TY - JOUR

T1 - Ablation of the canonical testosterone production pathway via knockout of the steroidogenic enzyme HSD17B3, reveals a novel mechanism of testicular testosterone production

AU - Rebourcet, Diane

AU - Mackay, Rosa

AU - Darbey, Annalucia

AU - Curley, Michael K

AU - Jørgensen, Anne

AU - Frederiksen, Hanne

AU - Mitchell, Rod T

AU - O'Shaughnessy, Peter J

AU - Nef, Serge

AU - Smith, Lee B

N1 - © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

PY - 2020/8

Y1 - 2020/8

N2 - Male development, fertility, and lifelong health are all androgen-dependent. Approximately 95% of circulating testosterone is synthesized by the testis and the final step in this canonical pathway is controlled by the activity of the hydroxysteroid-dehydrogenase-17-beta-3 (HSD17B3). To determine the role of HSD17B3 in testosterone production and androgenization during male development and function we have characterized a mouse model lacking HSD17B3. The data reveal that developmental masculinization and fertility are normal in mutant males. Ablation of HSD17B3 inhibits hyperstimulation of testosterone production by hCG, although basal testosterone levels are maintained despite the absence of HSD17B3. Reintroduction of HSD17B3 via gene-delivery to Sertoli cells in adulthood partially rescues the adult phenotype, showing that, as in development, different cell-types in the testis are able to work together to produce testosterone. Together, these data show that HS17B3 acts as a rate-limiting-step for the maximum level of testosterone production by the testis but does not control basal testosterone production. Measurement of other enzymes able to convert androstenedione to testosterone identifies HSD17B12 as a candidate enzyme capable of driving basal testosterone production in the testis. Together, these findings expand our understanding of testosterone production in males.

AB - Male development, fertility, and lifelong health are all androgen-dependent. Approximately 95% of circulating testosterone is synthesized by the testis and the final step in this canonical pathway is controlled by the activity of the hydroxysteroid-dehydrogenase-17-beta-3 (HSD17B3). To determine the role of HSD17B3 in testosterone production and androgenization during male development and function we have characterized a mouse model lacking HSD17B3. The data reveal that developmental masculinization and fertility are normal in mutant males. Ablation of HSD17B3 inhibits hyperstimulation of testosterone production by hCG, although basal testosterone levels are maintained despite the absence of HSD17B3. Reintroduction of HSD17B3 via gene-delivery to Sertoli cells in adulthood partially rescues the adult phenotype, showing that, as in development, different cell-types in the testis are able to work together to produce testosterone. Together, these data show that HS17B3 acts as a rate-limiting-step for the maximum level of testosterone production by the testis but does not control basal testosterone production. Measurement of other enzymes able to convert androstenedione to testosterone identifies HSD17B12 as a candidate enzyme capable of driving basal testosterone production in the testis. Together, these findings expand our understanding of testosterone production in males.

KW - androgens

KW - HSD17B12

KW - HSD17B3

KW - Leydig cell

KW - testis

KW - testosterone

UR - http://www.scopus.com/inward/record.url?scp=85087317625&partnerID=8YFLogxK

U2 - 10.1096/fj.202000361R

DO - 10.1096/fj.202000361R

M3 - Journal article

C2 - 32557858

VL - 34

SP - 10373

EP - 10386

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 8

ER -