Publications by authors named "Richard J Auchus"

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.

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  • Subfertility is common in men with classic 21-hydroxylase deficiency (21OHD), and a study tracked the long-term gonadal function of 27 men over a median of 12 years.
  • testosterone levels were found to be below the normal range for a significant number of participants, with those having testicular adrenal rest tissue (TART) showing initially higher testosterone levels and a greater increase over time compared to those without TART.
  • The results indicate that while testosterone levels are generally low in these men, they do not change much over time; hence, regular screening for TART isn't recommended, but monitoring Sertoli cell function is suggested for men with larger TART.
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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.

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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.

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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.

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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.

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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.

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The mitochondrial enzyme cytochrome P450 11B2 (aldosterone synthase) catalyzes the 3 terminal transformations in the biosynthesis of aldosterone from 11-deoxycorticosterone (DOC): 11β-hydroxylation to corticosterone, 18-hydroxylation, and 18-oxidation. Prior studies have shown that P450 11B2 produces more aldosterone from DOC than from the intermediate corticosterone and that the reaction sequence is processive, with intermediates remaining bound to the active site between oxygenation reactions. In contrast, P450 11B1 (11β-hydroxylase), which catalyzes the terminal step in cortisol biosynthesis, shares a 93% amino acid sequence identity with P450 11B2, converts DOC to corticosterone, but cannot synthesize aldosterone from DOC.

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Context: Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production.

Objective: To investigate the contributions of renin-independent aldosteronism and ACTH-mediated aldosteronism in individuals with a low-renin phenotype representing the entire continuum of blood pressure.

Design/participants: Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure.

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Article Synopsis
  • Aldosterone synthase deficiency is a rare illness that mainly affects babies, causing them to vomit, become dehydrated, and have high potassium levels, which can be dangerous.
  • A baby boy from Montreal was diagnosed with this condition just nine days after he was born; doctors started him on medications to help with his symptoms.
  • Researchers found a specific gene change that seemed harmless at first but actually contributed to his illness, showing that more testing is important to understand genetic conditions properly.
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  • This study investigates how early adulthood risk factors can predict the development of vasomotor symptoms (VMS) in women over time.
  • Using data from the CARDIA study, researchers analyzed responses from 1,966 women to identify distinct VMS trajectories: minimal (40%), increasing (27%), and persistent (33%).
  • Key risk factors for persistent VMS included Black race, low education, depressive symptoms, migraines, and cigarette use, highlighting the importance of addressing these issues early on for potential therapies.
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  • Adrenal insufficiency (AI) is a health problem that can be caused by different issues, like problems with adrenal glands or certain medications.
  • People with AI often feel really tired, lose their appetite, and might lose weight, and those with a specific type of AI may crave salt and have darker skin.
  • It can be hard to diagnose AI because its symptoms can be vague, but it's important to catch it early to prevent serious health issues, and new methods and treatments are being developed to help with this.
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Context: The prevalence of cardiovascular and metabolic complications among adults with 21-hydroxylase deficiency (21OHD) is unknown.

Objective: We sought to determine the prevalence of cardiovascular and metabolic morbidities among adults with 21OHD and to identify clinical factors and biomarkers associated with cardiovascular outcomes.

Methods: A 10-year retrospective cross-sectional analysis was conducted on adult patients with confirmed 21OHD, aged 18 to 70 years, who had at least one clinical visit for assessment at the University of Michigan.

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Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis and activation pathways. These conditions exhibit diverse clinical manifestations, which can be distinguished by their unique molecular mechanisms and steroid profiles. Timely diagnosis and customized management approach are crucial to mitigate unfavorable outcomes associated with uncontrolled hypertension and other related conditions.

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The two human steroid 5α-reductase (5αR) enzymes catalyze the conversion 3-keto-Δ-steroids to their 5α-reduced congeners. In the genital skin and prostate, the type 2 isoenzyme converts testosterone (T) to the more potent androgen 5α-dihydrotestosterone (DHT), and intracellular DHT is essential for the morphogenesis of the undifferentiated external genitalia to the male phenotype. Both isoenzymes also metabolize other 19- and 21-carbon 3-keto-Δ-steroids, both endogenous compounds and some steroid-based drugs.

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Objective: To describe the approach to primary aldosteronism as a common disease.

Methods: The study methods involved are literature review and personal experience.

Results: Primary aldosteronism is the most common form of endocrine hypertension, yet screening rates are abysmally low.

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Objective: To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.

Methods: The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first.

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Cholesterol, a significant constituent of the endoplasmic reticulum membrane, exerts a substantial effect on the membrane's biophysical and mechanical properties. Cholesterol, however, is often neglected in model systems used to study membrane-bound proteins. For example, the influence of cholesterol on the enzymatic functions of type 2 cytochromes P450, which require a phospholipid bilayer and the redox partner P450-oxidoreductase (POR) for activity, are rarely investigated.

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Multiple changes occur across various endocrine systems as an individual ages. The understanding of the factors that cause age-related changes and how they should be managed clinically is evolving. This statement reviews the current state of research in the growth hormone, adrenal, ovarian, testicular, and thyroid axes, as well as in osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism, with a specific focus on older individuals.

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