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St.Anna Kinderspital, Medical University of Vienna, Vienna, Austria
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Objective
Treatment of classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH but recommendations regarding dosage/administration are inconsistent. The aim of this study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicenter CAH registry.
Design
The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included.
Methods
A custom-made electronic health record software is used at the participating centers. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4.
Results
We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (604 boys; median age 7.2 years; 817 salt-wasting phenotype, 471 simple-virilizing phenotype). The mean (lower-upper quartiles) daily HC dose (mg/m² body surface area) was 19.4 (18.9–19.8) for patients <3 months (n = 329), 15.0 (14.6–15.3) for age ≥3–12 months (n = 463), 14.0 (13.7–14.3) for age 1–5.9 years (n = 745), 14.2 (14.0–14.5) for age 6 years to puberty entry (n = 669), and 14.9 (14.6–15.2) during puberty to 18 years (n = 801). Fludrocortisone was administered in 74.1% of patients with a median daily dosage of 88.8 µg.
Conclusion
Our analyses showed that still a high proportion of children are treated with HC doses higher than recommended. This evaluation provides comprehensive information on nationwide hydrocortisone substitution dosages in children with CAH underlining the benefit of systematic data within a registry to assess daily practice.
Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
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Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Centre for Gender Identity, Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
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Background
Gender dysphoria could be associated with low socioeconomic status (SES). SES could be modified by age, ethnic background, and medical morbidity.
Aim
To determine SES in a national study population including transgender persons in Denmark.
Methods
National register-based cohort study in Danish transgender persons and age-matched controls. The transgender study cohort included persons with ICD-10 diagnosis code of 'gender identity disorder' and/or persons with legal sex change and persons who fulfiled the inclusion criteria during 2000–2018. The main outcome measure was SES including personal income, occupational status, and education.
Results
The cohort included 2770 transgender persons and 27,700 controls. In the transgender study cohort, 1437 were assigned male at birth (AMAB), median age (interquartile range, IQR) 26.0 (17.3) years, and 1333 were assigned female at birth (AFAB), median age 22.5 (10.3) years. Adjusting for age and sex, the relative risk ratio (RRR) of low vs high personal income was 5.6 (95% CI: 4.9; 6.3) in transgender persons compared to controls. The RRR of low vs high income was 6.9 (5.8; 8.3) in persons AMAB compared to control males and 4.7 (3.9; 5.6) in persons AFAB compared to control females. The RRR of low vs high income was 3.7 (3.2; 4.3) in transgender persons of Danish origin compared to controls. The Charlson comorbidity index was comparable in transgender persons vs controls.
Conclusions
Being transgender was negatively associated with SES. In transgender persons, the risk of low vs high income could be more pronounced in transgender persons of foreign origin.
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Background
Hypogonadism is a key feature of Prader–Willi syndrome (PWS) but clear strategies for hormone replacement are lacking.
Objective
To evaluate the gonadal status and outcome in patients attending a Scottish PWS clinic from 1991 to 2019.
Methods
In 93 (35F:56M) patients, median follow-up 11.2 years, gonadal and pubertal status were assessed clinically. Pelvic ultrasound findings and basal/stimulated gonadotrophins were compared with age-matched controls.
Results
Females:of 22 patients aged > 11, 9 had reached B4–5, while 5 were still at B2–3, and 6 remained prepubertal. Eight patients experienced menarche aged 9.8–21.4 years, none with a normal cycle. Uterine length and ovarian volumes were normal but uterine configuration remained immature, with low follicular counts. Gonadotrophins were unremarkable, serum oestradiol 129 (70–520) pmol/L. Only 5 patients received oestrogen replacement. Males:fifty-four (96%) patients were cryptorchid (9 unilateral). Weekly hCG injections resulted in unilateral/bilateral descent in 2/1 of 25 patients. Of 37 boys aged > 11, 14 (9 with failed/untreated bilateral cryptorchidism) failed to progress beyond G1, 15 arrested at G2–3 (testes 3–10 mL), and 8 reached G4–5. Gonadotrophins were unremarkable except in boys at G2–5 in whom FSH was elevated: 12.3/27.3 vs 3.25/6.26 U/L in controls (P < 0.001). In males aged > 13, testosterone was 3.1 (0.5–8.4) nmol/L. Androgen therapy, given from 13.5 to 29.2 years, was stopped in 4/24 patients owing to behavioural problems.
Conclusion
Despite invariable hypogonadism, few females and only half the males with PWS in this study received hormone replacement. Double-blind placebo-controlled crossover trials of sex steroids are required to address unproven behavioural concerns.
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Abstract
Objective
The macimorelin test is approved for the diagnosis of adult growth hormone deficiency (AGHD) based on its efficacy vs the insulin tolerance test (ITT). Macimorelin has a significant advantage over ITT in avoiding hypoglycemia. Analyses were conducted to determine whether macimorelin performance is affected by age, BMI, or sex, and evaluate its performance vs ITT over a range of GH cutpoints.
Design
Post hoc analyses of data from a previous randomized phase 3 study included participants aged 18–66 years with BMI <37 kg/m2 and high (Group A), intermediate (Group B), or low (Group C) likelihood for AGHD based on pituitary history, and matched controls (Group D).
Methods
Probability of AGHD was estimated using unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted logistic models. Area under the curve (AUC) of the estimated receiver operating characteristic (ROC) curve (range, 0–1; 1 = perfect) was compared for adjusted vs unadjusted models. Separate analyses evaluated agreement, sensitivity, and specificity for macimorelin and ITT using cutpoints of 2.8, 4.0, 5.1, and 6.5 ng/mL.
Results
For participants in Group A (n = 41) and Group D (n = 29), unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted models had ROC AUCs (95% CIs) of 0.9924 (0.9807–1), 0.9924 (0.9807–1), 0.9916 (0.9786–1), and 0.9950 (0.9861–1), respectively.
Conclusions
Macimorelin performance was not meaningfully affected by age, BMI, or sex, indicating robustness for AGHD diagnosis. Of the 4 GH cutpoints evaluated, the cutpoint of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the ITT at the same cutpoint (87%).
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Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
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The objective of this study was to investigate whether there is a bidirectional association between testosterone concentrations and insulin resistance, in a prospective population study. A random population sample of 1400 men, aged 30–74, was examined in 2002–2005 in southwestern Sweden and followed up in 2012–2014 (N = 657). After excluding subjects without information on sex hormones and insulin resistance, 1282 men were included in the baseline study. Fasting measurements of plasma glucose, insulin and hormones were performed. Insulin resistance was defined using HOMA-Ir. Mean age at baseline was 47.3 ± 11.4 years. From the follow-up survey 546 men were included, mean age 57.7 ± 11.6 years. Low concentrations of total testosterone at baseline were significantly associated with high logHOMA-Ir at follow-up in a multivariable model including age, waist–hip ratio, physical activity, alcohol intake, smoking, LDL, CRP, hypertension, diabetes and logHOMA-Ir at baseline as covariates (β = −0.096, P = 0.006). Similar results were observed for bioavailable testosterone. Men within the lowest quartile of total testosterone at baseline had significantly higher logHOMA-Ir at follow-up than other quartiles (Q1 vs Q2 P = 0.008, Q1 vs Q3 P = 0.001, Q1 vs Q4 P = 0.052). Multivariable analysis of the impact of insulin resistance at baseline on testosterone levels at follow-up revealed no significant associations regarding testosterone concentrations (β = −0.003, P = 0.928) or bioavailable testosterone (β = −0.006, P = 0.873), when adjusting for baseline concentrations of total testosterone, age, waist–hip-ratio, LDL, CRP, physical activity, alcohol intake, smoking, hypertension and diabetes. Low testosterone concentrations at baseline predicted higher insulin resistance at follow-up, but high insulin resistance at baseline could not predict low testosterone at follow-up.
Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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NIHR Health Protection Research Unit on Chemical Radiation Threats and Hazards, Imperial College London, London, UK
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NIHR Health Protection Research Unit on Chemical Radiation Threats and Hazards, Imperial College London, London, UK
National Institute for Health Research (NIHR) Health Protection Research Unit in Environmental Exposures and Health, Imperial College London, London, UK
Mohn Centre for Children’s Health and Wellbeing, Imperial College London, London, UK
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NIHR Health Protection Research Unit on Chemical Radiation Threats and Hazards, Imperial College London, London, UK
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NIHR Health Protection Research Unit on Chemical Radiation Threats and Hazards, Imperial College London, London, UK
National Institute for Health Research (NIHR) Health Protection Research Unit in Environmental Exposures and Health, Imperial College London, London, UK
Mohn Centre for Children’s Health and Wellbeing, Imperial College London, London, UK
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Context
Salivary androgens represent non-invasive biomarkers of puberty that may have utility in clinical and population studies.
Objective
To understand normal age-related variation in salivary sex steroids and demonstrate their correlation to pubertal development in young adolescents.
Design, setting and participants
School-based cohort study of 1495 adolescents at two time points for collecting saliva samples approximately 2 years apart.
Outcome measures
The saliva samples were analyzed for five androgens (testosterone, androstenedione (A4), 17-hydroxyprogesterone, 11-ketotestosterone and 11β-hydroxyandrostenedione) using liquid chromatography-mass spectrometry; in addition, salivary dehydroepiandrosterone (DHEA) and oestradiol (OE2) were analysed by ELISA. The pubertal staging was self-reported using the Pubertal Development Scale (PDS).
Results
In 1236 saliva samples from 903 boys aged between 11 and 16 years, salivary androgens except DHEA exhibited an increasing trend with an advancing age (ANOVA, P < 0.001), with salivary testosterone and A4 concentration showing the strongest correlation (r = 0.55, P < 0.001 and r = 0.48, P < 0.001, respectively). In a subgroup analysis of 155 and 63 saliva samples in boys and girls, respectively, morning salivary testosterone concentrations showed the highest correlation with composite PDS scores and voice-breaking category from PDS self-report in boys (r = 0.75, r = 0.67, respectively). In girls, salivary DHEA and OE2 had negligible correlations with age or composite PDS scores.
Conclusion
In boys aged 11–16 years, an increase in salivary testosterone and A4 is associated with self-reported pubertal progress and represents valid non-invasive biomarkers of puberty in boys.
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Adult growth hormone deficiency (AGHD) is associated with an increased risk of cardiovascular (CV) disease. Long-term growth hormone (GH) treatment could improve CV outcomes. The objective of this study was to evaluate CV disease risk in patients with AGHD who received GH replacement therapy for up to 10 years as part of NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905). The studies were observational, non-interventional and multicentre, monitoring long-term effectiveness and safety of GH treatment. NordiNet® IOS involved 23 countries (469 sites) across Europe and the Middle East. The ANSWER Program was conducted in the USA (207 sites). This analysis included patients aged 18–75 years who were GH naïve at study entry, who had ≤10 years of GH treatment data and who could be assessed for CV risk for at least 1 follow-up year. The main outcome measure was risk of CV disease by age 75 years, as calculated with the Multinational Cardiovascular Risk Consortium model (Brunner score) using non-high-density lipoprotein cholesterol adjusted for age, sex and CV risk factors. The results of this analysis showed that CV risk decreased gradually over the 10-year period for GH-treated patients. The risk was lower for patients treated for 2 and 7 years vs age- and sex-matched control groups (not yet started treatment) (14.51% vs 16.15%; P = 0.0105 and 13.53% vs 16.81%; P = 0.0001, respectively). This suggests that GH treatment in people with AGHD may reduce the risk of CV disease by age 75 years compared with matched controls.
Osteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Kiel Institute for the World Economy, Kiel, Germany
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Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Science, Tehran, Iran
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Background
We aimed to document the current state of exposure to low bone mineral density (BMD) and trends in attributable burdens between 2000 and 2019 globally and in different World Health Organization (WHO) regions using the Global Burden of Disease (GBD) study 2019.
Methods
We reviewed the sex-region-specific summary exposure value (SEV) of low BMD and the all-ages numbers and age-standardized rates of disability-adjusted life years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), and deaths attributed to low BMD. We compared different WHO regions (Africa, the Eastern Mediterranean Region, Europe, Region of the Americas, Southeast Asia, and Western Pacific), age categories, and sexes according to the estimates of the GBD 2019 report.
Results
The global age-standardized SEV of low BMD is estimated to be 20.7% in women and 11.3% in men in 2019. Among the WHO regions, Africa had the highest age-standardized SEV of low BMD in women (28.8% (95% uncertainty interval 22.0–36.3)) and men (16.8% (11.5–23.8)). The lowest SEV was observed in Europe in both women (14.7% (9.9–21.0)) and men (8.0% (4.3–13.4)). An improving trend in the global rate of DALY, death, and YLL was observed during 2000–2019 (−5.7%, −4.7%, and −11.9% change, respectively); however, the absolute numbers increased with the highest increase observed in global YLD (70.9%) and death numbers (67.6%). Southeast Asia Region had the highest age-standardized rates of DALY (303.4 (249.2–357.2)), death (10.6 (8.5–12.3)), YLD (133.5 (96.9–177.3)), and YLL (170.0 (139–197.7)).
Conclusions
Overall, the highest-burden attributed to low BMD was observed in the Southeast Asia Region. Knowledge of the SEV of low BMD and the attributed burden can increase the awareness of healthcare decision-makers to adopt appropriate strategies for early screening, and also strategies to prevent falls and fragility fractures and their consequent morbidity and mortality.
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The global epidemic of obesity is closely linked to the development of serious co-morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several ‘mainstream’ hypotheses regarding obesity-related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies.
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Department of Pharmacology, Department of Biology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Room 4061 of KLSIC Building, 2146 West 39th Street, Kansas City, Kansas 66160, USA
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The endogenous estrogens are important modulators of the immune system and its functions. However, their effects are rather complex and many aspects have not been studied. In this study, we used the 1-chloro-2,4-dinitrobenzene (DNCB)-induced contact dermatitis as a disease model and investigated the effect of estriol (E3), along with two other estrogens, 17β-estradiol and estrone, on the pathogenesis of contact hypersensitivity. A series of parameters, such as ear swelling, skin inflammation, antigen-specific immunoglobulins, and lymphocyte compositions in peripheral lymphoid organs, were evaluated in mice following development of contact dermatitis. We found that administration of all three estrogens elicited strong inhibition of DNCB-induced dermatitis, while E3 exerted the strongest suppressive effect. Administration of E3 alleviated dermatitis, and this effect was accompanied by decreases in serum DNCB-specific immunoglobulins, such as IgA, IgG1, IgG2a, and IgG2b. Besides, treatment with E3 reduced B cell population, especially IgG-producing cells in the peripheral lymphoid organs following the induction of dermatitis. These observations consistently suggest that the antibody (Ab)-mediated humoral immune reactions play a critical role in the pathogenesis of DNCB-induced contact dermatitis. The results from this study demonstrate, for the first time, that estrogen administration has a strong suppressive effect on the pathogenesis of contact dermatitis. These findings offer important insights concerning the pathogenic role of antigen-specific Abs in contact dermatitis and the treatment of chemical-induced, Ab-mediated skin hypersensitivity reactions in humans.
