European Journal of Endocrinology最新文献

Hyponatremia is one of the most common electrolyte disorders encountering both in hospitalized and in outpatients. Across the past decades, several cross-sectional and observational studies have shown a strong association between low serum sodium levels and adverse bone outcomes such as osteoporosis, falls, and fractures, suggesting a potential direct link between serum sodium disturbances and bone health. However, association does not necessarily imply causality. Data from preclinical studies have shown a possible causative relationship between hyponatremia and activation of osteoclasts with consequent bone resorption, whereas clinical studies so far have shown mostly an association with increased bone formation rather than affection of bone resorption. In this narrative review, we provide an overview of the current evidence on the relationship between serum sodium disorders and bone health, starting with preclinical findings, followed by cross-sectional and association data and concluding with insights from prospective and interventional studies.

Objective: Chronically elevated circulating lipocalin-2 (LCN2) levels are implicated in poor energy regulation, increased cardio-metabolic disease risk, and poor physical function. Exercise is known to improve these factors, but whether LCN2 is modifiable by exercise is not clear. We examined the effect of acute and chronic exercise on LCN2 levels and whether this relates to glucose regulation, body composition, and physical function.

Design and methods: Thirty-three middle-aged and older adults (45-84 years, median body mass index 26.21 kg/m2) completed an acute high-intensity interval exercise session (HIIE). Participants were randomized to 4 weeks of high-intensity interval training (HIIT) or control. Lipocalin-2, insulin, glucose, and homeostatic model assessment for insulin resistance (HOMA-IR) were analysed in serum at baseline and immediately, 1 and 3 h post-HIIE, and post-4 weeks of HIIT. Urinary LCN2 was assessed pre and post 4 weeks of HIIT.

Results: A main effect for time for serum LCN2, insulin, glucose, and HOMA-IR was detected after acute-HIIE (P < .001). Circulating serum LCN2 levels increased significantly immediately post-HIIE compared to baseline (P < .001) and returned to levels similar to baseline by 60 and 180 min post-HIIE. Four weeks of HIIT improved VO2peak, yet had no significant effect on LCN2 levels or physical function.

Conclusions: Acute-HIIE, but not 4 weeks of HIIT, transiently increased circulating LCN2 and improved insulin sensitivity in middle-aged and older adults. It remains unclear if LCN2 is modifiable by chronic exercise training longer than 4 weeks or in people with poor glycaemic control.

Clinical trial registration: Australia New Zealand Clinical Trials Registry: ACTRN12622000337774.

Background: Idiopathic male infertility, characterized by impaired spermatogenesis without identifiable etiology, lacks targeted therapeutic strategies. Empirical hormonal treatments such as aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and follicle-stimulating hormone (FSH) are commonly employed, despite limited high-quality evidence.

Objective: To compare the efficacy of AIs, SERMs, and FSH in improving semen parameters among men with idiopathic oligozoospermia and/or asthenozoospermia, using a network meta-analysis (NMA) approach.

Methods: This systematic review and NMA included 24 controlled studies (n = 1676 men). Eligible trials compared FSH, SERMs, or AIs (eg, clomiphene, tamoxifen) to placebo or active comparators. Outcomes included post-treatment sperm concentration, total sperm number, and progressive motility. A frequentist random-effects model was used. Treatments were ranked using P-scores, with inconsistency assessed via node-splitting.

Results: Clomiphene citrate (CC) 25 mg every other day showed the greatest improvement in sperm concentration (mean difference [MD] = 22.00; 95% CI: 14.75-29.25; P-score = 99%). FSH 300 IU every other day also significantly improved sperm concentration (MD = 9.34; 95% CI: 5.14-13.53). For total sperm number, CC 25 mg every other day again ranked highest (MD = 66.70; 95% CI: 27.53-105.87). No intervention showed a significant effect on progressive motility in the NMA. A dose-response trend was observed for FSH (direct relationship) and SERMs (inverse relationship).

Conclusions: Both SERMs and FSH improve sperm concentration and count compared to placebo. Clomiphene at low doses and high-dose FSH may offer the greatest benefit. These findings support a personalized empirical treatment approach and emphasize the need for future trials stratified by clinical phenotype, such as the recently proposed APHRODITE criteria.

Introduction/objective: Bone can contribute to systemic and extra-skeletal processes through bone-derived hormones. The osteoblast-specific protein osteocalcin (OCN) has been reported to positively regulate male fertility, by directly favoring testicular testosterone biosynthesis. We previously demonstrated that aberrant hypoxia-inducible factor (HIF) signaling in osteoprogenitors drastically changes bone properties associated with suppressed OCN expression. This led us to question whether hypoxia signaling in bone could be an upstream determinant of male fertility, by indirectly impacting testosterone production and testicular function through bone-derived OCN.

Design/methods: To investigate the impact of hypoxia pathway activation in osteoprogenitors and/or osteoblasts on male fertility, we genetically deleted the negative HIF-regulator von Hippel-Lindau (VHL) in mice using two independent osteolineage-targeted Cre lines. In these Vhl conditional knockout (cKO) strains, we investigated OCN production, testosterone biosynthesis, testicular morphology, and male fertility, including functional evaluation of reproductive capacity.

Results: Our data demonstrate that loss of VHL in osteolineage cells consistently and strongly reduces the production of OCN in bone, leading to very low circulating levels of both carboxylated and undercarboxylated OCN. Testicular expression of selected enzymes of the testosterone biosynthesis pathway was decreased in Vhl cKO mice. However, our data did not show significant deficiencies in testosterone levels, reproductive organ weights, Leydig cell mass, sperm count, or breeding efficiency in the two strains of skeletal Vhl cKO mice.

Conclusions: These findings indicate that aberrant hypoxia signaling in bone suppresses OCN production without compromising male fertility, possibly reflecting a role for the broader physiological context as critical modulator of OCN's endocrine activity.

Achieving physiological glucose homeostasis in insulin-deficient diabetes remains challenging because exogenous insulin and devices cannot recapitulate the real-time, glucose-responsive secretion of pancreatic β-cells. This review aims to delineate the conceptual framework and recent advances in regulating insulin expression and release through gene- and cell-based therapies, emphasizing strategies that approximate native β-cell dynamics. We summarize progress in glucose-responsive insulin gene expression in hepatocytes, skeletal muscle, intestinal K/L cells, and residual pancreatic β-cells via synthetic promoters and circuit engineering that couple metabolic cues to transcription. We then evaluate rapid-release platforms that uncouple biosynthesis from secretion. These include endoplasmic reticulum retention-release switches and engineered vesicle-based exocytosis modules that, when actuated by metabolic, optical, electrical, or small-molecule cues, reproduce first-phase-like insulin kinetics. Finally, we highlight synthetic-biology frameworks integrating chemical, metabolic, optical, electrical, and magnetic inputs to program autonomous and reversible insulin output. We conclude with a focused translational agenda: strengthen biosafety and genetic stability; induce immune tolerance and alleviate reticulum retention stress; ensure durable, tissue-specific expression; standardize non-viral/viral delivery systems for scalable manufacturing; and integrate molecular circuits with continuous glucose monitors to achieve closed-loop, hypoglycemia-safe control. These priorities will accelerate clinical translation toward intelligent, patient-tailored insulin therapy.

Background: Growth hormone (GH) potently stimulates collagen turnover which underlies its anabolic effects on bone in children, whereas it may promote fibrosis in adults. Fibroblast activation protein-α (FAPα) is a serine protease which substrates include collagen and fibroblast growth factor 21 (FGF21). FAPα levels are reversibly elevated in active acromegaly.

Aim: To measure circulating FAPα activity and levels, as well as FAPα substrates, in adult patients with GH-deficiency (GHD) before and after GH replacement therapy.

Methods: FAPα activity and levels were analyzed in serum samples from two groups of GHD patients before and after 3-6 months GH replacement therapy as compared to non-GHD hypopituitary patients and a healthy reference group. Furthermore, collagen turnover biomarkers (PINP, PIIINP, CTx) and intact FGF21 were analyzed.

Results: FAPα activity (RFU/min) significantly increased after GH replacement in both GHD groups [290.6 ± 47.8 (before) vs. 428.5 ± 66.4 (after) P < .05; 291.0 ± 37.4 (before) vs. 403.0 ± 52.9 (after); P < .05]. Likewise, FAPα levels significantly increased by 40% after GH replacement in both groups (P < .01) and correlated closely with FAPα activity. PINP, PIIINP and CTx significantly increased after 3 months of GH replacement. Intact FGF21 remained unchanged.

Conclusions: (1) Our study documents for the first time that GH stimulates FAPα activity in vivo in human subjects. (2) The concomitant increase in collagen turnover and the lack of change in intact FGF21 suggest that GH-driven FAPα activity predominantly involves collagen breakdown, and (3) FAPα is a novel biomarker of GH/IGF-I activity and may be causally linked to GH-induced fibrosis.

The present report from the ESE Educational Program on Parathyroid Disorders (PARAT Program) presents recent developments and novelties in the clinical care of parathyroid disorders in a question-and-answer format, based on a satellite workshop held in relation to the European Congress of Endocrinology in Stockholm, May 2024. The workshop focused on clinical aspects of 3 main themes: primary hyperparathyroidism (PHPT), chronic hypoparathyroidism (HypoPT) in adults, and parathyroid disorders in pregnancy, with an emphasis on advances since the 2022 PARAT consensus report. The first section focuses on the long-term complications-including fractures, renal impairment, mental health, and quality of life-in patients with asymptomatic or mild forms of PHPT and on treatment strategies for syndromic PHPT (multiple endocrine neoplasia 1-4). In the latter, we explore appropriate surgical and non-surgical approaches, imaging techniques for gland localization, and preservation strategies in cases of multiglandular involvement. The second section addresses transient and partial forms of HypoPT in comparison to chronic and complete parathyroid hormone deficiency. It highlights the potential skeletal consequences of chronic HypoPT, the underlying etiologies, and discusses treatment modifications in light of the evolving therapeutic landscape. The final section, dedicated to the specific considerations of parathyroid disorders during pregnancy and lactation, focuses on pregnancy planning in patients with hereditary syndromic forms of PHPT, the differentiation between parathyroid-related and unrelated causes of hypercalcemia, and the associated risks for both mother and fetus. Additionally, it addresses the practical aspects of managing pregnant women with HypoPT, aiming to provide practical guidance for clinicians. Clinical vignettes featuring 3 cases illustrate common clinical situations.