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The Women's Health Study (WENDY) was conducted to improve insights into women's health and health burden. It provides a unique, comprehensive data source that can be broadly utilised to understand gynaecological symptoms, diseases, and their relation to metabolic and overall health more deeply in a population-based setting. The study was conducted in Finland from May 2020 to October 2022. It included 1,918 women (33-37 years old) who were born in Northern Finland between July 1985 and December 1987. Data collection comprised one three-to-four-hour study visit that included clinical measurements, biological samples, ultrasound examinations and an extensive questionnaire on gynaecological and reproductive history, physical and mental health, quality of life, lifestyles, current life situations, health awareness and opinions. The study also included a menstrual cycle follow-up and cognitive testing up to three months via a mobile application. Given that all participants' data can be linked to all Finnish national registers, and the NFBC participants' data can be linked to the birth cohort data set collected from gestational week 24 onwards, WENDY study forms one of the largest datasets worldwide to investigate gynecological and metabolic health burden in women.
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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.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Síndrome do Ovário Policístico , Tiazolidinedionas , Adulto , Humanos , Feminino , Rosiglitazona/uso terapêutico , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Insulina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Tiazolidinedionas/uso terapêuticoRESUMO
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.
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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.
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Índice de Massa Corporal , Diabetes Mellitus Tipo 2 , Síndrome do Ovário Policístico , Humanos , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/complicações , Feminino , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Adulto , Dinamarca/epidemiologia , Suécia/epidemiologia , Finlândia/epidemiologia , Estudos Prospectivos , Fatores de Risco , Estudos de Casos e Controles , Adulto Jovem , Estudos de Coortes , Sistema de Registros , Pessoa de Meia-IdadeRESUMO
The number of frozen embryo transfer (FET) cycles is increasing rapidly worldwide. Different endometrial preparations for FET result in comparable live birth rates. However, several recent publications have reported higher maternal risks for hypertensive disorders of pregnancy (HDP), pre-eclampsia and postpartum haemorrhage (PPH) in programmed cycles (PC-FET) compared with natural cycles and modified natural cycles with an intact corpus luteum. Nevertheless, PC-FET is frequently used in ovulatory women despite the increased risks for HDP, pre-eclampsia and PPH. Although randomized controlled studies have been suggested, PC-FET raises several methodological problems. Large study populations would be required to investigate the outcomes in question, and the inclusion of ovulatory women, where the intervention may increase the risk of a negative outcome, is ethically troublesome. In the authors' opinion, the existing evidence from large observational studies and systematic reviews is sufficiently strong to recommend an endometrial preparation strategy that aims to maintain or stimulate the corpus luteum to minimize the risk of HDP and pre-eclampsia after FET cycles.
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Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Criopreservação/métodos , Transferência Embrionária/efeitos adversos , Transferência Embrionária/métodos , Coeficiente de Natalidade , Corpo Lúteo , Estudos Retrospectivos , Taxa de GravidezRESUMO
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.
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Incontinência Urinária por Estresse , Incontinência Urinária , Pessoa de Meia-Idade , Humanos , Feminino , Estudos Transversais , Finlândia/epidemiologia , Coorte de Nascimento , Avaliação da Capacidade de Trabalho , Incontinência Urinária/epidemiologia , Incontinência Urinária/diagnóstico , Incontinência Urinária por Estresse/epidemiologiaRESUMO
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.
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Infertilidade Feminina , Síndrome do Ovário Policístico , Gravidez , Feminino , Humanos , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/terapia , Comorbidade , Infertilidade Feminina/etiologia , Infertilidade Feminina/terapia , Estilo de Vida Saudável , FertilidadeRESUMO
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.
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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.
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Doenças Cardiovasculares , Diabetes Gestacional , Fatores de Risco de Doenças Cardíacas , Humanos , Feminino , Diabetes Gestacional/epidemiologia , Gravidez , Finlândia/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Coorte de Nascimento , Estudos de Coortes , Índice de Massa Corporal , Fatores de Risco , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/complicações , Teste de Tolerância a Glucose , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicaçõesRESUMO
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.
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Acelerometria , Exercício Físico , Microbioma Gastrointestinal , Comportamento Sedentário , Humanos , Feminino , Microbioma Gastrointestinal/fisiologia , Estudos Transversais , Exercício Físico/fisiologia , Pessoa de Meia-Idade , FinlândiaRESUMO
PURPOSE: To describe the effects of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg on physical and emotional premenstrual and menstrual symptoms. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.
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Androstenos , Síndrome Pré-Menstrual , Autorrelato , Humanos , Feminino , Adulto , Federação Russa , Adulto Jovem , Síndrome Pré-Menstrual/tratamento farmacológico , Síndrome Pré-Menstrual/psicologia , Europa (Continente) , Androstenos/uso terapêutico , Pessoa de Meia-Idade , Adolescente , Combinação de Medicamentos , Inquéritos e Questionários , Dismenorreia/tratamento farmacológico , Dismenorreia/psicologiaRESUMO
OBJECTIVE: As part of the update of the International Evidence-Based Guidelines for the Assessment and Management of polycystic ovary syndrome (PCOS), a systematic review was performed to inform evidence-based recommendations. DESIGN: Systematic review. Only randomised controlled trial were included. PATIENTS: Women with PCOS; the use of combined oral contraceptive pills (COCP) was compared with no medical treatment. MEASUREMENTS: Outcomes were designed in collaboration with clinical experts, researchers, and consumers. Critical outcomes included hirsutism, irregular cycles, quality of life, body mass index (BMI), and weight. RESULTS: 1660 publications were identified, but only four studies were included. No studies could be combined for meta-analysis. COCP treatment improved cycle regularity compared with no medical treatment (100% vs. 0%, with low certainty of evidence). COCP showed no difference in improvement of hirsutism or BMI compared with placebo or lifestyle; a lower weight after COCP compared with no treatment (mean difference [MD] -8.0 (95% confidence interval, CI -11.67); -4.33 kg); and improvement in quality of life (MD 1.2 [95% CI 0.96]; 1.44), but these results were all very low certainty of evidence. CONCLUSION: Results show that COCP benefit cycle regulation, but other benefits or potential adverse effects were only identified with very low certainty of evidence. The COCP is frontline medical treatment in PCOS, but this is still based on established efficacy in the broader general population. Our results show that research in PCOS is seriously lacking and should be prioritised to capture core reproductive, metabolic and psychological outcomes important in PCOS.
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Síndrome do Ovário Policístico , Feminino , Humanos , Anticoncepcionais Orais Combinados/uso terapêutico , Hirsutismo/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Qualidade de VidaRESUMO
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 (â¼6000 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.
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Ginecologia , Síndrome do Ovário Policístico , Gravidez , Adulto , Feminino , Humanos , Criança , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/terapia , Síndrome do Ovário Policístico/epidemiologia , Qualidade de Vida , Austrália , Fatores de RiscoRESUMO
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.
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Slings Suburetrais , Incontinência Urinária por Estresse , Feminino , Humanos , Incontinência Urinária por Estresse/cirurgia , Seguimentos , Estudos Prospectivos , Procedimentos Cirúrgicos Urológicos/métodos , Incontinência Urinária de Urgência/cirurgia , Resultado do TratamentoRESUMO
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.
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Diabetes Mellitus Tipo 2 , Transtornos do Metabolismo de Glucose , Contracepção Hormonal , Estado Pré-Diabético , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos de Coortes , Anticoncepção/métodos , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Hormonais , Diabetes Mellitus Tipo 2/epidemiologia , Transtornos do Metabolismo de Glucose/induzido quimicamente , Transtornos do Metabolismo de Glucose/epidemiologia , Contracepção Hormonal/efeitos adversos , Perimenopausa , Estado Pré-Diabético/induzido quimicamente , Progestinas/efeitos adversos , Estudos ProspectivosRESUMO
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.
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Síndrome do Ovário Policístico , Adiposidade , Adolescente , Adulto , Androgênios , Feminino , Predisposição Genética para Doença , Humanos , Obesidade/complicações , Síndrome do Ovário Policístico/metabolismoRESUMO
Polycystic ovary syndrome (PCOS) is associated with a higher risk for pregnancy and birth complications according to the specific features associated with PCOS. The features include obesity before and during pregnancy, hyperandrogenism, insulin resistance, infertility, cardiometabolic risk factors, and poor mental health. PCOS is not often recognized as a risk factor for poor pregnancy and birth outcomes in pregnancy care guidelines, while its associated features are. Pregnancy-related risk profile should ideally be assessed for modifiable risk factors (e.g., lifestyle and weight management) at preconception in women with PCOS. Hyperglycaemia should be screened using a 75-g oral glucose tolerance test at preconception or within the first 20 weeks of pregnancy if it has not been performed at preconception and should be repeated at 24-28 weeks of pregnancy. In the absence of evidence of benefit for strategies specific to women with PCOS, the international evidence-based guidelines for the assessment and management of PCOS recommend screening, optimizing, and monitoring risk profile in women with PCOS (at preconception, during and postpregnancy) consistent with the recommendations for the general population. Recommended factors include blood glucose, weight, blood pressure, smoking, alcohol, diet, exercise, sleep and mental health, emotional, and sexual health among women with PCOS. The guidelines recommend Metformin in addition to lifestyle for assisting with weight management and improving cardiometabolic risk factors, particularly in those with overweight or obesity. Letrozole is considered the first-line pharmacological treatment for anovulatory infertility in PCOS. Individualized approach should be considered in the management of pregnancy in PCOS.
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Hiperandrogenismo , Infertilidade Feminina , Síndrome do Ovário Policístico , Prova Pericial , Feminino , Humanos , Hiperandrogenismo/complicações , Infertilidade Feminina/etiologia , Infertilidade Feminina/terapia , Obesidade/complicações , Obesidade/terapia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/terapia , GravidezRESUMO
STUDY QUESTION: Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe? SUMMARY ANSWER: We identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10). WHAT IS KNOWN ALREADY: PCOS is a common, complex disorder with unknown aetiology. While previous genome-wide association studies (GWAS) have mapped several loci associated with PCOS, the analysis of populations with unique population history and genetic makeup has the potential to uncover new low-frequency variants with larger effects. STUDY DESIGN, SIZE, DURATION: A population-based case-control GWAS was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified PCOS cases from national registers by ICD codes (ICD-10 E28.2, ICD-9 256.4, or ICD-8 256.90), and all remaining women were considered controls. We then conducted a three-stage case-control GWAS: in the discovery phase, we had a total of 797 cases and 140â558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2812 cases and 89â230 controls. Finally, we performed a joint meta-analysis of 3609 cases and 229â788 controls from both cohorts. Additionally, we reran the association analyses including BMI as a covariate, with 2169 cases and 160â321 controls from both cohorts. MAIN RESULTS AND THE ROLE OF CHANCE: Two out of the three novel genome-wide significant variants associating with PCOS, rs145598156 (P = 3.6×10-8, odds ratio (OR) = 3.01 [2.02-4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9×10-16, OR = 1.69 [1.49-1.91], MAF = 0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2 = 0.95) and a missense I157T (r2 = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 × 10-8, OR = 1.16 [1.10-1.23], MAF = 0.44). We also replicated four previous reported associations near the genes Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), DENN Domain Containing 1A (DENND1A), FSH Subunit Beta (FSHB) and Zinc Finger And BTB Domain Containing 16 (ZBTB16). When adding BMI as a covariate only one of the novel variants remained genome-wide significant in the meta-analysis (the EstBB lead signal in CHEK2 rs182075939, P = 1.9×10-16, OR = 1.74 [1.5-2.01]) possibly owing to reduced sample size. LARGE SCALE DATA: The age- and BMI-adjusted GWAS meta-analysis summary statistics are available for download from the GWAS Catalog with accession numbers GCST90044902 and GCST90044903. LIMITATIONS, REASONS FOR CAUTION: The main limitation was the low prevalence of PCOS in registers; however, the ones with the diagnosis most likely represent the most severe cases. Also, BMI data were not available for all (63% for FinnGen, 76% for EstBB), and the biobank setting limited the accessibility of PCOS phenotypes and laboratory values. WIDER IMPLICATIONS OF THE FINDINGS: This study encourages the use of isolated populations to perform genetic association studies for the identification of rare variants contributing to the genetic landscape of complex diseases such as PCOS. 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 (N.P.-G., T.L., T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Läkaresällskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript. The authors declare no conflicts of interest.
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Síndrome do Ovário Policístico , Feminino , Subunidade beta do Hormônio Folículoestimulante/genética , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Síndrome do Ovário Policístico/complicações , População Branca/genéticaRESUMO
INTRODUCTION: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. MATERIAL AND METHODS: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). CLINICAL TRIAL REGISTRATION: NCT02352090. RESULTS: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. CONCLUSIONS: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.
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Anticoncepcionais Orais Combinados , Nandrolona , Adolescente , Adulto , Anticoncepcionais Orais Combinados/farmacologia , Estradiol , Estrogênios , Etinilestradiol/farmacologia , Feminino , Fibrina , Humanos , Levanogestrel , Nandrolona/farmacologia , Progestinas , Trombina , Tromboplastina , Adulto JovemRESUMO
INTRODUCTION: This population-based follow-up study investigated the comorbidities, medication use, and healthcare services among women with polycystic ovary syndrome (PCOS) at age 46 years. MATERIAL AND METHODS: The study population derived from the Northern Finland Birth Cohort 1966 and consisted of women reporting oligo/amenorrhea and hirsutism at age 31 years and/or a PCOS diagnosis by age 46 years (n = 246) and controls without PCOS symptoms or diagnosis (n = 1573), referred to as non-PCOS women. The main outcome measures were self-reported data on symptoms, diagnosed diseases, and medication and healthcare service use at the age of 46 years. RESULTS: Overall morbidity risk was increased by 35% (risk ratio [RR] 1.35, 95% confidence interval [CI] 1.16-1.57) and medication use by 27% [RR 1.27, 95% CI 1.08-1.50) compared with non-PCOS women, and the risk remained after adjusting for body mass index. Diagnoses with increased prevalence in women with PCOS were migraine, hypertension, tendinitis, osteoarthritis, fractures, and endometriosis. PCOS was also associated with autoimmune diseases and recurrent upper respiratory tract infections and symptoms. Interestingly, healthcare service use did not differ between the study groups after adjusting for body mass index. CONCLUSIONS: Women with PCOS are burdened with multimorbidity and higher medication use, independent of body mass index.