Importance:Cardiovascular disease (CVD) is the leading cause of death among women worldwide. Pregnancy serves as a natural cardiovascular stress test and universal clinical encounter, yet few approaches leverage its insights to inform long-term cardiovascular risk. Objective:To determine whether clinical measures and biomarkers obtained during pregnancy may identify women at risk of long-term CVD. Design, Setting, and Participants:This was a registry-linked, population-based cohort study of all pregnancies reaching at least 22 weeks between June 2010 and October 2013 in Southern Denmark. Primary analyses were performed in a nested prospective subcohort of Odense Child Cohort participants with available pregnancy biomarker data. Women with preexisting CVD were excluded (n = 114). Follow-up was done through December 31, 2023. Among 38 455 eligible women, 2056 had biomarker data at week 12 or week 29. Analytic subsets with complete data were used for prognostic modeling at week 12 (n = 1379) and week 29 (n = 1389). Exposures:Clinical characteristics, obstetric outcomes, and pregnancy biomarkers including soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor, high-sensitivity cardiac troponin I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide. Main Outcomes and Measures:Incident maternal CVD, evaluated using Cox proportional hazards models. Results:In the biomarker cohort (median [IQR] age, 30.4 [27.4-33.8] years), 28 women (1.4%) developed CVD during a median (IQR) follow-up of 11.9 (11.2-12.5) years. Maternal age, hypertensive disorders of pregnancy (HDPs), and third-trimester concentrations of hs-cTnI and sFlt-1 were each independently associated with higher long-term CVD risk. A combined model including age and sFlt-1 measured at week 29 improved discrimination for CVD compared with a base model of age alone (ΔAUC, 0.16; 95% CI, 0.02-0.30), whereas a clinical model consisting of age, systolic blood pressure, and non-high-density lipoprotein cholesterol did not. Results were consistent in women without prior hypertension or HDPs and in nulliparous women. CVD incidence and the predictive value of the base model were comparable between the biomarker and the contemporaneous background cohorts (n = 36 274). Conclusions and Relevance:These findings support pregnancy as an opportunistic window for sex-specific cardiovascular risk assessment and prevention throughout a woman's life course. Further studies are warranted to validate these findings.

Background: Transgender individuals experience elevated depression and anxiety symptoms, often linked to gender dysphoria. While gender-affirming hormone therapy (GAHT) alleviates dysphoria, its effect on depression and anxiety remains unclear. Autism is prevalent among transgender individuals and may influence mental health trajectories. Aims: To examine changes in depression and anxiety during the first year of GAHT, considering gender, follow-up duration, and autism status. Methods: In this prospective study, 160 transgender individuals (71 transmasculine, median age 23 years, and 89 transfeminine, median age 24 years) completed the Patient-Health-Questionnaire-8 and Generalized-Anxiety-Disorder-7 at baseline, six weeks, and one year after GAHT initiation. Eighteen percent had autism. Mixed linear models examined effects of time, gender, and autism, adjusting for age and education. Post-hoc analyses stratified participants by clinically relevant (CR) baseline symptom levels (>= 10). Results: Baseline prevalence of CR depression was 34-42% and anxiety 16-32%. Overall, depression (beta = -1.9) and anxiety (beta = -1.1) decreased significantly (p < .001) after six weeks, returning to baseline after one year. However, those with baseline CR symptoms remained below baseline after one year (p < .05), whereas those without baseline CR symptoms exhibited increased scores after one year. Transmasculine reported higher anxiety than transfeminine individuals (beta = -1.6, p = .010) across time. Autism did not significantly affect depression and anxiety symptom level or trajectory. Conclusions: Mental health changes during the first year of GAHT were modest and heterogeneous. Depression and anxiety symptom trajectories were primarily related to baseline mental health rather than gender or autism status, which underscores the importance of mental health screening during GAHT.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Introduction Glucocorticoid therapy is prescribed for a variety of inflammatory conditions and is associated with severe adverse effects. A glucocorticoid withdrawal syndrome (GWS) may occur after prolonged glucocorticoid treatment—with or without biochemical glucocorticoid-induced adrenal insufficiency (GIAI). Previously, GWS was not considered an entity, probably due to the overlap between symptoms of GWS and GIAI. The Addison’s disease-specific quality of life questionnaire (AddiQoL-30) is a validated tool for quantifying symptoms of adrenal insufficiency resembling GWS. In the present study, we test the hypothesis that patients with a low AddiQoL-30 score and/or low cortisol response to a short Synacthen test (SST), after cessation of prednisolone treatment, may benefit from low-dose hydrocortisone therapy without increasing the risk of metabolic and cardiovascular disease during prolonged cortisol exposure.Methods and analysis REPLACE is a multi-centre, double-blinded, placebo-controlled randomised controlled trial in patients with polymyalgia rheumatica or giant cell arteritis after cessation of prednisolone treatment. Criteria for randomisation are an AddiQoL-30 score ≤85 and/or plasma cortisol response to SST, 30-min p-cortisol >100 and <420 nmol/L. Patients will be randomised to oral hydrocortisone (10 mg two times a day) or placebo for 16 weeks. Baseline and follow-up examinations comprise AddiQoL-30 questionnaire, SST, blood samples, standardised blood pressure, physical function tests and assessment of bone quality and body composition. At baseline, two comparator groups include: (1) patients with a SST-stimulated cortisol ≥420 nmol/L and AddiQoL-30 score >85; and (2) patients with a SST-stimulated cortisol ≤100 nmol/L.Ethics and dissemination The study is conducted in accordance with the Declaration of Helsinki, registered at the Clinical Trials Information System (CTIS: 2024-513822-53-00) and Clinicaltrials.gov (NCT05193396), and publications will be in accordance with the recommendations of the International Committee of Medical Journal Editors. The trial is monitored by local independent Good Clinical Practice units and overseen by the Danish Data Protection Agency (journal no. 21/27119), the Regional Committees on Health Research Ethics for Southern Denmark (project ID: S-20210076), the Danish Patient Safety Authority and the Danish Medicines Agency.Trial registration number NCT05193396.

Background Nonfunctioning pituitary neuroendocrine tumors (NFPitNETs) account for ∼30-35% of PitNETs; ∼75% arise from the SF1 lineage. Recurrence remains common despite resection (∼30% in 10 years), and routine histopathology/IHC has limited value in predicting recurrence risk. This study evaluated whether DNA methylation profiling improves recurrence risk stratification. Materials and Methods Genome-wide tissue methylation (Illumina EPIC v1, 850K) was analyzed in 117 retrospective NFPitNETs with clinical and imaging follow-up. Unsupervised consensus clustering defined methylation-based subgroups, followed by supervised differential methylation analysis to identify cluster-specific differentially methylated probes (DMPs). A classifier was trained using these signatures, with predicted subgroup memberships correlated with regrowth and progression-free survival (PFS). To ensure reliable estimations, longitudinal mixed-effects models were restricted to the interval of model stability (∼9 years), reflecting cohort follow-up. External validation was performed in 3 independent cohorts. Results Five clusters (k1-k5) emerged: 4 SF1-positive-predominant (k1, k2, k3, and k5) and 1 TPIT/PIT1-enriched NFPitNETs (k4). Among the 562 DMPs, many mapped to genes regulating cell-cycle and immune pathways. Compared with k1-k2, k3, k4, and k5 possessed significantly higher recurrence risk. Within SF1-lineage tumors, k3 exhibited postoperative tumor-volume expansion beginning at ∼6 years. The methylation-based classifier achieved ∼97% accuracy in assigning clusters and maintained prognostic separation across independent cohorts. Conclusions DNA methylation profiling identifies biologically and clinically distinct NFPitNET subgroups, particularly within the SF1 lineage, and may enhance prediction of recurrence risk. Prospective validation and demonstration of clinical utility are warranted to support integration into precision management workflows.

BACKGROUND:Cardiovascular disease (CVD) risk factors are prevalent in women with polycystic ovary syndrome (PCOS), but prospective data regarding CVD in population-based cohorts are limited. AIM:This study aims to investigate prospective risk of CVD in Nordic women with PCOS. DESIGN:This is a national register-based study in women with PCOS and age-matched controls originating from Denmark (PCOS Denmark, N = 27 298, controls, N = 135 019), Finland (PCOS Finland, N = 20 765, controls, N = 59 122), and Sweden (PCOS Sweden, N = 79 454, controls, N = 393 669). The main study outcome was CVD. Cardiovascular disease was defined according to ICD-10 diagnostic codes for major adverse cardiac events, pulmonary embolism, and/or deep venous thrombosis. Cox regression analyses estimated hazard ratio (HR) with 95% CI and adjusted analyses included body mass index (BMI) and education. RESULTS:The median age at cohort entry was 28 years (Denmark) and 29 years (Finland and Sweden) and the median follow-up time was 8.0-10.0 years. The unadjusted HR (95% CI) for CVD in women with PCOS was 1.30 (1.20; 1.41) in Denmark, 1.45 (1.31; 1.60) in Finland, and 1.52 (1.44; 1.60) in Sweden. Models remained significant after adjusting for obesity and level of education. In a combined meta-analysis including all countries (PCOS, N = 127 517, controls, N = 587 810), the adjusted HR for CVD in women with PCOS was 1.32 (1.25; 1.39). In women with BMI < 25 kg/m2 and no type 2 diabetes, the adjusted HR for CVD risk was 1.40 (1.26; 1.55). CONCLUSION:The risk of CVD was increased in women with PCOS across the 3 Nordic countries, also among women with BMI < 25 kg/m2.

Background:The mechanisms behind the increased occurrence of thrombosis associated with gender-affirming hormone treatment (GAHT) are not clarified. We hypothesized that GAHT alters fibrin clot characteristics (formation, lysis, and structure) in a prothrombotic direction. Objectives:To investigate changes in ex vivo fibrin clot characteristics after 12 months of feminizing or masculinizing GAHT. Methods:We included 251 transgender women and 320 transgender men aged >17 years in a prospective cohort study. Clot formation (velocity [V max], maximum absorbance [MA], and overall hemostasis potential [OHP]), clot lysis, and structure (fiber density and diameter) were studied by turbidity at baseline and after 12 months of feminizing GAHT (3 groups of oral/transdermal estradiol and cyproterone acetate) or masculinizing GAHT (7 groups of intramuscular/transdermal testosterone). Results:In transgender women, feminizing GAHT increased V max, MA, and OHP, while clot lysis decreased (total group, all P < .001). Oral estradiol was associated with the largest changes (Δ0-12 months: ΔOHP, 6.03 optical density × min; P = .02; Δclot lysis: -5.0%; P = .005). Fiber density and diameter remained unchanged. In transgender men, V max, MA, OHP, and fiber diameter decreased following masculinizing GAHT, whereas clot lysis and fiber density increased (total group, all P < .001). We observed no between-group differences in clot characteristics at 12 months or for changes (Δ0-12 months). Conclusion:Feminizing GAHT for 12 months had prothrombotic effects on the fibrin clot, whereas masculinizing GAHT had antithrombotic effects. The procoagulant effect was most evident with oral feminizing GAHT. This large cohort study provides important insights into the mechanisms linking GAHT to thrombotic risk.

BACKGROUND:Androgen receptors are highly expressed in upper body muscles, but changes in maximal muscle strength and power in major upper body muscles have not been investigated during gender-affirming hormone therapy (GAHT). OBJECTIVE:To assess prospective changes in maximal muscle strength and muscle power from before and after 1 year of GAHT. DESIGN AND METHODS:Clinical prospective study in 92 transgender persons: 26 transmasculine treatment-naïve (TransM_naïve), 27 transmasculine treatment-ongoing (TransM_ongoing), 29 transfeminine treatment-naïve (TransF_naïve), and 10 transfeminine treatment-ongoing (TransF_ongoing) were examined at baseline and after 1 year of GAHT. Primary outcomes were unilateral upper body maximal muscle strength (kg) and mean and maximal power (watt) measured by low-row dynamic testing. Dual-energy X-ray absorptiometry was conducted in all participants. RESULTS:In transmasculine persons, the median (quartiles) age was 22 (20; 30) years in TransM_naïve and 26 (22-29) years in TransM_ongoing (median GAHT duration 3 (2; 5) years) at study inclusion. Maximal muscle strength increased 6.3 kg (12%) in TransM_naïve (p ≤ 0.001) and 5.0 kg (7%) in TransM_ongoing (p ≤ 0.001), while maximal muscle power remained unchanged. ∆-muscle strength was positively associated with ∆-lean mass in arms and negatively associated with age at GAHT initiation. In transfeminine persons, the median age was 24 (22; 30) years in TransF_naïve and 40 (31-64) years in TransF_ongoing (median GAHT duration 4 (2; 6) years) at study inclusion. Maximal muscle strength decreased 17.5 kg (23%) in TransF_naïve and -5.0 kg (8%) in TransF_ongoing, which was accompanied by a decrease (23%) in maximal muscle power in TransF_naïve. CONCLUSION:Upper body muscle strength but not power increased during masculinizing GAHT, whereas muscle strength and power decreased within the first year of feminizing GAHT.

• Does adenomyosis increase risk of euploid pregnancy loss (PL)? • Is there a correlation of euploid PL and direct and/or indirect features of adenomyosis? No increased risk of euploid PL was observed in women with ultrasonographic signs of adenomyosis according to the revised MUSA (Morphological Uterus Sonographic Assessment) criteria. Adenomyosis is defined by benign invasion of the endometrium into the myometrium and disruption of the uterine anatomy. Diagnosis by histology is the gold standard, usually after hysterectomy. Recently, focus on non-invasive diagnostics has increased with the revised MUSA criteria for using transvaginal ultrasound for the diagnosis of adenomyosis. The impact of adenomyosis on fertility is conflicting as current literature range from showing no effect to lower live birth rates after in vitro fertilization and increased risk of PL in women with adenomyosis. The included patients are from an ongoing prospective cohort study in Denmark focused on PL from year 2020-2025, n = 2800. In a random sample of 375 women, two trained sonographers conducted a retrospective analysis of 3D ultrasound uterine volumes without Doppler. A questionnaire on physical health symptoms was answered 14 days after the pregnancy loss including questions on menstrual pain Women were included at the time of PL diagnosis. The ploidy status of the fetus, aneuploid or euploid, was determined using cell free fetal DNA analysis or direct sequencing of fetal tissue. 3D ultrasound uterine volumes without Doppler were performed four to eight weeks post-pregnancy loss. The revised MUSA-criteria were applied to describe adenomyosis by 3D ultrasonography by two sonographers. Women in the cohort were aged 20-45 years, with a mean BMI of 23.7 and with a mean gestational age of 9.3 weeks at time of the PL. In the evaluated 375 3D ultrasonographic scans, we did not observe any significant difference in the amount of direct and indirect MUSA features between women with euploid and aneuploid PL. Women with two or more PLs had a higher prevalence of irregular (OR = 1.57, p = 0.04) and disrupted junction zones (OR = 1.63, p = 0.03), compared to women with only one PL. Globular uterus tended to be more frequent in women with more than one PL (OR 1.7, p = 0.09), however insignificantly. Higher cumulative number of MUSA features was associated with higher age of the women, r-value 0.16 (p = 0.001). Women with severe menstrual pain more often experienced euploid PL, OR 1.44 (p = 0.03). The 3D-volumes were without Doppler, resulting in unassessed translesional vascularity, risking underestimating the effect of adenomyosis. Junctional-zone changes are more frequent in women with more than two PLs, indicating that changes in the junctional zone could be involved in the pathogenesis of some PL increasing the recurrence risk. The amount of direct and indirect MUSA features were comparable in women with euploid vs. aneuploid PL. No

Introduction:Testosterone and aggression have been positively associated, but it remains unclear whether gender-affirming hormone therapy (GAHT)-induced testosterone changes affect aggression in transgender persons. This study investigates aggression changes and associations between aggression and testosterone, depression, and anxiety during the first year of GAHT. Methods:Alternative-Short-Aggression-Questionnaire scores were assessed in transmasculine and transfeminine adults at baseline, six weeks, and one year post-GAHT initiation. Cisgender men and women were the comparison groups. Linear mixed effect models evaluated aggression score changes and group-differences, including effects of testosterone, depression, and anxiety, controlling for age and education. Results:Baseline data included 50 transmasculine (median age = 22 years), 62 transfeminine (median age = 24 years), 176 cisgender men (median age = 31 years), and 470 cisgender women (median age = 25 years). Seventy-one percent of transgender participants completed all follow-ups. Total and verbal aggression scores decreased after one year across transmasculine and transfeminine persons (mean difference (MD) = -1.6, p = .018 and MD = -0.8, p = .004), with no changes in other aggression dimensions. At baseline, transmasculine participants showed higher total aggression (MD = 3.4, p = .009) and anger (MD = 1.8, p < .001) scores than transfeminine persons. Transmasculine (MD = 3.3, p = .015) and transfeminine (MD = 6.5, p = <.001) persons had lower total aggression scores than cisgender men. Testosterone was not associated with aggression, whereas anxiety was significantly positively associated with aggression scores. Discussion:There was no GAHT-induced increased aggression in transmasculine persons. Total aggression scores decreased after one year across GAHT-types. Transgender aggression scores were significantly lower than cisgender men, indicating no risk of pathological aggression in the transgender population. Limitations included participant numbers and self-report measures.

AimsWomen with previous gestational diabetes mellitus (GDM) have an increased risk for later development of type 2 diabetes. During pregnancy, GDM affects the cardio-metabolic protein profile; however, it is unknown how GDM affects the cardio-metabolic protein profile in the long term and if it is associated with type 2 diabetes after GDM. We hypothesise that the cardio-metabolic protein profile is affected long term and is associated with the development of type 2 diabetes after GDM. Materials and MethodsA case-control follow-up study based on the Odense GDM Follow-Up Study (OGFUS) cohort, which included women with previous GDM (n = 128) and matched controls without previous GDM (n = 70). Blood samples from a follow-up assessment 8-10 years after delivery were analysed using a 29-plex panel of apolipoproteins, transport and inflammation/immune proteins using multiple-reaction-monitoring mass spectrometry. ResultsApolipoprotein A-I, D and M were significantly lower in women with previous GDM compared to controls (all p < 0.001), while apolipoprotein L-I, H, vitamin D binding protein, CRP, vitronectin, transthyretin and complement factors 3 and B were significantly higher (p = 0.008, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p = 0.005, respectively). All associations remained significant after adjustment for multiple testing except CRP, whereas apolipoprotein D, vitronectin and complement factors 3 and B were associated with the development of type 2 diabetes in women with previous GDM (p = 0.02, p = 0.001, p < 0.001, p = 0.004, respectively). ConclusionsThe cardio-metabolic protein profile 8-10 years after pregnancy is altered in women with previous GDM. Apolipoprotein D, vitronectin and complement factors 3 and B are candidate risk markers of type 2 diabetes after GDM pregnancy.

Context Maternal free testosterone (FT) increases during the third trimester and FT is higher in pregnant women with polycystic ovary syndrome (PCOS) compared to women without PCOS. Higher prenatal androgen exposure has previously been associated with increased catch-up growth in boys.Objective This work aimed to examine associations between maternal third-trimester testosterone and body composition in boys and girls.Methods This study comprised 1008 mother-child pairs (boys, n = 520) in the Odense Child Cohort (maternal PCOS, n = 101). Maternal FT was calculated from total testosterone (TT) analyzed by mass spectrometry at gestational week 28. Body composition assessments were performed in 7-year-old children by whole-body dual x-ray absorptiometry (DXA, n = 897) measuring body fat (fat mass index [FMI = fat mass(kg)/height(m)2]), percentages of total fat mass, gynoid, and android fat mass) and lean body mass, body weight, body mass index (BMI and BMI z scores), and abdominal circumference. The main outcome was body fat at age 7 years.Results In boys, a doubling in FT was associated with a 4.2% increase in FMI (P = .04) and an increase in BMI and BMI z score of 0.2 and 0.1 (P = .05 and .04), respectively. In girls, no statistically significant association was observed between maternal FT and body composition.Conclusion Boys exposed to higher prenatal levels of FT had higher fat mass, whereas no relation was seen in girls, suggesting a sex-specific susceptibility to prenatal testosterone exposure on child body composition.

IntroductionCardiovascular diseases (CVDs) present differently in women and men, influenced by host-microbiome interactions. The roles of sex hormones in CVD outcomes and gut microbiome in modifying these effects are poorly understood. The XCVD study examines gut microbiome mediation of sex hormone effects on CVD risk markers by observing transgender participants undergoing gender-affirming hormone therapy (GAHT), with findings expected to extrapolate to cisgender populations.Methods and analysesThis observational, longitudinal cohort study includes baseline, 1- and 2-year follow-ups with transgender participants beginning GAHT. It involves comprehensive phenotyping and microbiome genotyping, integrating computational analyses of high-dimensional data. Microbial diversity will be assessed using gut, skin, and oral samples via 16S rRNA and shotgun metagenomic sequencing of gut samples. Blood measurements will include sex hormones, CVD risk markers, cardiometabolic parameters, cytokines, and immune cell counts. Hair samples will be analysed for cortisol. Participants will complete online questionnaires on physical activity, mental health, stress, quality of life, fatigue, sleep, pain, and gender dysphoria, tracking medication use and diet to control for confounders. Statistical analyses will integrate phenomic, lifestyle, and multi-omic data to model health effects, testing gut microbiome mediation of CVD risk as the endocrine environment shifts between that typical for cisgender men to women and vice versa.Ethics and disseminationThe study adheres to Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the Charité Ethical Committee (EA1/339/21). Signed informed consent will be obtained. Results will be published in peer-reviewed journals and conferences and shared as accessible summaries for participants, community groups, and the public, with participants able to view their data securely after public and patient involvement review for accessibility.Trial registration numberThe XCVD study was registered on ClinicalTrials.gov (NCT05334888) as ‘Sex-differential host-microbiome CVD risk — a longitudinal cohort approach (XCVD)" on 4 April 2022. Data set link can be found athttps://classic.clinicaltrials.gov/ct2/show/NCT05334888.

OBJECTIVES:We aimed to investigate the potential associations between serum apolipoprotein levels in early pregnancy and the risk of gestational diabetes mellitus (GDM) and adverse pregnancy outcomes. METHODS:This was an observational study of the population-based Odense Child Cohort. Pregnant women were followed from inclusion until childbirth. Apolipoprotein levels, including 12 apolipoproteins (ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE, ApoH, ApoJ, and ApoM) were measured by targeted proteomics using liquid chromatography mass spectrometry on late first trimester serum samples stored in a biobank. GDM was defined by WHO 2013 diagnostic criteria. RESULTS:A total of 991 pregnant women were included, of which 415 (41.9%) were diagnosed with GDM. GDM was associated with increasing ApoB (adjusted odds ratio [OR]: 1.26, P = .002) and ApoD levels (adjusted OR: 0.84, P = .021). ApoB levels in early pregnancy correlated significantly and positively with insulin resistance (r = 0.22, P < .001) and beta-cell function in third trimester (r = 0.20, P < .001), whereas early pregnancy ApoD levels were inversely correlated with insulin resistance (r = -0.14, P < .001) and beta-cell function (r = -0.12, P < .001). Finally, high levels of ApoD was significantly associated with lower risk of large-for-gestational-age infants (adjusted OR: 0.78, P = .041). CONCLUSIONS:High levels of ApoB and low levels of ApoD in early pregnancy were independently associated with an increased risk of GDM, insulin resistance, and large-for-gestational-age infants (low ApoD only), suggesting potential roles for future management of pregnancy outcomes.

Importance: Mental and somatic health is often impaired among transgender persons. Studies regarding coexisting mental and somatic health outcomes among transgender persons are limited. Objective: To assess health diagnoses and medicine use among transgender persons compared with cisgender controls. Design, Setting, and Participants: This register-based national cohort study included data from January 1, 2000, to December 31, 2021. Transgender persons were included on the first date of receipt of a transgender identity contact code. Controls included 10 age-matched cisgender men (n = 5) and women (n = 5) for each transgender person. Statistical analyses were conducted from September to December 2024. Main Outcomes and Measures: The main outcomes were International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes and medicine use in a 5-year period up to the first date of transgender contact code for most commonly occurring mental and physical illnesses. The main outcomes were determined after data collection. Results: The cohort included 3812 transgender persons (1993 transmasculine persons [52.3%] with a median age of 19 years [IQR, 15-24 years] and 1819 transfeminine persons [47.7%] with a median age of 23 years [IQR, 19-33 years]) and 38120 cisgender controls. The odds for a mental health diagnosis was up to 12 times higher among transgender persons compared with cisgender controls. Among transmasculine and transfeminine persons, neurotic, stress-related disorders (transmasculine: adjusted odds ratio [AOR], 4.70 [95% CI, 4.02-5.50]; transfeminine: AOR, 5.27 [95% CI, 4.28-6.49]); developmental disorders, including autism (transmasculine: AOR, 11.67 [95% CI, 8.85-15.39]; transfeminine: AOR, 9.39 [95% CI, 7.05-12.50]); mood (affective) disorders (transmasculine: AOR, 5.41 [95% CI, 4.32-6.77]; transfeminine: AOR, 5.61 [95% CI, 4.16-7.57]); and behavioral disorders (transmasculine: AOR, 4.50 [95% CI, 3.61-5.62]; transfeminine: AOR, 4.15 [95% CI, 3.19-5.39]) were the most frequent mental health diagnoses compared with cisgender controls of the opposite sex at birth. Transmasculine persons had higher odds for somatic diagnosis codes of diabetes (AOR, 2.00 [95% CI, 1.12-3.56]), asthma (including chronic obstructive lung disease; AOR, 1.40 [95% CI, 1.06-1.85]), injury and poisoning (AOR, 1.28 [95% CI, 1.15-1.41]), and pain (AOR, 1.29 [95% CI, 1.12-1.49]) compared with control cisgender women. Among transfeminine persons, somatic diagnosis codes of infection (AOR, 1.68 [95% CI, 1.33-2.13]), anemia (AOR, 3.08 [95% CI, 1.36-6.97]), diabetes (AOR, 1.95 [95% CI, 1.25-3.05]), sleep apnea (AOR, 3.41 [95% CI, 1.84-6.31]), and pain (AOR, 1.31 [95% CI, 1.08-1.58]) were more frequent compared with control cisgender men. Transgender persons had higher use of psychopharmacologic medicine, antacids, and laxatives compared with cisgender controls (transmasculine persons vs control cisgender women, antipsychotics: AOR, 6.20 [95% CI, 5.07-7.59]; hypnotics-sedatives: AOR, 4.45 [95% CI, 3.78-5.23]; antacids: AOR, 1.25 [95% CI, 1.07-1.45]; and laxatives: AOR, 1.53 [95% CI, 1.17-1.99]; transfeminine persons vs control cisgender men, antipsychotics: AOR, 4.74 [95% CI, 3.92-5.74]; hypnotics-sedatives: AOR, 3.01 [95% CI, 2.53-3.57]; and antacids: AOR, 1.32 [95% CI, 1.12-1.56]). Mental health diagnoses and use of psychopharmacologic drugs were coexisting with somatic diagnoses and use of drugs for somatic diseases. Conclusions and Relevance: This cohort study of Danish transgender persons and cisgender controls found significantly higher risks for mental and somatic health diagnoses among transgender persons. Coexistence of mental health outcomes and somatic health outcomes among transgender persons could be associated with stress encountered due to belonging to a gender identity or sexual orientation minority group; mental and physical morbidity should be considered an integrated part of transgender care.

BACKGROUND:Pesticides are widespread in the environment and suspected endocrine disruptors that may interfere with sex hormones. Following the chlorpyrifos ban in 2020, use of alternative pesticides has increased; 2,4-Dichlorophenoxyacetic acid (2,4-D) remains widely used. This study examined the association between maternal pesticide exposure and pituitary, gonadal, and adrenal hormones in offspring during infancy. METHODS:We recruited pregnant women from 2010 to 2012 in the Odense Child Cohort, including 489 mother-child pairs. Maternal urinary concentrations of the generic pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA), the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCPY), and the herbicide 2,4-D were measured at gestational week 28. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), estrone (E1), estradiol (E2), 17-hydroxyprogesterone (17-OHP), Androstenedione (Adione), and Dehydroepiandrosterone sulfate (DHEAS) were assessed in infancy. Associations between prenatal pesticide exposure and offspring reproductive hormones (expressed as age- and sex-specific standard deviation (SD) scores) were assessed using multivariate linear regression. RESULTS:In girls, higher maternal urinary TCPY and 2,4-D concentrations were associated with lower LH (-0.07 SD, 95 % CI: - 0.13; - 0.01 and - 0.06 SD, 95 % CI: - 0.11; - 0.02, per 1 µg/L increase, respectively); there were trends towards associations between 3-PBA, TCPY, 2,4-D and lower LH, FSH, E1 and E2, respectively. No associations were seen in boys. CONCLUSION:In this low-exposed cohort, prenatal exposure to chlorpyrifos and 2,4-D may affect the reproductive hormones in girls, but not boys, during minipuberty, which may have long-term implications. This is of public health concern given the fact that > 90 % of participants were exposed.

Purpose: Gender affirmation surgery (GAS) refers to surgical procedures that align physical appearance with gender identity. Data are limited regarding GAS in national cohort studies and we aimed to assess GAS in Danish transgender persons.Methods: We conducted a national register-based cohort study in Danish transgender persons. Persons with International Classification of Diseases (ICD)-10 diagnosis code of "gender identity disorder" were included during 2000-2021 and surgical procedure codes were identified up to and including June 2022.Results: The cohort included 3812 transgender persons with median age (interquartile range) at study inclusion 19.0 (15.0; 24.0) years for persons assigned female sex at birth (AFAB, N=1993) and 23.0 (19.0; 33.0) years for persons assigned male sex at birth (AMAB, N=1819). The mean (standard deviation) follow-up duration was 4.5 (4.3) years. In persons AFAB, the 5-year cumulative incidence for GAS increased from 14.9 (7.0; 25.6) for persons diagnosed in 2000-2005 to 50.0 (45.9; 53.9) for persons diagnosed in 2014-2018. In persons AMAB, the 5-year cumulative incidence increased from 7.1 (3.5; 12.4) to 17.0 (13.8; 20.4). The mean waiting time from study inclusion to event of any GAS, top surgery or genital surgery, decreased throughout the study period in persons AFAB and persons AMAB. Genital constructive GAS was conducted in 1.4% transgender persons.Conclusions: The incidence of GAS increased and waiting time decreased for transgender persons diagnosed during 2000-2018. Genital constructive GAS was rarely performed in Danish transgender persons.