SVEP1 Upregulation Is a Prominent Molecular Response to Dietary Sodium Loading and Correlates with Inverse Salt Sensitivity.

Background: While some individuals exhibit salt sensitivity, others demonstrate salt resistance or inverse salt sensitivity-blood pressure reduction during high sodium intake. The molecular mechanisms underlying heterogeneous blood pressure responses to dietary sodium remain poorly understood. Deep proteomics provides a new tool to identify molecular mediators of salt resistance and inverse salt sensitivity.

Cushing Syndrome, Hypercortisolism, and Glucose Homeostasis: A Review.

Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S.

Reconstitution of adrenocortical functional zonation from human pluripotent stem cells.

The adrenal cortex produces essential steroid hormones through a concentric zonal architecture, established by the centripetal trans-differentiation of subcapsular progenitors within a capsule-derived niche. To capture this complexity, we establish a human pluripotent stem cell-derived adrenal organoid system that faithfully recapitulates this process. RSPO3/WNT signaling from the capsule specifies definitive zone (DZ) progenitors from the adrenal primordium, which then differentiate into a cortisol-producing transitional zone and an androgen-producing fetal zone under the influence of RSPO3 and ACTH.

Similar Rates of Second Electron Transfer and Single-Turnover Dehydroepiandrosterone Formation for Oxyferrous Human Cytochrome P450 17A1 (Steroid 17-Hydroxylase/17,20-lyase)-17-hydroxypregnenolone Complex with Either Human Cytochrome P450-Oxidoreductase or Human Cytochrome .

The 17-hydroxylase and 17,20-lyase activities of cytochrome P450 17A1 are required for androgen biosynthesis, which is the target of the prostate-cancer drug abiraterone acetate. Cytochrome (b5) stimulates the 17,20-lyase activity 8-fold in reconstituted systems containing P450-oxidoreductase (POR); however, the mechanism of the b5 effect and the rate-limiting step(s) of these catalytic cycles are not known. Using stopped flow spectroscopy and rapid chemical quench under single-turnover conditions, we determined the effects of b5 on rates of individual steps of the 17-hydroxylase and 17,20-lyase reactions.

Osilodrostat Treatment of Cushing Syndrome in Real-World Clinical Practice: Findings From the ILLUSTRATE study.

Context: In clinical trials, osilodrostat (11β-hydroxylase inhibitor) effectively reduced cortisol levels in patients with endogenous Cushing syndrome (CS).

Objectives: A real-world study (ILLUSTRATE) was conducted evaluating osilodrostat use in patients with various etiologies of CS in the United States.

Methods: A retrospective chart-review study was conducted of adults with CS treated with osilodrostat between May 1, 2020, and October 29, 2021.

Osilodrostat Treatment for Adrenal and Ectopic Cushing Syndrome: Integration of Clinical Studies With Case Presentations.

Although most cases of endogenous Cushing syndrome are caused by a pituitary adenoma (Cushing disease), approximately one-third of patients present with ectopic or adrenal causes. Surgery is the first-line treatment for most patients with Cushing syndrome; however, medical therapy is an important management option for those who are not eligible for, refuse, or do not respond to surgery. Clinical experience demonstrating that osilodrostat, an oral 11β-hydroxylase inhibitor, is effective and well tolerated comes predominantly from phase III trials in patients with Cushing disease.

Artifactual elevations of 11β-hydroxyandrostenedione and 11-ketoandrostenedione in mass spectrometry assays.

Comprehensive steroid profiling by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) can be achieved using small biospecimen samples. LC-MS/MS assays offer superior accuracy to immunoassays, but they also introduce layers of complexity and opportunities for errors. Validation and harmonization studies are essential to ensure reliable results, as these assays are being increasingly incorporated in clinical laboratories.

Osilodrostat improves blood pressure and glycemic control in patients with Cushing's disease: a pooled analysis of LINC 3 and LINC 4 studies.

Purpose: To evaluate the effect of osilodrostat and hypercortisolism control on blood pressure (BP) and glycemic control in patients with Cushing's disease.

Methods: Pooled analysis of two Phase III osilodrostat studies (LINC 3 and LINC 4), both comprising a 48-week core phase and an optional open-label extension. Changes from baseline in systolic and diastolic BP (SBP and DBP), fasting plasma glucose (FPG), and glycated hemoglobin (HbA) were evaluated during osilodrostat treatment in patients with/without hypertension or diabetes at baseline.

Future Directions in the Management of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Context: The traditional management of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is difficult and often suboptimal.

Objective: To review improvements in the diagnosis and management of 21OHD.

Design: Literature review, synthesis, and authors' experience.

Exploring the Predictive Role of 11-Oxyandrogens in Diagnosing Polycystic Ovary Syndrome.

Context: Hyperandrogenism is a hallmark of polycystic ovary syndrome (PCOS), yet the androgen(s) responsible remain ambiguous. Recent studies have suggested that 11-oxygenated C steroids (11-oxyandrogens), specifically 11-ketotestosterone, may be a good marker for hyperandrogenism in PCOS.

Objective: To investigate the utility of 11-oxyandrogens to differentiate women with and without PCOS relative to classical androgens.

Characterizing the Origins of Primary Aldosteronism.

Background: Renin-independent aldosterone production in normotensive people increases risk for developing hypertension. In parallel, normotensive adrenal glands frequently harbor aldosterone-producing micronodules with pathogenic somatic mutations known to induce primary aldosteronism (PA). A deeper understanding of these phenomena would inform the origins of PA and its role in hypertension pathogenesis.

Hormone-induced thrombosis is mediated through non-canonical fibrin(ogen) aggregation and a novel estrogen target in zebrafish.

Venous thrombosis is a well-known complication of sex hormone therapy, with onset typically within weeks to months after initiation. Worldwide, more than 100 million pre-menopausal women use combined oral contraceptives, with tens to hundreds of thousands developing thrombosis annually, resulting in significant morbidity and mortality. Although it is known that estrogens can alter expression of coagulation factors, the pathways and mechanisms that connect the two systems, as well as the proteins involved in progression to thrombosis, are poorly understood.

Pregnancy in Congenital Adrenal Hyperplasia.

Over the last several decades, children with all forms of classic congenital adrenal hyperplasia (CAH) are identified early and treated appropriately throughout childhood. As adults, women with CAH may desire to become mothers and their usual chronic therapy and disease control is often inadequate for conception. Subsequently, little data exist on their management during pregnancy.

Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone.

Introduction: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper ortisolism in P ients with Difficult to Control Type 2 Di betes Despite Receiving Standard-of-Care Therapies: Preva ence and Treatment with Korl m (Mifepri one) (CATALYST) trial.

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

Background: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH.

Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

Background: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels.

Abiraterone in Classic Congenital Adrenal Hyperplasia: Results of Medical Therapy Before Adrenalectomy.

We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite supraphysiological glucocorticoid therapy. We used abiraterone acetate, an inhibitor of the 17-hydroxylase/17,20-lyase enzyme, to suppress adrenal androgen synthesis and allow physiological glucocorticoid and mineralocorticoid therapy, as a proof-of-concept, before proceeding to bilateral adrenalectomy. We report the patient's clinical course, the changes in adrenal steroids, and the immunohistochemistry of the adrenals.