Clinical Endocrinology最新文献

Objective: Polycystic ovary syndrome (PCOS) is a common condition, that manifests as menstrual irregularities, subfertility, or symptoms of hyperandrogenism - including hirsutism, adult acne, and alopecia. Current pharmacological treatment of the hyperandrogenic symptoms includes the combined oral contraceptive pill. However, there are multiple contraindications and side-effects, which limit their use. Anti-androgens, such as spironolactone, are commonly prescribed off-label but its efficacy in PCOS is uncertain. This review aims to evaluate the efficacy and safety of spironolactone, when compared to other nonhormonal medications in the management of PCOS hyperandrogenic symptoms.

Methods: Comprehensive literature searches were conducted across MEDLINE, EMBASES, PUBMED and SCOPUS. RCTs published in English assessing the use of spironolactone for hyperandrogenism in PCOS were included. The quality of papers was assessed using Cochrane RoB 2.0 tool. Meta-analysis was conducted using a random-effects model, reporting as standardised mean differences and 95% confidence intervals.

Results: Of 3378 studies identified, five open-label RCTs met the inclusion criteria, three of which were included in the meta-analysis. Spironolactone, monotherapy or combination with metformin, showed no statistically significant difference in reducing Ferriman-Gallwey scores, total testosterone levels or BMI compared to metformin monotherapy. Side effects of spironolactone included menstrual irregularities, polyuria, and gastrointestinal symptoms.

Conclusion: Current evidence does not show any significant difference in the use of spironolactone when compared to metformin. Given its widespread use and limited safety concerns, spironolactone remains an off-label option, especially for those unable to take hormonal contraceptives. However, larger, better quality studies are needed to establish its efficacy in PCOS management.

Primary hyperparathyroidism induced hypercalcaemic crisis is defined as an albumin- adjusted calcium ≥3.50 mmol/L, occurring in the presence of organ dysfunction. This endocrine emergency requires medical optimisation prior to urgent parathyroidectomy. However, few guidelines exist on the most appropriate course of treatment, including the use of preoperative bisphosphonates to control severe hypercalcaemia. Such caution is, in part, driven by concerns about aggravating postoperative hypocalcaemia in a cohort of patients already at heightened risk of developing hungry bone syndrome; a postoperative phenomenon characterised by rapid sequestration of calcium into bone. We review the limited evidence around preoperative bisphosphonate administration in patients with hyperparathyroid crisis and examine the efficacy and safety of intravenous pamidronate in our own patient series. Whilst the management remains largely empirical, we suggest that bisphosphonates can be considered to safely facilitate parathyroidectomy, since intravenous fluid therapy alone is often insufficient to control severe hypercalcaemia. Preoperative calcium optimisation that includes intravenous bisphosphonate therapy should be prioritised over the theoretical risk of aggravating postoperative hypocalcaemia; the latter of which may be ameliorated by adequate preoperative vitamin D replacement.

Objective: Mild autonomous cortisol secretion (MACS) is associated with increased cardiometabolic risk factors including hypertension, type 2 diabetes and dyslipidaemia. By using evening doses of metyrapone, a short-acting 11-β hydroxylase inhibitor, it has been shown that it is possible to reset the abnormal circadian cortisol rhythm in MACS. This study aimed to evaluate the tolerability and impact of this approach on cardiometabolic outcomes in patients with MACS.

Design: We conducted a single-centre retrospective, longitudinal review of patients with MACS who received evening metyrapone (250-500 mg at 6 PM and 250 mg at 10 PM) to evaluate adverse events, tolerability, and cardiometabolic outcomes (systolic and diastolic blood pressure, HbA1c, weight and non-HDL cholesterol) at 6 months, compared to controls. Age and sex-matched controls were identified from patients with adrenal incidentalomas and non-suppressed serum cortisol following 1 mg overnight dexamethasone suppression testing.

Results: Fifteen patients and 15 matched controls were identified. Over 6 months there were no adrenal crises. Metyrapone was stopped in 2/15 patients in view of side effects. In the metyrapone group compared to controls, there were significant decreases in systolic blood pressure (-17.7 (SE 5.8) vs. +8.7 (5.7)mmHg, p = 0.008, n = 9) and diastolic blood pressure (-9.9 (4.2) vs. +3.0 (3.6)mmHg, p = 0.024). The differences between groups for HbA1c, weight and non-HDL cholesterol were not statistically significant.

Conclusion: Evening metyrapone was associated with significant reductions in systolic and diastolic blood pressure in patients with MACS, without causing adrenal insufficiency, indicating its potential safe clinical utility. A well-powered, controlled, prospective study is needed to validate these findings and comprehensively investigate the broader metabolic outcomes.

Introduction: Adrenal incidentalomas (AI) are commonly found on imaging done for indications other than to assess the adrenal glands. Prevalence increases with age and is around 10% in people over 80 years. The majority of AIs are benign adenomas, with 20%-50% exhibiting mild autonomous cortisol secretion (MACS). Clinical guidelines recommend the use of dexamethasone to improve outcomes in patients with COVID-19 requiring oxygen.

Hypothesis: Benign adrenal adenomas protect against severe COVID-19.

Methods: Reports for all computed tomography pulmonary angiogram (CTPA) scans at Sheffield Teaching Hospitals between 11 March 2020 and 10 November 2021 were assessed for details of AI. Scan requests mandated recording COVID-19 status. Patients with a positive COVID-19 test within 2 weeks before the CTPA were classed as COVID-19 positive for the analyses. Duplicate scans were removed.

Results: A total of 4307 CTPA scans were included. The median age was 65 (IQR 49-77) and the majority of patients were female (55.0%). Seventy-six (1.76%) patients had a benign adenoma. COVID-19 positivity was found in 897 (20.8%). The presence of a benign adenoma was associated with a 70% reduced odds of being COVID-19 positive (aOR 0.30, 95% CI 0.12-0.74, p = 0.01), adjusting for age and sex.

Conclusion: Prevalence of adrenal adenoma was associated with significantly reduced odds of being SARS-CoV2 positive in an inpatient cohort. Secretion of mild excess cortisol (MACS) may be protective against developing severe COVID-19.

Context: The bone health significance of incidentally detected low serum 25(OH)D in clinically asymptomatic individuals is debatable. We investigated the changes in bone mineral density (BMD) and trabecular bone score (TBS) after 1 year of cholecalciferol and calcium supplementation in asymptomatic individuals with low serum 25(OH)D and TBS.

Design and setting: Interventional longitudinal study at the tertiary-care centre.

Subjects and measurements: The study subjects were 50 healthy individuals (age 45 ± 9 years, BMI 26.7 ± 3.9 kg/m² and M:F = 29:21) with serum 25(OH)D < 50 nmol/L and low TBS (< 1.310) followed from an earlier study designed for generating TBS norms for Asian Indians. Participants received supervised 60,000 IU of cholecalciferol/week for 8 weeks, followed by 60,000 IU/month for the next 10 months and 500 mg daily elemental calcium. Serum 25(OH)D and related biochemical parameters, BMD, and TBS were evaluated before and after 6- and 12-months of supplementation. Changes were analysed using a generalised estimating equation.

Results: Mean serum 25(OH)D (nmol/L) showed a significant rise following supplementation (29.1 ± 11.7 at baseline to 68.8 ± 47.4 and 63.2 ± 22.2 at 6- and 12-months, respectively). Serum intact PTH, osteocalcin, and alkaline phosphatase showed a significant decrease within 6 months of supplementation. BMD improved significantly from baseline at lumbar-spine, total-hip, and femoral-neck at 6- and 12-months after supplementation (p < 0.01 for all). However, the mean TBS showed no significant change following cholecalciferol and calcium supplementation.

Conclusions: One year of cholecalciferol and calcium supplementation in asymptomatic individuals resulted in a significant rise in serum 25(OH)D, which was associated with increased BMD but not TBS.

Introduction: Craniopharyngioma (CP) is a rare, recurrent central nervous system tumor with significant hormonal, visual, and metabolic sequelae.

Methodology: This retrospective cohort study analyzes 37 years of experience managing pediatric and adult CP patients at a specialized referral center in Chile, stratified by age at onset. Clinical, biochemical, imaging, and neurosurgical data from 1986 to 2023 were reviewed.

Results: A total of 87 patients (1-68 years) were included, with 65 (75%) presenting in childhood (≤ 18 years) and 22 (25%) in adulthood. Mean follow-up was 9.3 years (IQR 3.7-14.1). Histology was adamantinomatous in 84%, papillary in 3%, and unspecified in 13%. The most common symptoms at presentation were headache (77%), visual disturbances (60%), and nausea (45%). At diagnosis, 54% had at least one pituitary dysfunction, most frequently thyrotropic (28.2%) and somatotropic (27.9%). Following initial treatment, pituitary dysfunction increased to 71%, with thyrotropic (59%) and corticotropic (48%) being the most affected axes. Anterior panhypopituitarism occurred in 25%, and permanent AVP deficiency in 32%. Tumor recurrence or progression was observed in 63%.

Conclusions: CP carries a high risk of recurrence and neuroendocrine complications. This study, based on 37 years of experience in a reference center, is the first national report on CP patients, with findings consistent with previous literature. The management of these patients is complex and demands a highly experienced multidisciplinary team to achieve optimal long-term outcomes.

Objective: Gonadal dysgenesis (GD) due to NR0B1 duplication is a subset of 46,XY disorder of sexual differentiation (DSD) characterised by variable external genitalia phenotypes ranging from complete GD (CGD) to partial GD (PGD) and may have syndromic associations. The DSD-phenotype spectrum and its correlation with genotype have not been systematically studied.

Design: A systematic review of 46,XY GD with NR0B1 duplication (n = 47, including two patients from our centre) was conducted to understand DSD phenotypes and their genotypic correlations.

Results: Large and submicroscopic duplications were observed in 61.7% and 38.3%, respectively, and maternal inheritance (asymptomatic carriers, except one) was reported in 63.3%. Median age at presentation was 1.0 (birth to 38) years, and syndromic manifestations were the cause in 55.3% and gonadal dysfunction-related symptoms in 42.5%. CGD, PGD, and typical male genitalia were seen in 66%, 27.7%, and 6.4%, respectively. Gender incongruence and fertility (except for one reported paternity) have not been reported. Gonadoblastoma and gonadal germ cell cancer were noted in 17% (median age: 11 years) and 2.1% (15 years of age) of cases, respectively. Compared with submicroscopic duplications, large duplications were associated with earlier presentation (0.7 vs. 15 years; p = 0.008) and higher prevalence of syndromic features (96.6% vs. 22.2%; p = 0.0001), while external genital phenotype, cryptorchidism, presence of mullerian structures, and gonadoblastoma rates were comparable.

Conclusions: 46,XY GD phenotype with NR0B1 duplication does not correlate with duplicated segment size. A delineated spectrum of gonadal dysfunction, gender identity, fertility, and gonadal malignancy risk presented here can help to optimise patient management.

Objective: Thyroid dysfunction is common in Down Syndrome (DS). The age of onset and etiology is largely unexplored. Murine models suggest role of DYRK1A gene in thyroid dysgenesis in DS. DYRK1A overexpression is associated with immune dysfunction and autoimmune diseases in DS. In this study, we aimed to determine the expression of the DYRK1A gene in relation to age of onset and autoimmune status in individuals with DS who have hypothyroidism.

Methods: This cross-sectional study was conducted in a tertiary care setting and included five groups: individuals with DS and hypothyroidism, DS with euthyroidism, congenital hypothyroidism without DS, autoimmune hypothyroidism without DS, and age-matched healthy controls without thyroid dysfunction. History, clinical details such as age of onset, thyroid function tests including antibodies, and DYRK1A expression were assessed.

Results: Of the 72 DS included, 24 were euthyroid. 48 (66.7%) had primary hypothyroidism and 28 (58.3%) of those were anti-TPO negative. Hypothyroidism was detected in 20 patients with DS below 1 year of age who were all anti-TPO-negative. The remaining 28 with DS with hypothyroidism developed disease after 3 years of age of whom 20 (71.4%) were anti-TPO positive. DS with hypothyroidism had higher expression (6.33-fold) of DYRK1A compared to euthyroid DS (p < 0.0001). DYRK1A expression was 5.17-fold and 7.27-fold higher in anti-TPO-positive and anti-TPO-negative respectively compared to healthy population (p < 0.0001). Individuals with DS without hypothyroidism, congenital hypothyroidism (without DS), autoimmune hypothyroidism (without DS) had DYRK1A expression of 1.36, 0.68, and 0.82-fold compared to healthy.

Conclusion: DYRK1A expression is overexpressed in individuals with Down syndrome with hypothyroidism, encompassing both early-onset non-autoimmune and later-onset autoimmune forms.

Context: Screening morning serum cortisol is used to select patients for ACTH stimulation testing to diagnose adrenal insufficiency (AI) but may be affected by pre-analytical factors. Careful consideration to discontinue confounding medications beforehand may preclude the need for subsequent stimulation testing.

Objective: To determine whether serum cortisol collected after discontinuation of confounding medications is more predictive of AI compared to screening morning cortisol without mandatory medication adjustment.

Methods: Retrospective chart review of 835 patients with ACTH stimulation testing (Short Synacthen Test [SST]). Linear regression to compare Roche Cortisol II immunoassay screening cortisol versus optimally collected cortisol measurements after removal of confounding medications. Receiver operating characteristic (ROC) curve analyses to identify 100% sensitivity threshold for AI.

Results: The majority of patients passed the SST (n = 756; 90.5%). There was a poor correlation between screening morning cortisol and optimally collected cortisol measurements, r = 0.34 (95% CI, 0.25-0.42). Real-world screening morning cortisol measurements had moderate discrimination for the diagnosis of AI (AUC 0.80; 95% CI, 0.77-0.82; p < 0.001) with a 100% sensitivity threshold for AI of 262 nmol/L. Applying this threshold would save 112 SSTs (13.4% of all tests). In contrast, an optimally collected serum cortisol had strong discrimination for AI (AUC 0.89; 95% CI, 0.87-0.91; p < 0.0001) and the threshold with 100% sensitivity for the diagnosis was 246 nmol/L which would save another 4.8% of all tests.

Conclusion: Careful attention to pre-test patient preparation and implementation of a lower cortisol threshold may significantly reduce the number of stimulation tests needed to screen for AI.

Objective: Low testosterone is common in men with type 2 diabetes and is associated with adverse metabolic outcomes. Our objective was to identify factors associated with low total and calculated free testosterone (CFT) in men with type 2 diabetes, with a focus on relative estrogen excess and subcutaneous adipose aromatase expression.

Design: Cross-sectional study.

Patients: One hundred eighty men with type 2 diabetes and 92 healthy men in the reference cohort.

Measurements: Sex steroid hormones were measured alongside body composition, metabolic biomarkers, adipose tissue aromatase gene expression, and genetic variants of aromatase. T-scores for testosterone and estradiol were calculated using a healthy reference cohort.

Results: HbA1c (p < 0.001), BMI (p = 0.007), leptin (p = 0.009) and insulin resistance (p = 0.026) were associated with lower total testosterone (<10 nM). Lower CFT (<220pM) was associated with age (p = 0.049), BMI (p < 0.001), interleukin-6 (p < 0.001), leptin (p = 0.003) and insulin (p = 0.020). Men with type 2 diabetes and low testosterone had relative estrogen excess (Estradiol T score-Testosterone T score 1.63 [0.94, 2.76]) compared to healthy controls (0.06 [-0.74, 0.51], p < 0.001). A common CYP19A1 variant was associated with increased adipose CYP19A1 expression (p = 0.044) and low CFT (p = 0.042). Multivariable analysis identified BMI (p < 0.001), CYP19A1 expression (p = 0.020) and HbA1c (p = 0.006) as independently associated with CFT.

Conclusion: In men with type 2 diabetes, low testosterone is associated with adiposity, glycaemic control, and increased adipose aromatase expression. Relative estrogen excess may contribute to hypothalamic-pituitary-testicular axis suppression and represents a novel target for diagnostic and therapeutic strategies.