Transgender healthcare: metabolic outcomes and cardiovascular risk.

Transgender identity is often associated with gender dysphoria and minority stress. Gender-affirming hormone treatment (GAHT) includes masculinising or feminising treatment and is expected to be lifelong in most cases. Sex and sex hormones have a differential effect on metabolism and CVD in cisgender people, and sex hormone replacement in hypogonadism is associated with higher vascular risk, especially in ageing individuals. Using narrative review methods, we present evidence regarding metabolic and cardiovascular outcomes during GAHT and propose recommendations for follow-up and monitoring of metabolic and cardiovascular risk markers during GAHT. Available data show no increased risk for type 2 diabetes in transgender cohorts, but masculinising GAHT increases lean body mass and feminising GAHT is associated with higher fat mass and insulin resistance. The risk of CVD is increased in transgender cohorts, especially during feminising GAHT. Masculinising GAHT is associated with a more adverse lipid profile, higher haematocrit and increased BP, while feminising GAHT is associated with pro-coagulant changes and lower HDL-cholesterol. Assigned male sex at birth, higher age at initiation of GAHT and use of cyproterone acetate are separate risk factors for adverse CVD markers. Metabolic and CVD outcomes may improve during gender-affirming care due to a reduction in minority stress, improved lifestyle and closer surveillance leading to optimised preventive medication (e.g. statins). GAHT should be individualised according to individual risk factors (i.e. drug, dose and form of administration); furthermore, doctors need to discuss lifestyle and preventive medications in order to modify metabolic and CVD risk during GAHT. Follow-up programmes must address the usual cardiovascular risk markers but should consider that biological age and sex may influence individual risk profiling including mental health, lifestyle and novel cardiovascular risk markers during GAHT.

Prospective risk of Type 2 diabetes in 99 892 Nordic women with polycystic ovary syndrome and 446 055 controls: national cohort study from Denmark, Finland, and Sweden.

STUDY QUESTION: What is the prospective risk of Type 2 diabetes (T2D) in Nordic women with polycystic ovary syndrome (PCOS) compared to controls? SUMMARY ANSWER: A diagnosis of PCOS and BMI ≥30 kg/m2 is a high-risk phenotype for a prospective risk of T2D diagnosis across Nordic countries. WHAT IS KNOWN ALREADY: The risk of T2D in women with PCOS is increased. The risk of T2D is related to BMI and the magnitude of risk in normal weight women with PCOS has been discussed. However, prospective data regarding risk of T2D in population-based cohorts of women with PCOS are limited. STUDY DESIGN, SIZE, DURATION: This national register-based study included women with PCOS and age-matched controls. The main study outcome was T2D diagnosis occurring after PCOS diagnosis. T2D was defined according to ICD-10 diagnosis codes and/or filled medicine prescriptions of anti-diabetic medication excluding metformin. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study cohort included women originating from Denmark (PCOS Denmark, N = 27 016; controls, N = 133 994), Finland (PCOS Finland, N = 20 467; controls, N = 58 051), and Sweden (PCOS Sweden, N = 52 409; controls, N = 254 010). The median age at cohort entry was 28 years in PCOS Denmark, Finland, and Sweden with a median follow-up time (interquartile range) in women with PCOS of 8.5 (4.0-14.8), 9.8 (5.1-15.1), and 6.0 (2.0-10.0) years, respectively. Cox regression analyses were adjusted for BMI and length of education. MAIN RESULTS AND THE ROLE OF CHANCE: The crude hazard ratio (HR, 95% CI) for T2D diagnosis in women with PCOS was 4.28 (3.98-4.60) in Denmark, 3.40 (3.11-3.74) in Finland, and 5.68 (5.20-6.21) in Sweden. In adjusted regression analyses, BMI ≥30 vs <25 kg/m2 was associated with a 7.6- to 11.3-fold risk of T2D. In a combined meta-analysis (PCOS, N = 99 892; controls, N = 446 055), the crude HR for T2D in PCOS was 4.64 (3.40-5.87) and, after adjustment for BMI and education level, the HR was 2.92 (2.32-3.51). LIMITATIONS, REASONS FOR CAUTION: Inclusion of more severe cases of PCOS in the present study design could have lead to an overestimation of risk estimates in our exposed population. However, some women in the control group would have undiagnosed PCOS, which would lead to an underestimation of T2D risk in women with PCOS. BMI data were not available for all participants. The present study should be repeated in study cohorts with higher background risks of T2D, particularly in populations of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: The prospective risk for diagnosis of T2D is increased in women with PCOS, and the risk is aggravated in women with BMI ≥30 kg/m2. STUDY FUNDING/COMPETING INTEREST(S): Funding in Denmark was from the Region of Southern Denmark, Overlægerådet, Odense University Hospital. Funding in Finland was from Novo Nordisk Foundation, Finnish Research Council and Sigrid Juselius Foundation, the National Regional Fund, Sakari Alhopuro Foundation and Finnish Diabetes Research Foundation. E.E. has received a research grant from Ferring Pharmaceuticals (payment to institution) and serves as medical advisor for Tilly AB, not related to this manuscript. The remaining authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Impact of androgenic anabolic steroid use on cardiovascular and mental health in Danish recreational athletes: protocol for a nationwide cross-sectional cohort study as a part of the Fitness Doping in Denmark (FIDO-DK) study.

INTRODUCTION: The use of androgenic anabolic steroids (AASs) among recreational athletes is steadily increasing. However, knowledge regarding the potentially harmful effects of AAS primarily originates from case reports and small observational studies. This large-scale study aims to investigate the impact of AAS use on vascular plaque formation, preclinical coronary disease, cardiac function, circulating cardiovascular risk markers, quality of life (QoL) and mental health in a broad population of illicit AAS users. METHODS AND ANALYSES: A nationwide cross-sectional cohort study including a diverse population of men and women aged ≥18 years, with current or previous illicit AAS use for at least 3 months. Conducted at Odense University Hospital, Denmark, the study comprises two parts. In part A (the pilot study), 120 recreational athletes with an AAS history will be compared with a sex-matched and age-matched control population of 60 recreational athletes with no previous AAS use. Cardiovascular outcomes include examination of non-calcified coronary plaque volume and calcium score using coronary CT angiography, myocardial structure and function via echocardiography, and assessing carotid and femoral artery plaques using ultrasonography. Retinal microvascular status is evaluated through fundus photography. Cardiovascular risk markers are measured in blood. Mental health outcomes include health-related QoL, interpersonal difficulties, body image concerns, aggression dimensions, anxiety symptoms, depressive severity and cognitive function assessed through validated questionnaires. The findings of our comprehensive study will be used to compose a less intensive investigatory cohort study of cardiovascular and mental health (part B) involving a larger group of recreational athletes with a history of illicit AAS use. ETHICS AND DISSEMINATION: The study received approval from the Regional Committee on Health Research Ethics for Southern Denmark (S-20210078) and the Danish Data Protection Agency (21/28259). All participants will provide signed informed consent. Research outcomes will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: NCT05178537.

Maternal selenium deficiency during pregnancy in association with autism and ADHD traits in children: The Odense Child Cohort.

BACKGROUND: Selenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce. METHODS: 719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9+/-0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90th percentile. Multivariable regression models adjusted for biologically relevant confounders were applied. RESULTS: 155 of 719 (21.6 %) children had ASD traits and 59 of 719 (8.2 %) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 µg/L increment in selenium was 0.76 (95 % CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 µg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes. CONCLUSIONS: The results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial.

Gender affirming treatment and employment rate in 3,812 Danish transgender persons and 38,120 controls.

OBJECTIVE: Gender affirming care could be associated with higher employment rate. We assessed employment rates in transgender persons compared to controls and demographic, health and treatment-related factors associated with employment in transgender persons. METHODS: National register-based cohort study in Danish persons with diagnosis code of gender dysphoria during year 2000-2021. Five age-matched controls of the same sex at birth and five age-matched controls of the other sex at birth were included. The date of study inclusion was the first date of transgender diagnosis. Employment was the primary study outcome. RESULTS: The cohort included 3,812 transgender persons and 38,120 cisgender controls. The median age (interquartile range) was 19 (15; 24) years for transgender men, n = 1,993 and 23 (19; 33) years for transgender women, n = 1,819. In transgender men compared to control cisgender women, the odds ratio (95% confidence interval) for employment was 0.33 (0.29; 0.38) before study inclusion and 0.24 (0.20; 0.29) in the fifth calendar year after index; in transgender women compared to control cisgender men, corresponding ORs were 0.30 (0.70; 0.34) and 0.21 (0.18; 0.25). Similar findings were found between transgender persons and cisgender controls of other sex. Use of gender affirming hormone in transgender men increased probability of employment at all time points with odds ratio after 5 years: 1.61 (1.08; 2.42), p = 0.02 (95% confidence interval). In transgender women, use of hormone treatment was not associated with changed employment rates, 5 years odds ratio 1.31 (0.94; 1.82), p = 0.11. CONCLUSION: Masculinizing hormone treatment was associated with higher probability of employment.

Thyroid autoimmunity in euthyroid pregnant women is associated with slower productive language acquisition: the Odense child cohort study.

Objective: Maternal thyroid autoimmunity and thyroid function in early pregnancy may impact fetal neurodevelopment. We aimed to investigate how thyroid autoimmunity and thyroid function in early pregnancy were associated with language acquisition in offspring at 12-36 months of age. Methods: This study was embedded in the prospective Odense child cohort. Mother-child dyads were excluded in case of maternal intake of thyroid medication during pregnancy. The parents completed MacArthur-Bates Communicative Development Inventories (MB-CDI) every third month to assess their offspring's productive vocabulary. All completed reports for each child were included in the analyses. Logistic growth curve models evaluated associations between MB-CDI scores and levels of maternal thyroid peroxidase antibodies (TPOAb), free thyroxine (FT4), and thyrotropin, respectively, measured in early pregnancy (median gestational week 12). All models were stratified by offspring sex and adjusted for maternal age, education, pre-pregnancy body mass index, parity, breastfeeding, and offspring age. Results: The study included 735 mother-child dyads. Children born to mothers with TPOAb ≥11 kIU/L, opposed to TPOAb <11 kIU/L, had a lower probability of producing words at age 18-36 months for girls (OR = 0.78, P < 0.001) and 33-36 months for boys (OR = 0.83, P < 0.001). The probability of producing words was higher in girls at 30-36 months of age with low-normal maternal FT4 vs high-normal FT4 (OR = 0.60, P < 0.001), and a similar trend was seen in boys. Results were ambiguous for thyrotropin. Conclusion: In women without known thyroid disease, TPOAb positivity in early pregnancy was negatively associated with productive vocabulary acquisition in girls and boys. This association was not mediated by a decreased thyroid function, as low-normal maternal FT4, unexpectedly, indicated better vocabulary acquisition. Our results support that maternal thyroid autoimmunity per se may affect fetal neurodevelopment.

Whole-body oxidative stress reduction during testosterone therapy in aging men: A randomized placebo-controlled trial.

BACKGROUND: Testosterone replacement therapy in aging men increases lean body mass and decreases whole-body fat. The safety of testosterone replacement therapy concerning cardiovascular disease is unresolved and assessment of whole-body oxidative stress may contribute to future decision making. OBJECTIVES: To determine whole-body oxidative stress during testosterone replacement therapy and placebo in aging men and evaluate if a change in oxidative stress was mediated by changed body composition. MATERIALS AND METHODS: This was a double-blinded, randomized, placebo-controlled study for 24 weeks in 38 men aged 60-78 years with bioavailable testosterone <7.3 nmol/L and waist circumference ≥94 cm who were randomized to testosterone replacement therapy (testosterone gel) (N = 20) or placebo (N = 18). At baseline and after 24 weeks, whole-body oxidative stress was assessed by oxidized derivatives of nucleic acids, 8-oxoguanosine and 8-oxo-2'-deoxyguanosine in 24-h urine samples by ultra-performance liquid chromatography tandem mass spectrometry. Lean body mass and whole-body fat were measured by dual X-ray absorptiometry. Subcutaneous and visceral adipose tissue were estimated by magnetic resonance imaging. Testosterone replacement therapy versus placebo was compared by Mann-Whitney tests on ∆-values (24-0 weeks). RESULTS: Baseline age was 67 (64-72) years (median [interquartile range]), body mass index 29.8 (26.6-33.3) kg/m2 , waist 107 (99-117) cm, and bioavailable testosterone 4.7 (3.7-5.9) nmol/L. During testosterone replacement therapy, 8-oxoguanosine in 24-h urine samples decreased from 21.6 (19.8; 27.7) nm to 15.0 (12.2; 18.8) nm (p = 0.038 vs. placebo), lean body mass increased (p < 0.01) and whole-body fat (p = 0.02) and subcutaneous adipose tissue (p < 0.01) decreased. 8-Oxoguanosine in 24-h urine samples was inversely associated with Δ-lean body mass (ρ = -0.38, p = 0.03), which remained significant after adjusting for Δ-total testosterone. 8-Oxo-2'-deoxyguanosine in 24-h urine samples was unchanged (p = 0.06) during testosterone replacement therapy and Δ-8-oxo-2'-deoxyguanosine in 24-h urine samples was associated with Δ-whole-body fat (kg) (ρ = 0.47, p < 0.01). Δ-Values of oxidative stress biomarkers were not associated with Δ-fasting insulin or Δ-homeostatic model assessment of insulin resistance. DISCUSSION: Oxidative stress decreased during testosterone replacement therapy compared to placebo, which could be mediated by changed body composition. CONCLUSION: Whole-body oxidative stress decreased during 24 weeks of testosterone replacement therapy in aging men.

Blood pressure responses to testosterone therapy are amplified by hematocrit levels in opioid-induced androgen deficiency: a double-blind, randomized, placebo-controlled trial.

Our study aimed to examine the effect of testosterone replacement therapy (TRT) on blood pressure in opioid-treated men with relative hypogonadism, and whether the effect of TRT on blood pressure was modified by body composition, red blood cell levels, or carotid intima media thickness. Men (over 18 years old) receiving opioid treatment and total testosterone less than 12 nmol were randomly assigned to receive either TRT or placebo. Baseline and 6-month measurements included anthropometric measurements, office blood pressure (OBPM), 24-h ambulatory blood pressure, blood samples, and carotid ultrasound. The mean systolic OBPM increased by 6.2 mmHg (0.2-12.1) in the TRT group and decreased by 7.0 mmHg (1.0-15.1) in the placebo group, with a mean difference of 13.2 mmHg (3.4-23.1), P  = 0.01. In the TRT group, a 10 mmHg increase in systolic OBPM was associated with an increase in hematocrit of 0.3% points (0.1-0.5) ( P  = 0.01), whereas no association was observed in the placebo group ( P  = 0.266). Daytime SBP showed a nonsignificant increase of 5.2 mmHg (-1.7, 12.1) ( P  = 0.134) in the TRT group compared to that in the placebo group. However, the impact of TRT on the increase in daytime ambulatory blood pressure was significantly accentuated by baseline values of BMI, hematocrit, and hemoglobin. In conclusion, TRT was associated with higher OBPM compared to placebo, and the increase in blood pressure was linked to higher hematocrit during TRT. Our data suggest that men with opioid-induced androgen deficiency, particularly those with obesity or red blood cell levels in the upper normal range, are more susceptible to increased daytime SBP during TRT.

Hepcidin Reduction during Testosterone Therapy in Men with Type 2 Diabetes: A Randomized, Double-Blinded, Placebo-Controlled Study.

High hepcidin is linked to low-grade inflammation and lower iron levels. The consequences of testosterone replacement therapy (TRT) on inflammation and the risk of cardiovascular disease (CVD) are undetermined. We investigate the effect of TRT on the inflammatory cardiovascular risk markers hepcidin-iron, fibroblast growth factor 23 (FGF23)-phosphate-klotho, and calprotectin pathways. METHODS: A randomized, placebo-controlled, double-blinded study at an academic tertiary-care medical center. Interventions were testosterone gel (TRT, n = 20) or placebo gel (n = 19) for 24 weeks. We included 39 men (50-70 years) with type 2 diabetes (T2D) on metformin monotherapy with bioavailable testosterone levels <7.3 nmol/L. Body composition was assessed with DXA- and MRI-scans; the main study outcomes were serum hepcidin-iron, FGF23, phosphate, klotho, and calprotectin. RESULTS: Hepcidin levels decreased during TRT (ß = -9.5 ng/mL, p < 0.001), lean body mass (ß = 1.9 kg, p = 0.001) increased, and total fat mass (ß = -1.3 kg, p = 0.009) decreased compared to placebo. Delta hepcidin was not associated with changes in lean body mass or fat mass. Iron and the pathways of FGF23-phosphate-klotho and calprotectin were unchanged during TRT. CONCLUSIONS: During TRT, the reduction in hepcidin was not associated with circulating iron levels, lean body mass, or fat mass; these findings suggested a direct anti-inflammatory effect of TRT and no indirect effect mediated through these factors.

Serum selenium, selenoprotein P, and glutathione peroxidase 3 during early and late pregnancy in association with gestational diabetes mellitus: Prospective Odense Child Cohort.

BACKGROUND: Diet is an important modifiable risk factor for gestational diabetes mellitus (GDM) and its related complications; however, the role of essential micronutrients such as selenium (Se), particularly in populations with low Se intake, is inconclusive. OBJECTIVES: The aim was to investigate the association of 3 established biomarkers of Se status with GDM, gestational glucose metabolism, and large for gestational-age offspring. METHODS: This study included 1346 pregnant females with 2294 serum samples from the prospective, population-based Odense Child Cohort study, Denmark. Serum Se, selenoprotein P (SELENOP) concentrations, and glutathione peroxidase 3 (GPX3) activity were measured in early and late pregnancy, and fasting glucose and insulin assessments in late pregnancy. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was calculated, and the GDM definition was according to the WHO 2013 threshold of fasting venous plasma glucose of ≥5.1 mmol/L. A subcohort underwent an oral glucose tolerance test. Regression models adjusted for various confounders quantified dose-dependent associations. RESULTS: Se and SELENOP declined during pregnancy. There were dose-dependent inverse associations of early GPX3 with late pregnancy GDM (WHO 2013), fasting glucose, insulin, HOMA-IR, and 2 h glucose. The odds ratio (OR) of GDM was 0.33 (95% CI: 0.16, 0.65) for 1 log-scale-increment in early GPX3 activity. Late pregnancy GPX3 and SELENOP were inversely associated with GDM and HOMA-IR; the OR of GDM was 0.21 (95% CI: 0.12, 0.38) and 0.52 (95% CI: 0.35, 0.77), for 1 log-scale-increment of GPX3 and SELENOP, respectively. A decline in Se biomarkers during pregnancy was associated with a higher risk of GDM and higher HOMA-IR. Low GPX3 activity in late pregnancy was associated with a higher risk of large for gestational-age offspring, partly (∼20%) mediated by fasting glucose concentrations (P = 0.006). CONCLUSIONS: Low serum Se in pregnancy, particularly GPX3 activity, is independently associated with risk of GDM and large for gestational age. Offering Se status assessment in pregnancy identifies females at high risk for GDM who may benefit from Se substitution.

Gender-affirming treatment and mental health diagnoses in Danish transgender persons: a nationwide register-based cohort study.

IMPORTANCE: Gender affirming treatment aims to improve mental health. OBJECTIVE: To investigate longitudinal mental health outcomes in Danish transgender persons. DESIGN: National register-based cohort study in Danish transgender persons with diagnosis code of "gender identity disorder" during the period 2000-2021. PARTICIPANTS: Five age-matched controls of the same sex at birth and five age-matched controls of the other sex at birth were included for each transgender person. MAIN OUTCOMES: Diagnosis codes of mental and behavioral disorders and/or prescription of psychopharmacological agents until June 2022. RESULTS: The cohort included 3812 transgender persons with median age (interquartile range) 19 (15; 24) years for persons assigned female at birth (AFAB, N = 1993) and 23 (19; 33) years for persons assigned male at birth (AMAB, N = 1819) and 38 120 controls. Follow up duration was up to 10 years with mean (standard deviation) 4.5 (4.3) years. In transgender persons AFAB compared to control women, the odds ratio (OR) (95% confidence interval) for mental and behavioral disorders was 6.7 (5.5; 8.1) before the index date, 9.9 (8.4; 11.7) at 1 year, 5.8 (4.4; 7.7) at 5 years, and 3.4 (2.1; 7.5) at 8 years follow up. In transgender persons AMAB compared to control men, corresponding ORs were 5.0 (4.0; 6.4), 11.3 (9.3; 13.7), 4.8 (3.5; 6.5), and 6.6 (4.2; 10.3) at 8 years follow up (all P < .001). CONCLUSION: The OR for mental health disorders was higher in transgender persons compared to controls and remained elevated throughout follow up, especially in transgender persons AMAB.

SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. DISCUSSION: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. TRIAL REGISTRATION: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Maternal cortisol levels in third trimester and early language development: A study of 1093 mother-child pairs from the Odense Child Cohort.

Language development during early childhood is considered an important marker of fetal neurodevelopment. Prenatal cortisol exposure plays a critical role in maturation of the fetal brain; however, the effect on offspring language development needs further investigation. In this prospective observational study we aimed to evaluate the association between maternal third trimester cortisol and early longitudinal offspring language development in the Odense Child Cohort (OCC) and to test whether there were sex differences in the association. The study cohort included 1093 mother-child dyads (570 boys and 523 girls). Fasting morning serum (s-) cortisol was collected from third trimester (gestational week 26-28) pregnant women and measured by liquid chromatography-tandem mass spectrometry. Offspring receptive and productive vocabulary assessments by MacArthur-Bates Communicative Development Inventories parent reports were completed every third month from children age 12-37 months. Levels of cortisol were higher in women carrying a girl (858 ± 214 nmol/L) than in women carrying a boy (820 ± 222 nmol/L). Higher third trimester maternal cortisol levels showed a positive association with development of productive vocabulary in boys at age 12-21 months (OR = 1.23, SE = 0.07, p = .005) and age 22-37 months (OR = 1.09, SE = 0.06, p = .967). Higher maternal cortisol levels in the third trimester were positively associated with receptive vocabulary in girls at 12-21 months of age (OR = 1.16, SE = 0.05, p = .002). Maternal third trimester s-cortisol levels were positively associated with early language development in children at age 12-37 months.

Maternal cortisol in 3rd trimester is associated with traits of neurodevelopmental disorder in offspring. Odense Child Cohort.

BACKGROUND: Prenatal cortisol exposure is essential for neurodevelopment. Maternal cortisol levels could be associated with offspring autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). AIM: To investigate associations between maternal 3rd trimester cortisol and offspring traits of ASD and ADHD. MATERIAL AND METHODS: Mother-child pairs were included from the prospective study Odense Child Cohort. Morning serum cortisol and 24-hour urine cortisol/cortisone were collected at gestational week 27-30. Offspring ASD and ADHD traits were assessed at age three and five years using the Child Behavior Checklist. Maternal cortisol measurements and offspring ASD and ADHD traits assessment were available in (n = 1131; 52% boys) mother-child pairs at age three and (n = 717; 54% boys) at five years of age. Maternal 24-hour urine measurement was available in a subset, at offspring three years of age (n = 300) and at five years of age (n = 217). Associations between maternal cortisol (continuous and tertiles) and offspring ASD or ADHD traits were examined in regression models adjusted for offspring sex, maternal age, pre-pregnancy BMI, parity, maternal education level, parental psychiatric disorders, and maternal smoking and stratified for offspring sex. RESULTS: Maternal mean age ( ± SD) was 30 years ( ± 4.4) and median BMI (25%; 75% percentiles) 23.5 kg/m2 (21.3; 26.6). Higher maternal serum cortisol levels were associated with higher prevalence of offspring ASD traits at three years of age in the total study cohort and in boys after stratifying for offspring sex. In the total population, tertiles of serum cortisol showed a significant dose-response relationship to ASD traits in unadjusted and adjusted models (p-values for linear trend, p < 0.01 and p = 0.02, respectively). In offspring at five years, associations between maternal cortisol and offspring ASD traits were non-significant (all p-values > 0.2). Maternal cortisol was not associated with offspring ADHD traits (all p-values > 0.07) in offspring at three and five years. Maternal 24-hour urine cortisol, cortisone, or cortisol/cortisone ratio were not associated with offspring ASD or ADHD traits. CONCLUSION: Higher maternal serum cortisol in 3rd trimester was associated with offspring ASD traits at three years of age in the whole study cohort and in boys, but not in girls. This association was non-significant at five years of age.

Effects of DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors and sulphonylureas on mortality, cardiovascular and renal outcomes in type 2 diabetes: A network meta-analyses-driven approach.

AIMS: The aim of our meta-analyses was to compare the effects of glucose-lowering drugs on mortality, cardiovascular and renal endpoints for a range of type 2 diabetes (T2D) subgroups defined by their specific cardiovascular risk profile. METHODS: Meta-analyses comparing drugs within the classes of GLP-1RAs and SGLT-2 inhibitors were performed and compared to sulphonylureas and DPP-4 inhibitors with available cardiovascular outcome trials. The comparison between the different classes of glucose-lowering drugs included analyses of T2D populations with low risk and high risk for cardiovascular disease including populations with established cardiovascular disease and/or kidney disease. Outcomes included mortality, major cardiovascular adverse events (MACE), hospitalisation for heart failure (HHF) and a composite renal endpoint as applied in the underlying clinical trials. RESULTS: SGLT-2 inhibitors and GLP-1RAs showed beneficial effects on mortality and MACE compared to the classes of DPP-4 inhibitors and sulphonylureas. SGLT-2 inhibitors were shown to be the most effective treatment in terms of HHF and kidney disease. Metformin was used as background therapy for the vast majority of participants in all included studies. Overall, the absolute effects of SGLT-2 inhibitors and GLP-1RAs on these important outcomes were evident for patients with established or at high risk for cardiovascular disease but limited for the low-risk subgroup. CONCLUSIONS: The findings from our analyses substantiate the relevance of treatment with SGLT-2 inhibitors or GLP-1RAs as an add-on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT-2 inhibitor treatment in patients with T2D and heart failure or established kidney disease.

Higher Maternal Cortisol Associated With Lower Blood Pressure in Offspring From 3 Months to 5 Years of Age in the Odense Child Cohort.

BACKGROUND: Synthetic glucocorticoid exposure in late pregnancy may be associated with higher blood pressure in offspring. We hypothesized that endogenous cortisol in pregnancy relates to offspring blood pressure (OBP). OBJECTIVE: To investigate associations between maternal cortisol status in third trimester pregnancy and OBP. METHODS: We included 1317 mother-child pairs from Odense Child Cohort, an observational prospective cohort. Serum (s-) cortisol and 24-hour urine (u-) cortisol and cortisone were assessed in gestational week 28. Offspring systolic blood pressure and diastolic blood pressure were measured at age 3, 18 months, and 3 and 5 years. Associations between maternal cortisol and OBP were examined by mixed effects linear models. RESULTS: All significant associations between maternal cortisol and OBP were negative. In boys in pooled analyses, 1 nmol/L increase in maternal s-cortisol was associated with average decrease in systolic blood pressure (ß=-0.003 mmHg [95% CI, -0.005 to -0.0003]) and diastolic blood pressure (ß=-0.002 mmHg [95% CI, -0.004 to -0.0004]) after adjusting for confounders. At 3 months of age, higher maternal s-cortisol was significantly associated with lower systolic blood pressure (ß=-0.01 mmHg [95% CI, -0.01 to -0.004]) and diastolic blood pressure (ß=-0.010 mmHg [95% CI, -0.012 to -0.011]) in boys after adjusting for confounders, which remained significant after adjusting for potential intermediate factors. CONCLUSIONS: We found temporal sex dimorphic negative associations between maternal s-cortisol levels and OBP, with significant findings in boys. We conclude that physiological maternal cortisol is not a risk factor for higher blood pressure in offspring up to 5 years of age.

Testosterone therapy increases the anticoagulant potential in men with opioid-induced hypogonadism: a randomized, placebo-controlled study.

Introduction: Hypogonadism is prevalent during opioid treatment, and low testosterone concentrations are associated with cardiovascular disease. The effect of testosterone replacement therapy (TRT) on the coagulation system in men with hypogonadism is not clarified. We investigate the effects of TRT on the tissue factor (TF) and contact activation pathways of coagulation in opioid-treated men. Materials and methods: This was a double-blinded, placebo-controlled study in 37 men with total testosterone < 12 nmol/L randomized to 24 weeks of testosterone injections (n = 17) or placebo (n = 20). Variables of the coagulation system were analysed at baseline and after 24 weeks. Measurements included the TF pathway (endogenous thrombin potential (ETP) and peak thrombin), the contact activation pathway (endogenous kallikrein potential (EKP) and peak kallikrein), coagulation factors (FVII, FX, prothrombin, and FXII), and inhibitors (tissue factor pathway inhibitor (TFPI), protein C, protein S, antithrombin, and C1 esterase inhibitor (C1inh)). Between-group differences at 24 weeks were determined with analysis of covariance. Within-group changes in TRT and placebo were analysed with paired t-test. Results: Between-group differences at 24 weeks were observed for ETP (P = 0.036), FVII (P = 0.044), FX (P = 0.015), prothrombin (P = 0.003), protein C (P = 0.004), and protein S (P = 0.038). Within the TRT group, ETP, peak thrombin, FVII, FX, prothrombin, TFPI, protein C, FXII, and C1inh decreased and protein S increased (all P < 0.05). Within the placebo group, coagulation outcomes were unchanged. Conclusion: TRT affects the coagulation system in an anticoagulant direction through suppressed TF pathway in men with opioid-induced hypogonadism.

Prenatal Androgen Exposure and Traits of Autism Spectrum Disorder in the Offspring: Odense Child Cohort.

Fetal androgen exposure may be associated with autism spectrum disorder (ASD). We studied 1777 mother-child pairs in the prospective Odense Child Cohort. Prenatal androgen exposure was assessed by maternal 3rd trimester testosterone concentrations, maternal polycystic ovary syndrome (PCOS), and 3 months offspring anogenital distance. ASD traits were assessed at age 3 years with the ASD-symptom scale of the Child Behavior Checklist for ages 1½-5 years. Maternal testosterone was positively associated with traits of ASD in boys (p < 0.05). Maternal PCOS was associated with increased offspring ASD traits (p = 0.046), but became non-significant after excluding parental psychiatric diagnosis. Offspring anogenital distance was not linked to ASD traits. Higher prevalence of ASD in boys could be linked to higher susceptibility to fetal androgen exposure.

Myoinositol vs. Metformin in Women with Polycystic Ovary Syndrome: A Randomized Controlled Clinical Trial.

Polycystic ovary syndrome (PCOS) is associated with insulin resistance. Few randomized controlled trials (RCT) compared myoinositol (MI) with metformin (MET) regarding insulin resistance in PCOS. This was an open-label six-month RCT in women with PCOS (n = 45) with interventions MI 4 g/day or MET 2 g/day. Primary outcome was the homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were fasting glucose, weight, cycle length, lipids, testosterone, adverse effects, quality of life, and depression scores. Median age was 26 years. Body mass was index was 34.4 kg/m2. HOMA-IR was unchanged during MI (p = 0.31) and MET (p = 0.11) (MI vs. MET, p = 0.09). Median fasting glucose changed +0.2 mmol/L during MI (p < 0.001) and −0.1 mmol/L during MET (p = 0.04) (MI vs. MET p < 0.001). Median weight changed −2.3 kg during MI (p = 0.98) and −6.1 kg during MET (p < 0.001) (MI vs. MET, p = 0.02). Median cycle length decreased nine days during MI (p = 0.03) and 13 days during MET (p = 0.03) (MI vs. MET, p = 0.93). High-density lipoprotein (HDL) changed +0.1 mmol/L during MET (p = 0.04) (MI vs. MET, p = 0.07). All other blood parameters and scores of quality of life and depression remained unchanged during MI and MET (all p > 0.06) (MI vs. MET, all p > 0.27). Adverse effects appeared in four women during MI and 16 women during MET (MI vs. MET, p = 0.001). In conclusion, there was no effect on the metabolic outcomes during MI, but positive effects on fasting blood glucose, weight, and HDL during MET. The effect on cycle length was comparable during MI and MET. Adverse effects were less frequent during MI.

Diabetes Mellitus Mediates Risk of Depression in Danish Women with Polycystic Ovary Syndrome-A National Cohort Study.

AIM: To investigate the risk of depression in Danish women with PCOS compared to controls and possible mediators for depression in PCOS. National register-based study in Danish women with PCOS (PCOS Denmark, N = 25,203) and age-matched controls (N = 112,414). PCOS Odense University Hospital (PCOS OUH, N = 998) was a sub-cohort of women with PCOS with available clinical and biochemical results. The main study outcome was depression occurring after PCOS diagnosis. Depression was defined according to hospital ICD-10 diagnosis codes and/or inferred from filled medicine prescription of antidepressants. Diabetes, medical comorbidity, infertility, hormonal anti-contraception and low family income were entered as mediators in Cox regression analyses for depression. In PCOS OUH, PCOS characteristics (age, BMI, Ferriman-Gallwey score) were entered in Cox regression analyses. The median age at cohort entry was 28 (interquartile range (IQR) 23; 35) years. The median follow-up time to incident depression or censuring was 4.8 (IQR 2.2; 8.8) years in PCOS Denmark and 5.2 (IQR 2.4; 9.2) years in controls. Women with PCOS had a 40% increased risk of depression compared to controls (Hazard Ratio 1.42 (95% CI 1.38; 1.47). In regression analyses, diabetes, medical comorbidity, infertility, hormonal anticonception, and low family income were significant mediators of depression. Mediation analyses showed that the proportion of the association explained by diabetes was 12.5% (95% CI 10.4; 14.5). In PCOS OUH, BMI, waist and Ferriman-Gallwey score predicted development of depression. CONCLUSION: The risk of depression was increased in PCOS. Diabetes was an important mediator of depression in PCOS.