Sarah Ying Tse Tan, Hong Chang Tan, Ling Zhu, Lih Ming Loh, Dawn Shao Ting Lim, Du Soon Swee, Yoke Ling Chan, Huee Boon Lim, Shiau Lee Ling, En Jun Ou, Wynn Ee Teo, Xiao Ping Zhang, Hui Fen Goh, and Peng Chin Kek
Adrenal insufficiency (AI) is potentially life-threatening, and accurate diagnosis is crucial. The first-line diagnostic test, the adrenocorticotrophic hormone (ACTH) stimulation test, measures serum total cortisol. However, this is affected in states of altered albumin or cortisol-binding globulin levels, limiting reliability. Salivary cortisol reflects free bioactive cortisol levels and is a promising alternative. However, few studies are available, and heterogenous methodologies limit applicability.
This study prospectively recruited 42 outpatients undergoing evaluation for AI, excluding participants with altered cortisol-binding states. Serum (immunoassay) and salivary (liquid chromatography tandem mass spectrometry) cortisol levels were sampled at baseline, 30 min, and 60 min following 250 µg synacthen administration. AI was defined as a peak serum cortisol level <500 nmol/L in accordance with guidelines.
The study recruited 21 (50%) participants with AI and 21 without AI. There were no significant differences in baseline characteristics, blood pressure, or sodium levels between groups. Following synacthen stimulation, serum and salivary cortisol levels showed good correlation at all timepoints (R2 = 0.74, P < 0.001), at peak levels (R2 = 0.72, P < 0.001), and at 60 min (R2 = 0.72, P < 0.001). A salivary cortisol cut-off of 16.0 nmol/L had a sensitivity of 90.5% and a specificity of 76.2% for the diagnosis of AI.
This study demonstrates a good correlation between serum and salivary cortisol levels during the 250 µg synacthen test. A peak salivary cortisol cut-off of 16.0 nmol/L can be used for the diagnosis of AI. It is a less invasive alternative to evaluate patients with suspected AI. Its potential utility in the diagnosis of AI in patients with altered cortisol-binding states should be further studied.
Patricia Arroyo Tardio, Gabriela Baldini, and Eleonora Seelig
Objective: Hypercortisolism is a risk factor for obesity. Cortisol increases in response to food intake in lean subjects. In obese subjects, disturbances of the food-induced cortisol peak were reported, but data from sufficiently powered and well-controlled trials are lacking. Understanding the cortisol response to food is essential as amplified, or recurrent cortisol surges could lead to hypercortisolism and contribute to obesity. Therefore, we investigate the cortisol response to food in lean and obese subjects.
Design: This is a non-randomized, open-label study.
Methods: We assessed serum cortisol values after a high-calorie meal in lean and obese male subjects. Cortisol levels were frequently assessed before and for 3 hours after food intake.
Results: 36 subjects (18 lean, 18 obese) were included. There was no difference in overall cortisol levels between both groups during the study (area under the curve (AUC) obese: 55409 ±16994, lean: 60334 ±18001, p=0.4). Total cortisol levels reached peak concentrations 20 minutes after food intake in both groups; the maximum cortisol increase was similar in both groups (cortisol increase obese: 69.6 ±135.5 nmol/l, lean: 134.7 ±99.7 nmol/l; p=0.1). There was no correlation between body mass index (BMI) and baseline cortisol values (R2=0.001, p=0.83), cortisol increase (R2= 0.05, p=0.17), or cortisol AUC (R2= 0.03, p=0.28).
Conclusions: This study demonstrates that high-calorie food intake causes an immediate and substantial cortisol response in lean and obese subjects and is independent of body weight.
Constantine A Stratakis
This is my first note as an Advisory Editor of our journal Endocrine Connections which seeks to expand coverage on the generic area of endocrine genetics. I am honoured to be selected to assist in this role. I have served endocrinology and genomic medicine for more than three decades and I am delighted to see the developments of the latter and their impact on the former. Endocrine Connections is right to want to cover more endocrine genetics, as precision medicine (that is largely based on genomics) becomes the cornerstone of prevention, diagnosis, and treatment of almost all conditions affecting human metabolism and are part of everyday clinical practice in endocrinology.
Tristan Avril, Quentin Hennocq, Anne-Sophie Lambert, Juliane Leger, Dominique Simon, Laetitia Martinerie, and Claire Bouvattier
Newborns with congenital hypogonadotropic hypogonadism (CHH) have an impaired postnatal activation of the gonadotropic axis. Substitutive therapy with recombinant gonadotropins can be proposed to mimic physiological male mini-puberty during the first months of life. The aim of this study was to compare the clinical and biological efficacy of two treatment modalities of gonadotropins administration during mini-puberty in CHH neonates.
Multicenter retrospective analytical epidemiological study comparing two treatments, pump vs injection, between 2004 and 2019.
Clinical (penile size, testis size, testicular descent) and biological parameters (serum concentrations of testosterone, anti-Müllerian hormone (AMH) and Inhibin B) were compared between the two groups by multivariate analyses.
Thirty-five patients were included. A significantly higher increase in penile length and testosterone level was observed in the injection group compared to the pump group (+0.16 ± 0.02 mm vs +0.10 ± 0.02 mm per day, P = 0.002; and +0.04 ± 0.007 ng/mL vs +0.01 ± 0.008 ng/mL per day, P = 0.001). In both groups, significant increases in penile length and width, testosterone, AMH, and Inhibin B levels were observed, as well as improved testicular descent (odds ratio of not being in a scrotal position at the end of treatment = 0.97 (0.96; 0.99)).
Early postnatal administration of recombinant gonadotropins in CHH boys is effective in stimulating penile growth, Sertoli cell proliferation, and testicular descent, with both treatment modalities.
Heleen I Jansen, Marijn M Bult, Peter H Bisschop, Anita Boelen, Annemieke C Heijboer, and Jacquelien J Hillebrand
In our hospital, physicians noticed high free thyroxine (fT4) concentrations without complete suppression of thyroid-stimulating hormone (TSH) in blood samples of patients at the outpatient clinic, which appeared to occur more often following the introduction of a new fT4 immunoassay. This discordance may be explained by incorrect reference intervals, analytical issues, or patient-related factors. We aimed to establish the contribution of the possible factors involved.
Reference intervals of both fT4 immunoassays were re-evaluated using blood samples of healthy volunteers and the new immunoassay’s performance was assessed using internal quality controls and external quality rounds. The frequency of discordant fT4 and TSH pairings obtained from laboratory requests were retrospectively analysed using a Delfia (n = 3174) and Cobas cohort (n = 3408). Last, a literature search assessed whether the time of blood draw and the time of levothyroxine (L-T4) ingestion may contribute to higher fT4 concentrations in L-T4 users.
The original reference intervals of both fT4 immunoassays were confirmed and no evidence for analytical problems was found. The Delfia (n = 176, 5.5%) and Cobas cohorts (n = 295, 8.7%) showed comparable frequencies of discordance. Interestingly, 72–81% of the discordant results belonged to L-T4 users. Literature indicated the time of blood withdrawal of L-T4 users and, therefore, the time of L-T4 intake as possible explanations.
High fT4 without suppressed TSH concentrations can mainly be explained by L-T4 intake. Physicians and laboratory specialists should be aware of this phenomenon to avoid questioning the assay’s performance or unnecessarily adapting the L-T4 dose in patients.
Hong Tang, Xiaomei Jiang, Yu Hua, Heyue Li, Chunlan Zhu, Xiaobai Hao, Minhui Yi, and Linxia Li
Polycystic ovary syndrome (PCOS) is an androgen disorder and ovarian dysfunction disease in women of reproductive age. The cell death of granulosa cells (GCs) plays an important role in the development of PCOS. However, the mechanism of GC death is still unclear.
In the current study, NEDD4L was found to be elevated in PCOS GEO (Gene Expression Omnibus) databases and mouse models. The cell viability was analyzed by CCK-8 and FDA staining. The expression of ferroptosis markers was assessed by ELISA and immunofluorescence. The direct interaction of GPX4 and NEDD4L was verified by co-immunoprecipitation assay.
Functionally, results from CCK-8 and FDA staining demonstrated that NEDD4L inhibited the cell viability of KGN cells and NEDD4L increased the levels of iron, malonyldialdehyde, and reactive oxygen species and decreased glutathione levels. Moreover, the cell death of KGN induced by NEDD4L was blocked by ferroptosis inhibitor, suggesting that NEDD4L regulates KGN cell ferroptosis. Mechanistically, NEDD4L directly interacts with GPX4 and promotes GPX4 ubiquitination and degradation.
Taken together, our study indicated that NEDD4L facilitates GC ferroptosis by promoting GPX4 ubiquitination and degradation and contributes to the development of PCOS.
Pernille H Hellmann, Jonatan I Bagger, Katrine R Carlander, Katrine B Hansen, Julie L Forman, Joachim Størling, Elizaveta Chabanova, Jens Holst, Tina Vilsbøll, and Filip K Knop
Preclinically, curcumin has been shown to protect against glucocorticoid-induced insulin resistance. We evaluated the effect of curcumin administered with prednisolone in healthy overweight or obese men.
In a double-blind, parallel-group trial, 24 overweight/obese non-diabetic men were randomised to one of three intervention groups (A) prednisolone placebo+curcumin placebo, (B) prednisolone (50 mg/day)+curcumin placebo or (C) prednisolone and curcumin (400 mg/day). Curcumin or curcumin placebo treatment started 1 day prior to 10-day prednisolone or prednisolone placebo treatment. The primary endpoint was change in prednisolone-induced insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA2-IR). Other endpoints included anthropometric measurements, magnetic resonance spectroscopy-assessed hepatic fat content, blood pressure, circulating metabolic markers and continuous glucose monitoring measures.
Baseline characteristics (mean ± s.d): age 44.2 ± 13.7 years, BMI 30.1 ± 3.5 kg/m2, HbAlc 33.3 ± 3.2 mmol/mol, HOMA2-IR 1.10 ± 0.45 and fasting plasma glucose 5.2 ± 0.4 mmol/L. Prednisolone significantly increased HOMA2-IR (estimated treatment difference 0.36 (95% CI 0.16; 0.57)). Co-treatment with curcumin had no effect on HOMA2-IR (estimated treatment difference 0.08 (95% CI −0.13; 0.39)). Prednisolone increased HbAlc, insulin, C-peptide, glucagon, blood pressure, mean interstitial glucose, time spent in hyperglycaemia and glucose variability, but no protective effect of curcumin on any of these measures was observed.
In this double-blind, placebo-controlled parallel-group study involving 24 overweight or obese men randomised to one of three treatment arms, curcumin treatment had no protective effect on prednisolone-induced insulin resistance or other glucometabolic perturbations.
Hanna F Nowotny, Jillian Bryce, Salma R Ali, Roberta Giordano, Federico Baronio, Irina Chifu, Lea Tschaidse, Martine Cools, Erica LT van den Akker, Henrik Falhammar, Natasha M Appelman-Dijkstra, Luca Persani, Guglielmo Beccuti, Ian L Ross, Simona Grozinsky-Glasberg, Alberto M Pereira, Eystein S Husebye, Stefanie Hahner, S Faisal Ahmed, and Nicole Reisch
Information on clinical outcomes of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce.
A collaboration between the European Society of Endocrinology (ESE) Rare Disease Committee and European Reference Network on Rare Endocrine Conditions via the European Registries for Rare Endocrine Conditions allowed the collection of data on 64 cases (57 adrenal insufficiency (AI), 7 Cushing’s syndrome) that had been reported by 12 centres in 8 European countries between January 2020 and December 2021.
Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID-19 infection was confirmed by testing. Primary insufficiency was present in 45/57 patients; 19 were affected by Addison’s disease, 19 by congenital adrenal hyperplasia and 7 by primary AI (PAI) due to other causes. The most relevant comorbidities were hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2.0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patients. Two patients were administered i.m. injection of 100 mg hydrocortisone, and 11/64 were admitted to the hospital. Two patients had to be transferred to the intensive care unit, one with a fatal outcome. Four patients reported persistent SARS-CoV-2 infection, all others complete remission.
This European multicentre questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcomes in case of duly dose adjustments and emphasizes the importance of patient education on sick day rules.
Victoria Chatzimavridou Grigoriadou, Lisa H Barraclough, Rohit Kochhar, Lucy Buckley, Nooreen Alam, and Claire E Higham
Background: Radiotherapy-related insufficiency fractures (RRIFs) represent a common, burdensome consequence of pelvic radiotherapy. Their underlying mechanisms remain unclear and data on the effect of osteoporosis are contradictory, with limited studies assessing BMD by DXA.
Methods: BMD by DXA (Hologic) scan and fracture risk (FRAX) following pelvic RRIF were retrospectively assessed in 39 patients (median age 68 years), at a tertiary cancer centre. Patient characteristics and treatment history are presented narratively; correlations were explored using univariate regression analyses.
Results: Additional cancer treatments included chemotherapy (n=31), surgery (n=20), brachytherapy (n=19). Median interval between initiation of radiotherapy and RRIF was 11 [7.5-20.8] and between RRIF and DXA 3 [1-6] months. Three patients had normal BMD, 16 had osteopenia and 16 osteoporosis, following WHO classification. Four patients were <40 years at time of DXA (all Z-scores>-2). Median 10-year risk for hip and major osteoporotic fracture were 3.1% [1.5-5.7] and 11.5% [7.1-13.8], respectively. Only 33.3% of patients had high fracture risk (hip fracture >4% and/or major osteoporotic >20%), and 31% fell above the intervention threshold per NOGG guidance (2017). Higher BMD was predicted by lower pelvic radiotherapy dose (only in L3, L4), concomitant chemotherapy and higher body mass index.
Conclusion: At the time of RRIF, most patients did not have osteoporosis, some had normal BMD, and overall had low fracture risk. Whilst low BMD is a probable risk factor, it is unlikely to be the main mechanism underlying RRIFs and further studies are required to understand the predictive value of BMD.