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Background: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. Methods: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. Results: A total of 103 participants underwent randomization, of whom 69 were assigned to crinecerfont and 34 to placebo; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter). At week 4, androstenedione was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol/liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], -268 ng per deciliter [-9.3 nmol/liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol/liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (LSMD, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. Conclusions: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.). [ABSTRACT FROM AUTHOR]

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Abstract: Biological sex is a primary determinant of athletic performance because of fundamental sex differences in anatomy and physiology dictated by sex chromosomes and sex hormones. Adult men are typically stronger, more powerful, and faster than women of similar age and training status. Thus, for athletic events and sports relying on endurance, muscle strength, speed, and power, males typically outperform females by 10%-30% depending on the requirements of the event. These sex differences in performance emerge with the onset of puberty and coincide with the increase in endogenous sex steroid hormones, in particular testosterone in males, which increases 30-fold by adulthood, but remains low in females. The primary goal of this consensus statement is to provide the latest scientific knowledge and mechanisms for the sex differences in athletic performance. This review highlights the differences in anatomy and physiology between males and females that are primary determinants of the sex differences in athletic performance and in response to exercise training, and the role of sex steroid hormones (particularly testosterone and estradiol). We also identify historical and nonphysiological factors that influence the sex differences in performance. Finally, we identify gaps in the knowledge of sex differences in athletic performance and the underlying mechanisms, providing substantial opportunities for high-impact studies. A major step toward closing the knowledge gap is to include more and equitable numbers of women to that of men in mechanistic studies that determine any of the sex differences in response to an acute bout of exercise, exercise training, and athletic performance., (Copyright © 2023 by the American College of Sports Medicine.)

Objective: To describe time to cessation of menses in adolescent and young adult transgender males with testosterone and/or other hormonal therapies DESIGN: Retrospective chart review SETTING: Tertiary children's hospital PARTICIPANTS: Patients, aged 10-24, who began gender-affirming hormonal therapy between January 2013 and January 2019 (n = 220) INTERVENTION(S): None MAIN OUTCOME MEASURE(S): Time to cessation of menses RESULTS: Most patients identified as transgender male or transmasculine (211/220, 95.9%), with an average age of 15.8 (±1.9) years. Approximately 53.6% (118/220) of patients reported regular menstrual cycles; 18.2% (40/220) reported irregular cycles. Median time to cessation of menses for all patients was 182 days. Patients treated with testosterone alone (n = 105) reported a median time to cessation of menses of 151 days. Patients who concurrently began testosterone and norethindrone acetate (NETA) (n = 5) had a median time to cessation of menses of 188 days, compared with 168 days for those on testosterone and depot medroxyprogesterone acetate (DMPA, n = 15). In 15 patients who began testosterone, a progestin therapy was later added to induce menstrual suppression, and the median time to cessation of menses was 168 days (+DMPA, n = 4) or 56 days (+NETA, n = 11). Patients treated with NETA (n = 14) or depot leuprolide (n = 11) reported a median time to cessation of menses of 78 days or 77 days, respectively. Considerable variability in prescribing patterns was noted in the remaining 36.4% of patients (n = 80)., Conclusion: Patients used a variety of different hormonal regimens for menstrual suppression. Less than half achieved cessation of menses within 6 months. NETA and depot leuprolide users reported the most rapid cessation of menses., (Copyright © 2022. Published by Elsevier Inc.)

Context: Studies on cardiometabolic health in transgender and gender-diverse youth (TGDY) are limited to small cohorts., Objective: This work aimed to determine the odds of cardiometabolic-related diagnoses in TGDY compared to matched controls in a cross-sectional analysis, using a large, multisite database (PEDSnet)., Methods: Electronic health record data (2009-2019) were used to determine odds of cardiometabolic-related outcomes based on diagnosis, anthropometric, and laboratory data using logistic regression among TGDY youth vs controls. The association of gender-affirming hormone therapy (GAHT) with these outcomes was examined separately among TGDY. TGDY (n = 4172) were extracted from 6 PEDSnet sites and propensity-score matched on 8 variables to controls (n = 16 648). Main outcomes measures included odds of having cardiometabolic-related diagnoses among TGDY compared to matched controls, and among TGDY prescribed GAHT compared to those not prescribed GAHT., Results: In adjusted analyses, TGDY had higher odds of overweight/obesity (1.2; 95% CI, 1.1-1.3) than controls. TGDY with a testosterone prescription alone or in combination with a gonadotropin-releasing hormone agonist (GnRHa) had higher odds of dyslipidemia (1.7; 95% CI, 1.3-2.3 and 3.7; 95% CI, 2.1-6.7, respectively) and liver dysfunction (1.5; 95% CI, 1.1-1.9 and 2.5; 95% CI, 1.4-4.3) than TGDY not prescribed GAHT. TGDY with a testosterone prescription alone had higher odds of overweight/obesity (1.8; 95% CI, 1.5-2.1) and hypertension (1.6 95% CI, 1.2-2.2) than those not prescribed testosterone. Estradiol and GnRHa alone were not associated with greater odds of cardiometabolic-related diagnoses., Conclusion: TGDY have increased odds of overweight/obesity compared to matched controls. Screening and tailored weight management, sensitive to the needs of TGDY, are needed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Limited data are available on changes in metabolic parameters in transgender youth on testosterone therapy in comparison with cisgender females. Data from 42 transgender males on testosterone therapy were retrospectively analyzed. Body mass index (BMI) and lipid profile changes were compared with BMI-matched females. There was a significant increase in BMI over time in the transgender males as compared with the cisgender females, and a decrease in high-density lipoprotein in the transgender males after starting testosterone therapy. Longitudinal prospective studies with cisgender controls are needed to better define effects of testosterone therapy in adolescents., Competing Interests: A.V., A.B., G.C., J.I., S.L., L.N.: No competing financial interests exist. N.N.: Previously consulted for Antares Pharma, Inc., (Copyright 2021, Mary Ann Liebert, Inc., publishers.)

Study Objective: Based on updated guidelines and expressed patient needs, we created a multidisciplinary clinic including endocrinology, gynecology/adolescent medicine, dermatology, psychology, and nutrition to provide comprehensive care to adolescent girls with polycystic ovary syndrome (PCOS). We describe the patient population presenting to this clinic, and prescribing patterns when a multidisciplinary approach is used., Design: Retrospective chart review., Setting: Tertiary care hospital., Participants: Female patients, aged 11-24 years, presenting for initial assessment in a multidisciplinary PCOS clinic., Interventions: None., Main Outcome Measures: Medical history, physical examination findings, laboratory measurements and prescribed therapies., Results: A total of 92 patients seen from 2014 to 2018 are described (age 15.9 years, range 11-24 years, body mass index 35.6 kg/m 2 , range 19.9-53.5). Metabolic syndrome features were common: 26% had a prediabetes hemoglobin A1c (>5.6%), 83% had a high-density lipoprotein (HDL) <50 mg/dL, 40% had a systolic blood pressure >120 mm Hg, and 43% had an alanine aminotransferase level of >30 U/L. Dermatologic findings included acne 93%, hirsutism 38%, acanthosis nigricans 85%, hidradenitis suppurativa 16%, and androgenic alopecia 2%. Of the patients, 33% had a diagnosis of depression or anxiety, 16% of patients had a diagnosis of obstructive sleep apnea, and an additional 59% had symptoms warranting a sleep study The most commonly prescribed medications were topical acne preparations (62%), followed by estrogen-containing hormonal therapy (56%) and metformin (40%)., Conclusion: In adolescents with PCOS and obesity, metabolic, dermatologic, and psychologic co-morbidities are common. The use of a multidisciplinary clinic model including dermatology in addition to endocrinology, gynecology, psychology, and lifestyle experts provides care for most aspects of PCOS., (Copyright © 2021 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)