The Journal of Clinical Endocrinology & Metabolism

INTRODUCTIONTesticular adrenal rest tumors (TART) are a known consequence for males with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. TART are associated with potential infertility in adults. However, little is known about TART in very young males with CAH. OBJECTIVEWe assessed the prevalence of TART in newborn, infant, and toddler males with classical CAH via scrotal ultrasound. METHODSMales with CAH had scrotal ultrasounds during the first 4 years of life, evaluating testes for morphology, blood flow, and presence of TART. Newborn screen 17-hydroxyprogesterone (17-OHP) and serum 17-OHP at the time of ultrasound were recorded. Bone ages were considered very advanced if [≥] 2SD above chronological age. RESULTSThirty-one ultrasounds in 16 males were performed. An initial ultrasound was obtained in four newborns at diagnosis (6.8 {+/-}2.1 days), six infants (2.2 {+/-}0.9 months), and six toddlers (2.4 {+/-}0.9 years). Eleven males had at least one repeat ultrasound. A large proportion (11/16) were in poor hormonal control with an elevated 17-OHP (325 {+/-}298 nmol/L). One infant was in very poor hormonal control (17-OHP 447 nmol/L) at initial ultrasound, and two toddlers had advanced bone ages (+3.2 and +4.5 SD) representing exposure to postnatal androgens. However, no TART were detected in any subjects. CONCLUSIONSTART were not found in males up to 4 years of age with classical CAH despite settings with expected high ACTH drive. Further research into the occurrence of TART in CAH may elucidate factors which contribute to the detection and individual predisposition to TART.

ContextPatients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. ObjectiveTo identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency exposed to major stress. Design and ParticipantsCross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N=83], sepsis [N=100], and combat stress [N=105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200mg hydrocortisone over 24 hours in four different delivery modes (continuous intravenous infusion; six-hourly oral, intramuscular or intravenous bolus administration). Main Outcome MeasureWe measured total serum cortisol and cortisone, free serum cortisol and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modelling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. ResultsSerum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modelling identified continuous intravenous infusion of 200mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. ConclusionsContinuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

ObjectiveReliable data on prevalence of differences of sex development (DSD) are lacking. We aimed to estimate population-based prevalence of DSD in Switzerland. DesignRetrospective population-based study including children and adolescents with DSD according to Chicago Consensus, born in Switzerland from 2000-2019. MethodsEndocrine care centers in ten Swiss Childrens Hospitals and eight private endocrine practices collected DSD data through the I-DSD registry or case report forms. We calculated prevalence for DSD diagnostic groups and analyzed trends in prevalence. ResultsOver the 20-year study period, we identified 561 individuals with DSD. Almost half (n=266, 47%) had sex chromosome DSD, 177 (32%) had 46,XY DSD and 118 (21%) had 46, XX DSD. Causes for 46,XY DSD were disturbed androgen synthesis or action (37/177, 21%), atypical gonadal development (28/177, 16%), or other causes (112/177, 63%). Causes for 46,XX DSD were androgen excess (99/118, 84%), atypical gonadal development (8/118, 7%), or other causes (11/118, 9%). On average, 28 new cases were born with DSD annually. Prevalence was 17 for sex chromosome DSD, 12 for 46,XY DSD and 8 for 46,XX DSD per 100000 live births and year. One per 7500 newborn girls had 46,XX congenital adrenal hyperplasia (CAH). ConclusionPrevalence of sex chromosome DSD was lower than expected because of underreporting due to late diagnosis. Prevalence of 46,XX CAH is similar to newborn screening data, suggesting good completeness of cases. For complex DSD cases, we expect complete coverage. This study provides a valuable resource for policymaking and (inter)national research on DSD.

Cushings disease is caused by the overproduction of cortisol. The effects of this disease are well known in a general population, including high blood pressure, diabetes, and weight gain. Cushings disease causes both obesity and metabolic related symptoms, and it can be difficult to discern the obesity-dependent from the obesity-independent mechanisms of Cushings disease. To identify patients with Cushings disease, we identified 476 Michigan Medicine patients between January 1st 2000-2025 along with propensity-matched control cases. We stratified our participants by obesity status and into a Cushings disease group and a control group. As expected, the Cushings group had an elevated BMI compared to the control group (34 kg/m2 vs 29 kg/m2). We found a higher proportion of females diagnosed with Cushings compared to males (287 vs 72). Cushings disease was associated with an increase in the fasting glucose levels in both non-obese and obese patients. In both the obese, and non-obese patients, there was an increase in ALT and AST levels regardless of Cushings disease status, but the increase due to Cushings disease was much greater in the patients with obesity (73.4 vs 35.1 mg/dL). Cushings disease also had a moderating effect on blood pressure, with participants a BMI under 30 kg/m2 increasing by 12.6 mmHg and participants with obesity increasing by only 7.9 mmHg. These findings highlight the need to consider obesity status when evaluating the effects of Cushings disease.

ContextPolycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and frequent metabolic disturbances, including insulin resistance (IR), and is commonly accompanied by chronic low-grade inflammation. Complete blood count (CBC)-derived indices provide inexpensive markers reflecting systemic inflammatory and hematologic status; however, their relationships with androgen-related features in PCOS remain incompletely characterized. ObjectiveTo evaluate associations between androgen-related biomarkers and CBC-derived indices in young women with PCOS and to determine whether these associations persist after accounting for insulin resistance. DesignCross-sectional observational study. SettingSingle-center Gynecological Endocrinology Clinic in Katowice, Poland. ParticipantsWomen aged 16-25 years diagnosed with PCOS (Rotterdam criteria) between 2018 and 2025 (N = 1,300). Available-case and complete-case analyses were performed. Main Outcome MeasuresNeutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW), and platelet-to-lymphocyte ratio (PLR). Associations with free androgen index (FAI), total testosterone, and dehydroepiandrosterone sulfate (DHEAS) were assessed using Spearman correlation and multivariable linear regression models adjusted for age and log-transformed HOMA-IR with heteroskedasticity-consistent (HC3) standard errors. False discovery rate (FDR) correction was applied. ResultsFAI was positively associated with NLR in both available-case and complete-case analyses (Spearman {rho} = 0.201; FDR-adjusted q < 0.001). DHEAS showed a positive association with NLR in complete-case analysis (q = 0.040). In multivariable models adjusted for age and log(HOMA-IR) (n = 885-888 depending on outcome), higher FAI was independently associated with lower RDW ({beta} = -0.075; 95% CI -0.141 to -0.009; q = 0.032) and lower PLR ({beta} = -2.37; 95% CI -4.60 to -0.14; q = 0.042). Higher DHEAS was independently associated with lower RDW ({beta} = -0.00056; 95% CI -0.00109 to -0.00004; q = 0.042). In complete-case analysis, total testosterone was inversely associated with PLR ({beta} = -3.91; 95% CI -7.58 to -0.24; q = 0.038). Associations between androgen markers and NLR were attenuated after adjustment. ConclusionsAmong young women with PCOS, androgen-related biomarkers are independently associated with selected CBC-derived indices, particularly RDW and PLR, whereas associations with NLR appear partly explained by shared metabolic correlates. These findings suggest that androgen excess may be linked to subtle hematologic alterations in early-stage PCOS beyond insulin resistance.

PurposeInfants and toddlers with classical congenital adrenal hyperplasia (CAH) are at high risk for adrenal crisis and associated sequelae. To better understand acute illness at this early age, we determined the frequency and severity of acute illness and hospitalizations between 0-4 years of age, both within CAH and compared to controls. We also evaluated the impact of pre-hospital stress-dose hydrocortisone on Emergency Department (ED) visits and hospitalizations. MethodsWe performed a retrospective study of 40 CAH youth and 27 age-matched controls at a tertiary center. Characteristics of acute illnesses during the first 4 years of life were recorded, including fever, vomiting, diarrhea, ED visits, hospitalizations, abnormal electrolytes, and stress-dose hydrocortisone usage. ResultsCAH youth had more frequent illnesses requiring stress-dosing when they were younger than 2 years old [4.0 (1.0-6.0)] compared to when they were 2-4 years old [3.0 (1.0-4.0), P < 0.05], with the most illnesses during their first year of life. As well, CAH infants and toddlers had more hospitalizations younger than 2 years old compared to 2-4 years old (36 vs 2). 25% (3/12) of CAH youth with abnormal electrolytes in the ED did not receive any stress-dosing (oral/IM) prior to the ED, and only 25% (3/12) had received intramuscular hydrocortisone at home. CAH youth had more frequent ED visits (7.4 times as many) and hospitalizations (38 to 0) compared to controls. ConclusionsVery young children with classical CAH are at high risk for acute illness and hospitalizations during their first 2 years of life, and do not receive adequate stress-dosing prior to the ED despite appropriate education. Our findings underscore the need for earlier recognition of acute illness in this vulnerable population and improved education regarding administration of stress-dose hydrocortisone to prevent morbidity.

ContextPolycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder associated with reproductive dysfunction and long-term cardiometabolic risk. Traditional phenotype classifications based on diagnostic criteria may not fully capture the multidimensional biological variability underlying endocrine and metabolic risk profiles, particularly in young women. ObjectiveTo identify data-driven endocrine-metabolic phenotypes in young women with PCOS and evaluate their association with established cardiometabolic risk markers. Design and SettingCross-sectional study conducted at a tertiary Gynecological Endocrinology Clinic in Poland between January 2018 and May 2025. ParticipantsA total of 1300 young women diagnosed with PCOS according to Rotterdam criteria were included. The primary analytic cohort comprised 1032 participants aged 16-25 years with complete endocrine-metabolic biomarker data. Main Outcome MeasuresEndocrine-metabolic phenotypes were derived using principal component analysis followed by Gaussian mixture model clustering. Cardiometabolic risk endpoints included impaired glucose tolerance (2-hour plasma glucose during an oral glucose tolerance test [&ge;]140 mg/dL), an atherogenic lipid profile (triglycerides (TG)/high-density lipoproteins (HDL-C) ratio >3.50), elevated non-HDL cholesterol ([&ge;]130 mg/dL), and a composite outcome of any abnormality. ResultsPrincipal component analysis retained 10 components explaining 81.9% of total variance. Unsupervised clustering identified two stable phenotypes (silhouette = 0.392; ARI = 0.842). Cluster 0 (n=954; 92.4%) represented a mixed endocrine-metabolic profile, whereas cluster 1 (n=78; 7.6%) was enriched for thyroid/autoimmune features, with higher anti-thyroid peroxidase antibody levels and higher thyroid-stimulating hormone. Cluster 1 showed a higher prevalence of an atherogenic lipid profile compared with cluster 0, while differences in glucose intolerance and non-HDL cholesterol were modest. Logistic regression analyses suggested phenotype-specific variation in cardiometabolic risk markers. ConclusionsIn a large cohort of young women with PCOS, data-driven analysis identified two reproducible endocrine-metabolic phenotypes, including a distinct thyroid/autoimmune-enriched subgroup. These findings highlight clinically relevant heterogeneity beyond traditional diagnostic phenotypes and support the potential value of integrated endocrine-metabolic profiling for early risk stratification in PCOS.

ContextWomen with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can increase visceral adiposity (VAT) and impair vascular function. GH releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion. ObjectiveWe tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS. MethodsEighteen women with PCOS participated in a double-blinded, cross-over study. They received sitagliptin 100 mg vs. placebo daily for one month separated by an eight-week washout. During each treatment, women underwent a 75-gram oral glucose tolerance test (OGTT), assessment of vascular function and body composition. Overnight GH secretion was assessed via venous sampling every 10 minutes for 12 hours and analyzed using an automated deconvolution algorithm. ResultsDuring OGTT, sitagliptin increased GLP-1 (p<0.001), early insulin secretion (from mean insulinogenic index 1.9{+/-}1.2 (SD) to 3.2{+/-}3.1; p=0.02) and decreased peak glucose (mean -17.2 mg/dL [95% CI -27.7, -6.6]; p<0.01). At one month, sitagliptin decreased VAT (from 1141.9{+/-}700.7 to 1055.1{+/-}710.1 g; p=0.02) but did not affect vascular function. Sitagliptin increased GH half-life (from 13.9{+/-}3.6 to 17.0{+/-}6.8 min, N=16; p=0.04) and interpulse interval (from 53.2{+/-}20.0 to 77.3{+/-}38.2 min, N=16; p<0.05) but did not increase mean overnight GH (p=0.92 vs. placebo). ConclusionsSitagliptin decreased the maximal glucose response to OGTT and VAT. Sitagliptin did not increase overnight GH but increased GH half-life and the interpulse interval. PrecisSitagliptin improved body composition and blood glucoses following oral glucose load in women with PCOS. Sitagliptin potentiated GH half-life but did not increase overnight GH levels.

ObjectivesThere is currently insufficient evidence linking COVID-19 infection with Graves disease (GD). Following the complete lifting of COVID-19 restrictions on December 13, 2022, widespread infection in Guangzhou provides a basis for this study. This research aims to investigate the correlation between COVID-19 infection and GD onset, explore the epidemiological characteristics of newly diagnosed GD post-infection, and offer a scientific basis for treatment. MethodsThe study population included 494 GD outpatients treated in the Department of Endocrinology at the Second Affiliated Hospital of Guangzhou Medical University from January 1 to June 30 each year between 2021 and 2023. They were divided into two groups: 2023 (N=219) and 2021-2022 (N=275), based on the time node of widespread COVID-19 infection in 2023. The new diagnosis rate, general clinical characteristics, and serological test results of GD patients were analyzed before and after the outbreak of COVID-19. ResultsCompared with the 2021-2022 group, the new diagnosis rate of GD patients in 2023 showed a significant increase (12.8% vs. 8.4%, P<0.001). Furthermore, there was a significant decrease in pre-treatment thyrotropin receptor antibody levels (P=0.01), white blood cell count (P=0.02), and neutrophil proportion (P=0.04), while there was a significant increase in the proportion of patients with a family history (P=0.047). Follow-up until June 30 of that year revealed that the proportion of newly diagnosed GD patients developing hypothyroidism during treatment in 2023 significantly increased compared to the 2021-2022 group (P<0.001). ConclusionsAfter widespread infection of COVID-19, the diagnosis rate of newly diagnosed GD increased, which may influence the epidemiological characteristics of related GD patients before initial treatment and during treatment.

IntroductionCushings disease (CD) is a rare endocrine disorder characterized by excessive cortisol production due to a pituitary adenoma secreting ACTH, leading to a range of systemic effects including obesity, hypertension, and hyperglycemia. The condition is often underdiagnosed, with an incidence of 2-3 cases per million people annually. While surgery remains the first-line treatment, adjunctive medical therapies are essential for non-surgical candidates or those with recurrent disease. This systematic review and network meta-analysis (NMA) evaluate the comparative efficacy and safety of medical treatments for Cushings disease. MethodsA comprehensive literature search was conducted across PubMed, Scopus, Cochrane Library, and Web of Science for randomized controlled trials (RCTs) and observational studies published between 2010 and 2023. Studies were included if they assessed the efficacy and/or safety of medical treatments for Cushings disease. Data extraction was performed independently by two reviewers. Risk of bias was assessed using the Cochrane Risk of Bias tool for RCTs and ROBS 2.0 for observational studies. Network meta-analysis was performed using a random-effects model to compare treatments across different outcomes. ResultsA total of 29 studies involving 1,736 patients were included in the analysis. The patient cohort comprised 600 males (34.5%) and 1,132 females (65.5%), with an average age of 41.09 years. Among the treatments, 960 patients (55.3%) received Pasireotide, 143 (8.2%) Osilodrostat, 126 (7.3%) Mifepristone, and 176 (10.1%) Levoketoconazole. In terms of 24-hour urinary free cortisol (UFC) reduction, Levoketoconazole showed a mean difference of -329 (95% CI: -2.33e+03, 1.70e+03), Mifepristone -381 (95% CI: -3.27e+03, 1.74e+03), Osilodrostat -214 (95% CI: -1.60e+03, 1.25e+03), and Pasireotide -331 (95% CI: -1.75e+03, 1.09e+03). Despite all treatments reducing UFC levels, the broad confidence intervals suggest substantial uncertainty in the efficacy estimates. Regarding the change in cortisol levels, Mifepristone showed a mean difference of 290 (95% CI: -285, 888), Osilodrostat 15.6 (95% CI: -806, 835), and Pasireotide -6.17 (95% CI: -821, 815), indicating considerable variability in treatment effects. The analysis of ACTH levels revealed similar trends, with Levoketoconazole and Mifepristone showing more pronounced reductions compared to Osilodrostat. In terms of overall survival, Levoketoconazole demonstrated a survival rate of 0.82 (95% CI: 0.72-0.91), while Mifepristone had a pooled survival rate of 0.94 (95% CI: 0.86-1.02). The analysis of disease-free survival indicated an overall pooled survival rate of 0.80 (95% CI: 0.70-0.90). Quality of life (QOL) improvements were variable, with Osilodrostat showing a mean difference of -11.72 (95% CI: -18.32, -5.12). There were no significant differences in the risk of gastrointestinal, cardiovascular, or neurological adverse events between treatments. ConclusionThis systematic review and network meta-analysis provide valuable insights into the comparative efficacy and safety of medical treatments for Cushings disease. While Pasireotide and Levoketoconazole consistently reduce UFC levels, Mifepristone and Osilodrostat also show potential, albeit with greater variability in clinical outcomes. The high heterogeneity observed across studies suggests the need for further research to refine treatment strategies and optimize patient management. Personalized treatment approaches, incorporating both efficacy and safety considerations, will be crucial for improving outcomes and minimizing the burden of this disease.

ObjectiveSome evidence suggests that higher serum TSH may be a part of normal aging, but current studies are limited to 13-year follow-up. We examined TSH changes during 22 years of follow-up across the adult lifespan. DesignLongitudinal analyses of the population-based HUNT Study in Norway, with TSH measurements from 1995-97, 2006-08 and 2017-19. MethodsIn the overall population and in individuals without thyroid medication or disease, we estimated i) geometric mean serum TSH by age, integrating cross-sectional and longitudinal measurements using linear mixed models, ii) percentiles of the TSH distribution by age, and iii) within-individual TSH change during follow-up, expressed by geometric mean ratios (GMR) reflecting the fold change in geometric mean TSH. ResultsWe included 136,925 TSH measurements among 84,342 participants, of whom 40,615 had [&ge;]2 measurements and 13,613 had [~]22-year follow-up. Mean TSH was higher at older age in men, but weaker and less consistent in women. The TSH distribution widened at older age in men and women. Among individuals without thyroid medication or disease, mean TSH increased modestly by 0.13 mIU/L (GMR 1.09; 95%CI 1.08,1.11) during 22-year follow-up in men, but not in women (GMR 0.99; 95%CI 0.98,1.00). This increase was stronger at 0.5 mIU/L in men aged [&ge;]70 years at baseline (GMR 1.32; 95%CI 1.18,1.48). ConclusionsMean serum TSH increased with age in older men, but showed only modest or no age-related change in younger men and in women. The wider TSH distribution at older age supports the need for age-specific TSH reference ranges. Significance statementPrevious evidence of higher TSH concentrations at older age comes from cross-sectional studies and longitudinal studies with up to 13-year follow-up. We utilized a large population-based study to extend the evidence on within-individual TSH changes to [~]22-year follow-up across the adult lifespan. Mean TSH increased with age in men, modestly at 0.13 mIU/L overall, but stronger at 0.5 mIU/L in men followed from their 70s to their 90s. In women, mean serum TSH appeared stable during follow-up, but more frequent thyroid hormone supplementation may have skewed the TSH distribution away from higher, but still physiological levels. The TSH distribution widened at older age in both men and women, supporting the need for age-specific TSH reference ranges.

ObjectivesGlucocorticoids, mediated by the activation of the HPA axis, affect metabolic responses, insulin resistance, lipolysis and body fat distribution. Dehydroepiandrosterone-sulfate (DHEA-S) is a hormone produced by the adrenal glands and a precursor of sex hormones. The balance and interaction between cortisol and DHEA-S can significantly affect body composition. This study aimed to investigate the relationship between cortisol and DHEA-S levels, cortisol/DHEA-S ratio, and body composition in Korean men and women. MethodsIn total, 802 adults participated in this study between January 2018 and March 2023. Socio-demographic data and lifestyle factors were assessed using questionnaires. Body composition, clinical blood pressure, and metabolic variables, including cortisol and DHEA-S levels, were assessed. Cortisol and DHEA-S scores were analyzed in relation to height, body weight(BW), body mass index(BMI) and waist circumference(WC) according to age and sex. ResultsParticipants had a mean age of 52.6{+/-}11.7 years. Cortisol levels adjusted for age and gender were negatively correlated with BW, WC and BMI. This result was more significant in women than in men. DHEA-S levels were positively correlated with height, BW and WC after adjusting for age. The cortisol/DHEA-S ratio was associated with lower height and BW after adjusting for gender. Logistic regression for cortisol, DHEA-S and the cortisol/DHEA-S ratio in the prediction of central obesity was significant for men after adjusting for age and BMI. ConclusionsElevated cortisol concentrations are associated with lower adiposity. DHEA-S levels were positively correlated with height and body mass. The prediction of central obesity was associated with cortisol and the cortisol/DHEA-S ratio in men and negatively associated with DHEA-S.

ImportanceDiagnosis of polycystic ovary syndrome (PCOS) in adolescence is challenging because menstrual irregularity and hyperandrogenism are common in adolescents. Recent international guidelines highlighted an at risk for PCOS category based on either menstrual regularity or hyperandrogenism; however, its population prevalence and genetic correlates remain unknown. ObjectiveTo estimate the prevalence of PCOS and at risk for PCOS in adolescence and evaluate associations with genetic risk for PCOS. Design, Settings, and ParticipantsPopulation-based analysis of 1,533 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) with sufficient reproductive data. ExposurePolygenic score (PGS) for PCOS derived from the largest genome-wide association study in European women. Main Outcomes and MeasuresGuideline-defined PCOS (presence of both irregular menses and hyperandrogenism) and at risk for PCOS (presence of one feature). ResultsPCOS prevalence was 3.2%, while 27.2% met criteria for being at risk for PCOS. A higher PCOS PGS was associated with hyperandrogenism (OR per SD increase in PGS: 1.22; 95% CI, 1.07-1.39; P=4x10-3) but not irregular menses. Conclusions and RelevanceOver one-fourth of adolescents met criteria for being at risk for PCOS. Genetic risk for PCOS was associated with hyperandrogenism but not isolated menstrual irregularity, suggesting that androgen excess is a more specific early manifestation of inherited PCOS liability.

BackgroundAmong people with gestational diabetes mellitus (GDM), there is inter-individual variability in clinical outcomes that appears to be related to factors beyond glycemia. However, the precise factors (information on the unique pathophysiology within a person, environment, and/or context) that may help refine the diagnosis of GDM remain unclear. To determine if a precision medicine approach could refine the diagnosis of GDM, we conducted a systematic review of a variety of potential precision markers analyzed in studies among individuals with GDM. MethodsSystematic literature searches were performed in PubMed (https://pubmed.ncbi.nlm.nih.gov/) and EMBASE (https://www.embase.com) databases from inception to March 2022 for observational studies and controlled trials. Studies were included if they reported data on, and compared outcomes between, individuals with GDM. The following categories of precision markers were included in the current search: non-glycemic biochemical markers (cholesterol, insulin profiles); genetics/genomics or other -omics (proteomics, lipidomics, metabolomics, metagenomics); maternal/fetal anthropometric (eg., maternal BMI, gestational weight gain, fetal biometry ultra-sound measures); clinical risk factors (medical/familial history, prior delivery complicated by macrosomia or a large for gestational age [LGA] neonate); sociocultural or environmental modifiers (diet, smoking, race/ethnicity, socioeconomic status). ResultsWe focused on synthesizing the literature on genetics, -omics, non-glycemic biomarkers, maternal anthropometry/fetal biometry, and clinical/sociocultural risk factors. A total of 5,905 titles and abstracts were screened, 775 underwent full-text review, and 137 studies that included a total of 432,156 GDM cases were synthesized. Of the studies on non-glycemic biomarkers (n=33), lipids and insulin sensitivity/secretion indices were the two most common precision markers, with elevated maternal triglycerides and insulin resistance generally associated with greater risk of LGA and macrosomia. Studies of genetics or other -omics were scarce (n=5); however, differences in genetic variants in adiponectin or adiponutrient genes and non-coding RNAs accounted for variability in perinatal outcomes. The majority of studies (n=77) evaluated maternal anthropometry or fetal biometry as a precision marker, and these studies demonstrate that individuals with adiposity who develop GDM are at a substantially higher risk of LGA or macrosomia than those with GDM and lower adiposity. There were 49 studies evaluating GDM risk factors or sociocultural markers, with only six studies examining multiple risk factors as a composite marker. There were inconsistent findings that GDM risk factors, such as older maternal age, accounted for variation in adverse outcomes. ConclusionsOur review demonstrates that a major gap exists in studies examining non-glycemic biochemical, genetic, or other omic precision markers among individuals with GDM. Given that people meeting current diagnostic criteria for GDM may have different risk profiles, our review identifies several factors (including obesity, insulin resistance, hypertriglyceridemia) that may be useful in risk stratification of GDM, setting the stage for a precision approach to its diagnosis.

ContextThyroid hormones play an important role in the metabolic homeostasis of the body and have been associated with cardiometabolic risk. ObjectiveTo examine the association of cardiometabolic risk factors (CMRF) with TSH levels in youth at population level in the US. Design & SettingCross-sectional study of youth aged 12-18 years without known thyroid abnormalities from National Health and Nutrition Examination Survey 1999-2012. Subclinical hypothyroidism (SH) was defined as TSH levels 4.5-10 mIU/L. Assessed CMRF included abdominal obesity (waist circumference > 90thpercentile), hypertriglyceridemia (TG [&ge;] 130 mg/dL), low HDL cholesterol (HDL-C < 40 mg/dL), elevated blood pressure (SBP and DBP [&ge;] 90thpercentile), hyperglycemia (FBG [&ge;] 100 mg/dL, or known diabetes), insulin resistance (HOMA-IR > 3.16) and elevated alanine transferase (ALT [&ge;]50 U/L for boys and [&ge;]44 U/L for girls). Age and sex-specific percentiles for thyroid parameters were calculated for youth with normal weight. ResultsIn this cohort of youth (51.3% male), 31.2% had overweight/obesity. The prevalence of SH was 2.0 % (95% CI 1.2-3.1). The median TSH levels were higher in youth with overweight/obesity (p<.001). Adjusting for age, sex, race/ethnicity and level of obesity, youth with TSH in the 4th quantile had higher odds of abdominal obesity (OR 2.53 [1.43-4.46], p = .002), higher HOMA-IR (OR 2.82 [1.42-5.57], p=.003) and [&ge;] 2 CMRF (OR 2.20 [1.23-3.95], p=.009). ConclusionsThe prevalence of SH is low in US youth. The higher odds of insulin resistance and CMRF in youth with TSH levels > 75th percentile requires further study.

Objective/BackgroundWhile PCOS research has extensively explored genomic, transcriptomic, proteomic, and metabolomic milieus, our study examines the plasma glycome, comparing women with PCOS to age-matched healthy controls. MethodsIn this observational study, an n = 47 women with PCOS were screened and enrolled at the UC Davis Health campus, the comparator group constituted an n = 25 age-matched healthy women. During a study visit, body composition was measured using a bioelectrical impedance scale, and fasted plasma samples were obtained to measure glucose, insulin, circulating lipids and leptin, among other parameters, in all groups. In addition, in the PCOS group, circulating androgens and other endocrine hormones were measured. The plasma glycome was measured using a UHPLC-MS protocol. ResultsAs expected, women with PCOS had more body weight (p<0.01), body fat (p = 0.004), fasting leptin (p=0.01), insulin (p = 0.003) and glucose (p = 0.004). The plasma glycome milieu displayed increased tetraantennary (glycans with 4 branches: p = 0.05) and reduced hybrid-type glycans (p = 0.019) in women with PCOS compared to healthy controls. Logistic regression models predicting PCOS vs control binary outcomes indicated a higher tetraantennary and lower hybrid glycan profile to represent women with PCOS more than controls both with (AUCROC = 0.94) and without body weight (AUCROC = 0.84). Further, in women with PCOS, total testosterone was positively associated with tetra-antennary glycans (r = 0.322, p = 0.029). ConclusionsHighly branched glycans, that have been shown to be elevated in pro-inflammatory and metabolic disease states, are also elevated in PCOS. However, the link between circulating androgens and protein glycosylation in women remains unknown, and future investigations should focus on this.

BackgroudAdrenal venous sampling (AVS) is a gold standard procedure to determine the dominant side of aldosterone secretion in patients with primary aldosteronism. Unsuccessful cannulation of right adrenal vein (RAV) is a common problem in performing AVS. ObjectiveTo use calculated aldosterone concentration in the RAV (cAldoRAV) for identifying the dominant side of aldosterone secretion. DesignRetrospective study, 2011-2023. MethodsBased on the assumption that cortisol production from both adrenal glands is equal, aldosterone concentration in the RAV was calculated by using the data from left adrenal vein (LAV) and inferior vena cava. The aldosterone concentration in the LAV (AldoLAV) compared to the cAldoRAV (AldoLAV:cAldoRAV ratio) was then used to determine the dominant side of aldosterone secretion in patients with primary aldosteronism. ResultsOf 117 patients with successful AVS, 95 (81.2%) had concordant results between adrenal imaging and AVS study and were used as the gold standard for studying diagnostic performance. The AldoLAV:cAldoRAV ratio with the cutoff values of [&ge;]3 and [&le;]0.33 could identify unilateral diseases (left-sided and right-sided disease, respectively) with 93.8% sensitivity and 100% specificity. In 22 patients who had discordant results between adrenal imaging and standard AVS interpretation, 11 had concordant results when using the AldoLAV:cAldoRAV ratio. ConclusionsThe AldoLAV:cAldoRAV ratio can determine the dominant side of aldosterone secretion with high sensitivity and specificity. It can not only be used for patients with unsuccessful cannulation of RAV but also increase the concordance rate in those who have discordance between adrenal imaging and standard AVS interpretation.

IntroductionShort stature and thyroid autoimmunity are among the most common traits in Turner syndrome (TS). Recombinant human growth hormone (rhGH) treatment benefits height growth in Turner syndrome individuals when applicable. This study aims to investigate the association of thyroid autoimmunity and the response to rhGH treatment in Turner Syndrome patients. MethodsMedical records of 494 patients with TS were reviewed. Among 126 patients who regularly tested for thyroid autoantibodies, 108 patients had received rhGH treatment. Clinical characteristics, including karyotype and the presence of autoimmune thyroid diseases, as well as rhGH treatment records were analyzed. Height velocity (HV) of patients with or without thyroid autoimmunity was compared to assess the response to rhGH treatment. For patients who received rhGH treatment and positive for thyroid autoantibodies, height velocity before and after antibody presence was compared. Results45XO monosomy presented in 36% (176/496) of patients. 42.1% of patients (53/126) had elevated circulating anti-thyroid peroxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb). In 108 patients who received rhGH treatment, a negative correlation was found between circulating TPOAb concentration and HV (n=53, r = -0.276, P<0.05). For patients who developed thyroid autoantibodies during rhGH treatment, HVs after thyroid autoantibody presence significantly decreased compared with HVs before thyroid autoantibody detection (n=44, p=0.0017). ConclusionsOur data suggested that in preadult TS patients who developed thyroid autoantibodies during rhGH treatment, the response to rhGH is negatively associated with the development of thyroid autoimmunity.

OBJECTIVEAcromegaly is a rare neuroendocrine condition that can lead to significant morbidity; therefore, large studies are invaluable for understanding the disease burden. Despite Chinas vast population size, studies on acromegaly remain sparse. In this report, we aimed to investigate clinical characteristics and predictors of biochemical remission after surgery for acromegaly. METHODSA retrospective nationwide study was conducted using patient-reported data from the China Acromegaly Patient Association (CAPA) from 1998 to 2018. Univariate analyses were performed using Wilcoxon rank-sum tests, two-sample t-tests, and chi-squared tests. Using the purposeful selection method, multivariate logistic regression analysis was employed to determine independent predictors of biochemical remission at 3 months in patients after surgery. RESULTSOf the 575 cases (mean age: 37.3 years; 59% female), macroadenomas and invasive tumors (Knosp score 3-4) were 87% and 61%, respectively. Ninety-five percent of patients were treated first with surgery (5.1% transcranial and 94.9% endonasal) and 38.3% exhibited biochemical remission at 3-months postoperatively. The following independent predictors of biochemical remission were identified: preoperative growth hormone (GH) levels between 12 and 28 g/L [odds ratio (OR)=0.61; 95% confidence interval (CI), 0.39-0.96; p=0.031], preoperative GH levels >28 g/L (OR=0.56; 95% CI, 0.35-0.90; p=0.016), macroadenoma (OR=0.57; 95% CI, 0.33-0.97; p=0.041), giant adenomas (OR=0.17; 95% CI, 0.06-0.44; p=0.0005), Knosp score 3-4 (OR=0.39; 95% CI, 0.25-0.59; p<0.0001), and preoperative medication usage (OR=2.16; 95% CI, 1.38-3.39; p=0.0008). CONCLUSIONSIn this nationwide study spanning over two decades, we highlight that higher preoperative GH levels, large tumor size, and greater extent of tumor invasiveness are associated with a lower likelihood of biochemical remission at 3-months after surgery, while preoperative medical therapy increases the chance of remission.

BackgroundSubclinical hypothyroidism (SH) is biochemically defined by increased TSH, and normal thyroid hormones and its management is a matter of debate. Herein, we investigated thyroid function in euthyroid and children with SH using published data from population-based curves and a structure parameter inference approach (SPINA) model. MethodsThe study included 179 children and adolescents with SH and 311 healthy controls. The predicted and calculated secretory capacity of thyroid gland (SPINA-GT) was calculated in all euthyroid children divided into quartiles according to TSH values, and in children with SH, further subcategorized into those with mild SH (TSH: 4.5 - 10 mIU/L) and severe SH (TSH > 10 mIU/L). ResultsCalculated SPINA-GT values decreased significantly (P < 0.001) from the 1st to the 2nd quartile of normal TSH values in euthyroid children. It was also significantly decreased in mild SH compared to euthyroid children with TSH values within the upper 2 quartiles of TSH range and in severe SH compared to mild SH. ConclusionsThe implementation of SPINA model for thyroid function gives a wider perspective of thyroid glands performance within the euthyroid range of TSH, as well as in SH and add to the discussion for the long-term effects of SH and its management.