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.

Preoperative Amiodarone and Primary Graft Dysfunction in Heart Transplantation.

BACKGROUND: Preoperative amiodarone effects on postorthotopic heart transplant (OHT) outcomes remain controversial. OBJECTIVE: The purpose of this study was to determine the effect of cumulative pre-OHT amiodarone exposure on severe primary graft dysfunction (PGD). METHODS: We retrospectively reviewed adult OHT recipients between August 2012 and June 2018. Primary outcome was severe PGD in patients receiving amiodarone at 3, 6, and 12 months prior to OHT compared with those not receiving amiodarone. Secondary outcomes included intensive care unit (ICU) and hospital length of stay, duration of mechanical ventilation, early graft failure (EGF), mortality at 3, 6, and 12 months post-OHT, and 30-day incidence of postoperative tachyarrhythmias, bradycardia, permanent pacemaker implantation, and rejection. RESULTS: Incidence of severe PGD was 12.5% in those who received amiodarone compared to 6.8% in those who did not (14 vs 6, P = 0.18). Cumulative preoperative amiodarone significantly increased the odds of severe PGD at 3 months (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.001-1.06; P = 0.044) and 6 months (OR: 1.02, 95% CI: 1.003-1.044; P = 0.024) in a multivariate logistic regression. Patients on amiodarone had significantly higher rates of postoperative bradycardia (13.4% vs 4.5%, P = 0.03). CONCLUSION AND RELEVANCE: A trend toward increased PGD was present in patients receiving preoperative amiodarone. This finding combined with the regression showing significantly increased odds of PGD with increasing 3 and 6 month cumulative amiodarone dose is clinically concerning. Escalation of care with pacemaker implantation was required more frequently in patients on pre-OHT amiodarone.

The efficacy of sleep lifestyle interventions for the management of overweight or obesity in children: a systematic review and meta-analysis.

BACKGROUND: Childhood obesity remains a significant public health concern. Sleep duration and quality among children and youth are suboptimal worldwide. Accumulating evidence suggests an association between inadequate sleep and obesity risk, yet it is unclear whether this relationship is causal. This systematic review examines the efficacy of sleep interventions alone or as a part of lifestyle interventions for the management of overweight or obesity among children and adolescents. METHODS: A keyword/reference search was performed twice, in January 2021 and May 2022 in MEDLINE/PubMed, EMBASE/Ovid, PsycINFO/EBSCO, The Cochrane Library, Web of Science Core Collection/Web of Science, SciELO/Web of Science, and CINAHL/EBSCO. Study eligibility criteria included youth with overweight or obesity between 5 and 17, were RCTs or quasi-randomized, and focused on the treatment of overweight and obesity with a sleep behavior intervention component. Risk of bias was assessed using the Cochrane Risk of Bias assessment tool (RoB2). A Meta-analysis was conducted to estimate the effect of interventions with a sleep component on BMI. The study protocol was registered in PROSPERO (CRD42021233329). RESULTS: A total of 8 studies (2 quasi-experiments, 6 RCTs) met inclusion criteria and accounted for 2,231 participants across 7 countries. Only one study design isolated the effect of sleep in the intervention and reported statistically significant decreases in weight and waist circumference compared to control, though we rated it at high risk of bias. Our meta-analysis showed no significant overall effect on children's BMI as a result of participation in an intervention with a sleep component (Cohen's d = 0.18, 95% CI= -0.04, 0.40, Z = 1.56, P = .11), though caution is warranted due to substantial heterogeneity observed across studies (Tau2 = 0.08; X2 = 23.05, df = 7; I2 = 83.73%). CONCLUSIONS: There were mixed results on the effect of sleep interventions across included studies on BMI, other weight-related outcomes, diet, physical activity, and sleep. Except for one study at low risk of bias, three were rated as 'some concerns' and four 'high risk of bias'. Findings from this study highlight the need for additional RCTs isolating sleep as a component, focusing on children and adolescents living with overweight and obesity.

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.

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.

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.

Changes in the bile acid pool and timing of female puberty: potential novel role of hypothalamic TGR5.

CONTEXT: The regulation of pubertal timing and reproductive axis maturation is influenced by a myriad of physiologic and environmental inputs yet remains incompletely understood. OBJECTIVES: To contrast differences in bile acid isoform profiles across defined stages of reproductive maturity in humans and a rat model of puberty; to characterize the role of bile acid signaling via hypothalamic expression of bile acid receptor populations in the rodent model. DESIGN: Secondary analysis and pilot studies of clinical cohorts, rodent models, ex vivo analyses of rodent hypothalamic tissues. MAIN OUTCOME MEASURE: Bile acid concentrations. RESULTS: Lower circulatory conjugated:deconjugated bile acid concentrations and higher total secondary bile acids were observed in the post-menarcheal versus pre/early-pubertal adolescents, with similar shifts observed in infantile (PN 14) versus early juvenile (PN 21) rats alongside increased tgr5 receptor mRNA expression within the mediobasal hypothalamus of female rats. 16S rRNA gene sequencing of the rodent gut microbiome across postnatal life revealed changes in the gut microbial composition predicted to have Bile Salt Hydrolase activity, which was observed in parallel with the increased deconjugated and increased concentrations of secondary bile acids. We show that TGR5-stimulated GnRH release from hypothalamic explants is mediated trough Kisspeptin-receptors and that early overexpression of human-TGR5 within the arcuate nucleus accelerates pubertal onset in female rats. CONCLUSION: Bile acid isoform shifts along stages of reproductive maturation are conserved across rodents and humans, with pre-clinical models providing mechanistic insight for the neuroendocrine-hepatic-gut microbiome axis as a potential moderator of pubertal timing in females.

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.

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.

Induction and maintenance immunosuppression in lung transplantation.

Immunosuppression for lung transplant recipients is a critical part of post-transplant care, to prevent acute and chronic rejection. Treatment protocols consist of induction and maintenance immunotherapy. Induction agents provide an immediate state of immunosuppression following transplantation and over time, and their use has become more commonplace. Several agents are available for clinical use, including anti-thymocyte globulin, alemtuzumab, and basiliximab, the latter being most commonly employed. Each induction agent has unique side effects and caveats to their use, of which we must be aware. Maintenance immunosuppression is initiated following transplant but requires multiple doses prior to reaching therapeutic levels. A calcineurin inhibitor, an anti-metabolite, and a corticosteroid are traditionally used, most commonly tacrolimus, mycophenolate mofetil, and prednisone. Dosing regimens and goal trough levels vary and are tailored to a patient's clinical status and duration post-transplant. Future clinical studies may be able to assist in determining the optimal induction and maintenance immunosuppression regimens. In the interim, we use cohort and registry data to guide our therapies.

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.

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.

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.

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.

COVID-19 pandemic: Challenges and solutions from the cardiology pharmacist's perspective.

The recent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges pharmacists worldwide. Alongside other specialized pharmacists, we re-evaluated daily processes and therapies used to treat COVID-19 patients within our institutions from a cardiovascular perspective and share what we have learned. To develop a collaborative approach for cardiology issues and concerns in the care of confirmed or suspected COVID-19 patients by drawing on the experiences of cardiology pharmacists across the country. On March 26, 2020, a conference call was convened composed of 24 cardiology residency-trained pharmacists (23 actively practicing in cardiology and 1 in critical care) from 16 institutions across the United States to discuss cardiology issues each have encountered with COVID-19 patients. Discussion centered around providing optimal pharmaceutical care while limiting staff exposure. The collaborative of pharmacists found for the ST-elevation myocardial infarction patient, many institutions were diverting COVID-19 rule-out patients to their Emergency Department (ED). Thrombolytics are an alternative to percutaneous coronary intervention (PCI) allowing for timely treatment of patients and decreased staff exposure. An emergency response grab and go kit includes initial drugs and airway equipment so the patient can be treated and the cart can be left outside the room. Cardiology pharmacists have developed policies and procedures to address monitoring of QT prolonging medications, the use of inhaled prostacyclins, and national drug shortages. Technology has allowed us to practice social distancing, while staying in close contact with our teams, patients, and colleagues and continuing to teach. Residents are engaged in unique decision-making processes with their preceptors and assist as pharmacist extenders. Cardiology pharmacists are in a unique position to work with other pharmacists and health care professionals to implement safe and effective practice changes during the COVID-19 pandemic. Ongoing monitoring and adjustments are necessary in rapidly changing times.

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.

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.