Journal of the Endocrine Society最新文献

Context: Patients with aggrecan (ACAN) deficiency present with dominantly inherited short stature, as well as early-onset joint disease.

Objective: The objective of this study was to evaluate the efficacy and safety of recombinant human GH (rhGH) on linear growth in ACAN-deficient children.

Methods: Open-label, single-arm, prospective study over 3 years recruiting 10 treatment-naïve patients with heterozygous mutations in ACAN, age ≥2 years, prepubertal, and normal IGF-I concentration. Patients were treated with rhGH (initially, 50 mcg/kg/day). Main outcomes were change in (Δ) height SD score (HtSDS) and height velocity (HV).

Results: Ten patients (6 females) enrolled with median chronological age (CA) of 5.6 years (range, 2.4-9.7). Baseline median HtSDS, HV, and bone age/CA were -2.5 (range, -4.3 to -1.1), 5.2 cm/year (range, 3.8 to 7.1), and 1.2 (range, 0.9 to 1.5), respectively. The cumulative median ΔHtSDS over 3 years was +1.21 (range, +0.82 to +1.94). Median HV increased to 8.3 cm/year (range, 7.3-11.2), 7.7 cm/year (range, 5.9-8.8), and 6.8 cm/year (range, 4.9-8.6) during years 1, 2, and 3, respectively. The median Δ predicated adult height was +6.8 cm over 3 years. Four female subjects entered puberty; nevertheless, median Δbone age/CA was -0.1. No adverse events related to rhGH were observed.

Conclusion: Linear growth improved in a cohort of ACAN-deficient patients treated with rhGH, albeit somewhat attenuated in older participants who entered puberty. Longitudinal follow-up is needed to assess the long-term efficacy of rhGH and adult height outcome.

Context: For Muslim patients on levothyroxine (L-T4) therapy, the best approach for L-T4 intake during Ramadan fasting remains unclear.

Objective: We compared 2 practical approaches for L-T4 intake during Ramadan.

Methods: We randomly assigned 69 patients (21 males, 48 females, median age 44 years) with differentiated thyroid cancer (DTC) who underwent thyroidectomy in the past and are on stable LT4 doses to 2 arms. Arm A (33 patients) ingested their pre-Ramadan L-T4 dose at the evening meal and ate immediately. Arm B (36 patients) increased their pre-Ramadan dose by 25 µg if their regular L-T4 dose was ≤150 µg/day or by 50 µg if their pre-Ramadan dose was >150 µg/day and ate immediately.

Results: At the beginning of Ramadan (baseline), the median thyrotropin (TSH) level and the numbers of patients in euthyroidism, subclinical hyperthyroidism (Shyper), or subclinical hypothyroidism (Shypo) were comparable between the 2 arms (P = .69 and P = .65, respectively). At the end of Ramadan, in arm A there were 17 (51.5%), 3 (9.1%), and 13 (39.4%) patients in euthyroidism, Shyper, and Shypo compared with 17 (47.2%), 14 (38.9%), and 5 (13.9%) patients, respectively, in arm B (P = .005). The mean ± SD TSH levels in arms A and B at the end of Ramadan were 5.6 ± 6.0 mU/L and 1.67 ± 2.6 mU/L, respectively (P = .0001).

Conclusion: No overt thyroid dysfunction developed but there were more cases of Shypo in arm A and Shyper in arm B. Arm B achieved desirable levels of TSH (normal or slightly suppressed) in 86% of cases and might be a preferable approach, especially for patients who need TSH suppression (eg, DTC).

The Endocrine Society formally addressed the issue of retirement for its members for the first time in a Workshop held on June 4 at ENDO 2024 in Boston, Massachusetts. Preparation for the workshop included 4 steps: (1) completion of a survey; (2) advice from a retirement expert; (3) extensive literature review; and (4) multiple pre-workshop discussions among the presenters. The survey found that retired endocrinologists are involved in a wide variety of professional and nonprofessional activities. The retirement expert and the literature review outlined several concepts underlying a successful retirement and the questions and decisions needed during the planning process. The presenters described several illustrative examples of retirement activities. A "Piece of My Mind" essay in the Journal of the American Medical Association written by the moderator (C.B.) expressed ethical considerations made feasible by the independence of her retirement status. The first presenter (A.R.) noted that the time available during retirement allowed mentorship, teaching in foreign countries and other institutions, and participation on international committees. The second speaker (K.F.) commented that expertise gained during practice of Endocrinology can be used for expert legal, pharmaceutical, and financial opinions. She also noted that volunteering for professional or nonprofessional groups provides an avenue for "giving back" to others. The final presenter (R.S.) stated that retirement provides an opportunity to embark on new clinical endeavors, such as managing patients via telemedicine in rural underserved areas. In summary, retirement is an important phase of a career and can be highly rewarding and enjoyable.

Obesity is a pervasive public health problem that causes debilitating complications across the life course. One opportunity for preventing the onset of obesity is to focus on its social determinants. Socioeconomic status (SES), which includes factors such as income, educational attainment, occupational prestige, and access to resources, is a key determinant of obesity. In this scoping mini-review, we summarized review articles and meta-analyses of the SES-obesity association. From the 1980s to the present, cross-sectional studies have demonstrated a persistent socioeconomic gradient in obesity in which the association is negative in developed countries and positive in developing countries. Longitudinal studies have revealed the bidirectionality of the SES-obesity association; some studies demonstrate that socioeconomic adversity precedes the onset of obesity, while others provide evidence of reverse causality. While earlier studies relied on anthropometric assessments of weight and height to define obesity, the use of modern technologies like dual-energy x-ray absorptiometry and bioelectrical impedance have demonstrated that the socioeconomic gradient in obesity is robust across multiple indicators of body composition, including direct measures of lean and fat mass. More recently, examination of mediators and moderators of the SES-obesity association have highlighted causal pathways and potential intervention targets, with a focus on health behaviors, environmental conditions, psychological factors, and biological processes. We describe current gaps in knowledge and propose opportunities for future innovation to reduce the burden of obesity and related socioeconomic disparities.

Purpose: To assess the safety of zoledronic acid (ZOL) and denosumab (Dmab) administered following hip fracture in a hospital setting.

Methods: Patients older than 65 years were treated by a fracture liaison service following hip fracture. Generally, patients who had a glomerular filtration rate (eGFR) > 35 mL/min were treated with ZOL, whereas patients who had previously received bisphosphonates or had a eGFR between 20 and 35 mL/min were treated with Dmab. Adverse events included hypocalcemia (calcium corrected for albumin less than 8.5 mg/day), renal functional impairment (0.5 mg/dL or more increase in serum creatinine) within 30 days of treatment, or a fever (>38 °C) within 48 hours of drug administration.

Results: Two hundred twenty-eight and 134 patients were treated with ZOL and Dmab, respectively. Mean body temperature was elevated following ZOL administration (0.18 °C P < .001) but remained below 38 °C. Hypocalcemia occurred in 18% and 29% of the ZOL and Dmab groups, respectively (P = .009). Renal functional impairment was observed in 9 and 6 patients (4% and 5%) in the ZOL and Dmab groups, respectively (P = .8). Pretreatment calcium above 9.3 mg/dL was associated with a lower risk of posttreatment hypocalcemia (odds ratio 0.30, 95% confidence interval 0.13-0.68, P = .004). While the absolute risk of hypocalcemia was higher in the Dmab group, multivariate analysis did not find that the choice of drug was predictive of hypocalcemia.

Conclusion: In-hospital parenteral osteoporosis treatment was rarely associated with fever or renal function impairment but was associated with hypocalcemia. Posttreatment hypocalcemia risk did not vary significantly between patients receiving ZOL or Dmab.

Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neuropeptide and endocrine peptide precursors; it is expressed in neuroendocrine tissues as well as in immune cells. In response to endotoxemia, global PC1/3 knockout mice mount a cytokine storm and die rapidly. Further, immune cells isolated from these mice have a pro-inflammatory signature, suggesting that PC1/3 activates an unknown anti-inflammatory peptide precursor in immune cells. Here, we tested this hypothesis using tissue-specific PC1/3 ablation models. Knocking out PC1/3 in the myeloid or the hematopoietic compartment did not induce any phenotype. In contrast, proopiomelanocortin (POMC)-specific PC1/3 knockout mice phenocopied global PC1/3 knockout mice, including an enlarged spleen size and a hyperinflammatory sepsis phenotype in response to mild endotoxemia. This phenotype was prevented by steroid therapy and mimicked by blocking corticoid receptors in wild-type mice. Thus, our data suggest that sepsis hypersensitivity in PC1/3 deficiency is uncoupled from immune cell intrinsic PC1/3 expression and is driven by a lack of anti-inflammatory glucocorticoids due to an impairment in the hypothalamic-pituitary-adrenal axis.

Rheumatoid arthritis (RA) is characterized by erosive pathology associated with joint inflammation and a sexual dimorphism with increased prevalence in females. Here, we aim to determine whether androgen is protective against inflammatory-erosive disease in TNF-transgenic (TNF-Tg) mice. Wild-type (WT) and TNF-Tg male mice underwent sham (WT, n = 3; TNF-Tg, n = 7) or orchiectomy (WT, n = 3; TNF-Tg, n = 7) surgery at 1 month old to remove androgen production confirmed by serum testosterone concentration. Cohorts of orchiectomized TNF-Tg males were treated with either 5ɑ-dihydrotestosterone (.025 mg/day) (n = 3) or placebo (n = 3) via subcutaneous pellet insertion. Weekly clinical measures, along with mid-hindpaw bone volumes and ankle histology at 3 months old were evaluated for all groups. Orchiectomies in TNF-Tg males significantly decreased serum testosterone (P < .05), weight gain (P < .001), and mid-hindpaw bone volumes (P < .05) in comparison to sham TNF-Tg mice. The cuboid bone also had increased synovitis by histology with the loss of androgen (P < .05). Treatment of orchiectomized TNF-Tg males with 5ɑ-dihydrotestosterone protected against the changes in weight gain (P < .01) and bone erosion (P < .05) associated with decreased osteoclast number in the cuboid (P < .01). In the TNF-Tg model of chronic inflammatory arthritis, androgen is protective in erosive disease. The loss of endogenous androgen significantly accelerated the progression of inflammatory-erosive arthritis in male TNF-Tg mice to a similar severity as age-matched female mice. In addition, treatment with exogenous androgen prevented this observed bone loss in orchiectomized TNF-Tg males. Overall, androgen delays and limits bone erosion even in the presence of active inflammation and future studies are warranted to elucidate the associated mechanisms.

Electronic consultations (e-consults) are a mode of referral increasingly used to provide access to endocrine specialty care without the need for a patient in-person visit. This scoping review aimed to describe the models being used to deliver endocrine care via e-consult, what is known about outcomes of endocrine e-consult, and research gaps. The review was completed using an established methodological framework. PubMed, Embase, CINAHL, and Cochrane were searched for articles published in English between January 1, 2000, and March 21, 2024, that reported on e-consults for endocrine specialty care. The database search yielded 2522 articles, of which 19 underwent data extraction and synthesis. The overall body of endocrine e-consult literature is small and largely observational. Various models for endocrine e-consult programs exist. Findings on feasibility, acceptability, and timeliness are positive and consistent with the larger body of e-consult literature. Data on outcomes are limited but suggest that e-consults are no worse than other referral approaches to lowering A1C. Improvements in outcomes are greater for patients whose primary care providers implement e-consult recommendations. In summary, existing studies support the benefits of e-consults in various aspects of endocrine care quality, but the literature is nascent and there are significant research gaps. Future research should examine how e-consults can best address specific endocrine conditions, with a broad set of outcomes that addresses multiple quality dimensions. Advanced study designs and qualitative methods can help address unresolved questions about e-consults relevant to all specialties, including impact on care coordination and costs and best practices for reimbursement and workflow.

During weight loss, reductions in body mass are commonly described using molecular body components (eg, fat mass and fat-free mass [FFM]) or tissues and organs (eg, adipose tissue and skeletal muscle). While often conflated, distinctions between body components established by different levels of the 5-level model of body composition-which partitions body mass according to the atomic, molecular, cellular, tissue/organ, or whole-body level-are essential to recall when interpreting the composition of weight loss. A contemporary area of clinical and research interest that demonstrates the importance of these concepts is the discussion surrounding body composition changes with glucagon-like peptide-1 receptor agonists (GLP-1RA), particularly in regard to changes in FFM and skeletal muscle mass. The present article emphasizes the importance of fundamental principles when interpreting body composition changes experienced during weight loss, with a particular focus on GLP-1RA drug trials. The potential for obligatory loss of FFM due to reductions in adipose tissue mass and distribution of FFM loss from distinct body tissues are also discussed. Finally, selected countermeasures to combat loss of FFM and skeletal muscle, namely resistance exercise training and increased protein intake, are presented. Collectively, these considerations may allow for enhanced clarity when conceptualizing, discussing, and seeking to influence body composition changes experienced during weight loss.

Context: The neuropeptide RFRP-3 (RFamide-related peptide-3) is thought to play a role in the negative regulation of fertility. However, the exogenous administration of RFRP-3 yields varying results depending on the dose and route of administration, sex of the subject, and many other variables. Manipulation of in vivo neuronal activity using DREADDs (designer receptor exclusively activated by designer drugs) technology enables investigation of cell type-specific neuronal activation in a manner that better reflects endogenous neuronal activity.

Objective: To test the effects of RFRP neuronal activation on pulsatile luteinizing hormone (LH) secretion.

Methods: We generated mice expressing the stimulatory hM3Dq designer receptor exclusively in RFRP cells using 2 different Cre-loxP-mediated approaches: (1) we bred mice to express hM3Dq in all Rfrp-Cre-expressing cells, including some that transiently expressed Rfrp-Cre neonatally (RFRP × hM3Dq mice), and (2) we stereotaxically injected Cre-dependent hM3Dq into the dorsomedial nucleus of RFRP-Cre mice to drive hM3Dq expression exclusively in a subpopulation of adult Rfrp-Cre neurons (RFRP-AAV-hM3Dq mice). We then investigated the effects of acute hM3Dq activation on LH pulse frequency in RFRP × hM3Dq mice, RFRP-AAV-hM3Dq mice, and their respective controls.

Results: In both female RFRP × hM3Dq and RFRP-AAV-hM3Dq mice, chemogenetic activation of Cre-driven hM3Dq led to a significant 35% to 50% reduction in LH pulse frequency compared with controls, while no differences in pulse amplitude or mean LH concentration were observed. In marked contrast, RFRP activation did not cause any changes to LH pulse dynamics in male mice.

Conclusions: These data show for the first time that activation of neurons that have expressed Rfrp, or of a subset of adult RFRP neurons, can independently suppress LH pulsatility in female, but not male mice.