Impact of a hypocaloric dietary intervention on antral follicle dynamics in eumenorrheic women with obesity.

STUDY QUESTION: Do antral follicle dynamics change in women with obesity and regular ovulatory cycles after a 6-month hypocaloric dietary intervention? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: A pre-post pilot study of 12 women who participated in a 6-month hypocaloric dietary intervention. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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). MAIN RESULTS AND THE ROLE OF CHANCE: 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 <10 ng/ml did not differ pre- versus post-intervention (all, P > 0.05). In Month 7, follicle dynamics and endocrine profiles were similar to the reference cohort across all measures. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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. TRIAL REGISTRATION NUMBER: NCT01927432 and NCT01785719.

Ovarian Morphology in Girls Longitudinal Cohort Study: Pilot Evaluation of Ovarian Morphology as a Biomarker of Reproductive and Metabolic Features during the First Gynecological Year.

OBJECTIVE: The objective was to establish whether aspects of ovarian morphology correlate with reproductive and metabolic features during the first postmenarcheal year using data from the Ovarian Morphology in Girls (OMG!) cohort study. The feasibility of transabdominal ultrasonography to assess ovarian features was also determined. METHODS: Healthy adolescent females enrolled in a prospective cohort study. Study visits occurred at 6-10, 11-13, 17-19, and 23-25 months postmenarche and entailed a physical exam, transabdominal ultrasound, and fasting blood draw. Participants maintained menstrual diaries throughout the study. The present analysis reflects participants who completed the study visit at 6-10 months postmenarche. Associations between ovarian morphology or average cycle length with reproductive and metabolic features were assessed by Spearman correlations and linear regression. RESULTS: Forty participants enrolled in the OMG! STUDY: Thirty-one participants initiated study procedures at 6-10 months postmenarche, and data were available for analysis for 29 participants. Image quality was judged as partially visible or excellent in 90% of the left and 78% of the right ovaries assessed, with all images collected having sufficient image quality to provide measurements of at least 1 ovarian marker. The follicle number per ovary and ovarian volume were positively associated with anti-Müllerian hormone levels and negatively associated with fasting insulin. The average cycle length was only associated negatively with triglycerides. CONCLUSION: Transabdominal ultrasonography in the early postmenarcheal period provides sufficient resolution to enable estimations of antral follicle count and ovarian size. Ovarian features in early gynecological life may correspond with measures of reproductive and metabolic function.

Overnight Melatonin Concentration and Sleep Quality Are Associated with the Clinical Features of Polycystic Ovary Syndrome.

Circulating melatonin is elevated in women with polycystic ovary syndrome (PCOS); whether circadian disruptions coincide with sleep disturbances in women with PCOS or their symptom severity is unclear. The objective of this observational pilot study was to determine whether altered patterns of melatonin excretion are associated with reduced sleep quality in women with versus without PCOS. Participants underwent a clinical assessment, transvaginal ultrasound, and reproductive hormone testing. Morning and evening urine samples were assayed for urinary 6-sulfatoxymelatonin (MEL) as a proxy for melatonin production. The night (morning MEL)-to-day (evening MEL) ratio, or N:D ratio, was determined to approximate the rhythm of MEL production. Sleep quality and duration were assessed using the Pittsburgh Sleep Quality Index (PSQI) and wrist actigraphy. No differences were detected in overnight MEL, daytime MEL, or the N:D ratio in participants with PCOS versus controls. The PCOS group experienced reduced weekend sleep efficiency vs. controls (81% vs. 88% p < 0.05). The number of follicles per ovary (FNPO) was positively associated with overnight MEL (r = 0.359, p < 0.05). Weekend sleep time and overnight MEL concentrations were dependent on PCOS status. Therefore, diagnostic features of PCOS were associated with MEL production and sleep disturbances, suggesting that women with a more severe clinical presentation of PCOS may be more likely to experience altered MEL production or sleep disturbances.

Diagnostic Performance of Ovarian Morphology on Ultrasonography across Anovulatory Conditions-Impact of Body Mass Index.

The study objectives were to determine whether ovarian morphology can distinguish between women with regular menstrual cycles, normo-androgenic anovulation (NA-Anov), and PCOS and whether body mass index (BMI)-specific thresholds improved diagnostic potential. Women with PCOS (biochemical and/or clinical hyperandrogenism and irregular cycles; N = 66), NA-Anov (irregular cycles without clinical and/or biochemical hyperandrogenism; N = 64), or regular cycles (controls; cycles every 21-35 days in the absence of clinical or biochemical hyperandrogenism; N = 51) were evaluated. Participants underwent a reproductive history, physical exam, transvaginal ultrasound, and a fasting blood sample. Linear regression analyses were used to assess the impact of BMI on ovarian morphology across groups. The diagnostic performance of ovarian morphology for anovulatory conditions, and by BMI (lean: <25 kg/m2; overweight: ≥25 kg/m2), was tested using Receiver Operating Characteristic (ROC) curves. Follicle number per ovary (FNPO) and ovarian volume (OV), but not follicle number per cross-section (FNPS), increased across controls, NA-Anov, and PCOS. Overall, FNPO had the best diagnostic performance for PCOS versus controls (AUCROC = 0.815) and NA-Anov and controls (AUCROC = 0.704), and OV to differentiate between PCOS and NA-Anov (AUCROC = 0.698). In lean women, FNPO best differentiated between PCOS and controls (AUCROC = 0.843) and PCOS versus NA-Anov (AUCROC = 0.710). FNPS better distinguished between NA-Anov and controls (AUCROC = 0.687), although diagnostic performance was lower than when thresholds were generated using all participants. In women with overweight and obesity, OV persisted as the best diagnostic feature across all analyses (PCOS versus control, AUCROC = 0.885; PCOS versus NA-Anov, AUCROC = 0.673; NA-Anov versus controls, AUCROC = 0.754). Ovarian morphology holds diagnostic potential to distinguish between NA-Anov and PCOS, with marginal differences in diagnostic potential when participants were stratified by BMI suggesting that follicle number may provide better diagnostic performance in lean women and ovarian size in those with overweight.

Obesity is associated with alterations in antral follicle dynamics in eumenorrheic women.

STUDY QUESTION: Are ovarian antral follicle dynamics altered in women with obesity and regular ovulatory cycles? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: This was a prospective, longitudinal study of 42 women conducted over one inter-ovulatory interval (IOI). PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 21 women with obesity (total percent body fat ≥35%) and a group of 21 women without obesity (total percent body fat <35%) underwent transvaginal ultrasonography and venipuncture every-other-day for one IOI at an academic clinical research unit. Participants were aged 19-38 years and had a history of self-reported regular menstrual cycles (21-35 days). Follicle number and diameter (≥2 mm) were quantified at each visit. Individual growth profiles for all follicles that grew to ≥7 mm were assessed. Blood samples were assayed for gonadotropins, AMH, estradiol, and progesterone. MAIN RESULTS AND THE ROLE OF CHANCE: Women with obesity exhibited fewer recruitment events (mean ± SD, 1 ± 1 vs 2 ± 1 events; P = 0.010) and fewer selectable follicles (4 ± 3 vs 8 ± 6 follicles per participant; P = 0.022) during an IOI compared to women without obesity. AMH levels were lower in women with obesity (4.40 ± 3.01 vs 5.94 ± 2.49 ng/ml; P = 0.023), while gonadotropin profiles were similar between groups, across the IOI. Of the individual follicles tracked, fewer follicles progressed to >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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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. TRIAL REGISTRATION NUMBER: NCT01927432, NCT01785719.

Gender diversity in adolescents with polycystic ovary syndrome.

OBJECTIVES: The objective of our study was to describe the prevalence of gender diverse (GD) youth  among adolescents with polycystic ovary syndrome (PCOS). METHODS: We conducted a retrospective chart review on patients who met NIH criteria for PCOS in our Multidisciplinary Adolescent PCOS Program (MAPP). We compared those with PCOS to MAPP patients who did not meet PCOS criteria as well as to non-PCOS patients from the Adolescent Specialty Clinic (ASC). Variables analyzed included gender identity, androgen levels, hirsutism scores, and mood disorders. We used chi-square, Fisher's exact, t-tests, and Wilcoxon rank sum tests to compare groups.  Gender identities self-reported as male, fluid/both or nonbinary  were pooled into the GD category. RESULTS: Within the MAPP, 7.6% (n=12) of PCOS youth self-identified as GD compared to 1.8% (n=3) of non PCOS youth (p=0.01, chi-square). When compared to non-PCOS GD adolescents from ASC (4.4%; n=3), the difference to PCOS youth was no longer significant (p=0.56). Among MAPP patients, gender diversity was associated with higher hirsutism scores (p<0.01), but not higher androgen levels. In PCOS, depression/anxiety was higher in GD vs cisgender youth (100% vs. 37.6%, p<0.01 and 77.8% vs. 35.8%, p=0.03 respectively). CONCLUSIONS: Gender diversity was observed more commonly in those meeting PCOS criteria. PCOS GD youth were more hirsute and reported more depression/anxiety. Routine screening for differences in gender identity in comprehensive adolescent PCOS programs could benefit these patients, as alternate treatment approaches may be desired to support a transmasculine identity.

Combined Oral Contraceptive Treatment Does Not Alter the Gut Microbiome but Affects Amino Acid Metabolism in Sera of Obese Girls With Polycystic Ovary Syndrome.

Background: The gut microbiome is altered in obese adolescents with polycystic ovary syndrome (PCOS), and is associated with free testosterone, metabolic markers, and insulin resistance. Combined oral contraceptives (OCP) are a primary treatment for PCOS and decrease testosterone, but the effect on the serum metabolome or gut microbiome in obese adolescents with PCOS is unknown. Objective: Contrast gut microbiome profiles, targeted serum metabolomics, hormone levels, and metabolic measures in adolescents with PCOS and obesity with and without OCP treatment. Methods: Adolescent girls with obesity and PCOS underwent stool and fasting blood collection and MRI for hepatic fat fraction. Fecal bacteria were profiled by high-throughput 16S rRNA gene sequencing and fasting serum metabolomics performed with high resolution mass spectrometry. Groups were contrasted using t-tests and principle least squares discrimination analysis (PLS-DA). Associations between bacterial taxa, baseline metabolic measures, hormone levels and the metabolome were conducted using Spearman analysis. Analyses were adjusted for false discovery rate. Results: 29 adolescents with obesity [Untreated N = 21, 16 ± 1.2 years, BMI%ile 36.5 ± 3.0; OCP N = 8, 15.5 ± 0.9 years, BMI%ile 32.5 ± 3.9] participated. Of the untreated adolescents, N = 14 contributed serum for metabolomic analysis. Participants on OCP therapy had lower free testosterone and free androgen index (p < 0.001) and higher sex hormone binding globulin. There was no difference in measures of fasting glucose, insulin, lipids or HOMA-IR between groups. PLS-DA of serum metabolomics showed discrimination between the groups, secondary amino acid changes. Untreated and OCP had similar stool microbiome α-diversity based on evenness (p = 0.28), richness (p = 0.39), and Shannon diversity (p = 0.24) and global microbial composition (ß-diversity, p = 0.56). There were no differences in % relative abundance at any level. Bacterial α-diversity was negatively associated with serum long chain fatty acids and branched chain amino acids. A higher %relative abundance of family Ruminococcaceae was significantly associated with serum bile acids and HOMA-IR. Conclusion: Despite hormone and serum amino acid differences, girls treated with OCP had similar metabolic and gut microbiome profiles compared to the untreated PCOS group. The association between bacterial α-diversity, Ruminococcaceae, clinical markers and long chain fatty acids suggests a potential role of the gut microbiome in the pathogenesis of the metabolic comorbidities in PCOS.

Reliability and Agreement of Ultrasonographic Measures of the Ovarian Stroma: Impact of Methodology.

OBJECTIVES: Increased ovarian stromal area (SA), stromal-to-ovarian area ratio (S/A), and echogenicity (SEcho) on ultrasonography have been proposed as diagnostic markers for polycystic ovary syndrome. Although several methods to evaluate the stroma exist, their reproducibility has not been defined which limits clinical utility. This study aimed to determine the interrater reliability and agreement of methods to evaluate SA, S/A, and SEcho. METHODS: Five raters tested 3 methods to obtain SA and S/A, and one to obtain SEcho on 30 ovarian cineloops under two imaging conditions, simulating real-time (free-choice) or offline (fixed-frame) imaging. For SA, Method 1 subtracted follicular area from the ovarian area, Method 2 involved outlining the periphery of the stroma, and Method 3 represented a hybrid approach in which central follicles were subtracted from the outlined stroma. SEcho was scored on a subjective 3-tiered scale. Intraclass correlation coefficients (ICCs) and the coefficient of variation were determined for SA and S/A, and Fleiss' kappa agreement statistics (κ) were determined for SEcho. RESULTS: Interrater reliability of SA was superior using Method 1 (ICC = 0.558 and ICC = 0.705) versus Method 2 (ICC = 0.522 and ICC = 0.230) or Method 3 (ICC = 0.429 and ICC = 0.305) under free-choice and fixed-frame imaging conditions, respectively. Interrater reliability of S/A was also moderate to poor across methods. SEcho was also not reliably assessed across raters (κ = <0.500). CONCLUSIONS: Ultrasonographic assessments of the ovarian stroma were associated with moderate to poor reproducibility. Indirect estimates of the ovarian stroma (Method 1) could be optimized to yield a reproducible approach, clarifying the clinical relevance of the stroma.

A comparison of two- and three-dimensional ultrasonographic methods for evaluation of ovarian follicle counts and classification of polycystic ovarian morphology.

OBJECTIVES: To determine the level of agreement across assessments of follicle number per ovary (FNPO) and classifying of polycystic ovarian morphology (PCOM; FNPO ≥25) with the use of various real-time (RT) and off-line two-dimensional (2D) and three-dimensional (3D) ultrasonographic methods. DESIGN: Method comparison study. SETTING: University-based clinical research unit. PATIENT(S): Sixteen women with and without PCOM. INTERVENTION: Thirty-two ovaries were analyzed with the use of eight ultrasonographic methods: 2D-Grid (reference method), 2D-RT, 2D-RT with Grid, multiplanar view (MPV), MPV-RT, tomographic ultrasound imaging (TUI), TUI-RT, and semiautomated volume calculation (SonoAVC). MAIN OUTCOME MEASURE(S): FNPO, PCOM status, and time to obtain FNPO. Clinical feasibility, defined as the time taken to obtain FNPO, also was evaluated. RESULT(S): 2D-RT overestimated FNPO versus 2D-Grid (3 ± 9 follicles) owing to overcounting in non-PCOM ovaries (6 ± 6 follicles). However, systematic bias was not detected when a grid overlay was incorporated (2D-RT with Grid). SonoAVC underestimated FNPO (-3 ± 5 follicles), particularly in PCOM ovaries (-4.1 ± 5.0 follicles). No bias in FNPO was detected between MPV, TUI, or TUI-RT versus 2D-Grid. 2D-RT significantly misclassified ovaries as PCOM. All methods except MPV took less time to complete FNPO assessments compared with 2D-Grid. CONCLUSION(S): Variability in FNPO across ultrasonographic methods limits their interchangeable use, particularly when a precise metric is needed. 2D-RT may be problematic owing to its propensity to misclassify PCOM. 2D-RT with Grid and MPV-RT could represent clinically feasible alternatives to obtain FNPO and classify PCOM. Efforts to reduce variation in FNPO will clarify the relevance of PCOM in women's health.

Ultrasonographic features of ovarian morphology capture nutritional and metabolic influences on the reproductive axis: implications for biomarker development in ovulatory disorders.

Ultrasonographic imaging of ovarian morphology is used widely to inform reproductive health status in women. Metabolic disturbances induced by a negative energy balance (e.g. undernutrition) or positive energy balance (e.g. overnutrition, obesity) are known to drive or exacerbate reproductive dysfunction. Whether the utility of ultrasonographic metrics of ovarian morphology could be extended as biomarkers that detect and monitor the integration of metabolic and reproductive dysfunction is an emerging research area, and recent evidence is discussed. We note that unique variations in ovarian morphology emerge across the adiposity spectrum and highlight the potential for reproductive and metabolic 'tipping points' upon which such morphological variations may be detected on ultrasonography.

Ultrasound Characterization of Disordered Antral Follicle Development in Women with Polycystic Ovary Syndrome.

CONTEXT: The mechanism of oligo-anovulation in polycystic ovary syndrome (PCOS) is unknown. OBJECTIVES: To evaluate follicular and endocrine characteristics of anovulatory and sporadic ovulatory cycles in women with PCOS. DESIGN: Prospective, longitudinal study. SETTING: Academic clinical research unit. PARTICIPANTS: 26 reproductive-aged women (18-38 years) with PCOS, observed during natural anovulatory (PCOS-Anov; n = 12) and sporadic ovulatory cycles (PCOS-Ov; n = 14), and 12 controls. INTERVENTIONS: Transvaginal ultrasonography and venipuncture were performed every other day for 4 to 6 weeks in women with PCOS or at 1 interovulatory interval in control subjects. MAIN OUTCOME MEASURES: Follicle number and diameter (ie, ≥2 mm) were quantified at each visit. Individual growth profiles were assessed for all follicles that grew to ≥7 mm. Blood samples were assayed for follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone. RESULTS: Follicular excess, or heightened follicle number versus controls, was observed across anovulatory and sporadic ovulatory cycles in PCOS. In PCOS-Anov, follicles emerged cyclically in some women (6/12; 50%) and continuously in others (6/12; 50%), then grew to a mean maximum diameter of 7.2 mm and regressed within 4.7 days. In PCOS-Ov, follicles mostly emerged cyclically as part of a cohort and dominant follicles showed normal growth to ovulation-albeit mean and maximum luteal progesterone concentrations were significantly lower versus controls. CONCLUSIONS: Follicle growth and regression were detected on ultrasonography amidst perpetual follicular excess in PCOS. Documentation of continuous follicle recruitment and turnover, the absence of persistence, and altered luteal progesterone following sporadic ovulation, provide formative data on antral follicle development in PCOS.

Obesity, Insulin Resistance, and Hyperandrogenism Mediate the Link between Poor Diet Quality and Ovarian Dysmorphology in Reproductive-Aged Women.

The relationship between diet quality and ovarian morphology has biological plausibility yet remains unclear and was therefore evaluated. In a multicenter cross-sectional analysis, four dietary patterns were scored for 111 consecutive reproductive-aged women (18-45 years) using (1) Healthy Eating Index (HEI-2015); (2) alternative HEI-2010; (3) alternate Mediterranean Diet (aMED); (4) and Dietary Approaches to Stop Hypertension (DASH) indices. Ovarian volume (OV) and follicle number per ovary (FNPO) were evaluated on transvaginal ultrasonography. Relationships between dietary and ovarian morphology indices were evaluated by linear regression and mediation analyses. Associations between aMED and DASH scores and OV/FNPO were completely mediated by obesity, insulin resistance, and hyperandrogenism (All: p < 0.05), unlike direct associations (All: p ≥ 0.89). Namely, a 1-standard deviation [SD] increase in aMED score was associated with decreases in OV (0.09 SD; 0.4 mL) through reducing waist circumference. Likewise, a 1 SD increase in aMED and DASH score was associated with decreases in OV (0.07 SD; 0.3 mL) by reducing glucose response to a 75 g glucose tolerance test. A 1 SD increase in DASH score was associated with decreased FNPO (0.07 SD; 2 follicles) by reducing free androgen index (All: p < 0.05). Adherence to aMED and DASH eating plans was indirectly associated with significant improvements in ovarian form, providing novel mechanistic insights for future interventions about contributions of diet quality on ovarian function.

Dietary and Physical Activity Behaviors in Women with Polycystic Ovary Syndrome per the New International Evidence-Based Guideline.

Lifestyle modifications are recommended as first-line therapy in polycystic ovary syndrome (PCOS). However, usual dietary and physical activity (PA) behaviors of women with PCOS remain uncertain, likely owing to controversy in diagnostic criteria. Our objective was to contrast the usual dietary and PA behaviors of women with PCOS (n = 80) diagnosed by the 2018 International Evidence-based Guideline for the Assessment and Management of PCOS to that of controls (n = 44). Study outcomes were dietary intake, diet quality (Healthy Eating Index-2015), and PA (questionnaire, waist-worn accelerometers). Women with PCOS met the acceptable macronutrient distribution ranges for carbohydrate, fat, and protein, but did not meet the recommended dietary reference intakes for vitamin D (mean (95% confidence interval); 6 (5-7) µg/d), vitamin B9 (275 (252-298) µg/d), total fiber (24 (22-26) g/d), or sodium (4.0 (3.6-4.4) g/d). Women with PCOS also met the US recommendations for PA. No differences were detected in dietary intake, diet quality, or PA levels between groups (p ≥ 0.11). In conclusion, women with and without PCOS have comparable dietary and PA behaviors. A lack of unique targets for dietary or PA interventions supports the position of the new guideline to foster healthy lifestyle recommendations for the management of PCOS.

Impact of right-left differences in ovarian morphology on the ultrasound diagnosis of polycystic ovary syndrome.

OBJECTIVE: To assess right-left differences in ultrasonographic markers of ovarian morphology and determine the impact on the diagnosis of polycystic ovarian morphology (PCOM). DESIGN: A cross-sectional study of data collected from 2006 to 2018. SETTING: Academic clinical research centers. PATIENT(S): Women with polycystic ovary syndrome (PCOS; n = 87) and controls (n = 67). INTERVENTION(S): None. MAIN OUTCOMES MEASURE(S): Follicle number per ovary (FNPO), follicle number per cross-section (FNPS), and ovarian volume (OV) were assessed in both ovaries using transvaginal ultrasonography. PCOM was identified based on recent international consensus guidelines or proposed diagnostic thresholds. RESULT(S): Overall, mean right-left differences were two follicles for FNPO, one follicle for FNPS, and 2 mL for OV. FNPO showed the strongest correlation between ovaries. Its assessment in a single ovary did not impact the diagnosis of PCOM in women with PCOS. However, there were differences in the probability of unilateral versus bilateral PCOM based on FNPS and OV in both groups. CONCLUSION(S): FNPO is the most reliable unilateral marker of PCOM in light of right-left differences in ovarian morphology. Use of FNPS or OV to define PCOM is discouraged when only one ovary is visualized.

GnRH Agonist Improves Hyperandrogenism in an Adolescent Girl With an Insulin Receptor Gene Mutation.

Type A insulin resistance (IR) is caused by heterozygous mutations in the insulin receptor gene. It presents with mild acanthosis nigricans, severe IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to improve insulin sensitivity and decrease androgens. An adolescent girl was evaluated for secondary amenorrhea and prominent hirsutism. She had a normal body mass index, and laboratory testing revealed an elevated LH to FSH ratio (LH 11.6 mIU/mL, FSH 4.2 mIU/mL), testosterone 96 ng/dL (reference range <50 ng/dL), free testosterone 2.21 ng/dL (reference range <1.09 ng/dL), normal glucose, and HbA1c of 5.6%. She received a diagnosis of polycystic ovary syndrome (PCOS) and was referred to our Multi-Specialty Adolescent PCOS Program. There, oral glucose tolerance test showed fasting glucose and insulin of 80 mg/dL and 63.1 mIU/mL, respectively. The 2-hour glucose and insulin were 199 mg/dL and 1480 µIU/mL, respectively. Because of hyperandrogenism with severe IR, dysglycemia, and normal lipids, type A IR was considered. Genetic testing revealed a heterozygous mutation in the insulin receptor gene [c.3095G>A(pGly1032Asp)]. After standard treatment of hirsutism and hyperinsulinism failed, a trial of GnRH agonist therapy improved hyperandrogenism and reduced ovarian size while severe IR persisted. We describe an adolescent with type A IR who experienced resolution of clinical and biochemical hyperandrogenism during GnRH agonist treatment. Given the patient's marked reduction in testosterone and hirsutism despite persistent hyperinsulinism, this case challenges the idea that insulin increases steroidogenesis independently of gonadotropin effect. GnRH agonist therapy should be considered in the treatment of hyperandrogenism in severe cases of IR.

Age-related changes in luteal dynamics: preliminary associations with antral follicular dynamics and hormone production during the human menstrual cycle.

OBJECTIVE: The aim of the study was to test the hypothesis that the development of luteal phase dominant follicles (LPDFs) as women age is associated with abnormal luteal function. METHODS: Luteal and antral follicle diameter were quantified in ovulatory women of midreproductive age (MRA; 18-35 y; n = 9) and advanced reproductive age (ARA; 45-55 y; n = 16) every 1 to 3 days during one complete interovulatory interval. Blood was drawn at each visit and assayed for progesterone, estradiol, inhibin A, follicle-stimulating hormone, and luteinizing hormone. Luteal diameter and hormone profiles were compared within MRA and ARA women with versus without LPDFs. RESULTS: Luteal growth and regression profiles were similar in MRA women with typical versus no LPDFs (13.9, 14.8 mm; P > 0.1); however, luteal phase estradiol and progesterone were greater in MRA women with typical (91.1 ng/L, 8.81 µg/L) versus no (48.8 ng/L, 7.32 µg/L) LPDFs, respectively (LPDF effect, P < 0.1). In the ARA group, mean luteal diameter was lowest in women with atypical LPDFs (12.3 mm), greatest in those with typical LPDFs (16.0 mm), and moderate in those with no LPDFs (13.6 mm), (P < 0.1). Reduced luteal growth in ARA women with atypical versus typical and/or no LPDFs occurred simultaneously to greater luteal phase estradiol (199 vs 69.0, 78.4 ng/L) lower progesterone (7.38 vs 10.7, 13.8 ug/L), and lower inhibin A (36.3, 35.6, 51.2) (P < 0.1). CONCLUSIONS: The development of LPDFs as women age was associated with reduced luteal growth, greater estradiol, lower progesterone, and lower inhibin A. These findings provide preliminary evidence that variations in antral folliculogenesis contribute to luteal insufficiency during the menopausal transition.

Ovarian Morphology by Transabdominal Ultrasound Correlates With Reproductive and Metabolic Disturbance in Adolescents With PCOS.

PURPOSE: To determine whether ovarian morphology imaged using transabdominal ultrasonography reflects clinical and metabolic features in adolescents with polycystic ovary syndrome (PCOS). METHODS: A retrospective pilot study was conducted in 33 adolescents (12-18 years) with PCOS as defined by hyperandrogenism and irregular cycles. Adolescents underwent the following assessments at a random time during the menstrual cycle: transabdominal ultrasonography, physical examination (height, weight, and systolic and diastolic blood pressure), fasting hormonal tests (free, percent free, and total testosterone, androstenedione, follicle stimulating hormone, luteinizing hormone), and metabolic tests (including an oral glucose tolerance test, fasting and 2-hour insulin and glucose, homeostatic model assessment of insulin resistance, and whole-body insulin sensitivity index). Ultrasound images were analyzed offline for ovarian area (OA), ovarian volume (OV), follicle number per cross section (FNPS), and follicle distribution pattern. Associations among endocrine and metabolic variables with sonographic features were assessed by Spearman's rank correlation coefficients and stepwise multiple linear regression. RESULTS: Total testosterone and androstenedione, but not free testosterone, or percent free testosterone, positively correlated with OA (ρ = .515, ρ = .422, respectively), OV (ρ = .451, ρ = .382), and FNPS (ρ = .394, ρ = .474). Luteinizing hormone:follicle stimulating hormone ratio also positively correlated with ovarian size (OA, ρ = .520 and OV, ρ = .409). Unexpectedly, body mass index (ρ = -.503) and fasting glucose levels (ρ = -.393) were inversely correlated with FNPS. Total testosterone was an independent predictor of FNPS, OA, and OV as judged by stepwise multiple regression analyses. CONCLUSIONS: Some aspects of ovarian morphology in adolescents with PCOS using transabdominal ultrasonography associate with markers of reproductive dysfunction and provide rationale to further investigate how ovarian morphology may reflect concurrent metabolic dysfunction.

Sonographic markers of ovarian morphology, but not hirsutism indices, predict serum total testosterone in women with regular menstrual cycles.

OBJECTIVE: To determine whether sonographic markers of ovarian morphology or male pattern hair growth scores predict androgen levels in women with regular or irregular menstrual cycles. DESIGN: Cross-sectional observational study. SETTING: Clinical research unit. PATIENT(S): Seventy-six women of reproductive age (18-39 years) were evaluated for male-pattern hair growth (using a modified Ferriman-Gallwey scoring system), ovarian morphology (by transvaginal ultrasonography), and total serum testosterone (T) (by liquid chromatography tandem mass spectrometry). INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Regional and total modified Ferriman-Gallwey scores, number of follicles per follicle size category, follicle number per ovary, ovarian volume, ovarian area, stromal to ovarian area ratio, stromal echogenicity index, total testosterone (total T), and menstrual cycle length. RESULT(S): Neither regional nor total modified Ferriman-Gallwey scores correlated with total T concentrations in women with regular or irregular menstrual cycles, as judged by the Least Absolute Shrinkage and Selection Operator technique. By contrast, a sonographic marker (follicle number per ovary 6-9 mm) significantly predicted total T concentrations in women with regular menstrual cycles but not in women with irregular menstrual cycles. CONCLUSION(S): Sonographic markers of ovarian morphology, but not hirsutism scores, predicted total T levels. However, the predictive value of ovarian morphology for total T differed by menstrual cycle status. That sonographic markers did not predict androgen levels in a diverse cohort of women with cycle irregularity suggests the potential for distinct variations in ovarian morphology for androgenic and nonandrogenic types of cycle irregularity. Overall, our findings support that an assessment of ovarian morphology may be helpful in reflecting total T levels.

Associations Between Antral Ovarian Follicle Dynamics and Hormone Production Throughout the Menstrual Cycle as Women Age.

BACKGROUND: The physiological origins of age-related changes in hormone production during the menstrual cycle are uncertain. OBJECTIVE: The objective of the study was to test the hypothesis that changes in antral follicle dynamics are associated with changes in hormone production as women age. METHODS: A prospective, observational study was conducted in ovulatory women of midreproductive age (MRA; 18-35 y; n = 10) and advanced reproductive age (ARA; 45-55 y; n = 20). The numbers and diameters of all follicles of 2 mm or greater were quantified ultrasonographically every 1-3 days for one interovulatory interval; the growth profiles of individually identified follicles of 4 mm or greater were tabulated. Blood samples were assayed for FSH, LH, estradiol, progesterone, inhibin A and B, and anti-Mullerian hormone. RESULTS: Fifty percent of women in both the MRA and ARA groups developed one to two luteal-phase dominant follicles (LPDFs). MRA women with typical LPDFs had greater luteal-phase inhibin B (44.2 vs 17.0 ng/L) and estradiol (91.3 vs 51.7 ng/L) compared with those without LPDFs (P < .05). Luteal-phase estradiol was greater (184 vs 79 ng/L), inhibin B was greater (25.3 vs 12.7 ng/L), and progesterone was lower (6.98 vs 13.8 µg/L) in ARA women with atypical vs no LPDFs (P < .01). CONCLUSION: Changes in antral follicle dynamics are associated with changes in hormone production as women age. The development of LPDFs in women of MRA was associated with elevated luteal-phase estradiol. A similar but exaggerated elevation in late luteal-early follicular-phase estradiol, accompanied by lower progesterone, was observed in ARA women with atypically large and persistent LPDFs.

Ultrasound features of polycystic ovaries relate to degree of reproductive and metabolic disturbance in polycystic ovary syndrome.

OBJECTIVE: To reexamine associations between polycystic ovarian morphology (PCOM) and degree of symptomatology in polycystic ovary syndrome (PCOS) using a well-defined PCOS population, newer ultrasound technology, and reliable offline assessments of sonographic parameters. DESIGN: Cross-sectional observational study. SETTING: Academic hospital and clinical research unit. PATIENT(S): Forty-nine women with PCOS as defined by hyperandrogenism and oligoamenorrhea. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number of follicles per follicle size category, antral follicle count (AFC), ovarian volume (OV), follicle distribution pattern, stromal area, ovarian area, stromal to ovarian area ratio (S/A) and stromal echogenicity index (SI), total (TT), androstenedione, LH, FSH, cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, C-reactive protein, glucose, insulin, and hemoglobin A1C, menstrual cycle length, hirsutism score, body mass index (BMI), waist:hip ratio, and blood pressure. RESULT(S): AFC, but not OV, was positively associated with TT (ρ = .610), androstenedione (ρ = .490), and LH:FSH (ρ = .402). SI was positively associated with androgen markers and LH:FSH, while S/A was negatively associated with these variables. Follicles ≤4 mm were negatively associated with various metabolic markers, whereas larger follicles (5-8 mm) showed positive associations. Stromal markers were not associated with cardiometabolic measures. LH:FSH best predicted follicles ≤4 mm, and BMI predicted 5- to 9-mm follicles. Dominant follicles ≥10 mm were best predicted by age. CONCLUSION(S): AFC, and not OV, reflected the severity of reproductive dysfunction in PCOS. Associations among different sized follicles were consistent with recruitable sized follicles, which reflects the severity of metabolic dysfunction in PCOS.