Journal of the Endocrine Society最新文献

Polychlorinated biphenyls (PCBs) pose a global challenge to environmental and human health. Although toxic and carcinogenic at higher exposure levels, at lower concentrations they can act as endocrine-disrupting chemicals. Individuals are more vulnerable to endocrine-disrupting effects of PCB exposures during the perinatal period, when the neuroendocrine system is developing, although assessing the full impact of PCB exposure is difficult because of the often-latent onset of adverse effects. The goal of this study was to determine developmental effects of an estrogenic PCB mixture, Aroclor 1221 (A1221), on KNDy and kisspeptin neuron numbers in the hypothalamic arcuate nucleus and anteroventral periventricular nucleus (AVPV), together with measures of hypothalamic-pituitary-gonadal hormones and postnatal development. We conducted RNAscope of kisspeptin, prodynorphin, neurokinin B, and estrogen receptor alpha genes in the P30 hypothalamus. Early-life PCBs caused small but significant changes in development (body weight and anogenital index) but had no effect on puberty. We found sex-specific effects of treatment on serum LH, FSH, and estradiol in a sex- and developmental age-dependent manner. RNAscope results revealed increased prodynorphin in the AVPV of male rats, but no effects on kisspeptin or neurokinin B in AVPV or arcuate nucleus. An unexpected species difference was found: we were unable to detect prodynorphin coexpression with kisspeptin within KNDy neurons in rats, unlike mice, sheep, and primates. These data show that early-life PCBs can induce developmental and hormonal changes that together with other reports showing latent effects on behavior and the hypothalamic-pituitary-gonadal axis, indicate adverse endocrine and neurobehavioral outcomes.

Objective: To study pregnancy outcomes and complications in women with congenital adrenal hyperplasia (CAH).

Methods: A retrospective multicenter study was conducted at tertiary reference centers in 5 countries (Austria, Germany, Italy, Sweden, USA), including 72 adult women with CAH (nonclassic [NC] n = 34, simple virilizing [SV] n = 21, salt wasting [SW] n = 17).

Results: A total of 133 pregnancies, 112 live births, and 25 abortions were documented. Prolonged latency to pregnancy was observed (median 11 months in SW, 24 months in SV, 8 months in NC), with a notable use of fertility-enhancing medication (25.6%) and assisted reproductive techniques (30.8%). Over half of the women in each group took more than 12 months to conceive. The average number of live births (1.4-1.6 children per woman) was similar across CAH phenotypes and comparable to the general population. Spontaneous abortion rates (18.0%) were also similar across phenotypes. Primary cesarean section rates (60.9%) were higher than in the general population, though 23.8% of women with SV and 29.4% of women with SW gave birth naturally, despite most having undergone genital surgery. Children categorized as small for gestational age were 20.5%. Pregnancy, delivery, and postpartum complications were rare for mothers and neonates.

Conclusion: The study indicates a prolonged latency to pregnancy and high use of fertility treatments in CAH patients, regardless of phenotype. Abortion rates were not increased, and overall pregnancy and perinatal outcomes were favorable.

Context: Many studies have moved toward saliva and peripheral blood sampling for studying cortisol, even in relation to disorders of the brain. However, the degree to which peripheral cortisol reflects central cortisol levels has yet to be comprehensively described. Data describing the effect that biological characteristics such as age and sex have on cortisol levels across compartments is also limited.

Objective: To assess the relationships of cortisol levels across cerebrospinal fluid (CSF), saliva, and plasma (total and free) compartments and describe the effects of age and sex on these relationships.

Design: Multisite cross-sectional observation study.

Setting: Samples collected in academic outpatient settings in 2001-2004.

Patients or other participants: Healthy community volunteers (n = 157) of both sexes, aged 20-85 years.

Interventions: None.

Main outcome measures: This study was a secondary analysis of data collected from a previously published study.

Results: CSF cortisol correlated more strongly with plasma (r = 0.49, P < .0001) than with saliva cortisol levels. Sex but not age was a significant modifier of these relationships. CSF cortisol levels trended higher with older age in men (R² = 0.31, P < .001) but not women. Age-related cortisol binding globulin trends differed by sex but did not correlate with sex differences in cortisol levels in any compartment.

Conclusion: Variability in the correlations between central and peripheral cortisol discourages the use of peripheral cortisol as a direct surrogate for central cortisol measures. Further investigation of how mechanistic drivers interact with biological factors such as sex will be necessary to fully understand the dynamics of cortisol regulation across fluid compartments.

Context: Despite a growing number of studies, the genetic etiology in many cases of ovarian dysgenesis is incompletely understood.

Objectives: This work aimed to study the genetic etiology causing absence of spontaneous pubertal development, hypergonadotropic hypogonadism, and primary amenorrhea in 2 sisters.

Methods: Whole-exome sequencing was performed on DNA extracted from peripheral lymphocytes of 2 Palestinian sisters born to consanguineous parents. Following a BMP15 variant identification, confirming genetic segregation studies were performed in family members. Three-dimensional (3D) modeling for BMP15 dimer and BMP15-GDF-9 heterodimer were followed by functional studies in human ovarian COV434 granulosa cells cotransfected with plasmid harboring either the variant or a wild-type (WT) control, and a second plasmid harboring a luciferase-reporter-gene with a BMP-responsive element.

Results: A novel homozygous c.G959A/p.C320Y BMP15 mutation was identified in both sisters, and segregated with the disease in the family. By 3D-structure modeling, the mutations were predicted to damage a cysteine-knot motif, disrupt BMP15 dimerization, and severely impair activation of the BMP pathway. The homologous mutation C53Y occurring and identified spontaneously in sheep results in sterility in homozygotes, mimicking the human phenotype here. A 3.8-fold decrease in BMP15 signaling was observed in vitro in cells expressing the homozygous BMP15 mutant when compared to the WT control.

Conclusion: The novel homozygous missense C320Y mutation is the first homozygous human BMP15 variant causing impaired signaling ability, which correlates with the predicted 3D-structural changes leading to ovarian dysgenesis. The homologous mutation in sheep mimics the human phenotype by infertility. Beyond genetic counseling, and considering ovarian preservation, the ovine model enables further elucidation and interventions in the BMP signaling.

Context: The liver/foregut satiety hormone liver-expressed antimicrobial peptide 2 (LEAP2) is an inverse agonist at the acyl ghrelin receptor (GHSR), increasing after food intake and decreasing after bariatric surgery and short-term nonsurgical weight loss, but effects of long-term dietary weight loss are unknown.

Objective: The objective of this study was to examine and compare the effects of these interventions on fasting and postprandial plasma LEAP2 and investigate potential metabolic mediators of changes in plasma LEAP2.

Methods: Plasma LEAP2 was measured in a previously published 2-year trial comparing standard medical management (SMM) (including 600-kcal/day deficit) with duodenal-jejunal bypass liner (DJBL, Endobarrier) insertion (explanted after 1 year) in adults with obesity and inadequately controlled type 2 diabetes mellitus.

Results: In the SMM group (n = 25-37), weight decreased by 4.3%, 8.1%, 7.8%, and 6.4% at 2, 26, 50, and 104 weeks and fasting plasma LEAP2 decreased from baseline mean ± SD 15.3 ± 0.9 ng/mL by 1.7, 3.8, 2.1, and 2.0 ng/mL, respectively. Absolute/decreases in fasting plasma LEAP2 positively correlated with absolute/decreases in body mass index, glycated hemoglobin A_1c, fasting plasma glucose, serum insulin, homeostatic model assessment for insulin resistance, and serum triglycerides. Despite greater weight loss in the DJBL group (n = 23-30) at 26 to 50 weeks (10.4%-11.4%), the decrease in fasting plasma LEAP2 was delayed and attenuated (vs SMM), which may contribute to greater weight loss by attenuating GHSR signaling. Plasma LEAP2 did not increase with weight regain from 50 to 104 weeks after DJBL explant, suggesting a new set point with weight loss maintenance. Increases in plasma LEAP2 after a 600-kcal meal (10.8%-16.1% at 1-2 hours) were unaffected by weight loss, improved glucose metabolism, or DJBL insertion (n = 9-25), suggesting liver rather than duodenum/jejunum may be the primary source of postprandial LEAP2 secretion.

Conclusion: These findings add to our understanding of the regulation and potential physiological role of plasma LEAP2.

Globally, nearly 9 million people are living with type 1 diabetes (T1D). Although the incidence of T1D is not affected by socioeconomic status, the development of complications and limited access to modern therapy is overrepresented in vulnerable populations. Diabetes technology, specifically continuous glucose monitoring and automated insulin delivery systems, are considered the gold standard for management of T1D, yet access to these technologies varies widely across countries and regions, and varies widely even within high-income countries. This review focuses on disparities in diabetes technology use among adolescents and young adults with T1D, barriers to access and use, and summarizes common themes emerging across countries and regions. We conducted a survey among medical technology manufacturers and physicians in various countries across diverse geographical regions and performed extensive literature searches. Across all countries and regions, economic barriers stand out as the largest and most common barriers, either preventing market penetrance of technology into a country or limiting its access to the individual with diabetes due to high out of pocket costs. Other common barriers include structural or accessibility barriers, such as stringent eligibility requirements by insurance providers, regardless of whether the insurance was private or government-based, and provider/individual level barriers. Based on the evidence presented, we suggest the need for a joint effort involving governments, private health insurers, technology manufacturers, and healthcare providers to address the global disparities of diabetic technology utilization and ensure equitable access for all individuals living with T1D worldwide.

Context: Oxytocin supplementation improves obstructive sleep apnea (OSA), and animal studies suggest involvement of oxytocin in respiratory control. However, the relationship between endogenous oxytocin signaling and human sleep status remains undetermined.

Objective: In this study, we approached the contribution of the intrinsic oxytocin-oxytocin receptor (OXTR) system to OSA by genetic association analysis.

Methods: We analyzed the relationship between OXTR gene polymorphisms and sleep parameters using questionnaire data and sleep measurements in 305 Japanese participants. OSA symptoms were assessed in 225 of these individuals.

Results: The OXTR rs2254298 A allele was more frequent in those with OSA symptoms than in those without (P = .0087). Although total scores on the Pittsburgh Sleep Quality Index questionnaire did not differ between the genotypes, breathlessness and snoring symptoms associated with OSA were significantly more frequent in individuals with rs2254298 A genotype (P = .00045 and P = .0089 for recessive models, respectively) than the G genotype. A multivariable analysis confirmed these genotype-phenotype associations even after adjusting for age, sex, and body mass index in a sensitivity analysis. Furthermore, objective sleep efficiency measured by actigraph was not significantly different between genotypes; however, subjective sleep efficiency was significantly lower in the rs2254298 A genotype (P = .013) compared with the G genotype. The frequency of the A allele is higher in East Asians, which may contribute to their lean OSA phenotype.

Conclusion: The OXTR gene may contribute to OSA symptoms via the respiratory control system, although it could be in linkage disequilibrium with a true causal gene.

Background: Cardiovascular disease (CVD) is the leading cause of noncancer-related mortality among differentiated thyroid cancer (DTC) survivors, which accounts for a large portion of subsequent primary malignancies in childhood cancer survivors. This study aims to assess the risk of cardiovascular mortality among DTC as a second primary malignancy (DTC-2) patients compared with DTC as a first primary malignancy (DTC-1) and the general population.

Methods: Using the Surveillance, Epidemiology, and End Results database, we conducted a population-based cohort study including 159 395 DTC-1 and 20 010 DTC-2 patients diagnosed older than 30 between 1975 and 2020 and the corresponding US population (71 214 642 person-years; 41 420 893 cardiovascular deaths). Compared with general-population and DTC-1 patients, we calculated incidence rate ratios (IRRs) of cardiovascular deaths among DTC-2 patients using Poisson regression. To adjust for unmeasured confounders, we performed a nested, case-crossover analysis among DTC-2 patients who died from CVD.

Results: Although DTC-2 patients had a comparable risk compared with the population (IRR 1.01) and a mildly increased risk of cardiovascular mortality compared with DTC-1 patients (IRR 1.26), the association was pronounced among individuals aged 30 to 74 years, especially 30 to 44 years (DTC-2 vs population: IRR 8.89; DTC-2 vs DTC-1: IRR 3.00). The risk elevation was greatest within the first month after diagnosis, compared with the population. The case-crossover analysis confirmed these results.

Conclusion: DTC-2 patients are at increased risk of cardiovascular mortality. Clinicians should carefully monitor CVD and manage other CVD-related factors, such as exogenous thyroxine and emotional distress, for DTC-2 patients, especially for those under 75 years.

Novelty and impact statements: This study is the first comprehensive investigation into the cardiovascular mortality of DTC-2, revealing a higher risk compared to DTC-1 and the general population, especially for cases between 30 and 74 years old. The risk elevation was greatest within the first month after diagnosis. These findings emphasize the restriction of thyroid hormone suppression therapy and reinforce stress management to prevent premature DTC-2 patients from cardiovascular death.

Context: Primary aldosteronism (PA), a frequent but underdiagnosed cause of hypertension, is associated with a significant burden of cardiovascular and renal complications. Studies have reported divergent results regarding the diagnostic performance of seated saline infusion test (SSIT) and oral sodium loading test (OSLT), 2 confirmatory tests recommended by the Endocrine Society Clinical Practice Guidelines. To our knowledge, no study directly compared the results of SSIT and OSLT to diagnose overt PA.

Objective: We assessed the diagnostic performance of SSIT and OSLT in a group of patients with hypertension and elevated screening aldosterone-renin ratio (ARR). The diagnostic standard was defined as hypertension with or without hypokalemia with an elevated screening ARR and at least 1 abnormal confirmation test including OSLT and SSIT.

Methods: A monocentric retrospective study was conducted, including 87 patients with hypertension with a positive screening who underwent both SSIT and OSLT. A diagnostic performance analysis was conducted using urinary aldosterone at a threshold of 27 nmol/day as the criterion for OSLT, in comparison to a plasma aldosterone concentration (PAC) exceeding 140 pmol/L following the saline infusion.

Results: A statistically significant difference in sensitivity was observed between OSLT and SSIT, with OSLT demonstrating superior performance (P = .025). The aforementioned test exhibited concordance in 59 cases (65.5%), indicating that these methods are not equivalent (McNemar test P = .036).

Conclusion: OSLT demonstrated a significantly higher sensitivity for diagnosing overt PA in comparison with the SSIT in our cohort of patients with hypertension with an abnormal screening ARR.