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.

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.

Heat Capacity of DPPC/Cholesterol Mixtures: Comparison of Single Bilayers with Multibilayers and Simulations.

The excess heat capacity (Δ C p) of mixtures of dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Chol) is examined in detail in large unilamellar vesicles (LUVs), both experimentally, using differential scanning calorimetry (DSC), and theoretically, using a three-state Ising model. The model postulates that DPPC can access three conformational states: gel, liquid-disordered (Ld), and liquid-ordered (Lo). The Lo state, however, is only available if coupled with interaction with an adjacent Chol. Δ C p was calculated using Monte Carlo simulations on a lattice and compared to experiment. The DSC results in LUVs are compared with literature data on multilamellar vesicles (MLVs). The enthalpy change of the complete phase transition from gel to Ld is identical in LUVs and MLVs, and the melting temperatures ( Tm) are similar. However, the DSC curves in LUVs are significantly broader, and the maxima of Δ C p are accordingly smaller. The parameters in the Ising model were chosen to match the DSC curves in LUVs and the nearest-neighbor recognition (NNR) data. The model reproduces the NNR data very well. It also reproduces the phase transition in DPPC, the freezing point depression induced by Chol, and the broad component of Δ C p in DPPC/Chol LUVs. However, there is a sharp component, between 5 and 15 mol % Chol, that the model does not reproduce. The broad component of Δ C p becomes dominant as Chol concentration increases, indicating that it involves melting of the Lo phase. Because the simulations reproduce this component, the conclusions regarding the nature of the phase transition at high Chol concentrations and the structure of the Lo phase are important: there is no true phase separation in DPPC/Chol LUVs. There are large domains of gel and Lo phase coexisting below Tm of DPPC, but above Tm the three states of DPPC are mixed with Chol, although clusters persist.

Ultrasonographic criteria in the diagnosis of polycystic ovary syndrome: a systematic review and diagnostic meta-analysis.

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.

Methods to detect mitophagy in neurons during disease.

Mitophagy is the selective degradation of mitochondria by autophagy. Methods to study mitophagy in neurons is of increasing importance as neurodegenerative diseases such as Parkinson's and Alzheimer's display disrupted mitophagy as part of their pathogenesis. Since the last decade, researchers have determined how selective mitophagy pathways such as PINK1/Parkin and Mul1 function at the cellular level. Thus, advances in techniques to study these pathways specifically in neurons and glia have arisen. This review will introduce mitophagy pathways studied in neurons and evaluate current techniques available to investigate mitophagy.