ESPE2022 Poster Category 1 Sex Differentiation, Gonads and Gynaecology, and Sex Endocrinology (56 abstracts)
Androgen receptor activity in genital skin fibroblasts in response to dihydrotestosterone, testosterone and androstenedione using the APOD assay
Lea Große-Schute 1 , Alexandra Kulle 2 , Ralf Werner 3 , Olaf Hiort 3 , Stenvert Drop 4 , Hans-Udo Schweikert 5 , Paul-Martin Holterhus 2 & Nadine Hornig 6
1University hospital Münster, Münster, Germany; 2Department of Paediatrics, Paediatric Endocrinology and Diabetes, University Hospital of Schleswig-Holstein, Kiel, Germany; 3Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany; 4Division of Pediatric Endocrinology, Sophia Children´s Hospital, Erasmus Medical Center, Rotterdam, Netherlands; 5Institute for Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany; 6Institute of Human Genetics, University Hospital of Schleswig-Holstein, Kiel, Germany
Introduction: Androgens are essential for the development of male sex characteristics. Testosterone (T) production from androstenedione (A) by the Hydroxysteroid 17-Beta Dehydrogenase 3 (HSD17B3) in gonadal Leydig cells triggers the differentiation of the Wolffian ducts into epididymis, vas deferens, seminal vesicles and the prostate. Shortly after, the virilisation of the external male genitalia starts through the conversion of T into dihydrotestosterone (DHT) by the Steroid 5 Alpha-Reductase 2 (SRD5A2) outside the gonad leading to the differentiation of the outer male genitalia. However, pubertal virilization has been observed in individuals with 17-Beta Dehydrogenase- or 5 Alpha-Reductase-deficiency.
Objective: To investigate if T and its precursor A can activate the AR in genital skin fibroblasts (GF) of male controls and individuals with 5 Alpha-Reductase-deficiency.
Methods: Previous in vitro assays have shown a dose dependent activation of an androgen response element reporter construct in response to A, T and DHT. The APOD assay offers the opportunity to study AR activation endogenously in genital skin fibroblasts, the peripheral target tissue for external genital development, by measuring androgen-dependent induction of the AR target gene Apoliprotein D (APOD). AR activity was determined in five male control GF cell lines and in eight GF cell lines with SRD5A mutations or low 5 Alpha-Reductase expression after incubation with DHT, T and A for 48h.
Results: All three steroid hormones were able to activate the AR in GF, with DHT being the most potent activator, followed by T and A. GF with 5 Alpha-Reductase deficiency showed a similar induction profile as compared to control GF.
Conclusion: A, T can activate AR function in GF albeit to a lower level as compared to DHT. The T-activation is likely to be direct as GF with 5 Alpha-Reductase deficiency and hence no DHT production did not show a significant lower AR-activity as compared to control GF.
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