Abstract
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.
Highlights
Male development, fertility, and lifelong health and wellbeing are all androgen-dependent
hydroxysteroid dehydrogenase 17beta 3 (HSD17B3) is expressed in testicular Sertoli cells where it functions to produce testosterone from androstenedione derived from the fetal Leydig cells
We determined the intratesticular concentrations of the same hormones. This revealed that, under basal conditions, progesterone, 17OHP, and androstenedione are all significantly increased in the testis of Hsd17b3 lentiviral particles (Hsd17b3)−/− males (Figure 4G-I), while testosterone is present in the same concentration as control littermates (Figure 4J)
Summary
Fertility, and lifelong health and wellbeing are all androgen-dependent. The presence or absence of male internal reproductive organs and external genitalia is critically dependent upon signaling via the androgen receptor (AR) during the masculinization programming window in fetal life.[9] Stimulation of AR with androgens prior to this window does neither induce premature masculinization,[10] nor can stimulation with androgens after this window has closed, drive the establishment of male internal genitalia if AR is blocked during the window.[9] During the programming window, testicular testosterone is the androgen that drives internal masculinization and it is curious, that some individuals lacking HSD17B3 show signs of internal masculinization during fetal life.[11] This may reflect the nature of the specific mutations that reduce, but do not completely ablate, testosterone production in the testis It may suggest the presence of another mechanism driving testosterone production that does not require the function of HSD17B3. These data identify an as yet uncharacterized, alternative mechanism driving testosterone production in the testis that functions independently of HSD17B3, which has implications for our understanding of testosterone production in males
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