Journal of Clinical Endocrinology & Metabolism最新文献

Context: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion.

Objective: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas.

Methods: A total of 25 treatment-naive patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. The main outcome measure was the effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement.

Results: In 4 of 7 patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = .0003). Somatotrophs were available from 3 of 4 of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion.

Conclusion: Of 25 patients with acromegaly, 7 had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in 4. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

The management of adrenal insufficiency (AI) is challenging, and the overall goals of treatment are to prevent life-threatening adrenal crises, to optimize linear growth, to control androgen levels without overdosing in patients with congenital adrenal hyperplasia (CAH), and to improve quality of life in affected individuals. Standard glucocorticoid formulations fail to replicate the circadian rhythm of cortisol and control the adrenal androgen production driven by adrenocorticotropin. To personalize and tailor glucocorticoid therapy and to improve patient outcomes, new pharmacological strategies have been developed that best mimic physiological cortisol secretion. Novel therapeutic approaches in the management of AI include new ways to deliver circadian cortisol replacement as well as various adjunctive therapies to reduce androgen production and/or androgen action/effects. Preclinical studies are exploring the role of restorative cell-based therapies, and a first recombinant adeno-associated virus-based gene therapy is also being developed in humans with CAH. In this article, we present 3 illustrative cases of AI with different underlying etiologies and times of presentation. Diagnostic and management processes are discussed with an emphasis on treatment and outcomes. We have also provided the most up-to-date evidence for the tailored management of children and adolescents with AI.

Context: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides.

Objective: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA).

Design: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012).

Setting: Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes.

Patients or other participants: This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB.

Main outcome measures: Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia.

Results: Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15; P = 2.5E-140] and 0.98 (1.04/0.92; P = 1.12E-225) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31; 95% CI: 1.16/1.47; P = 9.8E-06), independently of age and diabetes.

Conclusion: PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.

Context: Although complete surgical resection provides the only means of cure in adrenocortical carcinoma (ACC), the magnitude of the survival benefit of adrenalectomy in metastatic ACC (mACC) is unknown.

Objective: This work aimed to assess the effect of adrenalectomy on survival outcomes in patients with mACC in a real-world setting.

Methods: Patients with mACC aged 18 years or older with metastatic ACC at initial presentation who were treated between 2004 and 2020 were identified within the Surveillance, Epidemiology, and End Results database (SEER 2004-2020), and we tested for differences according to adrenalectomy status. Intervention included primary tumor resection status (adrenalectomy vs no adrenalectomy). Kaplan-Meier plots, multivariable Cox regression models, and landmark analyses were used. Sensitivity analyses focused on use of systemic therapy, contemporary (2012-2020) vs historical (2004-2011), single vs multiple metastatic sites, and assessable specific solitary metastatic sites (lung only and liver only).

Results: Of 543 patients with mACC, 194 (36%) underwent adrenalectomy. In multivariable analyses, adrenalectomy was associated with lower overall mortality without (hazard ratio [HR]: 0.39; P < .001), as well as with 3 months' landmark analyses (HR: 0.57; P = .002). The same association effect with 3 months' landmark analyses was recorded in patients exposed to systemic therapy (HR: 0.49; P < .001), contemporary patients (HR: 0.57; P = .004), historical patients (HR: 0.42; P < .001), and in those with lung-only solitary metastasis (HR: 0.50; P = .02). In contrast, no statistically significant association was recorded in patients naive to systemic therapy (HR: 0.68; P = .3), those with multiple metastatic sites (HR: 0.55; P = .07), and those with liver-only solitary metastasis (HR: 0.98; P = .9).

Conclusion: The present results indicate a potential protective effect of adrenalectomy in mACC, particularly in patients exposed to systemic therapy and those with lung-only metastases.

Inappropriate aldosterone excess plays a key role in the pathophysiology of various cardiovascular, endocrine, and renal diseases. Mineralocorticoid receptor antagonists (MRAs) such as spironolactone block of the harmful effects of aldosterone and are recommended treatment in these various conditions. However, the sexual adverse effects of spironolactone from its lack of specificity for the mineralocorticoid receptor and the risk of hyperkalemia in patients with decreased renal function, limit its use. While eplerenone is a more selective MRA, it is less potent than spironolactone. Newer nonsteroidal MRAs, though promising, are either unavailable globally or still under development. Moreover, aldosterone exerts both genomic and nongenomic effects, the latter not fully blocked by MRAs. Aldosterone synthase inhibitors (ASIs) have thus emerged as potential alternatives to MRAs, though the development of selective ASIs has been challenging. This is due to the close homology between the final step of aldosterone synthesis, mediated by CYP11B2 in the zona glomerulosa of the adrenal cortex, and cortisol synthesis, mediated by CYP11B1 in the zona fasciculata. Despite these challenges, new ASIs have demonstrated high in vitro as well as in vivo selectivity for CYP11B2, effectively reducing aldosterone production without affecting cortisol synthesis in humans across large dose ranges. Early phase II trials demonstrated that these ASIs decrease (1) blood pressure in uncontrolled hypertension and (2) urinary albumin excretion in proteinuric chronic kidney disease. Further longer term trials will evaluate their efficacy in lowering blood pressure as well as in reducing kidney disease progression and cardiovascular outcomes in heart failure when given alone or in combination with SGLT2 inhibitors.

Context: The enterohepatic circulation of bile acids depends on intestinal absorption by bile acid transporters and activation of bile acid receptors, which stimulates secretion of hormones regulating glucose and lipid metabolism and appetite. Distribution of bile acid transporters and receptors in the human gut and their potential involvement in type 2 diabetes (T2D) pathophysiology remain unknown.

Objective: We explored the expression of genes involved in bile acid metabolism throughout the intestines of patients with T2D and matched healthy controls.

Methods: Intestinal mucosa biopsies sampled along the intestinal tract in 12 individuals with T2D and 12 healthy controls underwent messenger RNA (mRNA) sequencing. We report expression profiles of apical sodium-dependent bile acid transporter (ASBT), organic solute transporter (OST) α/β, farnesoid X receptor (FXR), Takeda G receptor 5 (TGR5), fibroblast growth factor 19 (FGF19), and FGF receptor 4 (FGFR4).

Results: Expression of ASBT and OSTα/β was evident in the duodenum of both groups with increasing levels through the small intestine, and no (ASBT) or decreasing levels (OSTα/β) through the large intestine. The FXR expression pattern followed that of OSTα/β whereas FGFR4 was evenly expressed through the intestines. Negligible levels of TGR5 and FGF19 were evident. Patients with T2D exhibited lower levels of FGF19, FXR, ASBT, and OSTα/β mRNAs compared with healthy controls, although the differences were not statistically significant after adjusting for multiple testing.

Conclusion: We demonstrate distinct expression patterns of bile acid transporters and receptors through the intestinal tract with signs of reduced ASBT, OSTα/β, FXR, and FGF19 mRNAs in T2D.

Context: Existing guidelines often lack sex-specific prevention strategies for type 2 diabetes mellitus (T2DM). Life's Essential 8 (LE8) highlights the role of health behaviors in influencing cardiovascular health (CVH). Due to inherent sex differences, the impact of CVH on T2DM risk may vary between men and women, especially across menopausal stages.

Objective: The purpose of this paper is to explore sex-based differences in CVH and the incidence of T2DM among women at different menopausal stages and men.

Methods: A prospective cohort study was conducted, involving 126 818 participants without preexisting T2DM from the UK Biobank. CVH was assessed using the LE8. Absolute risks (ARs) and hazard ratios (HRs) were separately employed to assess the association between increased CVH and T2DM risk. The accelerated failure time model assessed the effect of CVH on the time to T2DM onset.

Results: Over a mean follow-up of 168 months, 4315 cases of T2DM were documented. In men, each 1-point increase in CVH was associated with a 0.268% decrease in AR and a 6.4% decrease in HR for T2DM. In premenopausal, perimenopausal, and postmenopausal women, each unit increase in CVH resulted in a 0.105%, 0.180%, and 0.166% decrease in AR and a 7.7%, 5.2%, and 6.4% decrease in HR of T2DM. The adjusted median time to T2DM onset was delayed by 12.46, 9.83, 11.5, and 21.43 months in the highest quintile of men, premenopausal, perimenopausal, and postmenopausal women, respectively, compared with the lowest CVH quintile.

Conclusion: As CVH improved, the reduction in AR for T2DM was more prominent in men than in women. HR trends for CVH and T2DM were similar in men and postmenopausal women. Increased CVH delayed the onset of T2MD both in men and women, with the most significant delay observed in postmenopausal women.

Context: Abnormal endometrial extracellular matrix (ECM) remodeling compromises endometrial receptivity and diminishes the probability of a successful live birth. Serum amyloid A1 (SAA1), a modulator of inflammation, is elevated in the circulation of polycystic ovary syndrome (PCOS) patients and involved in ECM remodeling during tissue repair. However, the specific role of SAA1 in endometrial ECM remodeling and subsequent risk of pregnancy loss in PCOS patients remains unclear.

Objective: To examine the role and underlying mechanism of SAA1 in ECM remodeling in the endometrium of PCOS patients.

Design: Serum samples from PCOS and control patients were utilized to investigate the relationship between the abundance of SAA1 and pregnancy loss. Human endometrial tissues and primary human endometrial stromal cells were used to examine the role and underlying mechanism of SAA1 in ECM remodeling.

Results: Serum SAA1 concentration was elevated and could serve as an independent risk of pregnancy loss in PCOS patients. Increased SAA1 abundance was also observed in endometrium obtained from these patients. Further mechanistic studies showed that SAA1 stimulated collagen I chains synthesis (COL1A1 and COL1A2) in endometrial stromal cells, suggesting excessive SAA1 may contribute to endometrial ECM remodeling, resulting in a nonsupportive environment for ongoing pregnancy. This effect was abolished by either a toll-like receptor 2/4 antagonist or a nuclear factor κB inhibitor.

Conclusion: The locally elevated levels of SAA1 in endometrium contribute to ECM overdeposition by inducing collagen I synthesis in PCOS patients, which may hamper embryo implantation and increase the risk of pregnancy loss. These observations highlight the crucial role of heightened SAA1 in orchestrating endometrial dysfunction and shed light on potential therapeutic avenues for improving reproductive outcomes in PCOS patients.