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Carney syndrome is a rare, autosomal dominant, multi-system disorder comprising 8 well-characterized findings, only 2 of which need be present for a definitive diagnosis. Benign neoplasms are frequent, but malignancies are thought to be uncommon. We have studied a family to clarify the diagnosis and spectrum of clinical manifestations of the syndrome and to develop guidelines for management. The proposita, a 34-year-old woman had classic findings of Carney syndrome, invasive follicular carcinoma of the thyroid gland, Barrett metaplasia of the esophagus, neoplastic colonic polyps, bipolar affective disorder, and atypical mesenchymal neoplasm of the uterine cervix distinct from the myxoid uterine leiomyoma usually seen in this syndrome. Although thyroid gland neoplasm is rare in Carney syndrome, this patient's most aggressive manifestation was her thyroid carcinoma. The diagnosis of Carney syndrome was established in her 9-year-old son and is a probable diagnosis in her 12-year-old daughter. Endocrine manifestations were prominent in the family with at least 9 relatives in 3 generations affected with various endocrine abnormalities. The findings in this family indicate that the spectrum of manifestations in this pleiotropic gene apparently includes a malignant course with premalignant and endocrinologic disorders not previously recognized.

With the increasing incidence of diabetes mellitus (DM), it is imperative to develop novel treatments. Stem cells offer the potential for use as renewable sources of glucose-responsive, insulin-secreting cells. However, developing a consistent protocol to enrich beta-cells is not a trivial issue. The question whether embryonic, fetal, or adult stem cells offer particular advantages as the starting material remains to be resolved experimentally. While somatic cell nuclear transfer avoids many of the problems associated with heterologous transplantation, the problem of autoimmune destruction of the beta-cells in type 1 DM might still remain. This review summarizes the innovative treatment strategies for DM and considers the possible advantages and problems. [ABSTRACT FROM AUTHOR]

Unbalanced translocation between chromosomes X and Y is a recurring chromosomal rearrangement. The presence of a derivative chromosome X (derX), where a Yq11-qter segment is attached to the short arm of chromosome X, replacing a terminal Xpter-p22.31, poses challenges for interpretation of findings by prenatal cell-free DNA (cfDNA) screening, establishing genotype-phenotype correlation in male and female individuals, and for genetic counseling. In this report, we provide clinical outcomes, inheritance, and clinical implications of derX in three families referred to diagnostic testing due to discrepant results for sex chromosomes reported by cfDNA, abnormal prenatal ultrasound findings, recurrent pregnancy losses, or affected family members with derX transmitted through multiple generations. Reports of discrepant sex and risk for sex chromosome aneuploidy such as 45,X, 47,XXY and 47,XYY are common false positive outcomes of a prenatal cfDNA screening if either a mother or a fetus has unbalanced Xp-Yq translocation. In addition, mothers who carry der(X) facing a recurrent risk of ambiguity in prenatal testing. Pregnancy loss and neonatal death/stillbirth of male offspring are common in affected families, but this risk does not directly correlate with the size of deleted Xp region. This study emphasizes the importance of CMA and familial testing for accurate diagnosis and genetic counseling., (© 2024 Wiley Periodicals LLC.)

Background: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH., Methods: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control., Results: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups., Conclusions: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.)., (Copyright © 2024 Massachusetts Medical Society.)

Delayed puberty is defined as absent testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SDS later than the mean age at which these events occur in the population (traditionally, 14 years in boys and 13 years in girls). One cause of delayed/absent puberty is hypogonadotropic hypogonadism (HH), which refers to inadequate hypothalamic/pituitary function leading to deficient production of sex steroids in males and females. Individuals with HH typically have normal gonads, and thus HH differs from hypergonadotropic hypogonadism, which is associated with primary gonadal insufficiency., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Puberty is characterized by gonadarche and adrenarche. Gonadarche represents the reactivation of the hypothalamic-pituitary-gonadal axis with increased gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone secretion following the quiescence during childhood. Pubarche is the development of pubic hair, axillary hair, apocrine odor reflecting the onset of pubertal adrenal maturation known as adrenarche. A detailed understanding of these pubertal processes will help clarify relationships between the timing of the onset of puberty and cardiovascular, metabolic, and reproductive outcomes in adulthood. The onset of gonadarche is influenced by neuroendocrine signals, genetic variants, metabolic factors, and environmental elements., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This review focuses on primary amenorrhea and primary/premature ovarian insufficiency due to hypergonadotropic hypogonadism. Following a thoughtful, thorough evaluation, a diagnosis can usually be discerned. Pubertal induction and ongoing estrogen replacement therapy are often necessary. Shared decision-making involving the patient, family, and health-care team can empower the young person and family to successfully thrive with these chronic conditions., Competing Interests: Disclosure The authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Premature ovarian insufficiency (POI) is one of many potential long-term consequences of childhood cancer treatment in females. Causes of POI in this patient population can include chemotherapy, especially alkylating agents, and radiation therapy. Rarely, ovarian tumors lead to ovarian dysfunction. POI can manifest as delayed pubertal development, irregular menses or amenorrhea, and infertility. This diagnosis often negatively impacts emotional health due to the implications of impaired ovarian function after already enduring treatment for a primary malignancy. The emerging adult may be challenged by the impact on energy level, quality of life, and fertility potential. POI can also lead to low bone density and compromised skeletal strength. This review discusses the health consequences of POI in childhood cancer survivors (CCS). We also explore the role of fertility preservation for CCS, including ovarian tissue cryopreservation and other available options. Lastly, knowledge gaps are identified that will drive a future research agenda.

Context: Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Inositol may have insulin sensitizing effects; however, its efficacy in the management of PCOS remains indeterminate., Objective: To inform the 2023 international evidence-based guidelines in PCOS, this systematic review and meta-analysis evaluated the efficacy of inositol, alone or in combination with other therapies, in the management of PCOS., Data Sources: Medline, PsycInfo, EMBASE, All EBM, and CINAHL from inception until August 2022., Study Selection: Thirty trials (n = 2230; 1093 intervention, 1137 control), with 19 pooled in meta-analyses were included., Data Extraction: Data were extracted for hormonal, metabolic, lipids, psychological, anthropometric, reproductive outcomes, and adverse effects by 1 reviewer, independently verified by a second., Data Synthesis: Thirteen comparisons were assessed, with 3 in meta-analyses. Evidence suggests benefits for myo-inositol or D-chiro-inositol (DCI) for some metabolic measures and potential benefits from DCI for ovulation, but inositol may have no effect on other outcomes. Metformin may improve waist-hip ratio and hirsutism compared to inositol, but there is likely no difference for reproductive outcomes, and the evidence is very uncertain for body mass indexI. Myo-inositol likely causes fewer gastrointestinal adverse events compared with metformin; however, these are typically mild and self-limited., Conclusion: The evidence supporting the use of inositol in the management of PCOS is limited and inconclusive. Clinicians and their patients should consider the uncertainty of the evidence together with individual values and preferences when engaging in shared decision-making regarding the use of inositol for PCOS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

This systematic review and meta-analysis evaluated the efficacy of anti-obesity agents for hormonal, reproductive, metabolic, and psychological outcomes in polycystic ovary syndrome (PCOS) to inform the 2023 update of the International Evidence-based Guideline on PCOS. We searched Medline, EMBASE, PsycInfo, and CINAHL until July 2022 with a 10-year limit to focus on newer agents. Eleven trials (545 and 451 participants in intervention and control arms respectively, 12 comparisons) were included. On descriptive analyses, most agents improved anthropometric outcomes; liraglutide, semaglutide and orlistat appeared superior to placebo for anthropometric outcomes. Meta-analyses were possible for two comparisons (exenatide vs. metformin and orlistat + combined oral contraceptive pill [COCP] vs. COCP alone). On meta-analysis, no differences were identified between exenatide versus metformin for anthropometric, biochemical hyperandrogenism, and metabolic outcomes, other than lower fasting blood glucose more with metformin than exenatide (MD: 0.10 mmol/L, CI 0.02-0.17, I 2  = 18%, 2 trials). Orlistat + COCP did not improve metabolic outcomes compared with COCP alone (fasting insulin MD: -8.65 pmol/L, -33.55 to 16.26, I 2  = 67%, 2 trials). Published data examining the effects of anti-obesity agents in women with PCOS are very limited. The role of these agents in PCOS should be a high priority for future research., (© 2024 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

45,X/46,XY chromosomal mosaicism presents a range of clinical manifestations, including phenotypes from Turner syndrome through genital abnormalities to apparently unaffected phenotypic males; however, the full clinical spectrum has not yet been fully delineated since prior studies on the clinical phenotype and associated risk of gonadal tumors included small cohorts and limited follow-up. To better describe the clinical manifestations and long-term outcome of patients with 45,X/46,XY mosaicism. We conducted a retrospective chart review of patients with 45,X/46,XY from three health centers (Hospital for Sick Children and Mount Sinai Hospital in Canada, and University of Pittsburgh Medical Center in United States). Of 100 patients with 45,X/46,XY karyotype, 47 were raised as females and 53 as males. Females were significantly shorter than males (p = 0.04) and height Z-score was significantly decreased with age for both genders (p = 0.02). Growth hormone (GH) treatment did not result in a significant height increase compared to the untreated group (p = 0.5). All females required puberty induction in contrast to majority of males. Five females were diagnosed with gonadal tumors, while no males were affected. Around 58% of patients exhibited at least one Turner syndrome stigmata. This study expands the clinical spectrum, long-term outcomes, and associated tumor risk in a large cohort of patients with 45,X/46,XY mosaicism. Additionally, it highlights our experience with GH therapy and prophylactic gonadectomy., (© 2023 Wiley Periodicals LLC.)

Objective: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline., Design: Systematic review and meta-analysis of the literature., Patients: Women with PCOS and treatment with insulin sensitisers., Measurements: Hormonal and clinical outcomes, as well as side effects., Results: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: -4.39, 95% confidence interval [CI]: -7.69 to -1.08 kg), body mass index (MD: -0.95, 95% CI: -1.41 to -0.49 kg/m 2 ) and testosterone (MD: -0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations., Conclusions: Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit., (© 2023 John Wiley & Sons Ltd.)

Context: Polycystic ovary syndrome (PCOS) affects more than 1 in 10 women., Objective: As part of the 2023 International PCOS Guidelines update, comparisons between combined oral contraceptive pills (COCP), metformin, and combination treatment were evaluated., Data Sources: Ovid Medline, Embase, PsycINFO, All EBM, and CINAHL were searched., Study Selection: Women with PCOS included in randomized controlled trials (RCTs)., Data Extraction: We calculated mean differences and 95% CIs regarding anthropometrics, metabolic, and hyperandrogenic outcomes. Meta-analyses and quality assessment using GRADE were performed., Data Synthesis: The search identified 1660 publications; 36 RCTs were included. For hirsutism, no differences were seen when comparing metformin vs COCP, nor when comparing COCP vs combination treatment with metformin and COCP. Metformin was inferior on free androgen index (FAI) (7.08; 95% CI 4.81, 9.36), sex hormone binding globulin (SHBG) (-118.61 nmol/L; 95% CI -174.46, -62.75) and testosterone (0.48 nmol/L; 95% CI 0.32, 0.64) compared with COCP. COCP was inferior for FAI (0.58; 95% CI 0.36, 0.80) and SHBG (-16.61 nmol/L; 95% CI -28.51, -4.71) compared with combination treatment, whereas testosterone did not differ. Metformin lowered insulin (-27.12 pmol/L; 95% CI -40.65, -13.59) and triglycerides (-0.15 mmol/L; 95% CI -0.29, -0.01) compared with COCP. COCP was inferior for insulin (17.03 pmol/L; 95% CI 7.79, 26.26) and insulin resistance (0.44; 95% CI 0.17, 0.70) compared with combination treatment., Conclusions: The choice of metformin or COCP treatment should be based on symptoms, noting some biochemical benefits from combination treatment targeting both major endocrine disturbances seen in PCOS (hyperinsulinemia and hyperandrogenism)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Polycystic ovary syndrome (PCOS) is a heterogenous clinical syndrome defined by hyperandrogenism and irregular menses. In adult women with PCOS, discrete metabolic and reproductive subgroups have been identified. We hypothesize that distinct phenotypes can be distinguished between adolescent girls who are lean (LN-G) and girls with obesity (OB-G) at the time of PCOS diagnosis., Methods: Data were extracted from the CALICO multisite PCOS database. Clinical data collected at the time of diagnosis were available in 354 patients (81% with obesity) from 7 academic centers. Patients with body mass index (BMI) < 85th percentile for age and sex were characterized as lean (LN-G) and those with BMI percentile ≥ 95th percentile as obese (OB-G). We compared metabolic and reproductive phenotypes in LN-G and OB-G., Results: Reproductive phenotypes differed between the groups, with LN-G having higher total testosterone, androstenedione, and LH levels, while OB-G had lower sex hormone binding globulin (SHBG) and higher free testosterone. Metabolic profiles differed as expected, with OB-G having higher hemoglobin A1c, alanine aminotransferase, and serum triglycerides and more severe acanthosis nigricans., Conclusion: LN-G with PCOS had a distinct reproductive phenotype characterized by increased LH, total testosterone, and androstenedione levels, suggesting neuroendocrine-mediated ovarian androgen production. In contrast, phenotypes in OB-G suggest hyperandrogenemia is primarily driven by insulin resistance with low SHBG levels. These observations support the existence of distinct metabolic and reproductive subtypes in adolescent PCOS characterized by unique mechanisms for hyperandrogenemia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Anorexia nervosa is a primary psychiatric disorder characterized by self-induced negative energy balance. A number of hormonal responses and adaptations occur in response to starvation and low body weight including changes in adrenocortical hormones. Our objective was to systematically review adrenocortical hormone levels in anorexia nervosa., Design/methods: We searched MEDLINE and EMBASE for studies that reported at least one adrenocortical hormone, including dehydroepiandrosterone (DHEA), DHEA-sulphate (DHEA-S), progesterone, 17-hydroxyprogesterone, pregnenolone, cortisol (serum, urine, cerebrospinal fluid, and hair sample), aldosterone, androstenedione, and testosterone in patients with anorexia nervosa and normal-weight healthy controls from inception until October 2021. Means and standard deviations for each hormone were extracted from the studies to calculate a mean difference (MD). A pooled MD was then calculated by combining MDs of each study using the random-effects model., Results: We included a total of 101 studies with over 2500 females with anorexia nervosa. Mean cortisol levels were significantly higher in anorexia nervosa as compared to normal-weight controls for multiple forms of measurement, including morning cortisol, 12-hour and 24-hour pooled serum cortisol, 24-hour urine cortisol, and after an overnight dexamethasone suppression test. In contrast, mean serum total testosterone and DHEA-S levels were significantly lower among patients with anorexia nervosa., Conclusions: Women with anorexia nervosa have higher cortisol levels and lower DHEA-S and testosterone levels compared to women without anorexia nervosa. This finding is important to consider when evaluating low-weight women for disorders involving the adrenal axis, especially Cushing's syndrome., Competing Interests: Conflict of interest: P.K.F. is a consultant for Regeneron and Xeris Pharmaceuticals., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the validity of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) for evaluating thyroid nodules in children., Methods: Patients aged <19 years with thyroid nodule(s) evaluated by ultrasound (US) from 2007-2018 at a tertiary children's hospital were included. Two radiologists scored de-identified thyroid US images using ACR TI-RADS (from 1, "benign" to 5, "highly suspicious"). The radiologists recorded size and rated vascularity for each nodule. Ultrasound findings were compared to pathology results (operative cases, n = 91) and clinical follow-up without disease progression (non-operative cases, n = 15)., Results: Thyroid images from 115 patients were reviewed. Nine patients were excluded due to the absence of an evaluable nodule. Forty-seven benign and 59 malignant nodules were included. Median age at ultrasound was 15 years (range 0.9-18 years). Twenty (18.9%) patients were male. There was moderate agreement between TI-RADS levels assigned by the two raters (kappa = 0.57, p < 0.001). When the raters' levels were averaged, >3 as the threshold for malignancy correctly categorized the greatest percentage of nodules (68.9%). Eleven (18.6%) malignant nodules received a TI-RADS level of 2 (n = 3) or 3 (n = 8). Sensitivity, specificity, and positive and negative predictive values were 81.4%, 53.2%, 68.6%, and 69.4%, respectively. Although not part of TI-RADS, vascularity was similar between benign and malignant nodules (p = 0.56)., Conclusion: In a pediatric population, TI-RADS can help distinguish between benign and malignant nodules with comparable sensitivity and specificity to adults. However, the positive and negative predictive values suggest TI-RADS alone cannot eliminate the need for FNA., Level of Evidence: 3 Laryngoscope, 133:2394-2401, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Anti-androgens and combined oral contraceptive pills (COCPs) may mitigate hyperandrogenism-related symptoms of polycystic ovary syndrome (PCOS). However, their efficacy and safety in PCOS remain unclear as previous reviews have focused on non-PCOS populations. To inform the 2023 International Evidence-based Guideline in PCOS, we conducted the first systematic review and meta-analysis investigating the efficacy and safety of anti-androgens in the management of hormonal and clinical features of PCOS., Methods: We systematically searched MEDLINE, Embase, PsycInfo, All EBM reviews, and CINAHL up to 28th June 2023 for randomised controlled trials (RCTs) examining oral anti-androgen use, alone or in combination with metformin, COCPs, lifestyle, or other interventions, in women of any age, with PCOS diagnosed by Rotterdam, National Institutes of Health or Androgen Excess & PCOS Society criteria, and using a form of contraception. Non-English studies and studies of less than 6 months duration or which used the same anti-androgen regimen in both/all groups were excluded in order to establish efficacy for the clinical outcomes of interest. Three authors screened articles against selection criteria and assessed risk of bias and quality using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Critical outcomes (prioritised during guideline development for GRADE purposes) included weight, body mass index (BMI), irregular cycles, hirsutism, liver function, and quality of life. Random effects meta-analyses were conducted where appropriate. This study is registered with PROSPERO, CRD42022345640., Findings: From 1660 studies identified in the search, 27 articles comprising 20 unique studies were included. Of these, 13 studies (n = 961) were pooled in meta-analysis. Seven studies had a high risk of bias, nine moderate and four low. Anti-androgens included finasteride, flutamide, spironolactone, or bicalutamide. In meta-analysis, anti-androgens + lifestyle were superior to metformin + lifestyle for hirsutism (weighted mean difference [WMD] [95% CI]: -1.59 [-3.06, -0.12], p = 0.03; I 2  = 74%), SHBG (7.70 nmol/l [0.75, 14.66], p = 0.03; I 2  = 0%), fasting insulin and fasting insulin: glucose ratio (-2.11 μU/ml [-3.97, -0.26], p = 0.03; I 2  = 0% and -1.12 [-1.44, -0.79], p < 0.0001, I 2  = 0%, respectively), but were not superior to placebo + lifestyle for hirsutism (-0.93, [-3.37, 1.51], p = 0.45; I 2  = 76%) or SHBG (9.72 nmol/l [-0.71, 20.14], p = 0.07; I 2  = 31%). Daily use was more effective for hirsutism than use every three days (-3.48 [-4.58, -2.39], p < 0.0001, I 2  = 1%), and resulted in lower androstenedione levels (-0.30 ng/ml [-0.50, -0.10], p = 0.004; I 2  = 0%). Combination treatment with anti-androgens + metformin + lifestyle resulted in lower testosterone compared with metformin + lifestyle (-0.29 nmol/l [-0.52, -0.06], p = 0.01; I 2  = 61%), but there were no differences in hirsutism when anti-androgens + metformin + lifestyle were compared with either anti-androgens + lifestyle or metformin + lifestyle. In limited meta-analyses (n = 2 trials), combining anti-androgens with COCP resulted in poorer lipid profiles compared with COCP ± placebo, with no differences in other outcomes., Interpretation: Current evidence does not support the use of anti-androgens preferentially to COCPs to treat hyperandrogenism in PCOS. Anti-androgens could be considered to treat hirsutism in PCOS, where COCPs are contraindicated, poorly tolerated, or present a sub-optimal response after a minimum 6-month period, with consideration of clinical context and individual risk factors and characteristics., Funding: National Health and Medical Research Council (NHMRC) of Australia Monash University., Competing Interests: All authors declare no competing interests. JM received funding from the Orion Research Foundation and the Medical Society of Finland. MF received funding from the Gothenburg Medical Association, Sahlgrenska University Hospital, the Iris Foundation and the Hjalmar Svensson Foundation, as well as honoraria from Gedeon Richter. HT received funding from the National Health and Medical Research Council (NHMRC) through the Centre for Research Excellence for Women's Health in Reproductive Life (CRE-WHiRL). SFW received support from the NHMRC-funded guideline to attend the guideline meeting and is a member of the board of directors for the Paediatric Endocrine Society. CTT is supported by CRE- WHiRL and chairs the Androgen Excess and Polycystic Ovary Syndrome Society Early Career Special Interest Group. None of these funding organisations had any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. All other authors declare no competing interests., (© 2023 The Author(s).)

Objective: Available evidence has shown that metformin improves insulin sensitivity and weight management in polycystic ovary syndrome (PCOS). Nevertheless, key knowledge gaps remain regarding its efficacy and the specific outcomes in this population. This review evaluates the effectiveness of metformin and lifestyle modification compared with placebo in the management of PCOS and will inform the forthcoming, 2023 evidence-based PCOS guidelines., Design: Systematic review and meta-analysis of the literature., Methods: A search was performed in MEDLINE, EMBASE, PsycINFO, All EBM, and CINAHL. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and included randomized controlled trials published in English through July 2022., Results: Moderate certainty of evidence showed a larger reduction of body mass index (BMI) (mean difference [MD] -0.53, 95% confidence interval [CI] -0.95 to -0.12 kg/m2), homeostatic model assessment for insulin resistance (MD -0.50, 95% CI -0.91 to -0.09) (critical outcomes), and fasting glucose (MD -0.13, 95% CI -0.19 to -0.07 mmol/L) with metformin compared to placebo with increased mild gastrointestinal adverse effects (odds ratio [OR] 7.67, 95% CI 2.74-21.46). Low certainty of evidence showed a larger reduction of waist-hip ratio (MD -0.02, 95% CI -0.03 to -0.00), total cholesterol (MD -0.24, 95% CI -0.43 to -0.05 mmol/L), low-density lipoprotein (MD -0.16, 95% CI -0.30 to -0.01 mmol/L), and triglycerides (MD -0.11, 95% CI -0.20 to -0.02 mmol/L) with metformin than placebo., Conclusions: Metformin should be considered an efficacious adjunct to lifestyle interventions in adults with PCOS, especially for those with a higher BMI, to improve weight loss, insulin resistance, and lipids., Competing Interests: Conflict of interest: J.M. reports a postdoc research grant from Orion Research Foundation. D.R. reports an honorarium from Novo Nordisk for a lecture on PCOS and obesity. T.P. is on the editorial board of the European Journal of Endocrinology but was not involved in the review or editorial process of this paper. The other authors have no conflicts to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Context: Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP., Objective: This work aimed to screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro., Methods: Participants included 84 unrelated children with CPP (79 girls, 5 boys) and, when available, their first-degree relatives. Five academic medical institutions participated. Sanger sequencing of MKRN3 and DLK1 5' upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles., Results: Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, 2 were previously identified in patients with CPP, and 1 is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination., Conclusion: MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Some individuals with differences of sex development (DSD) conditions undergo medically indicated prophylactic gonadectomy. Gonads of individuals with DSD can contain germ cells and precursors and patients interested in future fertility preservation and hormonal restoration can participate in DSD-specific research protocols to cryopreserve this tissue. However, it is unclear how many providers or institutions offer gonadal tissue cryopreservation (GTC) and how widespread GTC for DSD is across the United States (US). The Pediatric Initiative Network (PIN) and Non-Oncologic Conditions committees of the Oncofertility Consortium sought to assess the current state of GTC for patients with DSD., Methods: An electronic survey was sent to providers caring for patients with DSD via special interest groups of professional societies and research networks., Results: The survey was administered between November 15, 2021 and March 14, 2022. A total of 155 providers responded to the survey, of which 132 respondents care for patients with DSD, and 78 work at facilities that offer medically indicated gonadectomy to patients with DSD diagnoses. They represented 55 US institutions including 47 pediatric hospitals, and 5 international sites (Canada, Denmark, Germany, Qatar). Of individual providers, 41% offer cryopreservation after prophylactic gonadectomy for patients with DSD (32/78). At an institutional level, GTC after medically indicated gonadectomy is available at 54.4% (24/46) of institutions. GTC is offered for a variety of DSD diagnoses, most commonly 45,X/46,XY DSD (i.e., Turner Syndrome with Y-chromosome material and mixed gonadal dysgenesis), ovotesticular DSD, complete androgen insensitivity syndrome (CAIS), and complete gonadal dysgenesis. Responses demonstrate regional trends in GTC practices with 83.3% of institutions in the Midwest, 66.7% in the Northeast, 54.6% in the West, and 35.3% in the South providing GTC. All represented institutions (100%) send gonadal tissue for pathological evaluation, and 22.7% preserve tissue for research purposes., Conclusions: GTC after gonadectomy is offered at half of the US institutions represented in our survey, though a minority are currently preserving tissue for research purposes. GTC is offered for several DSD conditions. Future research will focus on examining presence and quality of germ cells to support clinical decision making related to fertility preservation for patients with DSD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Siebert, Gomez-Lobo, Johnson, Nahata, Orwig, Pyle, Witchel, Finlayson and Laronda.)

Objectives/hypothesis: Hashimoto's Thyroiditis (HT) is a common cause of hypothyroidism. Among adults with differentiated thyroid cancer (DTC), HT appears to be associated with less severe disease burden. In the absence of information regarding HT and disease burden among children with DTC, we assessed the relationship between pediatric DTC severity and HT., Study Design: Retrospective cohort., Methods: Charts from 90 pediatric patients who underwent surgical removal of DTC from 2002 to 2017 at tertiary-care children's hospital were reviewed. Demographic, clinical, surgical, pathology, and outcome details were compared between patients with and without HT. Consistency among diagnostic modalities of HT was also evaluated., Results: Median age at presentation was 16.0 years (range 4.2-18.9 years). Twenty-two patients were male (24%). Forty-five patients (50%) had HT based on presence of thyroid autoantibodies and/or surgical pathology findings and 45 patients did not have HT. Patients with HT had increased odds of microcalcifications (odds ratio [OR]: 3.01, P = .031) and decreased odds of palpable nodules (OR: 0.212, P = .024) and T2 lesions (vs. T1) (OR: 0.261, P = .015) compared with non-HT. No significant differences in demographics and the incidence of multifocality, extrathyroidal extension, lymphovascular invasion, lymph node or pulmonary metastases, disease recurrence, or radioactive iodine treatment were found between the two groups. Thyroglobulin/thyroid peroxidase autoantibodies and surgical pathology indicative of HT were concordant in 82.4% (κ = 0.635, P < .001)., Conclusion: HT was present in 50% of children with DTC. Patients with DTC and HT presented with smaller tumors compared to non-HT patients. No significant differences in other markers of disease aggressiveness were found between the two groups., Level of Evidence: 3 Laryngoscope, 132:1668-1674, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Molecular testing (MT) enhances the diagnostic accuracy of thyroid fine-needle aspiration biopsy, reducing the need for diagnostic lobectomy in adult patients with indeterminate nodules (Bethesda class III/IV). However, little is known about genetic alterations in pediatric thyroid carcinoma (TC). Our aim was to analyze MT results of pediatric differentiated TC (DTC) cases to determine associations with histological and clinical features. Methods: A retrospective review identified all patients (aged <19 years) diagnosed with DTC from 2001 to 2017 at the University of Pittsburgh Medical Center. Histology was rereviewed to confirm diagnosis and identify tissue for MT using next-generation sequencing (ThyroSeq, version 3, TSv3). Correlation with histological and clinical features was analyzed using regression analysis. Results: Of 71 patients with MT results, 62 (87%) patients had papillary TC. All patients were alive at a median follow-up of 6 years (range 18 days to 18 years). Genetic alterations were identified in 65 (92%) patients. These alterations were grouped as BRAF -like point mutations or fusions (39, 55%), RAS -like mutations or fusions (21, 30%), or copy number alterations (5, 7%). On multiple regression analysis accounting for patient sex and tumor size in patients with papillary TC, increased tumor stage ( β : 0.234, p  < 0.001), multifocal disease (odds ratio [OR]: 3.60, p  = 0.042), and lymph node metastases (OR: 6.13, p  = 0.044) were associated with BRAF -like gene fusions. When considering individual mutations, ETV6/NTRK3 fusions were associated with increased tumor stage ( β : 2.07, p  = 0.023) and BRAF -like point mutations were associated with increased likelihood of surgery for recurrence over time (hazard ratio: 19.5, p  = 0.004). Conclusions: Among our cohort of pediatric TC patients who underwent comprehensive MT, >90% had an identifiable genetic alteration. Aggressive features were primarily associated with BRAF -like gene fusions. Preoperative MT results may be useful in guiding the extent of the initial operation in pediatric patients (aged <19 years) with TC.

Puberty is the process through which reproductive competence is achieved and comprises gonadarche and adrenarche. Breast development is the initial physical finding of pubertal onset in girls and typically occurs between 8 and 13 years. Menarche normally occurs 2 to 3 years after the onset of breast development. Pubertal onset is controlled by the gonadotropin-releasing hormone pulse generator in the hypothalamus; however, environmental factors such as alterations in energy balance and exposure to endocrine-disrupting chemicals can alter the timing of pubertal onset. Improvement in nutritional and socioeconomic conditions over the past two centuries has been associated with a secular trend in earlier pubertal onset. Precocious puberty is defined as onset of breast development prior to 8 years and can be central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic and is defined as lack of breast development by 13 years or lack of menarche by 16 years. Both precocious and delayed puberty may have negative effects on self-esteem, potentially leading to psychosocial stress. Patients who present with pubertal differences require a comprehensive assessment to determine the underlying etiology and to devise an effective treatment plan., Competing Interests: None declared., (Thieme. All rights reserved.)

Descriptions of probable PCOS can be found in ancient Roman writings and in Renaissance art. Attention to domesticated animal reproduction led ancient observers to understand the role of the testes in male phenotypes, proven experimentally by testicular transplantation (in chickens) in 1849. Testosterone was isolated and its structure determined in the 1930s, but the multiple pathways of androgen synthesis have only been delineated recently. Adrenarche as an event separate from puberty was described in 1937, but the mechanism(s) triggering its onset remains unclear, although most work points to intraadrenal events. The identification of 11-ketotestosterone as the principal adrenal androgen is very recent (2018). Definitions of PCOS have evolved with the elucidation of its complex biology. PCOS is now recognized as a complex disorder characterized by irregular menses and hyperandrogenism often associated with infertility; its prevalence may be as high as 20% of reproductive age women. Work in the 1980s associated premature exaggerated adrenarche with PCOS, linking the adrenal to an "ovarian" syndrome. Obesity has long been noted in many patients with PCOS, and associated insulin resistance was noted in the 1980s, possibly associated with fetal developmental events such as low birth weight, but the mechanistic link between carbohydrate metabolism and hyperandrogenism remains unclear, despite intensive investigation. Genome-wide association studies have identified apparently associated genes, but mechanistic links are apparent for only some of these. Adrenarche, PCOS, and adrenal and ovarian hyperandrogenism remain very active areas of clinical and basic research., (© 2022 S. Karger AG, Basel.)

Testes were associated with maleness from antiquity, and ancient societies had fanciful myths about the origins of the sexes and about fetal sexual development. 17th century anatomists developed the concept that mammals developed from eggs and discovered sperm in semen; in 1878, Hertwig observed sperm entering eggs (of sea urchins), establishing the cellular basis of sex development. Individuals with atypical genitalia were known clinically in the 17th century, with much debate about their origins, but by the late 19th century it was generally accepted that gonads determined sex, and that sex determined gender role. Testosterone was isolated in 1935, and Alfred Jost showed that both circulating testosterone and diffusible anti-Mullerian hormone were needed for male development. Patients with apparent androgen insensitivity were reported in 1937 and shown to be unresponsive to exogenous androgen by Lawson Wilkins in 1957; androgen receptor mutations were reported in 1989. Steroidogenic errors were associated with differences in sex development (DSDs) starting in the 1940s, and finding mutations in the responsible enzymes explained many forms of hyper- and hypo-androgenism in both sexes. Sex chromosomes were identified in the early 20th century; Y was associated with maleness, and the responsible SRY gene was identified in 1991. Early efforts to manage patients with DSDs were confounded by philosophical perspectives on the relative roles of prenatal biology versus postnatal environment. Approaches to natal sex assignment evolved in the later 20th century and now emphasize a team approach based on data, not guessing, parental involvement, cultural considerations, and the acknowledgement of uncertainty., (© 2022 S. Karger AG, Basel.)

Study Objective: Polycystic ovary syndrome (PCOS) can be challenging to diagnose in adolescents because the diagnostic criteria for adult women overlap with normal features of pubertal development. Previous studies have highlighted inconsistencies in diagnostic criteria used by health care providers. International consensus groups have introduced recommendations to aid diagnosis of this disorder among adolescents. In this study we explored diagnostic inconsistencies and provided education for providers regarding these consensus recommendations., Design: Quality improvement., Setting: Teaching hospital-affiliated adolescent medicine clinic., Participants: Adolescent medicine providers (n = 14) participated in the intervention., Interventions: Educational intervention on the basis of the 2015 international consensus recommendations was implemented to address provider inconsistencies., Main Outcome Measures: Use of laboratory assessment and documentation for diagnosis of girls evaluated for possible PCOS., Results: Preintervention, providers used diverse diagnostic criteria including obesity, insulin resistance, mild acne, and minimal hirsutism with no reference to published criteria. Laboratory studies to exclude other disorders were obtained in 24/87 (28%) preintervention patients. Postintervention, the percentage of laboratory studies increased to 40/65 (62%). Oral glucose tolerance tests performed to assess for glycemic comorbidities increased from 6/87 (7%) to 16/65 (25%). After this intervention, providers included more documentation of features associated with PCOS yet did not use "at risk for PCOS" terminology., Conclusion: After our educational intervention, providers showed greater awareness of diagnostic criteria for PCOS in adolescent girls. Medical record documentation and use of "at risk for PCOS" terminology needs improvement. Integration of specific PCOS templates in the electronic medical record might improve medical record documentation and appropriate diagnosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Age- and sex-related differences in asthma may be due to changes in sex hormone levels., Objective: To evaluate whether a change in free testosterone or free testosterone-to-estradiol ratio is associated with changes in lung function and eosinophils in the Puerto Rican youth., Methods: We tested for the association between the change in sex hormone levels and change in lung function or change in eosinophils in a prospective study of 317 children (with and without asthma) followed up from ages 6 to 14 years to ages 10 to 20 years (146 females, 171 males) in San Juan, Puerto Rico. Serum levels of testosterone, estradiol, sex hormone-binding globulin, and progesterone were measured at 2 study visits, approximately 4.9 years apart. Using testosterone and sex hormone-binding globulin levels, we derived free testosterone and the free testosterone-to-estradiol ratio. Multivariable linear regression was used for the analysis of change in lung function and eosinophils, conducted separately by sex., Results: In girls, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 2.03% increment in percent predicted forced expiratory volume in 1 second (FEV 1 )/forced vital capacity (FVC) between study visits. In males, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 3.27% increment in percent predicted FEV 1 and a 1.81% increment in percent predicted FEV 1 /FVC between study visits. In girls with asthma, an increased free testosterone-to-estradiol ratio was significantly associated with decreased eosinophils between visits (P=0.03)., Conclusion: In Puerto Rican youth, increased free testosterone-to-estradiol ratio over time was associated with an increased FEV 1 /FVC in both sexes, and with an increased FEV 1 in males., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Puberty, which in humans is considered to include both gonadarche and adrenarche, is the period of becoming capable of reproducing sexually and is recognized by maturation of the gonads and development of secondary sex characteristics. Gonadarche referring to growth and maturation of the gonads is fundamental to puberty since it encompasses increased gonadal steroid secretion and initiation of gametogenesis resulting from enhanced pituitary gonadotropin secretion, triggered in turn by robust pulsatile GnRH release from the hypothalamus. This chapter reviews the development of GnRH pulsatility from before birth until the onset of puberty. In humans, GnRH pulse generation is restrained during childhood and juvenile development. This prepubertal hiatus in hypothalamic activity is considered to result from a neurobiological brake imposed upon the GnRH pulse generator resident in the infundibular nucleus. Reactivation of the GnRH pulse generator initiates pubertal development. Current understanding of the genetics and physiology of the brake will be discussed, as will hypotheses proposed to account for timing the resurgence in pulsatile GnRH and initiation of puberty. The chapter ends with a discussion of disorders associated with precocious or delayed puberty with a focus on those with etiologies attributed to aberrant GnRH neuron anatomy or function. A pediatric approach to patients with pubertal disorders is provided and contemporary treatments for both precocious and delayed puberty outlined., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Polycystic ovary syndrome (PCOS) is a heterogeneous familial disorder often emerging during the peri-pubertal years concomitantly with the onset of gonadarche and adrenarche. Both gonadarche and PCOS reflect functional changes in the hypothalamic-pituitary-ovarian axis. During this transition, normal girls manifest features consistent with PCOS such as irregular menses, mild hyperandrogenism, and multi-follicular ovary morphology. Themes common to puberty and PCOS, neuroendocrine features, androgen exposure, and insulin sensitivity, will be considered to address the possibility that PCOS interferes with the normal pubertal transition., Competing Interests: Conflict of Interest Statement: Nothing declared. No conflicts of interest, financial or otherwise exist. The authors have agreed on the order of authorship. No competing interests.

Purpose of Review: Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when dehydroepiandrosterone sulfate (DHEAS) concentrations increase. This review provides an update on adrenal steroidogenesis and the differential diagnosis of premature development of pubic hair., Recent Findings: The complexity of adrenal steroidogenesis has increased with recognition of the alternative 'backdoor pathway' and the 11-oxo-androgens pathways. Traditionally, sulfated steroids such as DHEAS have been considered to be inactive metabolites. Recent data suggest that intracellular sulfated steroids may function as tissue-specific intracrine hormones particularly in the tissues expressing steroid sulfatases such as ovaries, testes, and placenta., Summary: The physiologic mechanisms governing the onset of adrenarche remain unclear. To date, no validated regulatory feedback mechanism has been identified for adrenal C19 steroid secretion. Available data indicate that for most children, premature adrenarche is a benign variation of development and a diagnosis of exclusion. Patients with premature adrenarche tend to have higher BMI values. Yet, despite greater knowledge about C19 steroids and zona reticularis function, much remains to be learned about adrenarche.

Background: Diagnosing polycystic ovary syndrome (PCOS) during adolescence is challenging because features of normal pubertal development overlap with adult diagnostic criteria. The international evidence-based PCOS Guideline aimed to promote accurate and timely diagnosis, to optimise consistent care, and to improve health outcomes for adolescents and women with PCOS., Methods: International healthcare professionals, evidence synthesis teams and consumers informed the priorities, reviewed published data and synthesised the recommendations for the Guideline. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied to appraise the evidence quality and the feasibility, acceptability, cost, implementation and strength of the recommendations., Results: This paper focuses on the specific adolescent PCOS Guideline recommendations. Specific criteria to improve diagnostic accuracy and avoid over diagnosis include: (1) irregular menstrual cycles defined according to years post-menarche; > 90 days for any one cycle (> 1 year post-menarche), cycles< 21 or > 45 days (> 1 to < 3 years post-menarche); cycles < 21 or > 35 days (> 3 years post-menarche) and primary amenorrhea by age 15 or > 3 years post-thelarche. Irregular menstrual cycles (< 1 year post-menarche) represent normal pubertal transition. (2) Hyperandrogenism defined as hirsutism, severe acne and/or biochemical hyperandrogenaemia confirmed using validated high-quality assays. (3) Pelvic ultrasound not recommended for diagnosis of PCOS within 8 years post menarche. (4) Anti-Müllerian hormone levels not recommended for PCOS diagnosis; and (5) exclusion of other disorders that mimic PCOS. For adolescents who have features of PCOS but do not meet diagnostic criteria an 'at risk' label can be considered with appropriate symptomatic treatment and regular re-evaluations. Menstrual cycle re-evaluation can occur over 3 years post menarche and where only menstrual irregularity or hyperandrogenism are present initially, evaluation with ultrasound can occur after 8 years post menarche. Screening for anxiety and depression is required and assessment of eating disorders warrants consideration. Available data endorse the benefits of healthy lifestyle interventions to prevent excess weight gain and should be recommended. For symptom management, the combined oral contraceptive pill and/or metformin may be beneficial., Conclusions: Extensive international engagement accompanied by rigorous processes honed both diagnostic criteria and treatment recommendations for PCOS during adolescence.

Polycystic ovary syndrome (PCOS), characterized by hormonal imbalance and ovarian dysfunction, often starts during adolescence. Inconsistent diagnostic criteria, variable provider knowledge, and lack of consensus pose specific challenges for the care of women with PCOS. These factors encourage inaccurate diagnosis with both under and overdiagnosis. This unfavorable diagnostic experience exasperates affected women and limits timely opportunities for intervention to minimize associated comorbidities, especially during the transition from pediatric to adult care. Recognition of these issues in the care of adolescents and women with PCOS inspired the development of the International Evidence-Based PCOS Guidelines, which emphasize the prevention, screening, and treatment of PCOS across the reproductive lifespan. The Guidelines and accompanying meta-analyses focus on three major categories of associated comorbidities: (1) reproductive; (2) metabolic; and (3) psychological. With the exception of infertility, this article considers common manifestations and comorbidities associated with PCOS throughout the lifecycle. Healthy lifestyle interventions with prevention of excess weight gain comprise the primary intervention for all comorbidities. Hence, early identification of girls "at risk" for PCOS and those with PCOS is a priority. Extensive guidelines for provider and patient education aim to decrease the medical, psychosocial, and economic burdens attributable to PCOS and its associated comorbidities.