Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted.
Anna Nordenström and Henrik Falhammar
Ingibjörg H Jonsdottir and Anna Sjörs Dahlman
Burnout has several different definitions, and attempts have been made to discriminate between burnout as a psychological construct and burnout as a clinical entity. A large body of research has focused on elucidating the biological link between stress exposure and burnout and/or finding a clinically usable biomarker for burnout. The objective of this narrative review is to summarize the main endocrine and immune findings in relation to burnout. The literature has primarily focused on dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. However, albeit the large body of studies, it cannot be concluded that clear effects are seen on HPA axis function in people with burnout. The HPA axis and anabolic acute reactivity to stress might be affected in clinical burnout. Plausible, effects of chronic stress might rather be seen when measuring responses to acute stress rather than resting state hormonal levels. Studies on other hormones, including thyroid hormones, prolactin and growth hormone in burnout subjects are inconclusive. It is important to note that this field is faced with many methodological challenges, one being the diurnal and pulsatile nature of many of the hormones of interest, including cortisol, which is not always considered. Another challenge is the heterogeneity regarding definitions and measurements of stress and burnout. Existing studies on burnout and immune function are heterogeneous regarding the results and no firm conclusion can be made if clinically relevant immune changes are present in burnout subjects. An overall conclusion is that existing research cannot confirm any homogenous reliable endocrinological or immunological changes related to burnout.
Aikaterini Lavrentaki, Asad Ali, Brendan G Cooper and Abd A Tahrani
Obstructive sleep apnoea (OSA) is a common disorder that is associated with serious comorbidities with a negative impact on quality of life, life expectancy and health costs. As OSA is related to obesity and is associated with sleep disruption, increased inflammation and oxidative stress, it is not surprising that OSA has an impact on the secretion of multiple hormones and is implicated in the development of many endocrine conditions. On the other hand, many endocrine conditions that can affect obesity and/or upper airways anatomy and stability have been implicated in the development or worsening of OSA. This bidirectional relationship between OSA and the endocrine system has been increasingly recognised in experimental and epidemiological studies and there are an increasing number of studies examining the effects of OSA treatment on endocrine conditions and vice versa. In this review article, we will critically appraise and describe the impact of OSA on the endocrine system including obesity, dysglycaemia, the pituitary, the thyroid, the adrenals, the reproductive system and the bones. In each section, we will assess whether a bidirectional relationship exists, and we will describe the potential underlying mechanisms. We have focused more on recent studies and randomised controlled trials where available and attempted to provide the information within clinical context and relevance.
Hanieh-Sadat Ejtahed, Raul Y Tito, Seyed-Davar Siadat, Shirin Hasani-Ranjbar, Zahra Hoseini-Tavassol, Leen Rymenans, Kristin Verbeke, Ahmad-Reza Soroush, Jeroen Raes and Bagher Larijani
The increasing prevalence of obesity over the past few decades constitutes a global health challenge. Pharmacological therapy is recommended to accompany life-style modification for obesity management. Here, we perform a clinical trial to investigate the effects of metformin on anthropometric indices and gut microbiota composition in non-diabetic, treatment-naive obese women with a low-calorie diet (LCD).
Randomized double-blind parallel-group clinical trial
Forty-six obese women were randomly assigned to the metformin (500 mg/tab) or placebo groups using computer-generated random numbers. Subjects in both groups took two tablets per day for 2 months. Anthropometric measurements and collection of blood and fecal samples were done at the baseline and at the end of the trial. Gut microbiota composition was assessed using 16S rRNA amplicon sequencing.
Twenty-four and twenty-two subjects were included in the metformin + LCD and placebo + LCD groups, respectively; at the end of trial, 20 and 16 subjects were analyzed. The metformin + LCD and placebo + LCD caused a 4.5 and 2.6% decrease in BMI from the baseline values, respectively (P < 0.01). Insulin concentration decreased in the metformin + LCD group (P = 0.046). The overall fecal microbiota composition and diversity were unaffected in the metformin + LCD group. However, a significant specific increase in Escherichia/Shigella abundance was observed after metformin + LCD intervention (P = 0.026). Fecal acetate concentration, but not producers, was significantly higher in the placebo + LCD group, adjusted for baseline values and BMI (P = 0.002).
Despite the weight reduction after metformin intake, the overall fecal microbiota composition remained largely unchanged in obese women, with exception of changes in specific proteobacterial groups.
Fabrice Bonneville, Louis-David Rivière, Stephan Petersenn, John S Bevan, Aude Houchard, Caroline Sert, Philippe J Caron and the PRIMARYS Study Group
Pituitary adenoma MRI T2 signal intensity associates with tumor characteristics including responsiveness to somatostatin analogs (SSAs). These analyses determined whether baseline T2 signal intensity predicts response to primary medical treatment with long-acting SSA.
Post hoc analyses of the prospective multicenter, open-label, single-arm PRIMARYS study in which patients with treatment-naïve GH-secreting pituitary macroadenomas received fixed-dose lanreotide autogel (120 mg) every 4 weeks for 48 weeks.
Associations were investigated between adenoma T2-signal hypo/iso/hyperintensity and treatment responses at week 48/last visit: hormonal control (GH ≤2.5 μg/L and IGF-1 normalization); tumor response (tumor volume reduction (TVR) ≥20%); separate GH/IGF-1 control and change from baseline in GH/IGF-1 and tumor volume.
Adenomas were hypointense at baseline in 50/85 (59%) patients using visual assessment. Of these, 40% achieved hormonal control and 76% achieved a tumor response. Significant univariate associations arose for hypo- vs isointensity with tumor response and achievement of GH ≤2.5 μg/L, but not IGF-1 normalization or overall hormonal control. In multivariate analysis, tumor response was six times more likely for hypo- vs iso-intense tumors (= 6.15; 95% CI: 1.36–27.88). In univariate change-from-baseline analyses, hypo- vs isointensity was associated with greater TVR and IGF-1 reduction but not change in GH. In multivariate analysis, IGF-1 decreased by an estimated additional 65 μg/L (P = 0.0026)) for hypo- vs isointense.
Patients with hypointense vs isointense GH-secreting macroadenomas had greater reductions in IGF-1 following primary treatment with lanreotide autogel and were more likely to achieve tumor response. Assessment of T2 signal intensity at baseline may help to predict long-term responses to primary treatment with SSAs.
Lara Naletto, Anna Chiara Frigo, Filippo Ceccato, Chiara Sabbadin, Riccardo Scarpa, Fabio Presotto, Miriam Dalla Costa, Diego Faggian, Mario Plebani, Simona Censi, Jacopo Manso, Jadwiga Furmaniak, Shu Chen, Bernard Rees Smith, Stefano Masiero, Francesca Pigliaru, Marco Boscaro, Carla Scaroni and Corrado Betterle
Adrenal cortex autoantibodies (ACAs) and/or 21-hydroxylase (21OHAb) are markers of autoimmune Addison’s disease (AAD) and progression to overt AAD. The reported cumulative risk of developing AAD varies from 0 to 90% in different studies.
To assess the predictive value of different parameters in the progression toward AAD in patients with ACA and/or 21OHAb-positive patients with autoimmune polyendocrine syndromes (APS).
Materials and methods
Twenty-nine patients with APS-1 and 114 patients with APS-2 or APS-4 were followed up for a median of 10 years (range 6 months to 33 years) and were assessed using ACTH test. The risk of AAD was estimated according to age, gender, stage of adrenal dysfunction, associated diseases and antibody titer. Univariate and multivariate Cox proportional hazard models were used for statistical analysis.
The cumulative risk (CR) of developing AAD was higher in APS-1 patients (94.2%) than in patients with APS-2/APS-4 (38.7%). The CR was high in both male and female APS-1 patients, while in patients with APS-2/APS-4 it was high only in males. Stage 1 (increased plasma renin) for patients with APS-1 and Stage 2 (no response of cortisol to ACTH test) for patients with APS-2/APS-4 were established as the points of no return in the progression to AAD. Adjusted hazard ratio analyses by multivariate Cox model for AAD showed that gender, diseases and adrenal function were independent risk factors for developing clinical AAD. The risk of developing clinical AAD appears to subside after 19 years of follow-up.
A model for estimating the probability to survive free of AAD has been developed and should be a useful tool in designing appropriate follow-up intervals and future therapeutic strategies.
Martin Kužma, Peter Vaňuga, Ivana Ságová, Dušan Pávai, Peter Jackuliak, Zdenko Killinger, Neil C Binkley, Renaud Winzenrieth, Harry K Genant and Juraj Payer
Impaired bone microarchitecture is involved in vertebral fracture (VF) development among acromegaly patients.
Aim of the study
Comparison of DXA-derived bone parameters, areal BMD (aBMD), trabecular bone score (TBS) and 3D-SHAPER parameters in acromegaly patients with healthy controls.
This cross-sectional study evaluated acromegaly patients and a control group of healthy subjects. In all subjects, a single measurement of pituitary axis hormone levels, bone turnover markers, aBMD, (total hip (TH) and lumbar spine (LS)), TBS and 3D-SHAPER of the proximal femur region was performed. All subjects underwent DXA assessment of VF using the semiquantitative approach.
One hundred six patients with acromegaly (mean age 56.6 years, BMI 30.2 kg/m2) and 104 control subjects (mean age 54.06 years, 28.4 BMI kg/m2) were included. After adjustment for weight, LS aBMD, TBS and TH trabecular volumetric BMD (vBMD) remained lower (P = 0.0048, <0.0001 and <0.0001, respectively) while cortical thickness (Cth) at TH and neck remained thicker (P = 0.006) in acromegaly patients compared with controls. The best multivariate model (model 1) discriminating patients with and without acromegaly included TBS, TH trabecular vBMD and TH Cth parameters (all P < 0.05). Twenty-two VFs (13 acromegaly subjects) were recognized. In these subjects after adjustment for age, FN aBMD, TH cortical sBMD and TH cortical vBMD remained significantly associated with the prevalent VF (OR = 2.69 (1.07–6.78), 2.84 (1.24–6.51) and 2.38 (1.11–5.10) for neck aBMD, TH cortical sBMD and TH cortical vBMD respectively)). The AUCs were similar for each parameter in this model.
Acromegaly patients, regardless of VF presence, have lower trabecular bone quantitative parameters, but those with VFs had decreased cortical density.
Salvatore Minisola, Luciano Colangelo, Cristiana Cipriani, Jessica Pepe, Dana Paulina Cook and Chantal Mathieu
Few topics have elicited more emotion than the issue of screening for vitamin D status and the discussion on the need for global supplementation with vitamin D metabolites. The importance of the problem is highlighted by the USPSTF posted draft research plan with the aim of making an update recommendations statement, possibly next year. Here, we discuss two different viewpoints on screening for vitamin D status: for and against. In the literature there are scientifically sound opinions supporting pro and cons positions. However, we believe that the best way to definitively elucidate this issue is the implementation of a randomized controlled trial evaluating clinical outcomes or harms in persons screened versus those not screened for vitamin D deficiency. The feasibility of such a trial is probably questionable owing to uncertainties still present concerning threshold for vitamin D sufficiency and end points (that is, for example, improved bone mineral density, reduced risk of falls and so on) to be reached.
Aliya A Khan, Christian A Koch, Stan Van Uum, Jean Patrice Baillargeon, Jens Bollerslev, Maria Luisa Brandi, Claudio Marcocci, Lars Rejnmark, Rene Rizzoli, M Zakarea Shrayyef, Rajesh Thakker, Bulent O Yildiz and Bart Clarke
Purpose: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults.
Methods: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords ‘hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy’. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism.
Results: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin D analogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults.
Main conclusions: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium.
C Nederstigt, B S Uitbeijerse, L G M Janssen, E P M Corssmit, E J P de Koning and O M Dekkers
The association between type 1 diabetes (T1D) and other auto-immune diseases is well known. However, a quantitative overview of all associated auto-immune diseases and their prevalence in T1D is lacking.
We searched PubMed, Web of Science, EMBASE and Cochrane library in September 2018 to identify relevant articles about the prevalence of the following associated auto-immune diseases in T1D cohorts: auto-immune thyroid disease, celiac disease, gastric autoimmunity including pernicious anemia, vitiligo and adrenal gland insufficiency. A meta-analysis was performed to estimate pooled prevalence using a random-effects model. Furthermore, random-effects meta-regression analysis was performed to assess the association between prevalence and mean age or diabetes duration.
One hundred eighty articles were eligible including a total of 293 889 type 1 diabetes patients. Hypothyroidism (65 studies) was prevalent in 9.8% (95% CI: 7.5–12.3) of patients. Meta-regression showed that for every 10-year age increase, hypothyroidism prevalence increased 4.6% (95% CI: 2.6–6.6, P < 0.000, 54 studies). Weighted prevalence of celiac disease was 4.5% (95% CI: 4.0–5.5, 87 studies). Gastric autoimmunity was found in 4.3% of patients (95% CI: 1.6–8.2, 8 studies) and vitiligo in 2.4% (95% CI: 1.2–3.9, 14 studies) of patients. The prevalence of adrenal insufficiency was 0.2% (95% CI: 0.0–0.4, 14 studies) and hyperthyroidism was found in 1.3 percent (95% CI: 0.9–1.8, 45 studies) of type 1 diabetes patients. For all analyses, statistical heterogeneity between studies was moderate to high.
The prevalence of antibody-mediated auto-immune disease is high among type 1 diabetes patients. Especially hypothyroidism and celiac disease are frequently found.