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Non-classical 11β-hydroxylase deficiency caused by a novel heterozygous mutation: a case report and review of the literature.
Endocrine
June 2024
Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, 200065, Shanghai, China.
Purpose: 11β-hydroxylase deficiency (11β-OHD) constitutes a rare form of congenital adrenal hyperplasia (CAH), typically accounting for ~5-8% of CAH cases. Non-classical 11β-OHD is reported even more rarely and frequently results in misdiagnosis or underdiagnosis due to its mild clinical symptoms.
Methods: A clinical, biochemical, radiological, and genetic study was conducted on a 9-year-old girl presenting with mild breast development, axillary hair growth, and advanced bone age.
Pharmacokinetic study of osilodrostat and identification of mono-hydroxylated metabolite in equine plasma for the purpose of doping control.
Rapid Commun Mass Spectrom
March 2024
Laboratory of Racing Chemistry, Utsunomiya, Japan.
Article Synopsis
- Osilodrostat is an inhibitor used to treat Cushing's disease and is banned in horseracing due to its anabolic properties; this study marks the first metabolic analysis of osilodrostat in horses.
- The researchers identified osilodrostat's potential metabolites using advanced mass spectrometry techniques on plasma samples collected before and after drug administration.
- Results showed that the mono-hydroxylated form of osilodrostat was the main metabolite found in plasma, and both the drug and its metabolite remained detectable for up to two weeks, suggesting the need for thorough doping tests in equine sports.
The intrafollicular concentrations of biologically active cortisol in women rise abruptly shortly before ovulation and follicular rupture.
Hum Reprod
March 2024
Faculty of Health and Medical Science, Institute for Clinical Medicine, University of Copenhagen, Copenhagen N, Denmark.
Study Question: What is the temporal activity and the concentration in follicular fluid (FF) of the anti-inflammatory steroid cortisol during the ovulatory process in humans?
Summary Answer: Intrafollicular concentrations of cortisol become massively upregulated close to ovulation concomitant with an exceptionally high biological activity securing a timely and efficient termination of inflammatory processes.
What Is Known Already: Ovulation has been described as a local, controlled inflammatory process resulting in the degeneration of the follicle wall which facilitate oocyte extrusion. Ovulation also affects the glucocorticoid metabolism of granulosa cells (GCs) and although de novo synthesis of cortisol only occurs in the adrenal cortex, the mid-cycle surge has been shown to induce a change from high expression of HSD11B2, inactivating cortisol to cortisone, to high expression of HSD11B1 which reversibly catalyses cortisol production from cortisone.
Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation.
Neuropsychopharmacology
June 2024
School of Arts & Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, 02115, USA.
Maternal immune activation (MIA) puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through maternal, placental, and fetal compartments contributes to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, on gestational day 15, pregnant rat dams were administered the bacterial mimetic lipopolysaccharide (LPS; to induce MIA) alongside metyrapone, a clinically available 11β-hydroxylase (11βHSD) inhibitor used to treat hypercortisolism in pregnant, lactating, and neonatal populations.
View Article and Find Full Text PDFStructural and clinical characterization of CYP11B2 inhibition by dexfadrostat phosphate.
J Steroid Biochem Mol Biol
December 2023
Department for BioMedical Research, University Hospital Inselspital, University of Bern, 3010 Bern, Switzerland; Department of Nephrology and Hypertension, University Hospital Inselspital, University of Bern, 3010 Bern, Switzerland.
Aldosterone synthase (CYP11B2) represents a promising drug target because its genetic dysregulation is causally associated with cardiovascular disease, its autonomous activity leads to primary aldosteronism, and its deficiency leads to salt wasting syndromes. The serendipitous discovery that the dextro-rotatory stereoisomer of the racemic aromatase (CYP19A1) inhibitor CGS16949A mediates potent CYP11B2 inhibition led to the purification and clinical development of dexfadrostat phosphate. To characterize the pharmacophore of dexfadrostat phosphate, structure-based enzyme coordination with CYP11B2, CYP11B1 and CYP19A1 was combined with steroid turnover upon in vitro and clinical treatment.
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