Journal of Clinical Endocrinology & Metabolism最新文献

Context: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia in childhood with considerable risk of lifelong neurological sequelae. Available pharmacological therapies are limited. Dasiglucagon is a glucagon analog for the treatment of hypoglycemia.

Objective: To assess efficacy and safety of dasiglucagon in children with CHI up to 1 year of age.

Methods: This study included a randomized, crossover, double-blind, placebo-controlled Part 1, and an open-label, single-arm Part 2 at four centers in Germany, UK, and USA. Participants comprised children with CHI aged 7 days to 12 months who were dependent on IV glucose. In Part 1, participants were randomized to dasiglucagon or placebo for 48 hours, then crossed over to the other treatment for 48 hours. In Part 2, all participants received dasiglucagon for 21 days. The primary outcome was mean IV glucose infusion rate (GIR) in the last 12 hours of Part 1.

Results: Between 6/19/2020 and 2/9/2022, 12 eligible participants were randomized to dasiglucagon-placebo (n = 7) or placebo-dasiglucagon (n = 5). The IV GIR was significantly reduced with dasiglucagon compared with placebo (least-squares mean 4.3 mg/kg/min [95% confidence interval [CI], 1.04 to 7.60 mg/kg/min] and 9.5 mg/kg/min [95% CI, 6.24 to 12.81 mg/kg/min], respectively; P = .004). The most frequent adverse events in both treatment groups were gastrointestinal, dermatological, and metabolism and nutritional disorders.

Conclusion: In infants with CHI, dasiglucagon significantly reduced the amount of IV glucose needed to maintain euglycemia compared with placebo. Dasiglucagon represents a promising treatment for the management of CHI.

Context: Women with prolactinoma are usually infertile, but can conceive after surgery or treatment with dopamine agonists (DA).

Objective: To evaluate the impact of pregnancy in prolactinoma's natural course and in maternal-fetal outcomes.

Data sources: MEDLINE, EMBASE, LILACS, and CENTRAL.

Study selection: Observational studies that included at least three pregnant women with prolactinoma.

Data extraction: Two independent reviewers selected studies, assessed the risk of bias, and extracted data from the included studies.

Data synthesis: Fifty-two studies were included, involving 2544 pregnancies in 1928 women. The Stata Statistical Software 18 was used for proportional meta-analyses. The overall frequency of pregnant women on DA treatment at conception was 97% and for either continuing or resuming treatment during pregnancy was 6%. The overall frequency of miscarriage was 10% (95% confidence interval [CI], 8%-12%), 3% for prematurity (95% CI, 2%-5%), 4% for symptomatic tumor growth during pregnancy (95% CI, 2%-8%), 4% for visual impairment (95% CI, 2%-7%), 6% for headache (95% CI, 4%-9%), and 4% for development of gestational diabetes (95% CI, 3%-7%). The overall frequency of congenital malformations was 2% (95% CI, 1%-4%), 2% for perinatal mortality (95% CI, 1%-2%), and 6% for low birth weight (95% CI, 3%-9%). Moreover, prolactinoma's size is a significant modifier for visual impairment.

Conclusion: Pregnancy in women with prolactinoma is safe in relation to fetal and maternal outcomes with low frequencies of miscarriage, prematurity, symptomatic growth, visual impairment, headache, congenital malformations, perinatal mortality, and low birth weight.

Introduction: Hypoparathyroidism denotes parathyroid hormone (PTH) deficiency and impaired mineral metabolism. MBX 2109, a novel prodrug yielding a biologically active PTH peptide agonist (PTH[1-32], extended by a fatty acylated Lys33), is being developed as a long-acting, once-weekly PTH replacement therapy. Here, we report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MBX 2109 in healthy volunteers.

Methods: This phase 1, randomized, double-blind, placebo-controlled, multiple ascending-dose study (NCT05158335) enrolled healthy adults, who were randomized 4:1 to receive MBX 2109 (200, 400, 600, and 900 μg; n = 8) or placebo (n = 2) by subcutaneous administration once weekly for 4 doses (days 1, 8, 15, and 22). The primary endpoint was safety and tolerability. Key secondary endpoints were PK and PD.

Results: Overall, 40 participants (MBX 2109 n = 32, placebo n = 8) were randomized (mean age, 43.3 years; 22.5% female). Treatment-emergent adverse events (TEAEs) occurred in 50%-88% of MBX 2109 groups and in 25% of placebo participants. In the MBX 2109 groups, no severe or serious TEAEs were observed. Injection-site reaction was the most common treatment-related TEAE. The half-lives were 79-95 hours for MBX 2109 and 184-213 hours for the fatty-acylated biologically active PTH peptide, which showed dose- and time-dependent exposure increases.

Conclusion: The sustained-action PTH prodrug MBX 2109 was well tolerated with no unexpected, off-target safety issues. The long half-life and flat exposure profile of MBX 2109's biologically active PTH agonist supports once-weekly administration. MBX 2109 doses were identified for future studies.

Most disorders of steroidogenesis, such as forms of congenital adrenal hyperplasia (CAH) are caused by mutations in genes encoding the steroidogenic enzymes and are often recognized clinically by cortisol deficiency, hyper- or hypo-androgenism, and/or altered mineralocorticoid function. Most steroidogenic enzymes are forms of cytochrome P450. Most P450s, including several steroidogenic enzymes, are microsomal, requiring electron donation by P450 oxidoreductase (POR); but several steroidogenic enzymes are mitochondrial P450s, requiring electron donation via ferredoxin reductase (FDXR) and ferredoxin (FDX). POR deficiency is a rare but well-described form of CAH characterized by impaired activity of 21-hydroxylase (P450c21, CYP21A2) and 17-hydroxylase/17,20-lyase (P450c17, CYP17A1); more severely affected individuals also have the Antley-Bixler skeletal malformation syndrome and disordered genital development in both sexes, and hence is easily recognized. The 17,20-lyase activity of P450c17 requires both POR and cytochrome b5 (b5), which promote electron transfer. Mutations of POR, b5, or P450c17 can cause selective 17,20-lyase deficiency. In addition to providing electrons to mitochondrial P450s, FDX and FDXR are required for the synthesis of iron-sulfur clusters, which are used by many enzymes. Recent work has identified FDXR mutations in patients with visual impairment, optic atrophy, neuropathic hearing loss and developmental delay, resembling the global neurologic disorders seen with mitochondrial diseases. Many of these patients have had life-threatening events or deadly infections, often without an apparent triggering event. Adrenal insufficiency has been predicted in such individuals but has only been documented recently. Neurologists, neonatologists and geneticists should seek endocrine assistance in evaluating and treating patients with mutations in FDXR.

Context: Guideline-directed medical therapy of heart failure (HF) primarily targets neurohormonal activation. However, growth hormone (GH) has emerged as a potential treatment for the multiple hormonal deficiency syndrome, which is associated with worse outcomes in HF.

Objective: This study evaluates the efficacy and safety of GH therapy in HF.

Data sources: A systematic search was conducted in PubMed, Cochrane Library, and ClinicalTrials.gov, according to PRISMA guidelines.

Study selection: Randomized, placebo-controlled trials studying GH therapy in adult HF patients were included. Of the 1,184 initially identified records, 17 studies (1.4%) met the inclusion criteria.

Data extraction: Two independent authors conducted the search, with any disagreements resolved by a third author. Study quality was assessed using predefined criteria, including randomization, blinding, and the presence of a placebo group.

Data synthesis: A random-effects model was applied due to heterogeneity across studies. GH therapy significantly improved left ventricular ejection fraction (3.34%, 95% CI: 1.09% to 5.59%, p=0.0037), peak oxygen consumption (2.84 mL/kg/min, 95% CI: 1.32 mL/kg/min to 4.36 mL/kg/min, p=0.0002), and New York Heart Association class (-0.44, 95% CI: -0.08 to -0.81, p=0.023). GH therapy also reduced the composite of death, worsening HF or ventricular tachycardia by 41% (95% CI: 0.39-0.90, p=0.013). Subgroup analyses indicated that patients with ischemic cardiomyopathy, baseline ejection fraction ≥30% and longer treatment duration experienced greater benefits.

Conclusions: GH therapy may improve cardiac function, exercise capacity, and HF symptoms, with a trend towards improvement in hard endpoints, such as worsening HF. Event-driven trials are necessary to validate these findings.

Context: 46,XY differences of sex development (DSD) are heterogeneous in etiology. The detailed phenotypes of 46,XY DSD patients with monogenic disorders have not been fully elucidated.

Objectives: To estimate the proportion of monogenic disorders in 46,XY DSD and to characterize the clinical phenotypes of patients with monogenic disorders.

Methods: A total of 185 Japanese patients (178 families) were enrolled. We sequenced 25 genes related to 46,XY DSD, and assessed the pathogenicity of the identified sequence variants according to the American College of Medical Genetics and Genomics guidelines, supplemented by in silico or in vitro analyses. We analyzed the clinical phenotypes of patients with monogenic disorders, with particular attention to the external or internal genitalia.

Results: We identified 51 patients (47 families) with any monogenic disorders (26%), who possessed pathogenic variants in AR (11%), SRD5A2 (4.5%), NR5A1 (4.0%), SRY (2.8%), WT1 (1.1%), STAR (1.1%), CYP17A1 (0.56%), HSD3B2 (0.56%), or MAP3K1 (0.56%). The proportion of monogenic disorders was significantly higher in subjects with detected Müllerian derivatives (57%) than in those undetected (26%) (P = 0.029), in subjects with female-typical genitalia (91%) than those with ambiguous genitalia (19%) (P < 0.001).

Conclusions: The proportion of monogenic disorders in Japanese 46,XY DSD patients was approximately 26%. Monogenic disorders were frequent among patients with severe undermasculinization of the external or internal genitalia.

Objective: Hypercortisolism in endogenous Cushing's syndrome (CS) results in decreased bone mineral density (BMD) and increased fracture risk. Although after remission BMD improves, fracture rate remains elevated, suggesting that BMD may not adequately reflect fracture risk in this group. The aim was to evaluate bone material properties, another component of bone quality, using Impact Microindentation (IMI) in patients with CS in remission.

Methods: Cross-sectional study in 60 patients and 60 age-, sex-, and BMD-matched controls at a tertiary referral center between 2019 and 2021. Bone material strength index (BMSi) was measured by IMI using the OsteoProbe® device at the tibia. In addition, laboratory investigation, BMD, and vertebral fracture assessment were performed.

Results: By design, patients and controls were comparable for age (median age 56.5 years), sex (48 women), BMD at the lumbar spine and femoral neck. They were also comparable regarding the number of fragility fractures (21 vs. 27, p=0.22). Median time of remission in patients was 6 years (range 1 to 41). Despite comparable BMD, BMSi was significantly lower in patients compared to controls (76.2±6.7 vs 80.5±4.9, p<0.001). In patients, BMSi was negatively correlated with BMI (r= -0.354, p=0.01), but not related to the presence of fracture, physiological hydrocortisone replacement use, other pituitary insufficiencies, or time since remission.

Conclusion: Bone material properties remain altered in patients with endogenous CS, even after long-term remission. These abnormalities, known to be associated with fractures in other populations, may play a role in the persistent bone fragility of steroid excess.