Journal of the Endocrine Society最新文献

Although most cases of endogenous Cushing syndrome are caused by a pituitary adenoma (Cushing disease), approximately one-third of patients present with ectopic or adrenal causes. Surgery is the first-line treatment for most patients with Cushing syndrome; however, medical therapy is an important management option for those who are not eligible for, refuse, or do not respond to surgery. Clinical experience demonstrating that osilodrostat, an oral 11β-hydroxylase inhibitor, is effective and well tolerated comes predominantly from phase III trials in patients with Cushing disease. Nonetheless, reports of its use in patients with ectopic or adrenal Cushing syndrome are increasing. These data highlight the importance of selecting the most appropriate starting dose and titration frequency while monitoring for adverse events, including those related to hypocortisolism and prolongation of the QT interval, to optimize treatment outcomes. Here we use illustrative case studies to discuss practical considerations for the management of patients with ectopic or adrenal Cushing syndrome and review published data on the use of osilodrostat in these patients. The case studies show that to achieve the goal of reducing cortisol levels in all etiologies of Cushing syndrome, management should be individualized according to each patient's disease severity, comorbidities, performance status, and response to treatment. This approach to osilodrostat treatment maximizes the benefits of effective cortisol control, leads to improvements in comorbid conditions, and may ameliorate quality of life for patients across all types and severities of Cushing syndrome.

Context: European and German consensus guidelines advocate preoperative therapy with α-adrenoreceptor antagonists in symptomatic patients with catecholamine-producing pheochromocytomas and paragangliomas (PPGLs) to avoid hypertensive crisis during adrenalectomy. This practice has been questioned recently.

Objective: This work aimed to assess current preoperative management of PPGLs across disciplines.

Methods: The study was conducted from November 2023 to February 2024 using the Delphi technique. Two consecutive surveys were conceived by a steering group and 46 experts were consulted using REDCap web application (response: 74%).

Results: There was general agreement about diagnostic tools and indication for adrenalectomy. In contrast, 20% of the panelists routinely administered α-adrenoreceptor antagonists to all patients, 50% only in case of symptoms, and about one-third of experts abandoned preoperative α-adrenoreceptor blockade. The prevention of anticipated intraoperative hypertensive crisis and cardiovascular complications (75%) as well as medicolegal considerations (25%) were the main motivations. Despite availability of short-acting α-adrenoreceptor antagonists, most experts (63%) continued to use phenoxybenzamine. Half of the experts preferred pretreatment in an outpatient setting, 13% routinely treated in the hospital, and 37% combined outpatient and inpatient treatment. Intraoperatively, urapidil and nitroprusside natrium were mainly used for blood pressure control. Postoperatively, around 60% of the experts routinely admitted patients to an intensive care or intermediate care unit.

Conclusion: Current guideline recommendations for preoperative treatment with α-adrenoreceptor antagonists in patients with PPGLs are generally adopted by treating teams but current practice is very heterogeneous even among expert centers. With the improvement of surgical techniques and intraoperative management, a more individualized approach may be considered.

Background: Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability.

Objective: To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab.

Methods: A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients.

Results: After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L).

Conclusion: The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).

Purpose: People with resistance to thyroid hormone due to defective thyroid receptor β (RTHβ) exhibit adverse cardiovascular outcomes and premature mortality. Whether this reflects increased global cardiovascular disease (CVD) risk or hyperthyroxinemia-associated effects on cardiac rhythm and contractility is unknown. We determined CVD risk and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations as a marker of reduced cardiac function in 99 individuals (mean age 41 years, 37% males) with RTHβ.

Results: The mean (SD range) QRISK3 score for 82 participants was 2.0% (0.5-8.8%) vs 1.3% (0.3-5.0%) for age, sex, and ethnicity-matched healthy controls (P = .005). The QRISK3 heart age of RTHβ participants was 49.8 ± 14.5 years vs actual age 44.5 ± 12.4 years [difference 5.3 (95% confidence interval: 4.0, 6.5) years; P < .001]. The mean (SD range) plasma NT-proBNP in 79 RTHβ participants was 51 (18-142) pg/mL; 10.1% of values were above the age-specific 97.5th percentile of a large control sample. In multiple linear regression, age and female sex were significant independent predictors of NT-proBNP (P ≤ .001), but free T3, free T4, TSH, and QRISK3 10-year CVD risk were not.

Conclusion: Elevated NT-proBNP concentrations, seen even in young people with RTHβ, suggest that myocardial dysfunction contributes to early adverse cardiovascular outcomes in this disorder, with increased atherosclerotic disease risk likely manifesting later in life. Measurement of NT-proBNP and assessment of cardiovascular risk should be considered at first presentation and periodically during follow-up of RTHβ.

Context: Obesity has been associated with changes in cortisol and dehydroepiandrosterone (DHEA) sulfate concentrations and increased stress levels and food addiction.

Objectives: We explored changes in morning salivary cortisol and DHEA in childhood obesity and their associations with body composition, metabolic profile, food addiction, food consumption, and stress in a cross-sectional study.

Methods: Children aged 7 to 12 years of both sexes were allocated into 2 groups according to body mass index-for-age: control group (n = 60) or obesity group (n = 98). Anthropometric, body composition, serum glucose, insulin, lipid profile, and DHEA were measured. Saliva was collected at different times to measure morning salivary cortisol concentrations. Food addiction, food consumption, and stress were assessed using questionnaires.

Results: Lower DHEA [1.04 (0.87-1.25) ng/mL vs 1.65 (1.30-2.07) ng/mL, P = .002] and salivary cortisol (6:00 Am: 1.17 ± 0.89 vs 1.45 ± 0.82 nmol/L, 6:30 Am: 1.53 ± 0.68 vs 1.83 ± 0.70 nmol/L, 7:30 Am: 0.72 ± 0.99 vs 1.31 ± 0.94 nmol/L, P-value of time < 0.001 and P-value of group = .002) were observed in children with obesity compared to the control. DHEA correlated negatively with waist circumference (r = -0.20, P < .05), body mass index-for-age(BMI-Z) (r = -0.21, P < .01), and weight (r = -0.25, P < .01). DHEA showed a positive correlation with the cortisol area under the curve (r = 0.29, P = .002). Food addiction was positively correlated with waist circumference (r = 0.21, P < .01), BMI-Z (r = 0.22, P < .01), body weight (r = 0.20, P < .05), total energy intake (r = 0.20, P < .05), and lipids (r = 0.24, P < .01).

Conclusion: Children with obesity showed lower concentrations of salivary cortisol and DHEA and higher food addiction compared to control children. These changes may contribute to the development of chronic diseases over time.

Context: Whether circulating testosterone, dihydrotestosterone, and estradiol levels or testosterone replacement therapy (TRT) affects the risk of COVID-19 and whether COVID-19 affects response to TRT remains unknown.

Objective: The study evaluated whether baseline testosterone, dihydrotestosterone, and estradiol levels or TRT are associated with risk of developing COVID-19 and whether COVID-19 affects treatment response to TRT.

Methods: Among 5204 men, aged 45 to 80 years, with hypogonadism in the TRAVERSE trial, 379 developed COVID-19. We compared baseline and on-treatment hormone levels, and safety and efficacy in participants with and without COVID-19 diagnosis.

Results: Neither baseline nor on-treatment testosterone, estradiol, and dihydrotestosterone levels prior to COVID-19 differed significantly between men with and without COVID-19 diagnosis. Incidence of COVID-19 was similar in participants randomized to TRT or placebo groups (3-year Kaplan-Meier incidence 8.0% in TRT and 8.6% in placebo group, P = .823). Incidences of COVID-19-related hospitalizations (38.5% vs 32.8%, P = .222) and deaths (12.8% vs 8.9%, P = .247) were similar in the TRT and placebo groups. Changes in hypogonadal symptoms, libido, energy, and hemoglobin/hematocrit in response to TRT were attenuated in testosterone-treated men who developed COVID-19. Incidences of major adverse cardiovascular events, venous thromboembolism, and acute kidney injury were similar in those with COVID-19 diagnosis and those without.

Conclusion: In men with hypogonadism and cardiovascular disease (CVD) or increased risk of CVD, baseline and pre-COVID-19 on-treatment testosterone, dihydrotestosterone, and estradiol levels were similar in those who developed COVID-19 and those who did not. TRT did not affect the risk of COVID-19. COVID-19 attenuated the treatment response to TRT.

Context: Estrogen receptor α (ERα) in the ventromedial (VMN) and arcuate (ARC) nuclei of female rodent mediobasal hypothalami (MBHs) provides a crucial molecular gateway facilitating estradiol (E₂) regulation of sexual behavior, reproductive neuroendocrinology, and metabolic function. In female nonhuman primates (NHPs) and women, however, its hypothalamic counterpart remains unknown.

Objective: We hypothesized that knockdown (KD) of ERα expression in the hypothalamic VMN and ARC of female marmosets would diminish sexual receptivity, while simultaneously disrupting gonadotropic and metabolic homeostasis.

Methods: We ovariectomized (OVX) adult female marmosets of comparable age and weight, immediately replaced E₂ at midcycle levels, and approximately 1 month later assigned monkeys to diet-induced obesity (DIO) within group (1) control, receiving scrambled short hairpin RNA (shRNA), or (2) ERαKD, receiving selective ERα gene silencing shRNA. Magnetic resonance imaging-guided neural surgery enabled hypothalamic infusion of viral vector shRNA and subsequent brain immunohistochemistry enabled observer-validated, NIS-elements computer software quantification of ERα knockdown.

Results: ERα expression was significantly diminished in the VMN and ARC, but not the preoptic area (POA), of ERαKD females coincident with elimination of timely female sexual responses, more than 80% loss of female receptivity, modestly elevated gonadotropin levels, hyperglycemia, and diminished calorie consumption. Density and intensity of ERα-expressing cells in the VMN correlated positively with female sexual receptivity and calorie consumption, negatively with timeliness of female sexual responses, and in the ARC, correlated negatively with calorie consumption.

Conclusion: ERα activation in the female NHP MBH is critically important for female sexual behavior and modestly contributes to gonadotropic and metabolic control.

Ectopic ACTH syndrome (EAS), in which Cushing syndrome is caused by excessive ACTH secretion from a tumor located outside of the pituitary, is associated with an impaired quality of life and an increased mortality rate. Outcomes can be improved with successful tumor localization and resection, which often proves difficult. In order to distinguish EAS from Cushing disease, a significantly more common condition where excessive ACTH is secreted from a pituitary tumor, bilateral inferior petrosal sinus sampling (IPSS) is often necessary. Correct performance and interpretation of IPSS hence becomes crucial to avoid inappropriate future interventions, including surgical procedures. Once an ectopic source of ACTH is confirmed biochemically, identifying the causative tumor is often challenging since they can be located in unexpected areas and potentially be very small. Additionally, EAS carries a risk of severe hypercortisolism, which sometimes needs urgent treatment to avoid disastrous outcomes. The cases here illustrate pitfalls in diagnostic biochemical testing, describe helpful imaging strategies to improve the chances of tumor detection, and review available options to rapidly normalize severe hypercortisolism in critical situations.

Context: Radioactive iodine (RAI) treatment is a well-established successful treatment for Graves disease (GD) but causes an increment in autoantibodies, particularly TSH receptor antibodies.

Objective: To assess the performance and prognostic role of Immulite thyroid-stimulating immunoglobulin (TSI) and Elecsys thyrotropin receptor antibodies (TRAbs) immunoassays in patients with GD undergoing RAI therapy.

Methods: Clinical and laboratory data of 188 patients (156 GD and 32 toxic nodule goiter), undergoing RAI therapy between January 2018 and January 2022 were prospectively collected over 12 months. Refractoriness was defined as persistent or recurrent hyperthyroidism 6 months post-RAI treatment without levothyroxine. Statistical analysis included descriptive statistics, logistic regression, and generalized estimated equations.

Results: Patients had a mean age of 46.4 years, and 78.2% were women. RAI therapy was indicated in 94.2% due to uncontrolled hyperthyroidism or ATD therapy relapse (median of 35 months). Immulite TSI showed higher clinical sensitivity and accuracy (area under the curve [AUC]: 0.98, sensitivity 92.0%, accuracy 98.4%) than Elecsys TRAb (AUC: 0.97, sensitivity 82.1%, accuracy 91.2%). Successful treatment was achieved in 112 of 126 GD patients (89%). Thyroid volume, 2-hour iodine-131 uptake, free thyroxine and thyroxine levels, Elecsys TRAb, and Immulite TSI were significantly higher in the refractory group (P < 0.05), despite most patients receiving >300 Gy of RAI. Longitudinal thyrotropin evaluation predicted treatment response at 12 months (P = .01), whereas autoantibodies did not.

Conclusion: Refractoriness to RAI therapy was associated with higher levels of Immulite TSI and Elecsys TRAb prior to treatment. Although AUCs for both assays were equivalent, Immulite TSI demonstrated superior clinical sensitivity and accuracy. Despite distinct autoantibody patterns emerging post-RAI, longitudinal monitoring did not predict treatment response after 1 year but indicated persistently high concentrations.

Purpose: To describe diagnostic approaches and management strategies for patients with primary hyperparathyroidism (PHPT) and recent fracture in England.

Methods: We developed a survey based on a patient at high fracture risk and a new diagnosis of probable PHPT. The survey was circulated among 50 secondary care professionals identified by the Society for Endocrinology Calcium and Bone special interest group. Descriptive statistics, combinatorial, and thematic analyses were employed.

Results: In the patient with hyperparathyroidism and a recent fracture, 54% of respondents favoured a 24-hour urinary calcium: creatinine clearance ratio, with 85% opting to do so after correcting vitamin D levels. Thirty-two percent (16/50) preferred the spot urinary calcium:creatinine clearance ratio, as a random test (56%, n = 9/16). Ninety-six percent of the respondents agreed they would include a fracture risk assessment in their management plan. Eighty-five percent of the respondents selected dual-energy X-ray absorptiometry scans of the lumbar spine, total hip, and femoral neck as the most popular choice. Before initiating antiosteoporotic medications (AOMs), 94% of the respondents preferred correcting vitamin D levels with diverse regimens. IV zoledronate acid was the preferred AOM, and 58% (n = 29/50) supported cinacalcet usage if the patient was ineligible for parathyroid surgery, while 26% (n = 13/50) opposed cinacalcet use entirely. No significant correlation was found between status as an endocrinology consultant or working in a tertiary care hospital and these management preferences.

Main conclusion: This study of National Health Service medical staff identified highly-varied clinical practices in managing PHPT in the setting of high fracture risk, highlighting the need for pragmatic guidelines and wider education.