Journal of the Endocrine Society最新文献

Context: Body composition and glucose metabolism change with aging. Whether different levels of body-mass-index (BMI) are needed to define diabetes risk across the adult lifespan is unknown.

Objective: This work aimed to investigate whether BMI similarly reflects relative fat mass (FM) and diabetes risk across age groups.

Methods: Participants without diabetes from the Baltimore Longitudinal Study of Aging (973 men, 1073 women), stratified by age (<50, 50-59, 60-69, ≥70 years) and categorized by either World Health Organization (WHO)-defined BMI categories (for normal weight, overweight or obesity) or BMI quartiles. The primary exposure was BMI. The primary outcome was diabetes incidence. The relationship of BMI to dual-energy x-ray absorptiometry-derived FM was also investigated in older vs younger participants.

Results: The median (range) follow-up time was 7.1 years (range, 0-29.0 years). Within WHO-defined BMI categories, different age groups demonstrated significantly different FM percentage, FM/lean mass, and waist circumference (P < .05). WHO-defined BMI categories for overweight and obesity were generally related to higher diabetes risk compared to normal weight in all ages except 50 to 59 years. When BMI was categorized by quartiles, diabetes incidence increased dramatically beginning in quartile 2 (23-25 kg/m²) in older groups. BMI cutoffs with equivalent diabetes incidence rate as BMI 25 kg/m² and 30.0 kg/m² in individuals younger than 50 years were 22.7 kg/m² and 25.2 kg/m² for ages 50 to 59 years; 22.8 kg/m² and 25.0 kg/m² for ages 60 to 69 years; and 23.2 kg/m² and 25.8 kg/m² for ages 70 years and older, respectively.

Conclusion: WHO-defined BMI categories do not reflect similar diabetes risk across the lifespan. Diabetes incidence is greater at lower levels of BMI in older adults and may lead to underestimation of diabetes risk with aging, particularly among those traditionally classified as normal-weight individuals.

Objective: To assess the usefulness of the upright posture stimulation test (UPT) in the confirmation of primary aldosteronism (PA) in patients in whom saline tests (ST) were inconclusive.

Methods: One hundred eighty-seven adult patients with possible PA were retrospectively included and compared to 25 control subjects. Blood samples were obtained after a 1-hour supine posture and during 2 hours of ambulation. An increase in plasma aldosterone concentration (PAC) ≥ 50% with a suppressed renin (≤10.1 ng/L; ≤1 ng/mL/hour) and a cortisol increase ≤50% were considered abnormal.

Results: PA patients had higher basal PAC and lower basal direct renin concentration (DRC) (P < .0001) and a higher maximal PAC (P = .0025) and lower maximal DRC (DRC_max) (P < .0001) during UPT compared to controls. PA was confirmed in 145 patients (77.5%), based on either oral/IV ST or UPT. DRC_max ≤12 ng/L during UPT was a predictor of PA (receiver operating characteristic curve sensitivity 93.8%, specificity 88%), and 95.6% of PA patients increased PAC ≥50% on UPT (median 222.2%), while renin remained suppressed. All 41 PA patients with false-negative IV ST (PAC < 162 pmol/L) and 88.9% with borderline response (162-240 pmol/L) had a DRC_max ≤12, while, respectively, 97.6% and 100% increased aldosterone by ≥50%. Similar responses to UPT were found in lateralized (28/63) and bilateral PA source (35/63). PA diagnosis increased from 23.6% to 88.8% using UPT results instead of IV ST and were confirmed at pathology and clinical outcome after adrenalectomy (n = 22).

Conclusion: UPT can be useful to confirm PA, particularly in patients with suspected false-negative ST.

Mounting evidence indicates that whereas some fundamental aspects of bone cell differentiation and function are similar in females and males, there is a clear contribution of sex/gender on the effects of signaling molecules on bone mass and strength and, consequently, on the effects of pharmacologic approaches to treat skeletal disorders. However, until recently, most studies were designed and performed using only 1 sex, resulting in a scarcity of published information on sexual dimorphism of the musculoskeletal system, including the mandible/masticatory muscles and the axial and appendicular bones and skeletal muscles. Further, it is now recognized that scientific rigor requires the study of both males and females. Therefore, there is an increasing need to understand the molecular and cellular basis for the differential outcomes of genetic manipulations and therapeutic agent administration depending on the sex of the experimental animals. Studies have shown higher muscle mass, cancellous bone mass, and long bone width in males compared with females as well as different traits in the pelvis and the skull, which are usually used for gender identification in forensic anthropology. Yet, most reports focus on the role of sex hormones, in particular, the consequences of estrogen deficiency with menopause in humans and in ovariectomized animal models. In addition, emerging data is starting to unveil the effects of gender-affirming hormonal therapy on the musculoskeletal system. We summarize here the current knowledge on the sex/gender-dependent phenotypic characteristics of the bone and skeletal muscles in humans and rodents, highlighting studies in which side by side comparisons were made.

Recent studies have highlighted leptin, a key hormone that regulates energy intake and induces satiety, due to the worldwide prevalence of obesity. In this study, we analyzed plasma leptin measurements from 18 women with premenopausal obesity before and after bromocriptine treatment. By using underlying pulses recovered through deconvolution, we modeled the leptin secretory pulses as marked point processes and applied statistical distributions to evaluate the dynamics of leptin, including the interpulse intervals and amplitudes of the secretion. We fit the generalized inverse Gaussian and lognormal distributions to the intervals and the Gaussian, lognormal, and gamma distributions to the amplitudes of pulses. We evaluated the models' goodness of fit using statistical metrics including Akaike's information criterion, Kolmogorov-Smirnov plots, and quantile-quantile plots. Our evaluation results revealed the effectiveness of these statistical distributions in modeling leptin secretion. Although the lognormal and gamma distributions performed the best based on the metrics, we found all distributions capable of accurately modeling the timing of secretory events, leading us to a better understanding of the physiology of leptin secretion and providing a basis for leptin monitoring. In terms of pulse amplitude, the evaluation metrics indicated the gamma distribution as the most accurate statistical representation. We found no statistically significant effect of bromocriptine intake on the model parameters except for one distribution model.

Context: Insufficient efficacy and safety data for off-label use of aromatase inhibitors to augment height in boys with short stature.

Objective: To compare anastrozole and letrozole in treatment of idiopathic short stature in pubertal boys.

Design: Open-label trial with 2 treatment arms.

Setting: Pediatric Endocrine Clinic at Stanford.

Participants: A total of 79 pubertal males ≥10 years with bone age (BA) ≤ 14 years, predicted adult height (PAH) < 5th percentile or >10 cm below mid-parental height.

Intervention: Anastrozole 1.0 mg or letrozole 2.5 mg daily for up to 3 years.

Main outcome measures: Annual hormone levels and growth parameters during treatment and a year posttherapy; annual BA and PAH (primary outcome measure); spine x-rays and dual energy X-ray absorptiometry at baseline and 2 years.

Results: Compared with anastrozole (n = 35), letrozole (n = 30) resulted in higher testosterone levels, lower estradiol and IGF-1 levels, and slower growth velocity and BA advance. The PAH increase observed at year 1 in both groups did not persist at years 2 and 3. Change in PAH from baseline was not different between treatment groups. In groups combined, PAH gain over 3 years vs baseline was +1.3 cm (P = .043) in linear mixed models.

Conclusion: Letrozole caused greater deviations than anastrozole in hormone levels, growth velocity, and BA advancement, but no group differences in PAH or side effects were found. Change in PAH after 2 to 3 years of treatment was minimal. The efficacy of AI as monotherapy for height augmentation in pubertal boys with idiopathic short stature may be limited, and safety remains an issue.

Mutations in the pituitary-specific transcription factor Prophet of Pit-1 (PROP1) are the most common genetic etiology of combined pituitary hormone deficiency (CPHD). CPHD is associated with short stature, attributable to growth hormone deficiency and/or thyroid-stimulating hormone deficiency, as well as hypothyroidism and infertility. Pathogenic lesions impair pituitary development and differentiation of endocrine cells. We performed single-cell RNA sequencing of pituitary cells from a wild-type and a Prop1-mutant P4 female mouse to elucidate population-specific differential gene expression. We observed a Smoc2+ve population that expressed low Sox2, which trajectory analyses suggest are a transitional cell state as stem cells differentiate into endocrine cells. We also detected ectopic expression of Sox21 in these cells in the Prop1^df/df mutant. Prop1-mutant mice are known to overexpress Pou3f4, which we now show to be also enriched in this Smoc2+ve population. We sought to elucidate the role of Pou3f4 during pituitary development and to determine the contributions of Pou3f4 upregulation to pituitary disease by utilizing double-mutant mice lacking both Prop1 and Pou3f4. However, our data showed that Pou3f4 is not required for normal pituitary development and function. Double mutants further demonstrated that the upregulation of Pou3f4 was not causative for the overexpression of Sox21. These data indicate loss of Pou3f4 is not a potential cause of CPHD, and further studies may investigate the functional consequence of upregulation of Pou3f4 and Sox21, if any, in the novel Smoc2+ve cell population.

Background: It is unclear whether targeted monitoring of acute adrenal insufficiency (AI) related adverse events (AE) such as sick day episodes (SDEs) and hospitalization rate in congenital adrenal hyperplasia (CAH) is associated with a change in the occurrence of these events.

Aim: Study temporal trends of AI related AE in the I-CAH Registry.

Methods: In 2022, data on the occurrence of AI-related AE in children aged <18 years with 21-hydroxylase deficiency CAH were compared to data collected in 2019.

Results: In 2022, a total of 513 children from 38 centers in 21 countries with a median of 8 children (range 1-58) per center had 2470 visits evaluated over a 3-year period (2019-2022). The median SDE per patient year in 2022 was 0 (0-2.5) compared to 0.3 (0-6) in 2019 (P = .01). Despite adjustment for age, CAH phenotype and duration of study period, a difference in SDE rate was still apparent between the 2 cohorts. Of the 38 centers in the 2022 cohort, 21 had also participated in 2019 and a reduction in SDE rate was noted in 13 (62%), an increase was noted in 3 (14%), and in 5 (24%) the rate remained the same. Of the 474 SDEs reported in the 2022 cohort, 103 (22%) led to hospitalization compared to 299 of 1099 SDEs (27%) in the 2019 cohort (P = .02).

Conclusion: The I-CAH Registry can be used for targeted monitoring of important clinical benchmarks in CAH. However, changes in reported benchmarks need careful interpretation and longer-term monitoring.

Context: Metabolic syndrome (MetS) is a cluster of metabolic risk factors that predict cardiovascular disease. Previous studies suggested that MetS impaired clinical outcomes in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF).

Objective: To evaluate the effects of MetS on IVF/intracytoplasmic sperm injection (ICSI) outcomes in women without PCOS.

Methods: This retrospective study collected 8539 eligible women without PCOS who came for their first cycle of IVF/ICSI to the Institute of Women, Children and Reproductive Health, Shandong University, from 2017 to 2020, including 1147 subjects in the MetS group and 7392 in the control group. The primary outcome was live birth. Secondary outcomes included other pregnancy outcomes and the risk of maternal and neonatal complications.

Results: Women in the MetS group had a lower live birth rate (50.6% vs 54.9%, adjusted odds ratio [aOR] 0.87, 95% CI 0.75-1.00, P = .045) and higher risks of late miscarriage (5.8% vs 3.3%, aOR 1.52, 95% CI 1.02-2.27, P = .041), gestational diabetes mellitus (13.7% vs 7.0%, aOR 1.84, 95% CI 1.30-2.60, P = .001), hypertensive disorder of pregnancy (7.8% vs 3.5%, aOR 1.79, 95% CI 1.14-2.83, P = .012), and preterm birth (9.0% vs 4.4%, aOR 2.03, 95% CI 1.33-3.08, P = .001). Singleton newborns in the MetS group were at higher risk of large for gestational age (33.3% vs 20.5%, aOR 1.66, 95% CI (1.31-2.13), P < .001) but at lower risk of small for gestational age (2.7% vs 6.2%, aOR 0.48, 95% CI 0.25-0.90, P = .023).

Conclusion: MetS was associated with adverse IVF/ICSI outcomes in women without PCOS.