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.

No abstract

Hydroxysteroid (17β) dehydrogenase type 3 (HSD17B3) is known to be the primary HSD17B enzyme converting androstenedione (A) to testosterone (T) in human testes, and thus, to be important for sexual maturation in boys and for reproductive health later in life. In particular, inherited HSD17B3 deficiency is a known cause of 46,XY disorder of sex development in humans, where affected males are born with outwardly female genitalia, but are virilized during puberty. In the present study, Hsd17b3 knockout mice (HSD17B3KO) were established and characterized. HSD17B3KO males were born apparently phenotypically normal, but presented signs of hypogonadism at adulthood, including delayed puberty, subfertility, a shortened anogenital distance and lowered weight of several androgen-sensitive tissues. The loss of HSD17B3 also affected the androgen levels both in the testes and in circulation. Compared with the wild-type mice, androstenedione concentration was increased 10-fold in the testes and 100-fold in the serum in adult HSD17B3KO animals, accompanied with 3-fold increase in serum testosterone. The serum testosterone/androstenedione ratio in the adult HSD17B3KO mice reduced 10-fold. We also observed that circulating LH was increased 40-fold in adult KO animals, with a 200-fold increase in testicular Lhcgr expression. In addition, several genes related to steroid and cholesterol biosynthesis were upregulated in the testes, those including Star, Cyp11a1, Cyp17a1, Cyp51, Nsdhl and Hsd17b7. Our results demonstrate that, similar to humans, HSD17B3 is essential for proper androgen homeostasis in adult mice. However, like in humans, other, still unknown, enzymes can partly compensate the HSD17B3 deficiency, resulting in high amounts of serum T and DHT at adulthood. The persisting hypogonadal phenotype in the presence of high LH levels and high serum T suggest that the lack of HSD17B3 results in a defect in the pituitary-gonadal feedback system, and reduced androgen sensitivity of the extragonadal androgen target tissues. The very similar endocrine disruption present in the adult mice and men with HSD17B3 deficiency provides us the possibility to use the HSD17B3KO mice as a model to further understand the mechanisms behind the altered endocrine phenotype of the patients carrying inactivating mutations at HSD17B3 gene, and to identify potential secondary complications caused by the disease later in the life.