Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Multiple compensatory mechanisms support androgen biosynthesis and fertility in male mice. (#9)

Ben M Lawrence 1 , Liza O'Donnell 2 , Anne-Louise Gannon 3 , Sarah Smith 3 , Peter J O'Shaughnessy 4 , Lee B Smith 2 , Diane Rebourcet 3 5
  1. The University of Melbourne, Parkville, Victoria, Australia
  2. Griffith University, Southport, Queensland, Australia
  3. The University of Newcastle, Callaghan, NSW, Australia
  4. University of Glasgow, Glasgow, United Kingdom
  5. University of Rennes, Rennes, France

Testosterone and dihydrotestosterone (DHT) are androgens essential for male sexual function and fertility. In the canonical pathway of androgen production, testosterone is produced by the enzyme HSD17B3 and 5α-reductase (SRD5A) converts testosterone to DHT. However, male Hsd17b3 knockout (KO) mice are fertile with normal testicular testosterone and DHT1,2 suggesting other pathways must maintain androgens. We hypothesised that androgen bioactivity could be maintained in these mice by the “alternate pathway”, where 5α-reductase synthesises DHT from precursors other than testosterone, and that a recently described pathway producing bioactive 11-keto androgens could also contribute. We compared Hsd17b3 KO adult males to those lacking Hsd17b3 and Srd5a1, the predominant 5α-reductase in the testis (dKO mice). Both Hsd17b3 KO and dKO males were fertile with normal reproductive tracts but a phenotype of steroidogenic compensation, with elevated LH and key steroidogenic enzyme expression. Alternate pathway steroids were detected in the testis and circulation of adult mice, and the loss of Hsd17b3 caused an increase in alternate pathway steroids in circulation. Srd5a1 ablation in Hsd17b3 KO males reduced circulating alternate pathway steroids, indicating that SRD5A1 and the alternate pathway contribute to extra-testicular alternate androgen biosynthesis in mice. In the testis, however, testicular DHT was maintained in dKOs and there was a marked increase in another 5α-reductase enzyme, Srd5a2, in both Hsd17b3 KO and dKO mice, suggesting induction of testicular Srd5a2 is a compensatory response to the loss of Hsd17b3. Finally, circulating 11keto-DHT was undetectable in wildtype but elevated in Hsd17b3 KO and dKO mice, suggesting increased 11-keto androgen production could contribute to androgen bioactivity. We conclude that, in the absence of the canonical pathway of androgen production in mice, multiple intra- and extra-gonadal compensatory mechanisms cooperate to maintain androgen-dependent sexual development and fertility.

 

1Rebourcet et al, 2020, FASEB J; 2Sipila et al, 2020, FASEB J.