Compensatory mechanisms that maintain androgen production in mice lacking key androgen biosynthetic enzymes.

Autor: Lawrence BM; College of Engineering, Science and Environment, The University of Newcastle, Callaghan, New South Wales, Australia.; School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia., O'Donnell L; Office of the Deputy Vice Chancellor (Research), Griffith University, Southport, Queensland, Australia., Gannon AL; College of Engineering, Science and Environment, The University of Newcastle, Callaghan, New South Wales, Australia., Smith S; College of Engineering, Science and Environment, The University of Newcastle, Callaghan, New South Wales, Australia., Curley MK; MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK., Darbey A; MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK., Mackay R; MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK., O'Shaughnessy PJ; School of Biodiversity, One Health & Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Garscube Campus, Glasgow, UK., Smith LB; Office of the Deputy Vice Chancellor (Research), Griffith University, Southport, Queensland, Australia., Rebourcet D; College of Engineering, Science and Environment, The University of Newcastle, Callaghan, New South Wales, Australia.; Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Univ Rennes, Rennes, France.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Nov 30; Vol. 38 (22), pp. e70177.
DOI: 10.1096/fj.202402093R
Abstrakt: Testosterone and dihydrotestosterone (DHT) are essential for male development and fertility. In the canonical androgen production pathway, testosterone is produced in the testis by HSD17B3; however, adult male Hsd17b3 knockout (KO) mice continue to produce androgens and are fertile, indicating compensatory mechanisms exist. A second, alternate pathway produces DHT from precursors other than testosterone via 5α-reductase (SRD5A) activity. We hypothesized that the alternate pathway contributes to androgen bioactivity in Hsd17b3 KO mice. To investigate contributions arising from and interactions between the canonical and alternate pathways, we pharmacologically inhibited SRD5A and ablated Srd5a1 (the predominant SRD5A in the testis) on the background of Hsd17b3 KO mice. Mice with perturbation of either the canonical or both pathways exhibited increased LH, testicular steroidogenic enzyme expression, and normal reproductive tracts and fertility. In the circulation, alternate pathway steroids were increased in the absence of HSD17B3 but were reduced by co-inhibition of SRD5A1. Mice with perturbations of both pathways produced normal basal levels of intratesticular testosterone, suggesting the action of other unidentified hydroxysteroid dehydrogenase(s). Strikingly, testicular expression of another SRD5A enzyme, Srd5a2, was markedly increased in the absence of Hsd17b3, suggesting a compensatory increase in SRD5A2 to maintain androgen bioactivity during HSD17B3 deficiency. Finally, we observed elevated circulating concentrations of the 11-keto-derivative of DHT, suggesting compensatory extra-gonadal induction of bioactive 11-keto androgen production. Taken together, we conclude that, in the absence of the canonical pathway of androgen production, multiple intra- and extra-gonadal mechanisms cooperate to maintain testosterone and DHT production, supporting male development and fertility.
(© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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