SUN-213 Hsd17b3 Knockout Mice Serve As A Model To Define Mechanisms Behind The Altered Endocrine Phenotype Of Patients With Hsd17b3 Mutations

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.