Associations of bisphenol and phthalate exposure and anti-Müllerian hormone levels in women of reproductive age.

Background: In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations. Methods: Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors. Findings: In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences -0.07 (95% CI -0.13, -0.02), -0.09 (-0.15, -0.02), -0.08 (95% CI -0.14, -0.02), and -0.08 (-0.13, -0.03) µg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values < 0.05). Interpretation: We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve. Funding: This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.

Business case for psychosocial interventions in clinics: potential for decrease in treatment discontinuation and costs.

RESEARCH QUESTION: From a value-based healthcare (VBHC) perspective, does an assessment of clinical outcomes and intervention costs indicate that providing cognitive behavioural therapy (CBT) or mindfulness to women seeking fertility treatment add value compared with no such intervention? DESIGN: Proof-of-concept business case based on a VBHC perspective that considers clinical outcomes and costs. Potential effects on psychological and fertility outcomes were based on existing research. Cost outcomes were estimated with a costing model for the Dutch fertility treatment setting. RESULTS: Thirty-two studies were identified; 13 were included. Women who received CBT had 12% lower anxiety, 40% lower depression and 6% higher fertility quality of life; difference in clinical pregnancy rates was six percentage points (CBT [30.2%]; control [24.2%]); difference in fertility discontinuation rates was 10 percentage points (CBT [5.5%]; control [15.2%]). Women who received training in mindfulness had 8% lower anxiety, 45% lower depression and 21% higher fertility quality of life; difference in mean clinical pregnancy rate was 19 percentage points (mindfulness [44.8%]; control [26.0%]). Potential total cost savings was about €1.2 million per year if CBT was provided and €11 million if mindfulness was provided. Corresponding return on investment for CBT was 30.7%, and for mindfulness 288%. Potential cost benefits are influenced by the assumed clinical pregnancy rates; such data related to mindfulness were limited to one study. CONCLUSIONS: The provision of CBT or mindfulness to women seeking fertility treatment could add value. Higher quality primary studies are needed on the effect of mindfulness on clinical pregnancy rates.

Anti-müllerian hormone as a diagnostic biomarker for polycystic ovary syndrome and polycystic ovarian morphology: a systematic review and meta-analysis.

IMPORTANCE: As part of the 2023 international evidence-based polycystic ovary syndrome (PCOS) guideline, this meta-analysis investigated the inclusion of Anti-Müllerian hormone (AMH) levels in the diagnostic criteria for PCOS. OBJECTIVE: To answer the following three questions: 1) Are AMH levels effective in diagnosing PCOS in adult women? 2) Are AMH levels effective in diagnosing PCOS in adolescents? Are AMH levels effective in diagnosing polycystic ovarian morphology (PCOM)? DATA SOURCES: Searches were conducted in six databases until July 31, 2023. STUDY SELECTION AND SYNTHESIS: Eligible studies were those conducted in humans, published in English, and reporting sensitivity, specificity, and/or area under the curve values. Extracted data included study population, age, body mass index, AMH assay, cut-off value of AMH levels, sensitivity, specificity, and area under the curve values. The risk of bias was assessed using the quality assessment of diagnostic accuracy studies tool. A random effects model was used to test diagnostic accuracy. MAIN OUTCOMES: Pooled sensitivity and specificity to use AMH levels for PCOS diagnosis in adults as well as adolescents and for detecting PCOM in adults. RESULTS: Eighty-two studies were included. The adult AMH-PCOS meta-analyses (n = 68) showed a pooled sensitivity and specificity of 0.79 (95% confidence interval [CI], 0.76-0.82; I2 = 86%) and 0.87 (95% CI, 0.84-0.89; I2 = 91%). The adolescent AMH-PCOS meta-analysis (n = 11) showed a pooled sensitivity and specificity of 0.66 (95% CI, 0.58-0.73; I2 = 74%) and 0.78 (95% CI, 0.71-0.83; I2 = 45%). The adult AMH-PCOM meta-analysis (n = 7) showed a pooled sensitivity and specificity of 0.79 (95% CI, 0.72-0.85; I2 = 94%) and 0.87 (95% CI, 0.78-0.93; I2 = 94%). CONCLUSION AND RELEVANCE: This study investigated the most profound change in the 2023 international evidence-based PCOS guideline, which now recommends AMH levels for defining PCOM in adults in accordance with the diagnostic algorithm. Antimüllerian hormone levels alone are insufficient for PCOS diagnosis and are nonspecific for PCOM in adolescents. Multiple factors influence AMH levels and cause heterogeneity as well as limitations in this study. Consequently, no international cut-off value could be recommended, emphasizing the need for research on more individualized cut-off values.

Clustering Identifies Subtypes With Different Phenotypic Characteristics in Women With Polycystic Ovary Syndrome.

CONTEXT: Hierarchical clustering (HC) identifies subtypes of polycystic ovary syndrome (PCOS). OBJECTIVE: This work aimed to identify clinically significant subtypes in a PCOS cohort diagnosed with the Rotterdam criteria and to further characterize the distinct subtypes. METHODS: Clustering was performed using the variables body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), testosterone, insulin, and glucose. Subtype characterization was performed by analyzing the variables estradiol, androstenedione, dehydroepiandrosterone, cortisol, anti-Müllerian hormone (AMH), total follicle count (TFC), lipid profile, and blood pressure. Study participants were girls and women who attended our university hospital for reproductive endocrinology screening between February 1993 and February 2021. In total, 2502 female participants of European ancestry, aged 13 to 45 years with PCOS (according to the Rotterdam criteria), were included. A subset of these (n = 1067) fulfilled the National Institutes of Health criteria (ovulatory dysfunction and hyperandrogenism). Main outcome measures included the identification of distinct PCOS subtypes using cluster analysis. Additional clinical variables associated with these subtypes were assessed. RESULTS: Metabolic, reproductive, and background PCOS subtypes were identified. In addition to high LH and SHBG levels, the reproductive subtype had the highest TFC and levels of AMH (all P < .001). In addition to high BMI and insulin levels, the metabolic subtype had higher low-density lipoprotein levels and higher systolic and diastolic blood pressure (all P < .001). The background subtype had lower androstenedione levels and features of the other 2 subtypes. CONCLUSION: Reproductive and metabolic traits not used for subtyping differed significantly in the subtypes. These findings suggest that the subtypes capture distinct PCOS causal pathways.

Living in a low socioeconomic status neighbourhood is associated with lower cumulative ongoing pregnancy rate after IVF treatment.

RESEARCH QUESTION: Does an association exist between neighbourhood socioeconomic status (SES) and the cumulative rate of ongoing pregnancies after 2.5 years of IVF treatment? DESIGN: A retrospective observational study involving 2669 couples who underwent IVF or IVF and intracytoplasmic sperm injection treatment between 2006 and 2020. Neighbourhood SES for each couple was determined based on their residential postal code. Subsequently, SES was categorized into low (p80). Multivariable binary logistic regression analyses were conducted, with the cumulative ongoing pregnancy within 2.5 years as the outcome variable. The SES category (reference category: high), female age (reference category: 32-36 years), body mass index (reference category: 23-25 kg/m2), smoking status (yes/no), number of oocytes after the first ovarian stimulation, embryos usable for transfer or cryopreservation after the first cycle, duration of subfertility before treatment and insemination type were used as covariates. RESULTS: A variation in ongoing pregnancy rates was observed among SES groups after the first fresh embryo transfer. No difference was found in the median number of IVF treatment cycles carried out. The cumulative ongoing pregnancy rates differed significantly between SES groups (low: 44%; medium: 51%; high: 56%; P < 0.001). Low neighbourhood SES was associated with significantly lower odds for achieving an ongoing pregnancy within 2.5 years (OR 0.66, 95% CI 0.52 to 0.84, P < 0.001). CONCLUSION: Low neighbourhood SES compared with high neighbourhood SES is associated with reducing odds of achieving an ongoing pregnancy within 2.5 years of IVF treatment.

Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.

OBJECTIVE: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SETTING: Not applicable. PATIENTS: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0 × 10-8) and 16 genome-wide suggestive (<5.0 × 10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors.

Polycystic ovary syndrome.

Despite affecting ~11-13% of women globally, polycystic ovary syndrome (PCOS) is a substantially understudied condition. PCOS, possibly extending to men's health, imposes a considerable health and economic burden worldwide. Diagnosis in adults follows the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome, requiring two out of three criteria - clinical or biochemical hyperandrogenism, ovulatory dysfunction, and/or specific ovarian morphological characteristics or elevated anti-Müllerian hormone. However, diagnosing adolescents omits ovarian morphology and anti-Müllerian hormone considerations. PCOS, marked by insulin resistance and hyperandrogenism, strongly contributes to early-onset type 2 diabetes, with increased odds for cardiovascular diseases. Reproduction-related implications include irregular menstrual cycles, anovulatory infertility, heightened risks of pregnancy complications and endometrial cancer. Beyond physiological manifestations, PCOS is associated with anxiety, depression, eating disorders, psychosexual dysfunction and negative body image, collectively contributing to diminished health-related quality of life in patients. Despite its high prevalence persisting into menopause, diagnosing PCOS often involves extended timelines and multiple health-care visits. Treatment remains ad hoc owing to limited understanding of underlying mechanisms, highlighting the need for research delineating the aetiology and pathophysiology of the syndrome. Identifying factors contributing to PCOS will pave the way for personalized medicine approaches. Additionally, exploring novel biomarkers, refining diagnostic criteria and advancing treatment modalities will be crucial in enhancing the precision and efficacy of interventions that will positively impact the lives of patients.

Sexual function in women with premature ovarian insufficiency (POI): Systematic review and meta-analysis.

Premature ovarian insufficiency (POI) is a rare condition characterized by loss of ovarian function before the age of 40. POI seems associated with mood disorders and sexual dysfunction. However, there is a lack of high-quality evidence relating to the impact of POI on sexual function. Therefore, we conducted a systematic review and meta-analysis to evaluate sexual function in women with POI compared to women without the condition. The following online databases were systematically searched up to January 2023: EMBASE, Medline (Ovid), Web of Science, Cochrane, PsychInfo, and Google Scholar. Random effects models were used for analyses, with data reported as Hedges' g and 95 % confidence interval, and the risk of heterogeneity was evaluated. The protocol of this study was registered with PROSPERO (CRD42023437203). A total of 10 studies were included in the systematic review and 5 studies involving 352 women with POI were included in the meta-analysis. Eight of the ten studies concluded that women with POI have reduced sexual function. An overall medium Hedges' g effect size of -0.72 was found (ranging between -0.20 and -1.29) in favor of control women, with moderate heterogeneity (I2 = 64 %). Stratified studies of women on systemic hormone replacement therapy (HRT) showed an even higher Hedges' g effect size, of -0.82 (95 % CI -1.18, -0.47). In conclusion, sexual function in women with POI is reduced compared with control women. Sexual function should be discussed with women with POI and they should be offered psychosexual counseling.

Diagnostic accuracy of oral glucose tolerance tests, fasting plasma glucose and haemoglobin A1c for type 2 diabetes in women with polycystic ovary syndrome: A systematic review and meta-analysis.

AIMS: To inform international guidelines, a systematic review and meta-analysis was conducted to assess the performance of diagnostic methods for type 2 diabetes in women with polycystic ovary syndrome (PCOS). METHODS: An updated systematic search was conducted on five databases from 2017 until October 2023 and combined with prior searches (from inception). Meta-analyses of diagnostic accuracy tests were conducted. RESULTS: Nine studies comprising 2628 women with PCOS were included. Against the oral glucose tolerance test, a haemoglobin A1C (HbA1c) ≥ 6.5% had a pooled sensitivity of 50.00% (95% confidence interval (CI): 35.53-64.47), specificity of 99.86% (95%CI: 99.49-99.98), and positive and negative predictive values of 92.59% (95%CI: 75.27-98.09) and 98.27% (95%CI: 97.73-98.68), respectively, with an accuracy of 98.17% (95%CI: 97.34-98.79). Fasting plasma glucose values ≥ 7.0 mmol/L had a pooled sensitivity of 58.14% (95%CI: 42.13-72.99), specificity of 92.59% (95%CI: 75.35-98.08), positive and negative predictive values of 92.59% (95%CI: 75.35-98.08) and 99.09% (95%CI: 98.71-99.36), respectively, and an accuracy of 99.00% (95%CI: 98.46-99.39) against the oral glucose tolerance test. CONCLUSIONS: To our knowledge, this is the first systematic review assessing the performance of diagnostic methods for type 2 diabetes in women with PCOS. We demonstrate that using a cut-off for HbA1c of ≥6.5% in this population may result in misdiagnosis of half of the women with type 2 diabetes. Our results directly informed the recommendations of the 2023 International PCOS Guideline, suggesting that the oral glucose tolerance test is the optimal method for screening and diagnosing type 2 diabetes in women with PCOS and is superior to fasting plasma glucose and HbA1c.

Age-related curves of AMH using the Gen II, the picoAMH and the Elecsys assays in women with polycystic ovary syndrome.

CONTEXT: Several challenges still exist to adopt the anti-Müllerian hormone (AMH) as a marker of polycystic ovary morphology (PCOM), as included in the recently updated international guideline. Although different evaluations of age- and assay-specific reference ranges have been published in the last years, these studies have mainly been conducted in normo-ovulatory or infertile women. OBJECTIVE: To develop an age-specific percentile distribution of AMH in patients with polycystic ovary syndrome (PCOS) measured by three different assays. DESIGN: Retrospective cross-sectional study. PATIENTS: 2,725 women aged 20 to 40 years with PCOS diagnosis were included. INTERVENTION (S): Serum AMH measurement by the Gen II (Beckman Coulter), the picoAMH (Ansh Labs), and the Elecsys (Roche) assays. MAIN OUTCOME MEAUSRE (S): Age-specific centile curves for all the assays and correlations between AMH, clinical, hormonal, and ultrasound characteristics. RESULTS: Age-related nomograms for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of AMH were calculated using the LMS method for all the assays. AMH levels were significantly different between PCOS phenotypes. AMH levels were positive correlated to luteinizing hormone (LH), LH/follicular stimulating hormone (FSH) ratio, testosterone, androstenedione, free androgen index, mean follicular number, and mean ovarian volume. CONCLUSIONS: To our knowledge this is the first study reporting age specific percentile nomograms of serum AMH levels measured by the Gen II, the picoAMH and the Elecsys assays in a large population of PCOS women. These findings may help to interpret AMH levels in PCOS patients and facilitate the use of AMH as a diagnostic tool across age ranges.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Can we predict menopause and premature ovarian insufficiency?

The prediction of menopause and premature ovarian insufficiency (POI) involves understanding the factors that contribute to the timing of these events. Menopause is a natural biological process marked by the cessation of menstrual periods, typically occurring around the age of 51. On the other hand, POI refers to the loss of ovarian function before the age of 40. Several factors have been used to predict menopause and POI such as age, antimüllerian hormone, inhibins and follicle-stimulating hormone serum levels, antral follicle counts, menstrual cycle length, and, recently, some genetic markers. It seems that age has the best predictive power and all the other ones are only adding in a very limited way to the prediction of menopause. Low levels of antimüllerian hormone in young women might indicate a greater risk for POI and could facilitate early diagnosis. It is, however, important to note that predicting the exact timing of menopause and POI is challenging, and individual variations are significant. Although these factors can provide some insights, they are not foolproof predictors. Advances in medical research and technology may lead to more accurate methods for predicting menopause and POI in the future.

Sexual function in women with polycystic ovary syndrome: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common and distressing endocrine disorder associated with lower quality of life, subfertility, diabetes, cardiovascular disease, depression, anxiety, and eating disorders. PCOS characteristics, its comorbidities, and its treatment can potentially influence sexual function. However, studies on sexual function in women with PCOS are limited and contradictory. OBJECTIVE AND RATIONALE: The aim was to perform a systematic review of the published literature on sexual function in women with PCOS and assess the quality of the research and certainty of outcomes, to inform the 2023 International Guidelines for the Assessment and Management of PCOS. SEARCH METHODS: Eight electronic databases were searched until 1 June 2023. Studies reporting on sexual function using validated sexuality questionnaires or visual analogue scales (VAS) in PCOS populations were included. Random-effects models were used for meta-analysis comparing PCOS and non-PCOS groups with Hedges' g as the standardized mean difference. Study quality and certainty of outcomes were assessed by risk of bias assessments and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) method according to Cochrane. Funnel plots were visually inspected for publication bias. OUTCOMES: There were 32 articles included, of which 28 used validated questionnaires and four used VAS. Pooled Female Sexual Function Index (FSFI) scores in random-effects models showed worse sexual function across most subdomains in women with PCOS, including arousal (Hedges's g [Hg] [95% CI] = -0.35 [-0.53, -0.17], I2 = 82%, P < 0.001), lubrication (Hg [95% CI] = -0.54 [-0.79, -0.30], I2 = 90%, P < 0.001), orgasm (Hg [95% CI] = -0.37 [-0.56, -0.19], I2 = 83%, P < 0.001), and pain (Hg [95% CI] = -0.36 [-0.59, -0.13] I2 = 90%, P < 0.001), as well as total sexual function (Hg [95% CI] = -0.75 [-1.37, -0.12], I2 = 98%, P = 0.02) and sexual satisfaction (Hg [95% CI] = -0.31 [-0.45, -0.18], I2 = 68%, P < 0.001). Sensitivity and subgroup analyses based on fertility status and body mass index (BMI) did not alter the direction or significance of the results. Meta-analysis on the VAS studies demonstrated the negative impact of excess body hair on sexuality, lower sexual attractiveness, and lower sexual satisfaction in women with PCOS compared to controls, with no differences in the perceived importance of a satisfying sex life. No studies assessed sexual distress. GRADE assessments showed low certainty across all outcomes. WIDER IMPLICATIONS: Psychosexual function appears to be impaired in those with PCOS, but there is a lack of evidence on the related distress scores, which are required to meet the criteria for psychosexual dysfunction. Health care professionals should discuss sexual function and distress and be aware of the multifactorial influences on sexual function in PCOS. Future research needs to assess both psychosexual function and distress to aid in understanding the degree of psychosexual dysfunction in PCOS. Finally, more diverse populations (e.g. non-heterosexual and more ethnically diverse groups) should be included in future studies and the efficacy of treatments for sexual dysfunction should also be assessed (e.g. lifestyle and pharmacological interventions).

Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss.

Recent studies have investigated if and how the vaginal and endometrial microbiome might affect endometrial receptivity and reproductive health. Although there is no consensus on the existence of a core uterine microbiome yet, evidence shows that the dominance of Lactobacillus spp. in the female reproductive tract is generally associated with eubiosis and improved chances of successful implantation and an ongoing pregnancy. Conversely, vaginal and endometrial dysbiosis can cause local inflammation and an increase of pro-inflammatory cytokines, compromising the integrity and receptivity of the endometrial mucosa and potentially hampering successful embryonic implantation. This review provides a critical appraisal of the influence of the vaginal and endometrial microbiome as parts of the female reproductive tract on fertility outcomes, focusing on repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It seems that RIF as well as RPL are both associated with an increase in microbiome diversity and a loss of Lactobacillus dominance in the lower female reproductive system.

Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts.

Aneuploidy, a deviation from the normal chromosome copy number, is common in human embryos and is considered a primary cause of implantation failure and early pregnancy loss. Meiotic errors lead to uniformly abnormal karyotypes, while mitotic errors lead to chromosomal mosaicism: the presence of cells with at least 2 different karyotypes within an embryo. Knowledge about mosaicism in blastocysts mainly derives from bulk DNA sequencing (DNA-Seq) of multicellular trophectoderm (TE) and/or inner cell mass (ICM) samples. However, this can only detect an average net gain or loss of DNA above a detection threshold of 20%-30%. To accurately assess mosaicism, we separated the TE and ICM of 55 good-quality surplus blastocysts and successfully applied single-cell whole-genome sequencing (scKaryo-Seq) on 1,057 cells. Mosaicism involving numerical and structural chromosome abnormalities was detected in 82% of the embryos, in which most abnormalities affected less than 20% of the cells. Structural abnormalities, potentially caused by replication stress and DNA damage, were observed in 69% of the embryos. In conclusion, our findings indicated that mosaicism was prevalent in good-quality blastocysts, whereas these blastocysts would likely be identified as normal with current bulk DNA-Seq techniques used for preimplantation genetic testing for aneuploidy.

Preconception maternal gastric bypass surgery and the impact on fetal growth parameters.

BACKGROUND: Bariatric surgery is increasingly performed in women of reproductive age. As bariatric surgery will result in postoperative rapid catabolic weight loss which potentially leads to fetal malnutrition and directly related impaired intra-uterine growth, it is advised to postpone pregnancy for at least 12-18 months after surgery. OBJECTIVES: To investigate the consequences of preconception gastric bypass surgery (pGB) on fetal growth parameters and maternal pregnancy outcome. SETTING: Maasstad Hospital, The Netherlands, general hospital and Erasmus Medical Center, The Netherlands, university hospital. METHODS: We included 97 pGB pregnancies (Maasstad hospital) and 440 non-bariatric pregnancies (Rotterdam Periconception cohort, Erasmus Medical Center). Longitudinal second and third trimester fetal growth parameters (head circumference, biparietal diameter, femur length, abdominal circumference, estimated fetal weight) were analyzed using linear mixed models, adjusting for covariates and possible confounders. Fetal growth and birthweight in pGB pregnancies were compared to non-bariatric pregnancies and Dutch reference curves. Maternal pregnancy outcome in the pGB group was compared to non-bariatric pregnancies. RESULTS: All fetal growth parameters of pGB pregnancies were significantly decreased at 20 weeks' gestation (P < .001) and throughout the remaining part of pregnancy (P < .05) compared with non-bariatric pregnancies (crude and adjusted models). In our cohort, gestational weight gain was not significantly associated with birthweight corrected for gestational age. Birthweight was significantly lower in pGB pregnancies (estimate -241 grams [95% CI, -342.7 to -140.0]) with a 2-fold increased risk of small-for-gestational-age (SGA) (adjusted odds ratio 2.053 [95% CI, 1.058 to 3.872]). Compared to the non-bariatric pregnancies, we found no significant differences in maternal pregnancy outcome. CONCLUSIONS: PGB is associated with overall reduced fetal growth trajectories and a 2-fold increased risk of SGA, without significant adverse consequences for maternal pregnancy outcome. We recommend close monitoring of fetal growth after pGB.

The prevalence of thyroid dysfunction and hyperprolactinemia in women with PCOS.

Introduction: Ovulatory dysfunction is usually caused by an endocrine disorder, of which polycystic ovary syndrome (PCOS) is the most common cause. PCOS is usually associated with estrogen levels within the normal range and can be characterized by oligo-/anovulation resulting in decreased progesterone levels. It is suggested that decreased progesterone levels may lead to more autoimmune diseases in women with PCOS. In addition, it is often claimed that there is an association between hyperprolactinemia and PCOS. In this large well-phenotyped cohort of women with PCOS, we have studied the prevalence of thyroid dysfunction and hyperprolactinemia compared to controls, and compared this between the four PCOS phenotypes. Methods: This retrospective cross-sectional study contains data of 1429 women with PCOS and 299 women without PCOS. Main outcome measures included thyroid stimulating hormone (TSH), Free Thyroxine (FT4), and anti-thyroid peroxidase antibodies (TPOab) levels in serum, the prevalence of thyroid diseases and hyperprolactinemia. Results: The prevalence of thyroid disease in PCOS women was similar to that of controls (1.9% versus 2.7%; P = 0.39 for hypothyroidism and 0.5% versus 0%; P = 0.99 for hyperthyroidism). TSH levels were also similar (1.55 mIU/L versus 1.48 mIU/L; P = 0.54). FT4 levels were slightly elevated in the PCOS group, although within the normal range (18.1 pmol/L versus 17.7 pmol/L; P < 0.05). The prevalence of positive TPOab was similar in both groups (5.7% versus 8.7%; P = 0.12). The prevalence of hyperprolactinemia was similarly not increased in women with PCOS (1.3%% versus 3%; P = 0.05). In a subanalysis of 235 women with PCOS and 235 age- and BMI-matched controls, we found no differences in thyroid dysfunction or hyperprolactinemia. In according to differences between PCOS phenotypes, only the prevalence of subclinical hypothyroidism was significantly higher in phenotype B (6.3%, n = 6) compared to the other phenotypes. Conclusion: Women with PCOS do not suffer from thyroid dysfunction more often than controls. Also, the prevalence of positive TPOab, being a marker for future risk of thyroid pathology, was similar in both groups. Furthermore, the prevalence of hyperprolactinemia was similar in women with PCOS compared to controls.

Trabecular bone density in middle-aged women with reproductive disorders.

Besides age, estrogen exposure plays a crucial role in changes in bone density (BD) in women. Premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS) are conditions in reproductive-aged women in which the exposure to estrogen is substantially different. Women with a history of preeclampsia (PE) are expected to have normal estrogen exposure. Within the CREw-IMAGO study, we investigated if trabecular BD is different in these women because of differences in the duration of estrogen exposure. Trabecular BD was measured in thoracic vertebrae on coronary CT scans. Women with an reduced estrogen exposure (POI) have a lower BD compared to women with an intermediate exposure (PE) (mean difference (MD) -26.8, 95% confidence interval (CI) -37.2 - -16.3). Women with a prolonged estrogen exposure (PCOS) have the highest BD (MD 15.0, 95% CI 4.3 - 25.7). These results support the hypothesis that the duration of estrogen exposure in these women is associated with trabecular BD.

Change in Androgenic Status and Cardiometabolic Profile of Middle-Aged Women with Polycystic Ovary Syndrome.

Understanding the cardiovascular disease (CVD) risk for women with polycystic ovary syndrome (PCOS) at reproductive age is crucial. To investigate this, we compared the cardiometabolic profiles of different PCOS groups over a median interval of 15.8 years. The study focused on three groups: (1) women with PCOS who were hyperandrogenic at both initial and follow-up screening (HA-HA), (2) those who transitioned from hyperandrogenic to normoandrogenic (HA-NA), and (3) those who remained normoandrogenic (NA-NA). At initial and follow-up screenings, both HA-HA and HA-NA groups showed higher body mass indexes compared to the NA-NA group. Additionally, at follow-up, the HA-HA and HA-NA groups exhibited higher blood pressure, a higher prevalence of hypertension, elevated serum triglycerides and insulin levels, and lower levels of HDL cholesterol compared to the NA-NA group. Even after adjusting for BMI, significant differences persisted in HDL cholesterol levels and hypertension prevalence among the groups (HA-HA: 53.8%, HA-NA: 53.1%, NA-NA: 14.3%, p < 0.01). However, calcium scores and the prevalence of coronary plaques on CT scans were similar across all groups. In conclusion, women with PCOS and hyperandrogenism during their reproductive years exhibited an unfavorable cardiometabolic profile during their post-reproductive years, even if they changed to a normoandrogenic status.

Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.

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 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. 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 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 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.