Therapeutic Advances in Endocrinology and Metabolism最新文献

Background: There is interest in repurposing bicalutamide for gender-affirming hormone therapy, but little data regarding efficacy and safety in the transgender population.

Objectives: To determine the effect of bicalutamide on serum total testosterone concentrations and liver function. Given bicalutamide is a pure androgen receptor antagonist, we hypothesized that serum total testosterone concentrations would be higher than the cisgender female reference range and those recommended for transgender individuals in consensus guidelines.

Design: Case series.

Methods: We identified transgender people attending outpatient clinics who were using bicalutamide for gender affirmation. The primary outcome was serum total testosterone concentration. Secondary outcomes included serum alanine transferase (ALT) concentration.

Results: Twenty-four transfeminine people prescribed bicalutamide were identified. The median (interquartile range) age was 29 (24-38) years, bicalutamide dose 25 (25-50) mg daily and bicalutamide duration 6 (4-10) months. The median serum total testosterone concentration was 7.7 (0.7-17.5) nmol/L, luteinizing hormone 2.9 (0.5-6.0) IU/L and ALT 20 (13-29) IU/L. One individual had asymptomatic transaminitis. Six individuals discontinued bicalutamide due to a lack of perceived benefit.

Conclusion: Bicalutamide was associated with significant variation in serum total testosterone concentration, likely related to concomitant estradiol or previous anti-androgen therapy. Median serum ALT concentrations remained within the normal reference range. Guideline recommendations for serum total testosterone within the cisgender female reference range may be inappropriate for people using bicalutamide. Further research is needed to establish the longer-term efficacy and safety of bicalutamide in the transfeminine population.

Ectopic corticotropin-releasing hormone (CRH) syndrome, a rare subtype of adrenocorticotropic hormone-dependent Cushing syndrome, is associated with tumors of diverse origins. Here, we present a case of a 37-year-old female diagnosed with ectopic CRH syndrome secondary to rectal large cell neuroendocrine carcinoma, a hitherto unprecedented site for CRH-secreting tumors. The patient presented with classical features of Cushing syndrome, supported by laboratory evidence of hypercortisolemia and disrupted diurnal cortisol secretion. Imaging studies ruled out a pituitary adenoma, whereas colonoscopy identified a rectal malignancy. Immunohistochemical staining confirmed the presence of ectopic CRH syndrome. Despite prompt chemotherapy initiation, the patient's condition rapidly deteriorated, highlighting the aggressive nature and dismal prognosis associated with rectal large cell neuroendocrine carcinoma linked to ectopic CRH syndrome. This case underscores the importance of early recognition and comprehensive management to optimize patient outcomes.

Background: Continuous glucose monitoring (CGM) with minimally invasive devices plays a key role in the assessment of daily diabetes management by detecting and alerting to potentially dangerous trends in glucose levels, improving quality of life, and treatment adherence. However, there is still uncertainty as to whether CGMs are accurate enough to replace self-monitoring of blood glucose, especially in detecting episodes of hypoglycemia.

Objectives: Evaluate clinical, numerical accuracy, sensitivity, and specificity of the CGM devices commercially available when compared to the reference standard of arterial or venous blood glucose.

Data sources and methods: We searched the Cochrane Library, PubMed, EMBASE, and LILACS databases. The quality was assessed with the Quality Assessment Diagnostic Accuracy Studies (QUADAS-2) tool. Clinical and numerical accuracy data were extracted. Sensitivity and specificity were calculated using Review Manager software. Heterogeneity was assessed by visual examination of forest plot and summary receiver operating characteristic curves.

Results: Twenty-two studies with a total of 2294 patients were included. The average mean absolute relative difference for overall diagnostic accuracy was 9.4%. None of the devices evaluated with ISO 15197:2013 criteria achieved values ⩾95% of measurements in the stipulated ranges in hypoglycemia (±15 mg/dL), but two devices did achieve it in hyperglycemia (±15%; Dexcom G6 and G7). Most of the devices evaluated with consensus error grids reached values above 99% in zones A and B only in overall accuracy and hyperglycemia. For hypoglycemia, the average sensitivity was 85.7% and specificity 95.33%, and for hyperglycemia was 97.45% and 96% respectively.

Conclusion: Currently available CGM devices have adequate accuracy for euglycemia and hyperglycemia; however, it is still inadequate for hypoglycemia, although it has improved over time.

Trial registration: Prospero registration ID CRD42023399767.

Background: Hyperglycemic emergencies (HGEs) are the major deadliest acute complications of diabetes. HGEs have reached an alarming stage and increased year-to-year leading to increased morbidity, hospitalization, and mortality. Despite HGEs causing this increased healthcare, psychological, social, and economic burden, studies conducted to address this burden and its predictive factors remain limited. Thus, this study aimed to investigate the incidence and predictors of HGEs among adult diabetic patients.

Methods: An institution-based retrospective follow-up study was employed on 538 systematically selected adult diabetic patients who had diabetic follow-up in Sidama region and Gedeo zone public hospitals from September 1, 2018, to September 1, 2022. The sample size was determined using STATA V-14. Data were collected using an extraction checklist, entered into EPI data version 4.4.2.2, and analyzed using STATA version 14. The Kaplan-Meier curve and log-rank test were used to determine the survival probabilities and to compare the survival status. The Cox proportional hazard regression model was used to determine the association and identify the predictor variables. A statistical significance was declared at a p-value of <0.05 in line with a 95% confidence interval (CI) and hazard ratios.

Results: The study was conducted on 538 diabetic adult patients with a response rate of 100%. The mean age of study participants was 44.5 years, and more than 66.7% were males. The incidence rate of HGEs was found to be 29 (95% CI: 25.3-33.2) per 1000 person-months with a total of 7176.5 person-month observations. Being farmer (adjusted hazard ratio (AHR) = 6.47; 95% CI: 2.61-16.04), poor glycemic control (AHR = 6.84; 95% CI: 3.47-13.49), less frequent diabetic follow-up (AHR = 4.00; 95% CI: 1.02-15.57), and having hypertension (HTN) (AHR = 2.94; 95% CI: 1.62-5.34) were significantly associated with increased hazard of acquiring HGEs among adult diabetic patients. Conversely, the hazard of experiencing HGE was 63% lower among patients who had diabetic nephropathy relative to those without diabetic nephropathy (AHR = 0.35; 95% CI: 0.15-0.83). Hence, setting and strengthening specific diabetic management strategies focused on the identified predictors could be paramount to reducing HGEs and their unwanted effects. Moreover, it's better to consider more frequent diabetic follow-up visits for all patients regardless of other complications.

Background: The aldosterone-to-renin ratio (ARR) is commonly used for screening primary aldosteronism (PA) in patients with difficult-to-control hypertension. Various thresholds have been proposed for the confirmatory tests, leading to inconsistency in the results.

Objectives: This study aimed to elucidate the performance of ARR screening in hypertensive patients.

Design: Systemic review and meta-analysis.

Data sources and methods: PubMed, Embase, and the Cochrane Library were systematically searched from inception to January 2024. Studies that used the ARR to screen for PA and provided a comprehensive probability panel specifically focusing on hypertensive individuals were considered for enrollment. Pooled diagnostic efficacy was evaluated, and subgroup analyses and meta-regression were conducted based on different demographic and clinical parameters.

Results: Eighteen observational studies encompassing 7150 participants were included in the meta-analysis. The overall prevalence of PA in the hypertensive cohort was 15.2%, and pooled sensitivity and specificity were 81.6% and 93.3%, respectively, resulting in a diagnostic odds ratio of 62.0. Fagan's nomogram showed that a positive ARR increased the post-test probability to 80% from a pre-test probability of 25%. Summary receiver operating characteristic curve analysis revealed an area under the curve of 94.7%. Notably, analysis of variability demonstrated that the diagnostic performance was consistent across either ARR based on plasma renin activity or direct renin concentration, geographic region, sex, mean age, potassium level, and systolic blood pressure.

Conclusion: ARR was validated as a viable screening methodology for PA in hypertensive individuals. Moreover, its diagnostic efficacy remained unchanged across diverse clinical contexts. Future studies are warranted to refine ARR methodologies and enhance diagnostic accuracy.

Trial registration: PROSPERO ID number CRD42023493680.

Infographics: Performance of PA screening by ARR. ARR, aldosterone-to-renin ratio; BP, blood pressure; DRC, direct renin concentration; hsROC, hierarchical summary receiver operating characteristic; PA, primary aldosteronism; PRA, plasma renin activity.

Background: There is limited data about the risk factors of clinically significant glycosylated hemoglobin (HbA1c) change and post-transplant diabetes mellitus (PTDM) in the first year post-kidney transplantation (KT), especially in the Middle East.

Objectives: To determine the trends of HbA1c levels, the risk factors associated with HbA1c increases, and predictors of clinically significant HbA1c change and PTDM in the first year post-KT.

Design: Retrospective chart review.

Methods: We included all KT recipients (KTRs) at our center from 2017 until 2020. The study focused on reviewing the patients' demographic information, cardiovascular risk factors, and HbA1c values at baseline, 6 months, and 12 months.

Results: A total of 203 KTRs were included. The mean age of the participants was 44.7 ± 15.5 years, 59.1% were men, and 80.3% received living donors. Eighty-two (40.4%) KTRs had pre-KT diabetes. At 12 months post-KT, the total HbA1c change was 0.87 ± 1.6. In total, 130 (64.04%) KTRs demonstrated clinically significant HbA1c change, and 19 (15.7%) nondiabetics developed PTDM. Pre-KT diabetics suffered greater increases than their nondiabetic counterparts (0.8 vs 0.6, p = 0.043). Increased age (adjusted odds ratio (aOR) = 1.053), weight change (aOR = 1.055), pre-KT hypertension (aOR = 3.015), and lower baseline HbA1c (aOR = 0.453) were independently associated with clinically significant HbA1c change. PTDM patients were older (p = 0.007) and had higher HbA1c levels at baseline (p = 0.033), 6 months (p = 0.002), and 1-year post-KT (p = 0.001). Gender, type of KT, dialysis, and cardiovascular risk factors were not different between PTDM and non-PTDM patients. Abnormal perfusion tests (p < 0.001) and coronary artery disease on coronary angiogram (p = 0.046) were more common in PTDM patients. Only age was independently associated with the presence of PTDM at 1-year post-KT (aOR = 1.044).

Conclusion: The incidence rate of PTDM in Saudi KT patients is similar to that of other populations. Several risk factors, including low baseline HbA1c and pre-KT hypertension, predict a clinically significant change in HbA1c. Patients with these risk factors may require stricter monitoring and control of HbA1c.

• The efficacy of weekly somatrogon injections was no different from that of daily somatropin injections to treat children who don't make enough growth hormone to grow adequately. ○ Efficacy refers to how well a drug works in a clinical trial. ○ Children treated with weekly somatrogon had an increased growth rate, similar to that of children treated with daily somatropin. • The safety of weekly somatrogon injections was similar to that of daily somatropin injections. The original scientific article on which this summary is based was published in The Journal of Clinical Endocrinology & Metabolism and can be accessed for free at: https://academic.oup.com/jcem/article/107/7/e2717/6566444. The details of the original article are as follows: Cheri L. Deal, Joel Steelman, Elpis Vlachopapadopoulou, Renata Stawerska, Lawrence A Silverman, Moshe Phillip, Ho-Seong Kim, CheolWoo Ko, Oleg Malievskiy, Jose F. Cara, Carl L. Roland, Carrie Turich Taylor, Srinivas Rao Valluri, Michael P. Wajnrajch, Aleksandra Pastrak, and Bradley S. Miller. Efficacy and safety of weekly somatrogon vs daily somatropin in children with growth hormone deficiency: a phase 3 study. J Clin Endocrinol Metab 2022; 107(7): e2717-e2728. The purpose of this plain language summary is to help you to understand the findings from recent research. • Somatrogon is used to treat growth hormone deficiency (the condition under study that is discussed in this summary). Approval varies by country; please check with your local healthcare provider for more details. • The results of this study may differ from those of other studies. Physicians/providers should make treatment decisions based on all available evidence and not on the results of a single study.

Background: Diabetic foot ulcer (DFU) is a common and highly morbid complication of diabetes with high unmet medical needs. AUP1602-C, a topical four-in-one gene therapy medicinal product (GTMP), consisting of a Lactococcus cremoris strain that produces fibroblast growth factor-2, interleukin-4, and colony-stimulating factor-1, is a promising novel treatment for DFU.

Objectives: The aim of this first-in-human study was to investigate whether AUP1602-C is safe and effective in improving wound healing and quality of life (QoL) in patients with non-healing DFU (nhDFU), and to determine the recommended phase II dose.

Design: Phase I, single-arm, open-label, uncontrolled, dose escalation study.

Methods: The study consisted of four cohorts of patients receiving AUP1602-C as a single dose of 2.5 × 10⁵ colony-forming units (CFU)/cm² ulcer size or as repeated doses between 2.5 × 10⁶ and 2.5 × 10⁸ CFU/cm² administered 3 times per week for 6 weeks. Within each cohort, a 3 + 3 scheme for monitoring safety, tolerability, and efficacy was applied.

Results: In total, 16 patients aged 53-80 years were included, 3 each in the safety and low dose, 4 in the medium dose, and 6 in the high-dose cohort. AUP1602-C demonstrated a favorable safety profile with almost 100% dosing compliance. The most frequently reported side effect related to treatment was skin maceration. No serious adverse reactions, systemic toxicity, deaths, or side effects suggestive of immunogenicity, hypersensitivity, allergic reaction, or dose-limiting toxicities related to treatment were reported. No biodistribution events were observed and shedding-related events were rare and did neither show accumulation nor dose dependency. The recommended phase II dose of 2.5 × 10⁸ CFU/cm² demonstrated complete healing in 83% of patients without recurrence of ulcers during follow-up.

Conclusion: AUP1602-C was safe and well tolerated and demonstrated dose-dependent efficacy in patients with nhDFU. Data supports further clinical development of AUP1602-C.

Trial registration: The study was registered in ClinicalTrials.gov (NCT04281992) and ClinicalTrialsRegister.eu (2018-003415-22).

• For children with growth hormone deficiency, once-weekly somatrogon injections were less of a burden than once-daily somatropin injections. • The safety of weekly somatrogon was similar to that of daily somatropin. • Compared with daily somatropin injections, children with growth hormone deficiency may be less likely to miss weekly somatrogon injections.  ○ This is because weekly somatrogon injections were less of a burden and were less likely to interfere with daily activities compared with daily somatropin injections. The purpose of this plain language summary is to help you to understand the findings from recent research. • Somatrogon is used to treat the condition under study that is discussed in this summary. Approval varies by country; please check with your local provider for more details. • The results of this study may differ from those of other studies. Health professionals should make treatment decisions based on all available evidence and not on the results of a single study. This original scientific article on which this summary is based was published in the Journal of the Endocrine Society and can be accessed for free at: https://academic.oup.com/jes/article/6/10/bvac117/6695276. The details of the original article are as follows: Aristides K. Maniatis, Mauri Carakushansky, Sonya Galcheva, Gnanagurudasan Prakasam, Larry A. Fox, Adriana Dankovcikova, Jane Loftus, Andrew A. Palladino, Maria de los Angeles Resa, Carrie Turich Taylor, Mehul T. Dattani, Jan Lebl. Treatment burden of weekly somatrogon versus daily somatropin in children with growth hormone deficiency: a randomized study. J Endocr Soc 2022; 6(10): bvac117. DOI: 10.1210/jendso/bvac117.

Background: Our objective was to assess the effect of a hybrid telemedicine approach, in conjunction with face-to-face follow-up, on the quality of life in recent users of an advanced hybrid closed-loop (AHCL) system.

Methods: A 1-year open randomized (1:1) clinical trial (ClinicalTrials.gov ID NCT04900636). Participants with type 1 diabetes (T1D) recent users of an AHCL system (Minimed^® 780G) for at least 2-6 months, and ⩾18 years old were eligible. The primary outcome was the change in quality of life measured by the Type 1 Diabetes Life (ViDa1) Questionnaire from baseline to 12 months of hybrid telemedicine plus face-to-face follow-up compared to standard clinical practice. Additionally, impacts on A_1c levels, glucose metrics, advert events, and safety outcomes were assessed.

Results: Between January and December 2021, 46 participants were randomly assigned in a 1:1 ratio to either the hybrid telemedicine group (n = 23) or the control group (n = 23); 45 participants completed the study, with only 1 from the control group withdrawing before visit 3. At baseline, mean age was 37 ± 15 years and A_1c was 6.9 ± 0.5%. After 12 months, no statistically significant differences in ViDa1 scores between groups were observed. Despite reducing in-person visits in the hybrid follow-up arm, there were no increases in adverse events. Overall, A_1c levels significantly decreased from 6.9 ± 0.5% at baseline to 6.7 ± 0.5% after 12 months (P = 0.006) without differences between treatment arms, accompanied by reductions in glycemic variability and time below the target range.

Conclusion: Our study suggests that there were no significant differences in ViDa1 scores between the two groups at the end of the follow-up. However, among adult patients with T1D who recently adopted an AHCL system, satisfactory glycemic control can be attained through a hybrid follow-up approach, reducing face-to-face visits, without increasing technical complications.