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

FASEB J. 2020 May;34(5):6111-6128. doi: 10.1096/fj.201902384R. Epub 2020 Mar 19.


Hydroxysteroid (17β) dehydrogenase type 3 (HSD17B3) deficiency causes a disorder of sex development in humans, where affected males are born with female-appearing external genitalia, but are virilized during puberty. The hormonal disturbances observed in the Hsd17b3 knockout mice (HSD17B3KO), generated in the present study, mimic those found in patients with HSD17B3 mutations. Identical to affected humans, serum T in the adult HSD17B3KO mice was within the normal range, while a striking increase was detected in serum A-dione concentration. This resulted in a marked reduction of the serum T/A-dione ratio, a diagnostic hallmark for the patients with HSD17B3 deficiency. However, unlike humans, male HSD17B3KO mice were born with normally virilized phenotype, but presenting with delayed puberty. In contrast to the current belief, data from HSD17B3KO mice show that the circulating T largely originates from the testes, indicating a strong compensatory mechanism in the absence of HSD17B3. The lack of testicular malignancies in HSD17B3KO mice supports the view that testis tumors in human patients are due to associated cryptorchidism. The HSD17B3KO mice presented also with impaired Leydig cell maturation and signs of undermasculinization in adulthood. The identical hormonal disturbances between HSD17B3 deficient knockout mice and human patients make the current mouse model valuable for understanding the mechanism of the patient phenotypes, as well as endocrinopathies and compensatory steroidogenic mechanisms in HSD17B3 deficiency.

Keywords: HSD17B3; Leydig cell maturation; disorder of sex development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / deficiency
  • 17-Hydroxysteroid Dehydrogenases / genetics
  • 17-Hydroxysteroid Dehydrogenases / physiology*
  • Animals
  • Female
  • Gonadal Steroid Hormones / blood*
  • Infertility, Male / etiology
  • Infertility, Male / pathology*
  • Leydig Cells / metabolism
  • Leydig Cells / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation*


  • Gonadal Steroid Hormones
  • 17-Hydroxysteroid Dehydrogenases
  • 17beta-hydroxysteroid dehydrogenase type 3