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Khyatisha Seejore, Marilena Giannoudi, Djoah Osborn, Julie M Lynch, Ahmed Al-Qaissi, Elaine Dunwoodie, Jane Hook, Maria Marples, and Robert D Murray

Context

The use of the CTLA4 inhibitor, ipilimumab, has proven efficacious in the treatment of melanoma, renal carcinoma and non-small cell lung cancer; however, it is associated with frequent immune-related adverse events (irAE). Ipilimumab-induced hypophysitis (IIH) is a well-recognised and not infrequent endocrine irAE.

Objective

To investigate the timing of onset and severity of adrenal and thyroid hormone dysfunction around the development of IIH in patients treated for melanoma.

Design

Aretrospective review of hormone levels in consecutive adult patients treated with ipilimumab (3 mg/kg) for advanced melanoma as monotherapy or in combination with a PD-1 inhibitor.

Results

Of 189 patients, 24 (13%; 13 males; 60.5 ± 12.2 years) presented with IIH at a median of 16.1 (range: 6.7–160) weeks after commencing treatment, occurring in 14 (58%) after the fourth infusion. At the presentation of IIH, corticotroph deficiency was characterised by an acute and severe decrease in cortisol levels to ≤83 nmol/L (≤3 μg/dL) in all patients, often only days after a previously recorded normal cortisol level. Free thyroxine (fT4) levels were observed to decline from 12 weeks prior to the onset of cortisol insufficiency, with the recovery of thyroid hormone levels by 12 weeks after the presentation of IIH. A median fall in fT4 level of 20% was observed at a median of 3 weeks (IQR: 1.5–6 weeks) prior to the diagnosis of IIH.

Conclusion

IIH is characterised by an acute severe decline in cortisol levels to ≤83 nmol/L at presentation. A fall in fT4 can herald the development of ACTH deficiency and can be a valuable early indicator of IIH.

Open access

Alessandro Prete, Richard J Auchus, and Richard J Ross

Background

Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.

Methods

Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.

Summary

Therapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.

Conclusions

CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

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Laura Potasso, Julie Refardt, Christian Meier, and Mirjam Christ-Crain

Objective

Hyponatremia is associated with an increased risk of bone fragility and fractures. Many studies suggest that hyponatremia stimulates osteoclast activation, whereas other studies rather reveal a possible role of acute hyponatremia in impairing osteoblast function. We aimed to assess whether and how correction of hyponatremia in hospitalized patients with the syndrome of inappropriate antidiuresis (SIAD) has an impact on bone metabolism.

Design and Methods

This was a predefined secondary analysis of 88 hospitalized patients with SIAD undergoing a randomized treatment with SGLT-2 inhibitors or placebo for 4 days. Biochemical markers of bone resorption (CTX) and bone formation (PINP) were collected in serum at baseline and after the intervention (day 5). Bone formation index (defined as PINP/CTX) and its difference between day 5 and baseline were calculated. Patients with steroid therapy (n = 6), fractures (n = 10), or whose data were missing (n = 4) were excluded from the analysis.

Results

Out of 68 patients, 27 (39.7%) were normonatremic at day 5. These patients showed an increase in serum PINP (P = 0.04), whereas persistent hyponatremic patients did not (P = 0.38), with a relevant difference between these two subgroups (P = 0.005). Serum CTX increased similarly in the two groups (P = 0.43). This produced a 47.9 points higher PINP/CTX difference between discharge and admission in normonatremic patients (95% CI: 17.0–78.7, P = 0.003) compared to patients with persistent hyponatremia, independent of age, sex, BMI, smoking habits, randomization arm, and baseline cortisol levels.

Conclusions

Our predefined post hoc analysis shows that correction of hyponatremia in hospitalized patients with SIAD might have a positive impact on osteoblast function.

Open access

Yongze Li, Zhongyan Shan, and Weiping Teng

Objective

Longitudinal studies have investigated the effects of changing iodine status on thyroid disorders, but the effect of a transition from more than adequate iodine to adequate iodine on national changes in prevalence adjusted for changing risk factors remains unclear.

Design

Two repeat nationwide surveys were conducted from 2009–2010 to 2015–2017 to assess changes in thyroid disorder prevalence and iodine status in China.

Methods

A multistage stratified random sampling method was used to obtain a nationally representative sample of urban adults aged 18 and older in mainland China in 2009 (n = 14 925) and 2015 (n = 12 553). Changes in thyroid disorder prevalence, urinary iodine concentration (UIC), and thyroid-stimulating hormone (TSH) levels were assessed. Logistic regression models were used to examine changes in prevalence over time.

Results

The median UIC decreased significantly from 219.7 to 175.9 μg/L (P < 0.0001). The weighted prevalence of overt hyperthyroidism, subclinical hyperthyroidism, Graves’ disease, and goitre decreased between 2009 and 2015 in the overall population (P < 0.05 for all). Despite no significant changes in subclinical hyperthyroidism or hypothyroidism or anti-thyroid peroxidase or anti-thyroglobulin antibody positivity prevalence, a significant increase in thyroid nodule prevalence (P < 0.0001) was found in the overall population. The 2.5th TSH percentile increased by 0.15 mIU/L (95% CI: 0.01 to 0.30 mIU/L, P = 0.04) from 2009 to 2015.

Conclusions

With the iodine status transition from more than adequate to adequate, thyroid disorder (except for thyroid nodules) prevalence remained stable or even decreased after adjusting for confounding factors among adults in mainland China between 2009 and 2015. Additional studies are needed to explore the reasons for the increased thyroid nodule prevalence.

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Amanda Sampaio Mangolim, Leonardo de Andrade Rodrigues Brito, and Vania dos Santos Nunes-Nogueira

Objective

This systematic review evaluated the effect of testosterone replacement therapy (TRT) in men with obesity having low testosterone levels (LTLs).

Design and methods

Search strategies were performed in MEDLINE, Embase, LILACS, and CENTRAL databases. Two reviewers selected the studies, assessed the risk of bias, and extracted data from the included studies. A random-effects model was used to pool results across studies, and the Grading of Recommendations Assessment, Development, and Evaluation was used to evaluate the certainty of evidence.

Results

A total of 16 randomized controlled trials were included. With moderate certainty of the evidence, no difference was found between TRT and placebo regarding total adverse events, TRT led to a 2-kg lean body mass gain and slightly improved low-density lipoprotein (LDL), without effects on the blood pressure. Due to imprecision/heterogeneity, effects in cardiovascular events (relative risk: 0.52, 95% CI: 0.26 to 1.05, 7 trials, 583 participants), high-density lipoprotein, hematocrit, prostate-specific antigen, HbA1c, and quality of life were unclear. TRT was effective for waist circumference and BMI; however, large between-study heterogeneity was found, with 95% prediction intervals crossing the null effect line. Meta-regression revealed that the average age of participants was a significant modifier for both outcomes.

Conclusion

TRT slightly improved the lean body mass and LDL in men with obesity having LTLs but did not affect the blood pressure. The effects of TRT on cardiovascular events, HbA1c, and quality of life are unclear. The mean age of participants significantly modified the effect of TRT on weight loss.

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

Objective

Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatization to estradiol (E2). However, no controlled study has assessed the effects of E2 in the absence of testosterone.

Design

Six-month randomized, placebo-controlled trial with the hypothesis that men randomized to E2 would reduce their fat mass.

Methods

Seventy-eight participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3, and month 6. The primary outcome was total fat mass.

Results

Serum E2 increased in the estradiol group over 6 months compared to placebo, and mean-adjusted difference (MAD) was 207 pmol/L (95% CI: 123–292), P  < 0.001. E2 treatment changed total fat mass, MAD 1007 g (95% CI: 124–1891), but not significantly, so P = 0.09. There were other consistent non-significant trends toward increased proportional fat mass, MAD 0.8% (95% CI: 0.0–1.6), P= 0.15; gynoid fat, MAD 147 g (95% CI: 2–293), P = 0.08; visceral fat, 53 g (95% CI: 1–105) P = 0.13; and subcutaneous fat, MAD 65 g (95% CI: 5–125), P = 0.11. Android fat increased, MAD 164 g (95% CI: 41–286), P = 0.04.

Conclusion

Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of testosterone, may increase total and regional fat mass in men. Given the premature closure of clinical trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether E2 promotes fat expansion in the absence of testosterone.

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Evert F.s. van Velsen, Robin P. Peeters, Merel T. Stegenga, Uwe Mäder, Christoph Reiners, F.j. van Kemenade, Tessa M. van Ginhoven, W. Edward Visser, and Frederik Anton Verburg

Background

The UICC/AJCC TNM staging system for differentiated thyroid cancer (DTC) involves a single age cutoff as a prognostic criterion. Because a single cutoff is a dichotomization of what might be a sliding scale, using multiple age cutoffs might result into a better stage definition. The aim of our study was to investigate if using a two-step age-based cutoff would improve the TNM staging system regarding disease specific survival (DSS).

Methods

We retrospectively studied two cohorts of adult DTC patients from The Netherlands and Germany. DSS was analyzed for papillary (PTC) and follicular thyroid cancer (FTC) separately, investigating several two-step age-based cutoffs for those with distant metastases; below lower threshold classified as stage I, between lower and upper threshold as stage II, and above upper threshold as stage IV.

Results

We included 3074 DTC patients (77% PTC). For PTC, an age cutoff of 45 with 50 years had the best statistical model performance, while this was 25 with 40 years for FTC. However, differences with the optimal single age cutoffs of 50 years for PTC and 40 years for FTC were small.

Conclusions

The optimal two-step age-based cutoff to predict DSS is 45 with 50 years for PTC, and 25 with 40 years for FTC, rather than 55 years currently used for DTC. Although, these two-step age-based cutoffs were marginally better from a statistical, from a clinical point of view the recently defined optimal single age cutoffs of 50 years for PTC, and 40 years for FTC might be preferable.

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Enora Le Roux, Agathe Turpin, Morgane Michel, Isabelle Tejedor, Florence Menesguen, Sabine Malivoir, Sandrine Bottuis, Hélène Mellerio, Michel Polak, and Philippe Touraine

Objective. To evaluate the effect of a new care organisation on multiple outcomes of transition success and its cost-effectiveness in patients with any endocrine or metabolic disease diagnosed during childhood and transferred to adult care.

Design. Non-randomized controlled trial in a French University Hospital.

Methods. Patients transferred to adult care during the control period (04/2014-08/2016) and the intervention period (09/2016-06/2018) were included. The intervention is based on case management involving liaising with paediatric services, personalising care pathways, and liaising with structures outside hospital (general practitioner, educational and social sector). The primary endpoint was the percentage of patients lost to follow-up at 24 months post transfer. Other outcomes were collected from medical files, consultation software, and questionnaires. A cost analysis was performed.

Results. 202 patients were included (101 per period) , the most represented pathologies were congenital and non-congenital hypopituitarism (respectively n=34 (17%) and n=45 (22%)) and thyroid diseases (n=21, 10%). Patients were aged 22.5 in median at 24 months post transfer where 12 were lost to follow up in the control group versus 9 with the intervention (p=0.49). The percentage of honoured consultation among those planned during 24 months was higher with intervention (p=0.0065). Patient satisfaction, physician trust, transfer delay did not differ between the groups. The incremental cost-effectiveness ratio was €179 per patient not lost to follow-up.

Conclusions. At 24 months post transfer the rate of lost to follow-up does not differ significantly, but indicators of a steadier follow-up are increased and the intervention appears to be cost-effective.

Free access

Rui M B Maciel and Ana Luiza Maia

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

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Sandeep Dhindsa, Husam Ghanim, Todd Jenkins, Thomas H. Inge, Carroll M. Harmon, Amit Ghoshal, Zengru Wu, Michael J. McPhaul, Farid Saad, and Paresh Dandona

Objective: Obesity in adolescent males is associated with lowering of total and free testosterone concentrations. Weight loss may increase testosterone concentrations.

Design and Methods: We evaluated changes in sex hormones following bariatric surgery in 34 males (age range 14.6 – 19.8 years) with obesity. These participants were part of prospective multicenter study, Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS). Participants were followed for five years after surgery. Total testosterone, total estradiol, LH, FSH, SHBG, CRP, insulin and glucose were measured at baseline, six months and annually thereafter. Free testosterone, free estradiol and HOMA2-IR were calculated.

Results: Study participants lost one-third of their body weight after bariatric surgery, with maximum weight loss achieved at 24 months for most participants. Free testosterone increased from 0.17 nmol/L(95% CI: 0.13, 0.20) at baseline to 0.34 (95% CI: 0.30, 0.38) at two years and 0.27(95% CI: 0.23, 0.32) nmol/L at five years (p<0.001 for both) respectively. Total testosterone increased from 6.7 nmol/L (95% CI: 4.7, 8.8) at baseline to 17.6(95% CI: 15.3, 19.9) and 13.8(95% CI: 11.0, 16.5) nmol/L at two and five years(p<0.001). Prior to surgery 73% of the participants had subnormal free testosterone(<0.23 nmol/L). After two years and five years, only 20% and 33%, respectively, had subnormal free testosterone concentrations. Weight regain was related to a fall in free testosterone concentrations.

Conclusions: Bariatric surgery led to a robust increase in testosterone concentrations in adolescent males with severe obesity. Participants who regained weight had a decline in their testosterone concentrations.