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

Abstract

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. K E Y W O R D S disorder of sex development, HSD17B3, Leydig cell maturation 6112 | SIPILÄ et aL. | 6115 SIPILÄ et aL.to the circumference of seminiferous tubules. Two testis crosssections were analyzed from each male.

The androgen receptor depends on ligand‐binding domain dimerization for transcriptional activation

“…HSD17B3 is the last enzyme in the synthesis of T and responsible for the conversion of A‐dione into T. In AR Lmon/Y testis, this final step is affected, resulting in an accumulation of A‐dione. Similar to AR Lmon/Y , it was recently shown that a HSD17B3 knockout mouse model also has very high circulating A‐dione levels, in combination with elevated serum T values, indicating that other enzymes can compensate for HSD17B3 in T synthesis (Rebourcet et al , 2020; Sipilä et al , 2020). In contrast, the disruption of the HPG axis in the AR −/Y mice leads to a more severe testicular phenotype: while LH levels are increased compared with WT males, T synthesis remains low although the defective LC cells still have some response as evidenced by the circulating A‐dione (De Gendt et al , 2004) and (Fig 3B).…”

Analyses of Molecular Characteristics and Enzymatic Activities of Ovine HSD17B3

“…Although the physiological significance of this activity is unclear, HSD17B3 may contribute to testicular E2 production. In support of this hypothesis, testicular E2 levels in Hsd17b3 KO mice were found to be decreased, despite E1 levels being increased [11]. Estrogen-estrogen receptor (ER) pathways are essential for spermatogenesis [37][38][39].…”

“…In addition to humans, it was recently reported in DSD dogs that truncation of the encoded protein was caused by 2-bp deletion of the HSD17B3 gene [10]. Furthermore, male Hsd17b3KO mice were reported to show a delay in puberty, owing to an abnormal A4/T ratio [11]. These findings indicate that the HSD17B3 gene plays important roles in sex differentiation in various mammalian species.…”

“…It contributes to the development of male sexual characteristics by converting A4 into T during fetal life and puberty. Mutations of HSD17B3 genes cause a disorder of sexual development (DSD) and undermasculinizaion as a result of low T production and an abnormal A4/T ratio in multiple species, such as human, dog, and mouse [6,[8][9][10][11]. In livestock, DSD represents one of the major causes of reduced productivity [12][13][14][15].…”

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

“…Since the in silico model establishment of the HSD17B3 deficiency in mice, two independent research groups have now reported the phenotypes of independently derived Hsd17b3 -deficient mouse lines [ 17 , 34 ]. These models were designed to mimic the human mutation causing HSD17B3 deficiency by blocking the conversion of androstenedione to the active androgen testosterone, subsequently causing disruption to the canonical androgen production pathway.…”