Obesity negatively impacts reproductive health, including ovarian function. Obesity has been posited to alter Anti-Müllerian hormone (AMH) production. Understanding biological factors that could impact AMH levels is necessary given the increasing use of AMH for predicting reproductive health outcomes in response to controlled ovarian stimulation, diagnosing ovulatory disorders, onset of menopause, and natural conception. In this narrative review, we evaluated the impact of obesity on AMH levels in healthy, regularly cycling reproductive-age women (18–48 years). Thirteen studies (n = 1214 women; (811, non-obese (body mass index; BMI < 30 kg/m²); 403, obese (BMI > 30 kg/m²))) were included, of which five reported decreased AMH levels with obesity, whereas eight showed comparable AMH levels between groups. Inclusion of women with higher obesity classes (Class 3 versus Class 1) may have been a factor in studies reporting lower AMH levels. Together, studies reporting AMH levels in otherwise healthy women remain limited by small sample sizes, cross-sectional designs, and lack of representation across the entire adiposity spectrum. Ultimately, the degree to which obesity may negatively impact AMH levels, and possibly ovarian reserve, in otherwise healthy women with regular menstrual cycles should be deemed uncertain at this time. This conclusion is prudent considering that the biological basis for an impact of obesity on AMH production is unknown.

BACKGROUND: Polycystic ovary morphology (PCOM) on ultrasonography is considered as a cardinal feature of polycystic ovarian syndrome (PCOS). Its relevance as a diagnostic criterion for PCOS was reaffirmed in the most recent International Evidence-Based Guideline for the Assessment and Management of PCOS. However, there remains a lack of clarity regarding the best practices and specific ultrasonographic markers to define PCOM. OBJECTIVE AND RATIONALE: The aim of this systematic review and diagnostic meta-analysis was to assess the diagnostic accuracy of various ultrasonographic features of ovarian morphology in the diagnosis of PCOS. SEARCH METHODS: Relevant studies published from 1 January 1990 to 12 June 2023 were identified by a systematic search in PubMed, Web of Science, Scopus, CINAHL, and CENTRAL. Studies that generated diagnostic accuracy measures (e.g. proposed thresholds, sensitivity, specificity) for PCOS using the following ultrasonographic markers met criteria for inclusion: follicle number per ovary (FNPO) or per single cross-section (FNPS), ovarian volume (OV), and stromal features. Studies on pregnant or post-menopausal women were excluded. Risk of bias and applicability assessment for diagnostic test accuracy studies were determined using the QUADAS-2 and QUADAS-C tool for a single index test or between multiple index tests, respectively. Diagnostic meta-analysis was conducted using a bivariate model of pooled sensitivity and specificity, and visualized using forest plots and summary receiver-operating characteristic (SROC) curves. OUTCOMES: From a total of 2197 records initially identified, 31 studies were included. Data from five and two studies were excluded from the meta-analysis due to duplicate study populations or limited data for the index test, leaving 24 studies. Pooled results of 20 adult studies consisted of 3883 control participants and 3859 individuals with PCOS. FNPO was the most accurate diagnostic marker (sensitivity: 84%, CI: 81–87%; specificity: 91%, CI: 86–94%; AUC: 0.905) in adult women. OV and FNPS had similar pooled sensitivities (OV: 81%, CI: 76–86%; FNPS: 81%, CI: 70–89%) but inferior pooled specificities (OV: 81%, CI: 75–86%; FNPS: 83%, CI: 75–88%) and AUCs (OV: 0.856; FNPS: 0.870) compared to FNPO. Pooled results from four adolescent studies consisting of 210 control participants and 268 girls with PCOS suggested that OV may be a robust ultrasonographic marker for PCOS diagnosis albeit the current evidence remains limited. The majority of the studies had high risk of bias for the patient selection (e.g. lack of randomized/consecutive patient selection) and index test (e.g. lack of pre-proposed thresholds for comparison) domains across all ultrasonographic markers. As such, diagnostic meta-analysis was unable to determine the most accurate cutoff for ultrasonographic markers to diagnose PCOS. Subgroup analysis suggested that stratification based on previously proposed diagnostic thresholds, age, BMI, or technology did not account for the heterogeneity in diagnostic accuracy observed across the studies. Studies that diagnosed PCOS using the Rotterdam criteria had improved sensitivity for FNPO. Studies from North America had lower diagnostic accuracy when compared to Asian studies (FNPO: sensitivity) and European studies (OV: specificity, diagnostic odds ratio and positive likelihood ratio). Geographic differences in diagnostic accuracy may potentially be due to differences in age, BMI, and diagnostic criteria of the PCOS group across regions. WIDER IMPLICATIONS: This diagnostic meta-analysis supports the use of FNPO as the gold standard in the ultrasonographic diagnosis of PCOS in adult women. OV and FNPS provide alternatives if total antral follicle counts cannot be accurately obtained. Our findings support the potential for ultrasonographic evidence of PCOM in adolescents as more data becomes available. Subgroup analysis suggests the need to investigate any relative contributions of geographical differences on PCOS phenotypes. These findings may provide the basis for the development of strategies and best practices toward a standardized definition of PCOM and a more accurate ultrasonographic evaluation of PCOS.

Are ovarian antral follicle dynamics altered in women with obesity and regular ovulatory cycles? Eumenorrheic women with obesity display evidence of suppressed antral follicle dynamics as judged by fewer recruitment events, selectable follicles, and anovulatory dominant follicles, as well as lower anti-Müllerian hormone (AMH) concentrations and an increased prevalence of luteal phase defects. Ovarian antral follicle development is a dynamic process involving distinct follicular and endocrine events that are critical for the occurrence of regular monthly ovulations. Follicle dynamics have not been prospectively evaluated in eumenorrheic women with obesity despite the known impact of obesity on gonadotropin production, ovarian steroid hormone concentrations, and fecundity. This was a prospective, longitudinal study of 42 women conducted over one inter-ovulatory interval (IOI). A group of 21 women with obesity (total percent body fat ≥35%) and a group of 21 women without obesity (total percent body fat 10 mm in the cohort with obesity (30 vs 40 follicles; P = 0.04) and fewer anovulatory follicles achieved dominance (9 vs 18 follicles; P = 0.041). Ovulatory follicles were selected at smaller diameters in women with compared to those without obesity (7.5 ± 1.6 vs 9.5 ± 1.9 mm; P = 0.001). Luteal phase defects were also more common in women with compared to those without obesity, as defined by either integrated (76 vs 29%, P = 0.002) or maximum (71 vs 24%, P = 0.002) luteal progesterone. This study was limited to an assessment of antral follicle dynamics and cannot inform on earlier stages of folliculogenesis. This study was observational and cannot address causation between obesity and altered antral follicle dynamics. Lastly, the data cannot be extrapolated to account for reduced fecundity and fertility in obesity. The increasing global prevalence of obesity necessitates an understanding of the mechanisms that underlie obesity-related adverse reproductive health outcomes. Eumenorrheic women with obesity demonstrate altered ovarian antral follicle and endocrine dynamics compared to their counterparts without obesity. The degree to which abnormal granulosa cell assembly and/or activity underlie the suboptimal luteinization and subfertility requires further investigation. Funding was provided by Cornell University, President’s Council of Cornell Women, United States Department of Agriculture (grant no. 8106), and National Institutes of Health (R01-HD0937848). B.Y.J. and H.V.B. were supported by doctoral training awards from the National Institutes of Health (T32-DK007158) and Canadian Institutes of Health Research (grant no. 146182), respectively. NCT01927432, NCT01785719

Do antral follicle dynamics change in women with obesity and regular ovulatory cycles after a 6-month hypocaloric dietary intervention? After a 6-month hypocaloric dietary intervention, women with obesity and regular ovulatory cycles displayed evidence of improved antral follicle dynamics defined by the emergence of more dominant follicles, larger ovulatory follicle diameter at selection, and increased luteal progesterone concentrations compared to pre-intervention. Precise events in antral folliculogenesis must occur in order for natural and regular monthly ovulation. In healthy women of reproductive age, antral follicles are recruited for growth in a wave-like fashion, wherein a subset of follicles are selected for preferential growth, and typically, one dominant follicle culminates in ovulation. Women with obesity and regular ovulatory cycles display evidence of suppressed antral follicle development, as evidenced by fewer recruitment events, fewer selectable and dominant follicles, smaller diameter of the ovulatory follicle at selection, and a higher prevalence of luteal phase defects. While improvements in gonadotropin and ovarian steroid hormone concentrations after weight loss have been documented in eumenorrheic women with obesity, the precise impact of weight loss on antral follicle dynamics has not been evaluated. A pre–post pilot study of 12 women who participated in a 6-month hypocaloric dietary intervention. Twelve women with obesity (total body fat ≥35%) underwent transvaginal ultrasonography and venipuncture every-other-day for one inter-ovulatory interval (IOI) both before (baseline) and during the final month (Month 7) of a six-month hypocaloric dietary intervention. Participants were aged 24–34 years and had a self-reported history of regular menstrual cycles (25–35 days). Follicle number and diameter (≥2 mm) were quantified at each study visit, and individual growth profiles for all follicles ≥7 mm were determined. Blood samples were assayed for reproductive hormones. Follicle dynamics and reproductive hormone concentrations were compared pre- and post-intervention. Further, post-intervention follicle and endocrine dynamics (Month 7 IOI) were compared to an age-matched reference cohort of lean women with regular ovulatory cycles (total body fat <35%, N = 21). Participants lost an average of 11% of their original body weight with the hypocaloric dietary intervention. More dominant follicles were detected (≥10 mm) at Month 7 compared to baseline (0. 3 ± 0.4 versus 0.4 ± 0.5 follicles, P = 0.001), and ovulatory follicles were selected at larger diameters post-intervention (7.3 ± 2.0 versus 10.9 ± 2.6 mm, P = 0.007). Luteal progesterone concentrations were increased at Month 7 compared to baseline (5.3 ± 3.65 versus 6.3 ± 4.74 ng/ml, P < 0.0001). However, risk for luteal phase dysfunction as judged by the prevalence of a luteal phase length <10 days, integrated luteal progesterone levels <80 ng/ml or peak progesterone 0.05). In Month 7, follicle dynamics and endocrine profiles were similar to the reference cohort across all measures. This study does not inform on the earliest stages of ovarian follicle development and is limited to providing knowledge on the later stages of antral follicle development. This study cannot fully address causation between weight loss and sustained improvements in antral follicle dynamics. The data cannot be extrapolated to comment on potential improvements in fertility and fecundity with weight loss. The small group sizes limit statistical power. The increasing prevalence of obesity necessitates an understanding of the mechanisms that underlie potential improvements in reproductive health outcomes with weight loss. Women with obesity and regular ovulatory cycles who undertook a 6-month hypocaloric dietary intervention demonstrated improvements consistent with benefits of lifestyle intervention on reproductive health even in those without overt signs of reproductive dysfunction. Potential improvements in the cellular makeup of follicles, which may underlie the restoration of normal follicle development and amelioration of subfertility, require further investigation. Cornell University, President’s Council of Cornell Women, United States Department of Agriculture (Grant No. 8106), and National Institutes of Health (R01-HD0937848). B.Y.J. and H.V.B. were supported by doctoral training awards from the National Institutes of Health (T32-DK007158) and Canadian Institutes of Health Research (Grant No. 146182), respectively. The authors have no competing interests. NCT01927432 and NCT01785719.

STUDY QUESTION: Does weight loss from a hypocaloric dietary intervention improve antral follicle dynamics in women with PCOS? SUMMARY ANSWER: During a 3-month hypocaloric dietary intervention, women with PCOS who experienced clinically meaningful weight loss showed more organized antral follicle development including fewer recruitment events, but no change in the overall frequency of selection, dominance, or ovulation. WHAT IS KNOWN ALREADY: There is a spectrum of disordered antral follicle development in women with PCOS including excessive follicle recruitment and turnover, decreased frequency of selection and dominance, and failure of ovulation. Lifestyle intervention aimed at weight loss is recommended to improve metabolic health in women with PCOS yet benefits on ovarian follicle development and ovulation are unclear. STUDY DESIGN, SIZE, DURATION: This was a prospective, single-arm lifestyle intervention study conducted over 4 months including a 1-month baseline assessment period and 3-month hypocaloric dietary intervention. Twenty women were allocated to the intervention with 0% attrition. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females, ages 18–38 years, with PCOS and obesity (BMI > 30 kg/m2) underwent every-other-day transvaginal ultrasonography and venipuncture at an academic clinical research unit for 4 months. The number and size of all follicles were evaluated at each study visit, with individual growth profiles plotted retrospectively for follicles that grew to at least 7 mm. Gonadotropin and ovarian steroid hormone concentrations were measured every-other-day. Reproductive, anthropometric, and metabolic status markers were assessed at baseline and at the end of the intervention. MAIN RESULTS AND THE ROLE OF CHANCE: Hypocaloric dietary intervention resulted in an average weight loss of 8 ± 3% with significant reductions in all anthropometric markers assessed including BMI, waist circumference, total percent fat, and trunk fat mass (all P < 0.05). Of the glucoregulatory and cardiovascular risk markers assessed, only diastolic blood pressure (P = 0.040) and 2-h insulin concentrations following a glucose challenge (P = 0.029) were decreased post-intervention. Antral follicle development appeared more cyclic following the intervention with the frequency of recruitment (P = 0.043), and number of follicles recruited per cohort (P < 0.0001), decreasing with weight loss. By contrast, the frequency of selection, dominance, and ovulation did not change with weight loss (all P < 0.05). When ovulation occurred during the intervention, the size at selection for ovulatory follicles decreased with weight loss (P < 0.0001), whereas maximum luteal progesterone levels increased with weight loss (P = 0.036). Participants (35%) who responded to the intervention with a shortened inter-menstrual interval had lower baseline trunk fat mass (P = 0.048), fasting insulin (P = 0.022), and homeostatic model assessment for insulin resistance (P = 0.017) compared to non-responders. LIMITATIONS, REASONS FOR CAUTION: The duration of the intervention may not have been sufficient to capture an impact of weight loss on ovulatory cyclicity. Analyses were limited to the antral stages of follicle development and any impact of hypocaloric dietary intervention on pre-antral folliculogenesis was not evaluated. The small study sample limits statistical power and generalizability of the findings. WIDER IMPLICATIONS OF THE FINDINGS: Short-term hypocaloric dietary intervention did not consistently improve ovulation frequency in women with PCOS despite clinically meaningful weight loss. Counseling related to the benefits of short-term hypocaloric dietary intervention on reproductive health outcomes should be tempered as improvements in ovulation are likely only in those with a more favorable metabolic profile at the onset. Improvements in the early stages of antral follicle development with weight loss suggest potential for longer dietary interventions to improve ovulatory cyclicity in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by funds from the President’s Council of Cornell Women, United States Department of Agriculture (Grant No. 8106), and National Institutes of Health (R01-HD0937848, R56-HD089962). F.E.C., B.Y.J., and H.V.B. were supported by doctoral training awards from the National Institutes of Health (5 T32-HD087137, T32-DK007158) and Canadian Institutes of Health Research (Grant No. 146182), respectively. The authors have no competing interests. TRIAL REGISTRATION NUMBER: NCT01785719.

Background/Objective: Lifestyle intervention is recommended as first-line treatment for polycystic ovary syndrome (PCOS). This pilot study aimed to determine if a short-term hypocaloric dietary intervention induced changes in the phenotypic presentation of PCOS. Methods: Twenty women with PCOS and overweight/obesity participated in a 3-month hypocaloric dietary intervention with a 6-month follow-up. At pre-intervention, post-intervention, and follow-up, assessments of menstrual cycle status, hyperandrogenism, and polycystic ovarian morphology were performed, and PCOS phenotype status was determined using the following scale of decreasing severity: Phenotype A (ovulatory dysfunction, hyperandrogenism, and polycystic ovaries), Phenotype B (ovulatory dysfunction and hyperandrogenism), Phenotype C (hyperandrogenism and polycystic ovaries), or Phenotype D (ovulatory dysfunction and polycystic ovaries). Results: The participants lost 8 ± 3% of their initial body weight with the intervention (p < 0.001). Eight (40%) participants experienced a favorable shift in PCOS phenotype, while the remaining 12 (60%) participants had an unfavorable shift or no change. Changes in PCOS phenotype were primarily driven by reductions in menstrual cycle length (p = 0.010) and follicle number per ovary (p = 0.017), albeit no baseline clinical variable predicted a favorable-change PCOS presentation. At the 6-month follow-up (N = 12), weight was increased (p < 0.05), and seven participants (58%) had reverted to a more severe phenotype. Conclusions: Weight loss may provide temporary improvement in the phenotypic presentation of PCOS, yet sustained lifestyle change may be required to maintain these benefits.