Testosterone synthesis in patients with 17β-hydroxysteroid dehydrogenase 3 deficiency

Area of Science:

• Endocrinology
• Genetics
• Biochemistry

Background:

• 17β-hydroxysteroid dehydrogenase 3 (17β-HSD 3) deficiency is a rare genetic cause of 46,XY disorders of sex development (DSD).
• Patients experience significant virilization at puberty due to elevated androstenedione and testosterone, but the source of testosterone synthesis remains unclear.

Purpose of the Study:

• To investigate the role of the isoenzyme AKR1C3 (17β-HSD 5) in testosterone synthesis in 17β-HSD 3 deficiency.
• To determine if patient-derived genital skin fibroblasts (GSF) can synthesize testosterone.

Main Methods:

• Analysis of AKR1C3 expression in testicular tissue and GSF.
• Measurement of androstenedione and testosterone in GSF culture supernatants and patient serum using liquid and gas chromatography/mass spectrometry.
• Assessment of androgenic potential of GSF supernatants via reporter gene assays in transfected cells.

Main Results:

• AKR1C3 is expressed in both testes and GSF, but GSF do not synthesize testosterone from androstenedione under normal conditions.
• GSF supernatants show declining androgen receptor transactivation potential within 48 hours.
• Testosterone synthesis by 17β-HSD 3-negative GSF occurs only at testis-equivalent androstenedione concentrations.
• Serum androstenedione and testosterone levels rapidly decrease after gonadectomy.

Conclusions:

• In 17β-HSD 3 deficiency, significant testosterone synthesis likely occurs in the testis, primarily mediated by AKR1C3.
• Peripheral testosterone synthesis in genital skin fibroblasts is unlikely to be a major contributor in these patients.