The Journal of Clinical Endocrinology & Metabolism

BackgroundThyroid autoimmunity (TAI) is frequently reported in women with polycystic ovary syndrome (PCOS), yet its clinical relevance for cardiometabolic and androgenic severity remains uncertain. We evaluated whether TAI identifies a metabolically or androgenically more severe PCOS phenotype using pre-specified exposure definitions and cardiometabolic endpoints. MethodsThis cross-sectional study included 1,300 women with confirmed PCOS in the source dataset. Thyroid autoimmunity was defined a priori using three definitions: anti-thyroid peroxidase antibodies above the laboratory upper limit of normal (TAI_A, primary definition), anti-TPO positivity combined with thyroid-stimulating hormone >4.0 mIU/L (TAI_B), and high-titer anti-TPO >100 IU/mL (TAI_C). The primary endpoint was triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C) >3.5. Secondary endpoints included non-HDL-C [≥]130 mg/dL and 120-minute oral glucose tolerance test (OGTT) glucose [≥]140 mg/dL. Associations were assessed using age-adjusted Firth logistic regression models in complete-case cohorts. Sensitivity analyses included restriction to euthyroid participants, alternative TAI definitions, trimming of extreme values (1-99%), and bootstrap-based confidence intervals. Exploratory hormonal comparisons were adjusted using the Benjamini-Hochberg false discovery rate. ResultsTAI_A was not significantly associated with the primary endpoint (TG/HDL >3.5) (OR 0.77, 95% CI 0.21-1.67). No significant associations were observed for secondary endpoints including non-HDL-C [≥]130 mg/dL (OR 1.09, 95% CI 0.61-1.76) or impaired glucose tolerance on OGTT (OR 1.27, 95% CI 0.63-2.18). Results remained directionally consistent across alternative TAI definitions and sensitivity analyses, including restriction to euthyroid women and trimming of extreme values. In exploratory analyses, thyroid-stimulating hormone levels differed between TAI-positive and TAI-negative women, while no androgenic or cardiometabolic parameters remained significant after false discovery rate correction. Model diagnostics did not indicate major violations of model assumptions. ConclusionIn this large cross-sectional cohort of women with PCOS, thyroid autoimmunity was not associated with an adverse cardiometabolic or androgenic phenotype. Anti-TPO positivity alone therefore does not appear to identify a metabolically high-risk PCOS subgroup under the studied conditions. Prospective studies are needed to clarify the longitudinal implications of thyroid autoimmunity in PCOS.

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.

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.

ObjectivesSex hormone-binding globulin (SHBG) and testosterone are differentially associated with type 2 diabetes (T2D) risk. We investigated whether these associations differ by HIV and menopausal status in Black South African women living with (WLWH) and without HIV (WLWOH). DesignCross-sectional observational. MethodsEighty one premenopausal (57 WLWOH, 24 WLWH) and 280 postmenopausal (236 WLWOH, 44 WLWH) women from the Middle-Aged Soweto Cohort (MASC) completed the following measures: circulating SHBG and sex hormones, body composition (dual energy x-ray absorptiometry), oral glucose tolerance test to estimate insulin sensitivity (Matsuda index), secretion (insulinogenic index, IGI) and clearance, and beta-cell function (disposition index, DI). Dysglycaemia was defined as either impaired fasting or postprandial glucose or T2D. ResultsSHBG was higher and total and free testosterone were lower in postmenopausal WLWH than WLWOH (all p<0.023). Irrespective of HIV serostatus, SHBG was positively associated with Matsuda index, insulin clearance and DI and inversely with HOMA-IR (all p<0.011). The association between SHBG and Matsuda index was stronger in premenopausal than postmenopausal women (p=0.043 for interaction). Free testosterone (and not total testosterone) was only negatively associated with basal insulin clearance (p=0.021), and positively associated with HOMA-IR in premenopausal and not post-menopausal women (p=0.015 for interaction). ConclusionsWe show for the first time that midlife African WLWH have higher SHBG and lower total and free testosterone than WLWOH, which corresponded to their higher beta-cell function, suggesting a putative protective effect of SHBG on T2D risk in WLWH. Significance statementThis study in midlife Black African women suggest that higher sex hormone binding protein (SHBG) and lower free testosterone in women living with HIV (WLWH) may be associated with reduced risk of type 2 diabetes (T2D) compared to women living without HIV. Further, this study provides a putative mechanism underlying the lower prevalence of T2D in WLWH and obesity compared to women living with obesity but without HIV. However, longitudinal studies are required to understand the clinical implications of these findings.

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.

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.

BackgroundObesity affects hormone metabolisms and contributes to gallstone disease more strongly in women than in men. This study assessed the sex-specific associations between serum levels of sex hormone-binding globulin (SHBG) and testosterone and risk of cholecystectomy, and their mediation role in the obesity-cholecystectomy association. MethodsIncluded were 176,909 men and 160,147 women from the UK Biobank. Serum SHBG and total testosterone were measured by immunoassay. Incident cases of cholecystectomy for gallstone disease were identified using hospital inpatient records. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) with 95% confidence interval (CI) of cholecystectomy associated with the serum hormones. A mediation analysis was performed to estimate the proportion of the obesity-cholecystectomy association potentially mediated by the two sex hormones. ResultsA total of 2877 men and 4607 women underwent cholecystectomies during the follow-up. Regardless of sex, higher levels of SHBG were associated with a lower risk of cholecystectomy. The HRs of cholecystectomy comparing the highest with the lowest quartiles of SHBG were 0.68 (95% CI: 0.59-0.77) in men (P-trend <0.001) and 0.39 (95% CI: 0.36-0.53) in women (P-trend <0.001). Higher levels of testosterone were associated with a higher risk of cholecystectomy in women (HRQ4 vs. Q1 = 1.28; 95% CI: 1.18-1.39; P-trend <0.001) but not in men (P-trend = 0.12). In women, it was estimated that 14.71% and 2.74% of the association between obesity and cholecystectomy was significantly medicated by SHBG and testosterone, respectively. ConclusionsSHBG levels are inversely associated with risk of cholecystectomy in both sexes, whereas higher testosterone levels are associated with a higher risk of cholecystectomy only in women. Both hormones mediate the obesity-cholecystectomy association in women.

IntroductionPrior studies demonstrate reduced risk of several malignancies among patients with type 2 diabetes mellitus (T2DM) prescribed glucagon-like-peptide-1 receptor agonists (GLP-1RA). A recent study however found expression of GLP-1R among neuroendocrine neoplasm (NEN) cell lines and growth promotion in xenografts treated with semaglutide. In this study, we evaluate incidence of NENs among patients diagnosed as overweight/obese and patients with T2DM prescribed GLP-1RA based drugs. MethodsThe TriNetX database was utilized for this study. Incidence of NENs between patients with overweight/obesity were compared to a control group without obesity within 15 years following index diagnosis of obesity or, in the control group, a non-specific outpatient visit. Groups were matched for demographics, tobacco use, family malignancy history, alcohol use, and socioeconomic factors. In a separate analysis, incidence of NENs among patients with T2DM were compared between those prescribed GLP-1RAs versus other antihyperglycemic agents (AHA) within 15 years following index prescription of GLP-1RA or comparator AHA. Patients with exposure to the comparator AHA were excluded from their respective groups. A subgroup analysis was performed among patients with overweight/obesity. Exclusion criteria included Merkel cell carcinoma, multiple endocrine neoplasia type 1, Cushings syndrome, Von Hippel-Lindau syndrome, tuberous sclerosis, and prior NEN. ResultsPatients with overweight/obesity had a significant increased risk of NENs when compared to the control group (3,840/794,235 (0.48%) vs. 2,785/794,235 (0.35%); RR: 1.38 (95% CI 1.31-1.45), P < 0.0001). Among patients with T2DM, GLP-1RA exposure was associated with significantly lower risk of NENs compared to insulin (70/31,171 (0.23%) vs. 137/31,171 (0.44%); RR: 0.51 (0.38, 0.68), P < 0.0001), but no significant difference was appreciated with other AHAs. In the subset of patients with obesity/overweight, GLP-1RAs were associated with decreased risk compared to insulin (43/15,230 (0.28%) vs. 68/15,230 (0.45%); RR: 0.63 (0.43, 0.93), p=0.02) and metformin (39/10,370 (0.38%) vs. 64/10,370 (0.62%); RR: 0.61 (0.41, 0.91), P = 0.01). ConclusionThis study suggests obesity to be significantly associated with incidence of NENs. Furthermore, our findings do not demonstrate an increased incidence of NENs with GLP-RA use among patients with T2DM and show decreased risk when compared to insulin exposure.

Background and aimsPrecision prevention involves using the unique characteristics of a particular group to determine their responses to preventive interventions. This study aimed to systematically evaluate the participant characteristics associated with interventions in gestational diabetes mellitus (GDM) prevention. MethodsWe searched MEDLINE, EMBASE, and Pubmed to identify lifestyle (diet, physical activity, or both), metformin, myoinositol/inositol and probiotics interventions of GDM prevention published up to May 24, 2022. ResultsFrom 10347 studies, 116 studies (n=40940 women) were included. Physical activity resulted in greater GDM reduction in participants with a normal body mass index (BMI) at baseline compared to obese BMI (risk ratio, 95% confidence interval: 0.06 [0.03, 0.14] vs 0.68 [0.26, 1.60]). Diet and physical activity interventions resulted in greater GDM reduction in participants without polycystic ovary syndrome (PCOS) than those with PCOS (0.62 [0.47, 0.82] vs 1.12 [0.78-1.61]) and in those without a history of GDM than those with unspecified history (0.62 [0.47, 0.81] vs 0.85 [0.76, 0.95]). Metformin interventions were more effective in participants with PCOS than those with unspecified status (0.38 [0.19, 0.74] vs 0.59 [0.25, 1.43]), or when commenced preconception than during pregnancy (0.22 [0.11, 0.45] vs 1.15 [0.86-1.55]). Parity, history of having a large-for-gestational-age infant or family history of diabetes had no effect. ConclusionsGDM prevention through metformin or lifestyle differs according to some individual characteristics. Future research should include trials commencing preconception and provide results stratified by participant characteristics including social and environmental factors, clinical traits, and other novel risk factors to predict GDM prevention through interventions. Plain language summaryPrecision prevention involves using a groups unique context to determine their responses to preventive interventions. This study aimed to evaluate the participant characteristics associated with interventions in GDM prevention. We searched medical literature databases to identify lifestyle (diet, physical activity), metformin, myoinositol/inositol and probiotics interventions. A total of 116 studies (n=40903 women) were included. Diet and physical activity interventions resulted in greater GDM reduction in participants without polycystic ovary syndrome (PCOS) and those without a history of GDM. Metformin interventions resulted in greater GDM reduction in participants with PCOS or when started during the preconception period. Future research should include trials starting in the preconception period, and provide results stratified by participant characteristics to predict GDM prevention through interventions.

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.

BackgroundCardiometabolic diseases are highly comorbid and associated with poor health outcomes. However, the investigation of the relationship between the genetic predisposition to cardiometabolic diseases with the risk of conditions unique to females such as breast cancer, endometriosis and pregnancy-related complications is highly understudied. This study aimed to estimate the cross-trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to females. MethodsWe obtained data for female participants in the Penn Medicine BioBank (PMBB; 21,837 samples) and the electronic MEdical Records and GEnomics (eMERGE; 49,171 samples) network. We examined the relationship between four cardiometabolic phenotypes (body mass index (BMI), coronary artery disease (CAD), type 2 diabetes (T2D) and hypertension (through blood pressure measurements)) and 23 female health conditions by performing four analyses: 1) Cross-trait genetic correlation analyses to compare genetic architecture. 2) Polygenic risk scores (PRS)-based association tests to characterize shared genetic effects on disease risk. 3) Mendelian randomization (MR) for significant associations to assess cross-trait causal relationships. 4) Chronology analyses to visualize the timeline of events unique to groups of females with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. ResultsWe observed high genetic correlation among cardiometabolic and female health conditions. PRS meta-analysis identified 29 significant associations reflecting potential shared biology among common cardiometabolic phenotypes and female health conditions. Significant associations include PRSBMI with endometrial cancer and polycystic ovarian syndrome (PCOS), PRSCAD with breast cancer, and the PRST2D with gestational diabetes and PCOS. Mendelian randomization provided additional evidence of independent causal effects between T2D and gestational diabetes and CAD and with breast cancer. Our results reflected inverse association between PRSCAD and breast cancer. Lastly, as visualized from chronology analyses, individuals with high PRS are also more likely to develop conditions such as PCOS and gestational hypertension at earlier ages. ConclusionsPolygenic susceptibility to cardiometabolic traits is associated with conditions unique to females. Several of these associations are likely to result from the complex pathophysiology of cardiometabolic risk, and others may reflect potential pleiotropic effects that go beyond cardiometabolic health in females.

ContextThe body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis. ObjectiveTo investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status. DesignCrossover clinical trial studying participants before and after VitD3-supplementation. SettingCommunity. Participants11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] [&le;]20 ng/mL). InterventionsVitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D[&ge;]30 ng/mL. ResultsVitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)2D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D[&ge;]50 ng/mL and achieved a minimum ([~]90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) ({rho}=-0.85; p=0.001) compared to total plasma 25(OH)D ({rho}=0.51; p=0.01) and the 24,25(OH)2D/25(OH)D ratio ({rho}=0.37; p=0.3). ConclusionsSuppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity - thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.

AimsThe distribution of abdominal adipose depots and their mechanistic links to type 2 diabetes remain incompletely understood. This study elucidated the relationship between type 2 diabetes presence and quantitative abdominal imaging traits, including hepatic steatosis, liver and spleen size, and adipose distribution, using unenhanced computed tomography (CT) scans from a large-scale, racially diverse, disease-focused medical biobank. Materials and MethodsDeep learning algorithms were applied to abdominal CT scans to automatically quantify image-derived phenotypes, including spleen-hepatic attenuation difference (SHAD) for hepatic steatosis, liver and spleen volumes (LV and SV, respectively), visceral and subcutaneous adipose tissue (VAT and SAT, respectively), and visceral-to-subcutaneous fat ratio (VSR). ResultsDiabetic individuals demonstrated a greater degree of hepatic steatosis and central adiposity than those without diabetes. Liver attenuation was lower (47.6 vs. 52.4 Hounsfield units (HU); lower values indicate greater steatosis), SHAD was higher (-5.41 vs. -8.41 HU; more positive values indicate greater steatosis), and steatosis prevalence increased (38.4% vs. 21.4%) (all p<2.2x10-{superscript 1}). VSR was also elevated (0.64 vs. 0.54, p=5.86x10-{superscript 1}3). These trends remained significant after stratification by sex. Multivariate analyses revealed independent associations of diabetes with SHAD (OR 1.04), LV (OR 1.59), SV (OR 3.95), VAT (OR 1.23), SAT (OR 1.05), and VSR (OR 2.27), after adjusting for age, sex, race, and BMI. ConclusionsHepatic steatosis, hepatomegaly, and visceral adiposity on CT imaging are predictive of type 2 diabetes presence. Notably, VSR showed a stronger association with diabetes than BMI, underscoring how body-fat distribution, rather than overall adiposity, more accurately reflects metabolic disease risk.

BackgroundCongenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is characterized by a broad clinical spectrum, ranging from salt-wasting to nonclassical forms. Genotype-phenotype correlations based on predicted residual enzymatic activity have been widely studied, but data from Latin American populations remain scarce. Additionally, the influence of mutational burden on phenotype prediction has not been fully explored. ObjectiveTo evaluate the genotype-phenotype correlation and the impact of mutational burden on predictive accuracy in a Colombian cohort of patients with CAH. MethodsWe conducted a cross-sectional study of patients with confirmed CAH enrolled in a specialized rare disease program. Genotypic classification was based on predicted residual enzymatic activity (Null, A, B, C), and clinical phenotype was categorized as salt-wasting (SW), simple virilizing (SV), or nonclassical (NC). Genotype-phenotype concordance was defined as exact category agreement. Mutational burden was defined as the total number of pathogenic variants, dichotomized as low ([&le;]2 mutations) or high (>2). Penalized logistic regression (Firth method) was used to evaluate associations between mutational burden, sex, and concordance. ResultsAmong 48 patients with available genetic data, genotype-phenotype concordance was highest in severe genotypes: 100% in Null and 85.7% in Group A. In contrast, concordance declined in Group B (33.3%) and Group C (44.4%). Individuals with high mutational burden had significantly lower odds of concordance (OR = 0.18; 95% CI: 0.03-0.94). No significant interaction between sex and mutational burden was observed. More than one-third of Group C patients exhibited more severe phenotypes than predicted. ConclusionsOur findings support established genotype-phenotype correlations in CAH, particularly for severe genotypes. However, increased mutational burden was associated with reduced predictive accuracy, suggesting the need to consider total mutation load in clinical assessment and genetic counseling.

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.

ImportanceRET pathogenic variants cause Multiple Endocrine Neoplasia type 2 (MEN2), characterised by medullary thyroid cancer (MTC). With increasing incidental identification of these variants in asymptomatic individuals outside family screening, their risk of MTC and all-cause mortality without intervention remain unknown in this context. ObjectiveTo determine the risk of MTC and all-cause mortality in clinically unselected individuals and assess how the risk of MTC differ from clinically ascertained cases. Design, Setting, and ParticipantsProspective cohort study of 383,914 unrelated individuals from the clinically unselected UK population (UK Biobank) and 122,640 from the US health system (Geisinger cohort). We compared MTC risk in these cohorts to 1,078 individuals who were clinically ascertained with suspicion of MEN2 from UK routine practice. ExposuresRET pathogenic variants causing MEN2 Main Outcomes and MeasuresFrequency and the spectrum of pathogenic RET variants, Risk of clinically presented MTC, all-cause mortality without thyroidectomy. ResultsPathogenic RET variants were found in 0.04% of individuals from UK population cohort and 0.08% of individuals from US health system cohort. They were predominantly from moderate-risk category as per American Thyroid Association guideline (99.4% and 94.8% respectively). MTC risk by age 75 in variant carriers in the UK population was 2.2% (95% CI 0.7-6.8) and 19% (95% CI 5.7-30) in US health system cohort. This was significantly lower than the clinically ascertained cohort with the matched variants (95.7%, 95% CI 82.1-99.7 p<0.0001). In the UK Biobank, most variant carriers (98.2%) did not undergo thyroidectomy and their all-cause mortality by age 75 was similar to non-carriers (6.1%, 95% CI 2.7-13.8 vs 5.7%, 5.6-5.8, p=0.79), with consistent findings in the US health system cohort. Conclusions and RelevanceModerate-risk RET variants are most common in incidental cases. These variants carry substantially lower MTC risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making.

Breastfeeding is associated with metabolic benefits for women with type 2 diabetes and their infants, yet breastfeeding rates in these women are poorly described. Obesity is associated with type 2 diabetes, and lower breastfeeding rates, making it difficult to disentangle type 2 diabetes vs. obesity effects on breastfeeding. AimsThe primary objective was to examine breastfeeding rates in women with type 2 diabetes, compared to normoglycaemic women with either (1) matched body mass index (BMI) or (2) normal BMI. The secondary objective was to examine variables associated with breastfeeding. MethodsPregnant women with type 2 diabetes (cases) or normoglycaemia (controls) were prospectively recruited. Each case was matched with two controls by age and parity and either (1) matched or (2) normal (18-25 kg/m{superscript 2}) BMI. Data were collected from in-person surveys antenatally, medical records, and a four-month postpartum telephone survey. Analysis included descriptive and inferential statistics. ResultsFour-month breastfeeding data were available for 29, 29 and 28 women in each group. Breastfeeding rates were similar in women with type 2 diabetes and BMI-matched controls, both significantly lower than normal-BMI controls. ConclusionsMaternal obesity, rather than type 2 diabetes, may be the major determinant of reduced breastfeeding rates four-months postpartum.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women, often accompanied by various symptoms including significant pain, such as dysmenorrhea, abdominal, and pelvic pain, which remains underexplored. This retrospective study examines electronic health records (EHR) data to assess the prevalence of pain in women with PCOS. Conducted on May 29, 2024, using data from 120 Health Care Organizations within the TriNetX Global Network, the study involved 76,859,666 women from diverse racial backgrounds. The analysis focused on the prevalence of pain among women with PCOS, both overall and in those prescribed PCOS-related medications. Relative risk ratios (RR) were calculated for future health outcomes and stratified by self-reported race. The study found that 19.21% of women with PCOS experienced pain, with the highest prevalence among Black or African American (32.11%) and White (30.75%) populations. Both the PCOS and PCOS and Pain cohorts exhibited increased RR for various health conditions, with significant differences noted across racial groups for infertility, ovarian cysts, obesity, and respiratory diseases. Additionally, women with PCOS who were treated with PCOS-related medications showed a decrease in pain diagnoses following treatment. In conclusion, this study highlights the critical need to address pain in the diagnosis and management of PCOS due to its significant impact on patient health outcomes. Impact StatementInsufficient data exist on the prevalence of pain in women with a PCOS diagnosis, and its associations with future health outcomes. Among, 444,348 women with PCOS in the TriNextX Global Network, 19.21% have dysmenorrhea, abdominal, and pelvic pain. Women with PCOS and Pain are at increased risk for developing ovarian cysts, infertility, T2D, and fatty liver disease and are at further risk when stratified by self-reported race groups.

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.