The results were robust when restricting the analyses to the first-born children or births to mothers without psychiatric diagnosis or purchase of psychotropic medication. Secondly, stratified analysis according to maternal BMI showed that the risk of any neuropsychiatric disorder was increased in offspring to normal-weight mothers with PCOS (HR 1.20; 95% CI 1.09-1.32), and markedly higher in those to severely obese mothers with PCOS (HR 2.11; 95% CI 1.76-2.53) compared to offspring to normal-weight mothers without PCOS. When excluding perinatal problems, mothers with PCOS were still associated with increased risks of any neuropsychiatric disorders in offspring (HR 1.28; 95% CI 1.22-1.34) compared to mothers without PCOS. However, an additional increase was observed for PCOS in combination with perinatal problems (HR 1.99; 95% CI 1.84-2.16). Likewise, excluding cases with maternal gestational diabetes (HR 1.30; 95% CI 1.25-1.36), cesarean delivery (HR 1.29; 95% CI 1.23-1.35) or fertility treatment (HR 1.31; 95% CI 1.25-1.36) did not eliminate the associations.Limitations, Reasons For Caution: The register-based prevalence of PCOS was lower than previously reported, suggesting that this study may capture the most severe cases. To combine anovulatory infertility with PCOS diagnosis as PCOS exposure might introduce diagnostic bias. It was not feasible to distinguish between subtypes of PCOS. Furthermore, familial factors might confound the association between maternal PCOS and neuropsychiatric disorders in offspring. Maternal BMI was available for birth cohort 2004-2014 only and there was no information on gestational weight gain.Wider Implications Of the Findings: This study provides further evidence that maternal PCOS and/or anovulatory infertility, independently and jointly with maternal obesity, perinatal problems, gestational diabetes and cesarean delivery, implies a broad range of adverse effects on offspring neurodevelopment. These findings may potentially help in counseling and managing pregnancies.Study Funding/competing Interest(s): This study was supported by the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C and C.L.), THL Finnish Institute for Health and Welfare: Drug and pregnancy project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. was supported by the China Scholarship Council during her training in Karolinska Institute. L.K. was supported by the China Scholarship Council for his PhD study in Karolinska Institute. The authors have no competing interests to disclose.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Low testosterone (T) levels in men associate with increased risks of obesity, type 2 diabetes, metabolic syndrome, and cardiovascular diseases. However, most studies are cross‐sectional with follow‐up‐time < 10 years, and data on early growth are limited. Objective: To compare prenatal factors and body mass index (BMI) development from birth to age 46 in relation to low T at age 31. Materials and methods: Men with low T (T < 12.1 nmol/L, n = 132) and men with normal T at age 31 (n = 2561) were derived from the Northern Finland Birth Cohort 1966. Prenatal factors, longitudinal weight and height data from birth to age 14, and cross‐sectional weight and height data at ages 31 and 46, and waist‐hip‐ratio (WHR) and T levels at age 31 were analyzed. Longitudinal modeling and timing of adiposity rebound (AR, second BMI rise at age 5–7 years) were calculated from fitted BMI curves. Results were adjusted for mother's pre‐pregnancy BMI and smoking status, birth weight for gestational age, alcohol consumption, education level, smoking status, and WHR at age 31. Results: Neither gestational age nor birth weight was associated with low T at age 31; however, maternal obesity during gestation was more prevalent among men with low T (9.8% vs. 3.5%, adjusted aOR: 2.43 [1.19−4.98]). Men with low T had earlier AR (5.28 vs. 5.82, aOR: 0.73 [0.56−0.94]) and higher BMI (p < 0.001) from AR onward until age 46. Men with both early AR and low T had the highest BMI from AR onward. Conclusions: In men, maternal obesity and early weight gain associate with lower T levels at age 31, independently of adulthood abdominal obesity. Given the well‐known health risks related to obesity, and the rising prevalence of maternal obesity, the results of the present study emphasize the importance of preventing obesity that may also affect the later reproductive health of the offspring. [ABSTRACT FROM AUTHOR]

Objective: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence‐based PCOS Guideline. Design: Systematic review and meta‐analysis of the literature. Patients: Women with PCOS and treatment with insulin sensitisers. Measurements: Hormonal and clinical outcomes, as well as side effects. Results: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: −4.39, 95% confidence interval [CI]: −7.69 to −1.08 kg), body mass index (MD: −0.95, 95% CI: −1.41 to −0.49 kg/m2) and testosterone (MD: −0.10, 95% CI: −0.18 to −0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. Conclusions: Metformin should remain the first‐line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine condition among women with pleiotropic sequelae possessing reproductive, metabolic, and psychological characteristics. Although the exact origin of PCOS is elusive, it is known to be a complex multigenic disorder with a genetic, epigenetic, and environmental background. However, the pathogenesis of PCOS, and the role of genetic variants in increasing the risk of the condition, are still unknown due to the lack of an appropriate study model. Since the debut of induced pluripotent stem cell (iPSC) technology, the ability of reprogrammed somatic cells to self-renew and their potential for multidirectional differentiation have made them excellent tools to study different disease mechanisms. Recently, researchers have succeeded in establishing human in vitro PCOS disease models utilizing iPSC lines from heterogeneous PCOS patient groups (iPSCPCOS). The current review sets out to summarize, for the first time, our current knowledge of the implications and challenges of iPSC technology in comprehending PCOS pathogenesis and tissue-specific disease mechanisms. Additionally, we suggest that the analysis of polygenic risk prediction based on genome-wide association studies (GWAS) could, theoretically, be utilized when creating iPSC lines as an additional research tool to identify women who are genetically susceptible to PCOS. Taken together, iPSCPCOS may provide a new paradigm for the exploration of PCOS tissue-specific disease mechanisms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m2. There is inadequate evidence to suggest the optimal COCP formulation, or dosing regimen and formulation of metformin. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. Overall, recommendations are strengthened and evidence is improved, but remain generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients 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 programme supports the Guideline with an integrated evaluation program. This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and the Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the sponsoring organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION Overall, recommendations are strengthened and evidence is improved, but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients 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) This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC. [ABSTRACT FROM AUTHOR]

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 (25 OHD) 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 25 OHD, 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 25 OHD 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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), lowdensity 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. [ABSTRACT FROM AUTHOR]

Study question: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary answer: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. What is known already: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from 6 continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very lowto low-quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensusbased to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, the evidence quality was low, and evidence-practice gaps persist. Study design, size, and duration: The 2023 International Evidence-based Guideline update re-engaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation, and ultimately recommendation strength, and diversity and inclusion were considered throughout. Participants/materials, setting, and methods: This summary should be read in conjunction with the full guideline for detailed participants and methods. Governance included a 6-continent international advisory and management committee, 5 guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health, and other experts, alongside consumers, project management, evidence synthesis, statisticians, and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and 5 face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across 5 guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council. Main results and the role of chance: The evidence in the assessment and management of PCOS has generally improved in the past 5 years but remains of low to moderate quality. The technical evidence report and analyses (~6000 pages) underpin 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include the following: (1) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm, and inclusion of anti-Müllerian hormone levels as an alternative to ultrasound in adults only; (2) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnoea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; (3) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care, and shared decision-making to improve patient experience, alongside greater research; (4) maintained emphasis on healthy lifestyle, emotional well-being, and quality of life, with awareness and consideration of weight stigma; and (5) emphasizing evidence-based medical therapy and cheaper and safer fertility management. Limitations and reasons for caution: Overall, recommendations are strengthened and evidence is improved but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. Wider implications of the findings: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients 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 programme supports the guideline with an integrated evaluation programme. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]