Hydroxysteroid (17β) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility

Abstract

The pituitary gonadotrophins and testosterone are the main hormonal regulators of spermatogenesis, but estradiol is also known to play a role in the process. The hormonal responses in the testis are partially mediated by somatic Sertoli cells that provide nutritional and physical support for differentiating male germ cells. Hydroxysteroid (17β) dehydrogenase 1 (HSD17B1) is a steroidogenic enzyme that especially catalyzes the conversion of low potent 17keto-steroids to highly potent 17β-hydroxysteroids. In this study, we show that Hsd17b1 is highly expressed in Sertoli cells of fetal and newborn mice, and HSD17B1 knockout males present with disrupted spermatogenesis with major defects, particularly in the head shape of elongating spermatids. The cell-cell junctions between Sertoli cells and germ cells were disrupted in the HSD17B1 knockout mice. This resulted in complications in the orientation of elongating spermatids in the seminiferous epithelium, reduced sperm production, and morphologically abnormal spermatozoa. We also showed that the Sertoli cell-expressed HSD17B1 participates in testicular steroid synthesis, evidenced by a compensatory up-regulation of HSD17B3 in Leydig cells. These results revealed a novel role for HSD17B1 in the control of spermatogenesis and male fertility, and that Sertoli cells significantly contribute to steroid synthesis in the testis.-Hakkarainen, J., Zhang, F.-P., Jokela, H., Mayerhofer, A., Behr, R., Cisneros-Montalvo, S., Nurmio, M., Toppari, J., Ohlsson, C., Kotaja, N., Sipilä, P., Poutanen, M. Hydroxysteroid (17β) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility.

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

“…Recently, Hsd17b1 expression was localized to Sertoli cells in mice in fetal life 29 . Ablation of this enzyme leads to disruption of the seminiferous epithelium and abnormal spermatozoa in adulthood, linking it to a role in the establishment of normal male fertility 29 . As Hsd17b1 is able to convert androstenedione to testosterone this raises the possibility that HSD17B1 is responsible for basal androgen production in fetal life, though as it is not expressed in the adult testis, is unable to explain the normal testosterone concentrations observed in the Hsd17b3 −/− adult males.…”

The lack of HSD17B3 in male mice results in disturbed Leydig cell maturation and endocrine imbalance akin to humans with HSD17B3 deficiency

“…The stage‐specific drying‐down preparations of testicular cells were made as previously described, followed by immunofluorescence stainings for Tubulin α (α‐tubulin mouse monoclonal antibody conjugated with Alexa Fluor 488, dilution 1:500, cat. # 322588, Invitrogen) and mounting with ProLong Diamond Antifade mountant (Thermo Fisher Scientific) containing 4′,6‐diamidine‐2′‐phenylindole dihydrochloride (DAPI) for nuclear staining, performed as previously described by us . The signal was visualized by fluorescent microscopy combined with phase‐contrast analysis (Leica DMRBE, Leica).…”

Activin A and Sertoli Cells: Key to Fetal Testis Steroidogenesis

“…In the rodent testis, testosterone production occurs via the Δ4 steroidogenic pathway ( Figure 1B , orange line) and concludes with conversion of androstenedione (A4) to testosterone (T) by the enzymes HSD17B3 ( 39 ) and HSD17B1 ( 40 ). The fetal and adult Leydig cell populations develop sequentially and are functionally distinct ( 41 ), so while T is produced in Leydig cells in adult mouse testes ( 42 ), fetal Leydig cells lack Hsd17b1 and Hsd17b3 and cannot convert A4 to T ( 39 , 40 ). Instead, exclusive expression of Hsd17b1 and Hsd17b3 in fetal mouse Sertoli cells ( 43 , 44 ) identifies Sertoli cells as the site of T synthesis in the fetal testis ( 33 ).…”