Journal of Clinical Endocrinology & Metabolism最新文献

Hirsutism affects approximately 10% of women globally, with significant economic and quality of life impact. Facial and body terminal hair growth in a male-like pattern is determined by a number of factors, including circulating androgens, and tissue androgen receptor, 5α-reductase, 3α- and 17β-hydroxysteroid dehydrogenase, and ornithine decarboxylase content. The presence of hirsutism is usually determined by the modified Ferriman Gallwey (mFG) visual scale, assessing the amount of terminal hair at nine body sites (upper lip, chin, chest, upper and lower back, upper and lower abdomen, upper arms and thighs). Specific diagnostic cut-offs vary somewhat by ethnicity, although hirsutism is usually defined by an mFG score of >4-6. Hirsutism is a sign of polycystic ovary syndrome in 80-90% of affected women, idiopathic hirsutism in 5-10%, and, depending on ethnicity, 21-hydroxylase deficient non-classic adrenal hyperplasia in 1-10%. Rarer causes include androgen-secreting neoplasms, iatrogenic/drug-induced, acromegaly, Cushing's syndrome, syndromes of severe insulin resistance/lipodystrophy, ovarian hyperthecosis, and chronic skin irritation. The choice of treatment for hirsutism depends on the severity of symptoms, the patient's reproductive goals, and the underlying cause. Clinicians should not underestimate the degree of patient distress caused by hirsutism. Further, women who complain of excess unwanted hair growth should be evaluated for underlying causes, regardless of the degree to which hirsutism is observable on examination. Management options include medical therapies, such as combined oral contraceptive pills and anti-androgens, and mechanical methods of hair removal. The most effective therapeutic strategy will involve a combination of these modalities, with shared decision-making a key driver.

Aims: Despite the efficacy of glucagon like peptide 1 receptor agonists (GLP-1 RAs), many patients with type 2 diabetes (T2D) require additional therapy to achieve HbA1c targets. Few studies have explored real-world outcomes following GLP-1 RA failure. This analysis evaluates different intensification approaches, timing, and outcomes in T2D patients on GLP-1 RAs.

Methods: This retrospective cohort study was based on AMD Annals database. From 191,041 patients on GLP-1 RAs between 2010 and 2022, individuals receiving a first therapeutic intensification were selected. Patients were stratified by intensification strategy; baseline characteristics were compared alongside glycated hemoglobin (HbA1c) and weight changes at 6 and 12 months.

Results: Among the 37,198 patients intensified, the majority received oral antihyperglycemic drugs (OADs), particularly those with higher BMI, lower HbA1c, and shorter disease duration. Basal insulin (BI) was mainly added in those with higher HbA1c (8.9%) and longer diabetes. Intensification with BI or switch to fixed ratio combinations (FRCs) yielded the greatest HbA1c reduction (-0.92 and -0.85%; p<0.001) and weight neutrality, whereas OADs led to a higher target achievement rate (36% with HbA1c <7%) and persistent weight loss. Switching to basal-bolus was reserved for more complicated patients and it was associated with weight gain (+2.9 kg; p<0.001) and lower target achievement rate (16.8% HbA1c <7%). Suboptimal insulin titration was observed across all strategies.

Conclusion: Adding OADs or BI/FRCs to GLP-1 RAs are optimal intensification strategies to provide glycemic control while avoiding weight gain. Target achievement rates are poor in individuals switched to insulin therapy. Therapeutic inertia remains a critical issue in clinical practice.

Objective: To investigate the effect of varying visit-to-visit glucose variability (GV) on brain morphometry and cognitive performance in patients with type 2 diabetes mellitus (T2DM).

Methods: This was a retrospective cohort study in which we recruited 426 participants (173 T2DM patients and 253 healthy controls) who underwent cognitive assessment and structural MRI. In patients with T2DM, visit-to-visit GV was calculated using the standard deviation of HbA1c during the follow-up period. Multiple linear regression models were used to analyze the associations between different levels of GV and brain morphometry as well as cognitive function after adjusting for mean HbA1c levels and other traditional risk factors.

Results: Higher GV is associated with poorer global cognitive performance and executive function. After full multivariate adjustment, higher GV is linked to cortical thinning in the left superior parietal cortex, right postcentral gyrus, and insula, as well as a reduction in total gray matter volume. In contrast, no association was observed between GV and cortical volume or surface area.

Conclusions: Our findings indicate that higher visit-to-visit GV is associated with reduced cortical thickness, total gray matter volume atrophy, and poorer cognitive performance in patients with T2DM, and these associations are independent of mean HbA1c levels.

Background and aims: Altered myocardial mechano-energetic efficiency (MEE) is a significant predictor of cardiovascular events and heart failure. Among the potential pathophysiological factors underlying MEE impairment, insulin-like growth factor-1 (IGF-1) may be a plausible candidate due to its role in the cardiovascular system. This study aimed to analyze the relationship between plasma IGF-1 concentrations and myocardial MEE in a cohort of older individuals aged >65 years, participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study.

Methods: Myocardial MEE per gram of left ventricular mass (MEEi) was measured in 490 older subjects with a broad spectrum of glucose tolerance using echocardiography.

Results: IGF-1 levels were positively associated with myocardial MEEi (r = 0.200, P < 0.001). Individuals in the highest tertile (tertile 3) of IGF-1 showed significantly lower heart rate and myocardial oxygen consumption, alongside a significant increase in myocardial MEEi compared to those in the lowest tertile. In multivariate linear regression analysis, IGF-1 levels were identified as the major determinant of MEEi, independently of well-established cardio-metabolic risk factors.

Conclusions: These findings suggest that low circulating IGF-1 levels are associated with depressed myocardial MEEi in older individuals. This highlights the potential importance of monitoring IGF-1 in clinical evaluations to assess cardiovascular health.

Context: Congenital hypogonadotropic hypogonadism (CHH) in infant boys is a rare disorder that can manifest as micropenis and/or cryptorchidism. Mini puberty is considered a window of opportunity for CHH diagnosis and treatment. The lack of testosterone (T) elevation during this period is the gold standard for CHH diagnosis, but hormonal evaluation is not always available at this time.

Objectives: The aim was to compare inhibin B (INHB), anti-Mullerian hormone (AMH), T, LH, and FSH between infant boys (1 to 365 days) with micropenis and/or cryptorchidism due to isolated CHH (iCHH), CHH as part of combined pituitary hormone deficiency (CPHD), or of idiopathic origin (controls), and to determine discriminating cutoffs for CHH diagnosis based on sensitivity (Se) and specificity (Sp).

Methods: This multicenter study from seven University Hospitals in France included 138 boys aged 0 to 12 months (58 with iCHH, including 28 with a positive molecular diagnosis, 32 with CPHD, and 48 controls). Four periods of interest were studied: between 1 to 4 days, 15 to 65 days (early mini puberty, corresponding to the T peak), 66 to 179 days (late mini puberty), and 180 to 365 days (post mini puberty).

Results: Out of mini puberty, the best-discriminating hormones were INHB between 1-4 days (Se/Sp 100%/75% at 150 pg/mL, and 89%/100% at 85 pg/mL), and INHB and AMH after 180 days (INHB, Se/Sp 100%/100% at 100 pg/mL)(AMH, Se/Sp 100%/92% at 600 pmol/L, and 75%/100% at 370 pmol/L). INHB and/or AMH discriminating performances were good (area under the ROC curve > 0.95) across all four periods.

Conclusion: Inhibin B and/or AMH can be used to diagnose CHH in boys < 1 year of age.

Context: Short-statured mid-pubertal boys with predicted adult height (PAHt) below the third percentile are a therapeutic challenge. Aromatase inhibitors (AI) delay estrogen-driven epiphyseal fusion and possibly enhance adult height (AHt).

Objective: To assess the efficacy of AI treatment on AHt in mid-pubertal boys with a short PAHt due to advanced bone age (BA) or idiopathic short stature (ISS).

Design: Retrospective study.

Setting: Tertiary pediatric endocrine referral center.

Patients and methods: Two groups of mid-pubertal boys treated with AI were studied: 27 boys with fast puberty compared to matched untreated controls and 16 boys with ISS treated with GH and AI compared to those treated with GH only. Anthropometric measurements, BA and PAHt, were tracked. AHt was compared across groups.

Main outcome measures: Achieved AHt in AI-treated boys versus controls and the PAHt.

Results: The median duration of AI treatment was 2.8 years for the AI-only group and 2 years for the GH&AI group. Throughout treatment, AI-treated groups gained height similarly to controls, showed a decrease in BASDS (AI only: P=0.009; GH&AI: P=0.029), and an improvement in PAHt (AI only: P=0.003; GH&AI: P=0.037). Compared to controls, AI-treated children achieved greater AHt (AI only: 166.6±3.1 cm vs. 163.4±1.3 cm, P=0.003; GH&AI: 167.3±6.1 cm vs. 164.9±3.5 cm, P=0.194). The difference between AHt and PAHt at baseline was more pronounced in the AI-treated groups (AI only: 3.8±3.5 cm vs. -0.3±5.0 cm, P=0.001; GH&AI: 7.5±5.2 cm vs. 4.3±3.6 cm, P=0.050).

Conclusions: AI treatment extends the growth period, resulting in an AHt surpassing initial predictions. Our findings underscore the potential of AI treatment in mid-pubertal boys with a short PAHt due to advanced BA and in those treated with GH for ISS.

Context: The transformation of follicular granulosa cells into luteal cells of the corpus luteum remains poorly understood in the human ovary.

Objective: To investigate the luteinization process and steroidogenic differences between granulosa cells from small antral and preovulatory follicles in vitro.

Design: Granulosa-lutein cells were obtained from 12 women undergoing IVF treatment, while follicular granulosa cells from unstimulated small antral follicles and corpus luteum were collected from 18 women undergoing ovarian tissue cryopreservation. Cells were cultured for up to 96 hours or 12 days with or without androstenedione or testosterone supplementation and analyzed using RT-qPCR and steroid hormone assays.Setting: University Hospital of Copenhagen, Denmark, and Wake Forest Institute for Regenerative Medicine, USA.

Results: In follicular granulosa cells, luteinization markers (CYP11A1, p<0.05; STAR, p<0.001) increased within 24-48 hours, while granulosa markers (HSD17β1, p<0.001; CYP19A1, p<0.05) decreased within 6-12 hours. LHCGR remained unchanged. By 48 hours, gene expression resembled that of the corpus luteum. In contrast, granulosa-lutein cells exhibited highly luteinized profiles from day 0, with significantly higher progesterone/(17)estradiol ratios. Androgen supplementation and long-term FSH exposure did not alter luteinization.

Conclusions: This study uniquely demonstrates that unstimulated follicular granulosa cells undergo a gradual, intrinsic luteinization process, independent of external hormonal triggers. In contrast, granulosa-lutein cells are already highly luteinized upon aspiration. These findings challenge conventional views on luteinization and highlight intrinsic cellular programming as a key driver, offering new insights into ovarian physiology and potential therapeutic targets for reproductive disorders.

Context: Recent research links bone marrow adiposity (BMAT) to osteoporosis and fracture risk. Typically, BMAT is assessed via magnetic resonance imaging (MRI), a costly and less accessible method. A new method uses high-resolution peripheral quantitative computed tomography (HR-pQCT) to quantify BMAT.

Objective: To investigate if BMAT, derived from HR-pQCT images, is associated with fracture incidence and osteoporosis prevalence in older women.

Methods: 2984 women aged 75-80 years from the SUPERB cohort were included between March 2013 and May 2016. Bone characteristics, including bone densitometry (DXA) and HR-pQCT of the ultra-distal tibia, were assessed. Bone marrow fat fraction (BMFF) was measured using HR-pQCT. Incident fractures were tracked until March 2023. Linear regression was used to analyze associations between BMFF, anthropometrics, and bone mineral density (BMD). Cox and Poisson regression examined BMFF's association to incident fractures.

Results: BMFF was inversely associated to body mass index (r= -0.21, p < 0.001) and hip BMD (r = -0.50, p < 0.001). Over a median follow-up of 7.3 years, 797 major osteoporotic fractures (MOF), 1069 any fractures, and 235 hip fractures occurred. Higher BMFF (per SD) increased the risk of MOF (HR = 1.24, 95% CI 1.15-1.34), any fracture (HR = 1.20, 95% CI 1.12-1.28), hip fracture (HR = 1.22, 95% CI 1.06-1.40), and vertebral fracture (HR = 1.24, 95% CI 1.12-1.38) in multivariable Cox models adjusted for age, body mass index and clinical risk factors. Mediation analysis indicated that a significant proportion of these associations were mediated by femoral neck bone mineral density (FN-BMD).

Conclusion: Higher BMFF is associated with lower BMD and higher fracture risk in older women.