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Open access

Hanna F Nowotny, Leah Braun, Frederick Vogel, Martin Bidlingmaier, Martin Reincke, Lea Tschaidse, Matthias K Auer, Christian Lottspeich, Stefan A Wudy, Michaela F Hartmann, James Hawley, Joanne E Adaway, Brian Keevil, Katharina Schilbach, and Nicole Reisch

Background

Symptoms of hyperandrogenism are common in patients with Cushing’s disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD.

Methods

We assessed saliva day profiles in females with CD pre (n  = 23) and post (n  = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (TS), 11-ketotestosterone (11KT), as well as metabolites of classic and 11-oxygenated androgens in 24-h urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotrophic hormone in plasma in patients and controls were investigated.

Results

Treatment-naïve females with CD showed a significantly elevated area under the curve of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, P = 0.0002; 11KT mrd 17.42; P = 0.0005), whereas A4, TS and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transsphenoidal surgery, 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 P < 0.0001; 11KT P = 0.0010) and urine (11-oxo-androsterone P = 0.0011; 11-hydroxy-androsterone P < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis.

Conclusion

Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.

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Lin Gan, Nanfang Li, Mulalibieke Heizati, Mengyue Lin, Qing Zhu, Jing Hong, Ting Wu, Ling Tong, Zuhere Xiamili, and Yue Lin

Objective

The hypothalamic–pituitary–adrenal (HPA) axis may be associated with cardiovascular disease (CVD) and the effects of diurnal cortisol features on future CVD remain unclear among patients with hypertension. This study aimed to evaluate the association between diurnal cortisol features and CVD in patients with hypertension.

Design and methods

Participants with cortisol rhythm test at baseline in Urumqi Research on Sleep Apnea and Hypertension (UROSAH) in 2011–2013 were enrolled and followed up till 2021. Incident events included coronary heart disease, stroke, and heart failure. Cox proportional hazards model was used to evaluate the relationship between diurnal cortisol features and incident CVD. Sex-specific and sensitivity analyses were also performed.

Results

In total, 2305 hypertensive participants comprised the current analytical sample. During a median follow-up of 7.2 years and 16374.9 person-years, there were 242 incident CVD cases. Multivariable Cox regression showed that steep diurnal cortisol slope (DCS) was significantly associated with decreased CVD risk (per s.d., hazard ratio (HR) = 0.86, 95% CI: 0.77–0.96, P = 0.011). Midnight cortisol was positively associated with an increased CVD risk (per s.d., HR = 1.24, 95% CI: 1.08–1.42, P = 0.002). Comparable results were observed in the sensitivity analyses. Neither midnight cortisol nor DCS was associated with incident CVD in the female subgroup.

Conclusions

Flatter DCS and higher midnight cortisol levels are associated with an increased risk of CVD in patients with hypertension, especially in men. The detection of diurnal cortisol rhythm may help identify patients with hypertension at high risk of CVD.

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Nicholas Russell, Rudolf Hoermann, Ada S Cheung, Jeffrey D Zajac, and Mathis Grossmann

Objective

Most men undergoing androgen deprivation therapy (ADT) for prostate cancer experience hot flushes. Current treatments have low or limited evidence of efficacy. It is likely that oestradiol depletion is the mediator of these hot flushes, and transdermal oestradiol might be an effective treatment.

Design

This is a 6-month randomised, placebo-controlled trial with the hypothesis that oestradiol would reduce hot flush frequency and intensity and improve quality of life (QoL).

Methods

Seventy-eight participants receiving ADT were randomised to 0.9 mg of 0.1% oestradiol gel per day or matched placebo. Hot flush frequency and severity were assessed by 7-day diary at baseline, month 1, month 3, and month 6. QoL was assessed by validated questionnaire.

Results

Oestradiol reduced daily hot flush frequency, with a mean adjusted difference (MAD) of –1.6 hot flushes per day (95% CI: –2.7 to –0.5; P = 0.04). The effect on weekly hot flush score was non-significant, with a MAD –19.6 (95% CI: –35.5 to –3.8; P = 0.11). On per protocol analysis, E2 significantly reduced daily hot flush frequency, with a MAD of –2.2 hot flushes per day (95% CI: –3.2 to –1.1; P = 0.001), and weekly hot flush score, with a MAD of –27.0 (–44.7 to –9.3; P = 0.02). Oestradiol had no significant effect on QoL.

Conclusion

We confirmed our hypothesis of a clinical effect of assignment to oestradiol to reduce hot flush frequency in men with castrate testosterone due to ADT. Transdermal oestradiol could be considered for men with burdensome hot flushes in whom other treatments have failed as long as the risk of breast effects and fat gain are considered.

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Daniel Alexander Heinrich, Marcus Quinkler, Christian Adolf, Laura Handgriff, Lisa Müller, Holger Schneider, Lisa Sturm, Heike Künzel, Max Seidensticker, Sinan Deniz, Roland Ladurner, Felix Beuschlein, and Martin Reincke

Objective

Cortisol measurements are essential for the interpretation of adrenal venous samplings (AVS) in primary aldosteronism (PA). Cortisol cosecretion may influence AVS indices. We aimed to investigate whether cortisol cosecretion affects non-adrenocorticotrophic hormone (ACTH)-stimulated AVS results.

Design

Retrospective cohort study at a tertiary referral center.

Methods

We analyzed 278 PA patients who underwent non-ACTH-stimulated AVS and had undergone at least a 1-mg dexamethasone suppression test (DST). Subsets underwent additional late-night salivary cortisol (LSC) and/or 24-h urinary free cortisol (UFC) measurements. Patients were studied from 2013 to 2020 with follow-up data of 6 months following adrenalectomy or mineralocorticoid antagonist therapy initiation. We analyzed AVS parameters including adrenal vein aldosterone/cortisol ratios, selectivity, lateralization (LI) and contralateral suppression indices and post-operative ACTH-stimulation. We classified outcomes according to the primary aldosteronism surgical outcome (PASO) criteria.

Results

Among the patients, 18.9% had a pathological DST result (1.9–5 µg/dL: n  = 44 (15.8%); >5 µg/dL: n  = 8 (2.9%)). Comparison of AVS results stratified according to the 1-mg DST (≤1.8 vs >1.8 µg/dL: P = 0.499; ≤1.8 vs 1.8 ≤ 5 vs >5 µg/dL: P = 0.811) showed no difference. Lateralized cases with post DST serum cortisol values > 5 µg/dL had lower LI (≤1.8 µg/dL: 11.11 (5.36; 26.76) vs 1.9–5 µg/dL: 11.76 (4.9; 31.88) vs >5 µg/dL: 2.58 (1.67; 3.3); P = 0.008). PASO outcome was not different according to cortisol cosecretion.

Conclusions

Marked cortisol cosecretion has the potential to influence non-ACTH-stimulated AVS results. While this could result in falsely classified lateralized cases as bilateral, further analysis of substitutes for cortisol are required to unmask effects on clinical outcome.

Free access

Abdallah Al-Salameh, Joe Balmain, and Rachel Desailloud

Open access

Johanna Pölönen, Pekka Pinola, Justiina Ronkainen, Alex I Blakemore, Jessica L Buxton, Juha S Tapanainen, Stephen Franks, Terhi T Piltonen, Sylvain Sebert, and Laure Morin-Papunen

Objective

Telomeres are DNA–protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular aging. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardiometabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population.

Design

This is a population-based cohort study comprising women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (age 31, n = 190; age 46, n = 207) and referent women (age 31, n = 1054; age 46, n = 1324) with data on LTL.

Methods

The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age.

Results

Women with PCOS had similar mean LTL at ages 31 and 46 (P > 0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P = 0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P < 0.001), but not in women with PCOS (P = 0.96).

Conclusions

This finding may suggest a difference in the LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms.

Restricted access

Joëlle Le Moal, Julie Chesneau, Sarah Goria, Priscilla Boizeau, Jérémie Haigneré, Florentia Kaguelidou, and Juliane Léger

Objective

Childhood hyperthyroidism is mostly caused by Graves’ disease, a rare autoimmune disease in children. Epidemiological data are scarce and the variability of within-region incidence is unknown. We aimed to provide the first description of temporal trends in pediatric hyperthyroidism in France and to explore spatial trends, with a view to identifying possible environmental triggers.

Design and methods

We performed an observational population-based study on data collected from the National Health Data System, covering the 2008–2017 period and the whole of France. We identified patients with an indicator reflecting incident cases of treated hyperthyroidism, in children aged 6 months–17.9 years, localized at the scale of the département (equivalent to a county) of residence. We performed descriptive analyses of incidence rate by sex, age, and year, and used a spatiotemporal model for estimation at département level.

Results

We identified 4734 incident cases: 3787 girls (80%) and 947 boys (20%). The crude incidence rate was 3.35 (95% CI: 3.26; 3.45) per 100 000 person-years over the study period. We estimated the increase in incidence between 2008 and 2017 at 30.1% (19.0%; 42.3%). Annual incidence rate increased linearly over the 10-year period in both girls and boys, rising similarly in all age groups and in all départements. The spatial model highlighted marked heterogeneity in the risk of childhood hyperthyroidism across France.

Conclusion

The trend toward increasing incidence observed may reflect changes in genetic and environmental interactions, and the marked spatial heterogeneity may reflect localized ethnic or environmental factors worthy of further investigation.

Free access

Heba Alwan, Fanny Villoz, Martin Feller, Robin P F Dullaart, Stephan J L Bakker, Robin P Peeters, Maryam Kavousi, Douglas C Bauer, Anne R Cappola, Bu B Yeap, John P Walsh, Suzanne J Brown, Graziano Ceresini, Luigi Ferrucci, Jacobijn Gussekloo, Stella Trompet, Massimo Iacoviello, Jae Hoon Moon, Salman Razvi, Isabela M Bensenor, Fereidoun Azizi, Atieh Amouzegar, Sergio Valdés, Natalia Colomo, Nick J Wareham, J Wouter Jukema, Rudi G J Westendorp, Ki Woong Kim, Nicolas Rodondi, Cinzia Del Giovane, and

Objective

Few prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes.

Methods

We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up.

Results

Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88–1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82–1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87–1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88–1.29). The results were robust in all sub-group and sensitivity analyses.

Conclusions

This is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes.

Significance statement

Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future.

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Mariska A M Schröder, Fred C G J Sweep, Antonius E van Herwaarden, Rod T Mitchell, Jitske Eliveld, Ans M M van Pelt, Alan E Rowan, Darren Korbie, Nike M M L Stikkelbroeck, Hedi L Claahsen-van der Grinten, and Paul N Span

Background

Testicular adrenal rest tumors (TART) are a common complication of unknown cellular origin in patients with congenital adrenal hyperplasia (CAH). These benign tumors have both adrenal and testicular characteristics and are hypothesized to either derive from cells of adrenal origin from the fetal adrenogonadal primordium or by atypical differentiation of adult Leydig-progenitor cells.

Objective

This study aims to unravel the identity and etiology of TART.

Methods

Co-expression of adrenal-specific CYP11B1 and Leydig cell-specific HSD17B3 in TART was studied using immunohistochemistry. We studied the possibility of TART being derived from atypical differentiation of adult Leydig-progenitor cells by the quantification of adrenal-specific enzyme expression upon adrenocorticotrophic hormone (ACTH)-like stimulation of ex vivo cultured platelet-derived growth factor receptor alpha-positive cells. By comparing the transcriptome of TART (n = 16) with the transcriptome of fetal adrenal (n = 13), fetal testis (n = 5), adult adrenal (n = 11), and adult testis (n = 10) tissues, we explored the identity of TART.

Results

We demonstrate co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART cells, indicating the existence of a distinct TART cell exhibiting both adrenal and testicular characteristics. Ex vivo cultured adult Leydig-progenitor cells did not express the ACTH-receptor MC2R but did express CYP11B1 upon stimulation. Unsupervised clustering of transcriptome data showed that TART was most similar to adult adrenal tissue, followed by adult testis tissue, and least similar to either fetal tissue.

Conclusion

Our data suggest that TART is induced − most likely via activation of a cAMP/protein kinase A-dependent receptor − from a progenitor cell into a unique mature adrenal-like cell type, sometimes exhibiting both adrenal and testicular features.