Activin A and Sertoli Cells: Key to Fetal Testis Steroidogenesis

Abstract

The long-standing knowledge that Sertoli cells determine fetal testosterone production levels is not widespread, despite being first reported over a decade ago in studies of mice. Hence any ongoing use of testosterone as a marker of Leydig cell function in fetal testes is inappropriate. By interrogating new scRNAseq data from human fetal testes, we demonstrate this situation is also likely to be true in humans. This has implications for understanding how disruptions to either or both Leydig and Sertoli cells during the in utero masculinization programming window may contribute to the increasing incidence of hypospadias, cryptorchidism, testicular germ cell tumours and adult infertility. We recently discovered that activin A levels directly govern androgen production in mouse Sertoli cells, because the enzymes that drive the conversion of the precursor androgen androstenedione to generate testosterone are produced exclusively in Sertoli cells in response to activin A. This minireview addresses the implications of this growing understanding of how in utero exposures affect fetal masculinization for future research on reproductive health, including during programming windows that may ultimately be relevant for organ development in males and females.

New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice

“…11β-hydroxysteroids synthesised in the human adrenal gland can be converted to 11-keto androgens, predominantly occurring in peripheral tissues, and these can have androgen activity by acting on AR [ 45 ]. There is emerging evidence that the 11-keto androgens, including 11-ketotestosterone and 11-keto-DHT, play a role in male physiology in both humans and mice, however, whether they have a role in postnatal testis function is not established [ 40 , 46 , 47 ]. Whilst 11-keto-testosterone has been detected in both humans [ 45 ] and mice [ 48 ], 11-keto-testosterone is another modification of testosterone and therefore does not explain the testosterone synthesis in the HSD17B3 deficient mice [ 17 , 34 ].…”

“…While HSD17B3 in Leydig cells is considered as the predominant enzyme responsible for testosterone synthesis in males, the situation is more complex during fetal testis development with both fetal Sertoli cells and fetal Leydig cells being required for testosterone synthesis [ 64 ]. In the fetal mouse testis, there is increasing evidence supporting that HSD17B1 and HSD17B3 both contribute to testicular testosterone production [ 18 , 47 , 64 , 66 ]. Human HSD17B1 can also convert androstenedione into testosterone, however, is less efficient compared to the mouse enzyme [ 47 , 67 ].…”

“…In the fetal mouse testis, there is increasing evidence supporting that HSD17B1 and HSD17B3 both contribute to testicular testosterone production [ 18 , 47 , 64 , 66 ]. Human HSD17B1 can also convert androstenedione into testosterone, however, is less efficient compared to the mouse enzyme [ 47 , 67 ]. Virilisation during fetal development in the HSD17B3 KO male mice could be a result of the fetal Sertoli cells expressing HSD17B1, and as mouse HSD17B1 is more efficient at synthesising testosterone compared to human HSD17B1, this may partly explain the differences in the phenotype amongst the species [ 64 , 66 ].…”

“…Virilisation during fetal development in the HSD17B3 KO male mice could be a result of the fetal Sertoli cells expressing HSD17B1, and as mouse HSD17B1 is more efficient at synthesising testosterone compared to human HSD17B1, this may partly explain the differences in the phenotype amongst the species [ 64 , 66 ]. Whether androgen action as a result of HSD17B1 activity is also true for the human fetal testis is unclear, however there is evidence for the preferential expression of HSD17B1 and HSD17B3 in human fetal Sertoli cells compared to Leydig cells [ 47 ]. While HSD17B1 is expressed in the mouse testis during fetal development, this expression is reduced to undetectable levels in adulthood [ 17 , 18 , 59 , 66 ].…”

Androgens, brain and androgen deprivation therapy in paraphilic disorders: A narrative review

“…Testosterone and its active, nonaromatizable metabolite, dihydrotestosterone (DHT), are synthesized in both the testes (O'Donnell et al, 2022) and the brain (Brandt et al, 2020; Fester & Rune, 2021) including the medial prefrontal cortex and other nodes of the mesocorticolimbic system (Tomm et al, 2022). Circulating testosterone can bind and activate the classical nuclear ARs directly or indirectly through DHT (McEwan & Brinkmann, 2000).…”