THU574 Hsd17b1 Partially Compensates For The Lack Of Hsd17b3 In Testicular Testosterone Production In Fetal Mice, But Not In Adults

Abstract

Abstract Disclosure: M. Poutanen: None. A. Junnila: None. P. Sipilä: None. I.T. Huhtaniemi: None. Hydroxysteroid (17β) dehydrogenase type 3 (Hsd17b3) is the primary enzyme converting androstenedione to testosterone in human testes. HSD17B3 deficiency is a known cause of a disorder of sex development (DSD), where XY individuals are born with a female appearance, but are virilized during puberty as testosterone starts to suddenly rise due to unknown compensatory mechanisms. We have previously established and characterized an Hsd17b3 knockout mouse line (HSD17B3KO). HSD17B3KO males were born phenotypically normal, but presented various signs of under-masculinization at later ages. However, although they have very high circulating androstenedione at adulthood, they also maintain normal-to-high concentrations of testosterone. Indeed, testosterone was only seen to be low during certain fetal and pubertal time points. We suspected that Hsd17b1, capable of catalyzing the same reaction and expressed in testes towards the end of the fetal development, could be responsible for the compensation in the testosterone production, especially in the presence of higher than normal concentrations of androstenedione. To test this, we created an Hsd17b1-Hsd17b3 double KO (DKO) mouse line. The loss of both Hsd17b1 and Hsd17b3 had a more drastic effect on the phenotype of the male animals than was observed in HSD17B3KO. The outward appearance of the DKO males was completely feminized both as newborns and at adulthood, with an anogenital distance comparable to females. The male internal genitalia were present, but compared to HSD17B3KO they were further reduced in size, as were several other androgen-sensitive tissues. However, the testes and epididymides of the DKO contained high number of mature spermatozoa. The loss of both enzymes had a clear effect on the testis steroidogenesis of the newborn animals, with a 2-fold increase in intra testis androstenedione and 6-fold decrease in testosterone concentration compared to WT and HSD17B3KO males. In contrast, at the age of 3 months, no difference in the circulating steroid concentrations was observed between the DKO and HSD17B3KO, and high concentrations of androstenedione and testosterone was present in both mice. This, along with the active spermatogenesis, imply that in a presence of high LH, a further compensatory mechanism of testosterone production is present in the adult testes. In conclusion, our results demonstrate that in the absence of Hsd17b3, Hsd17b1 is crucial for the remaining testosterone production capacity in fetal mouse testis. However, in adult animals, the compensatory role is taken over by other, so far unknown, enzymes. Compared to HSD17B3KO, the overall phenotype of the DKO male mice is more similar to that of the humans with HSD17B3 deficiency, while the phenotype of HSD17B3KO is less feminized. Presentation Date: Thursday, June 15, 2023