Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland.
Turku Center for Disease Modeling (TCDM), Institute of Biomedicine, University of Turku, Turku, Finland.
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.
17β-羟类固醇脱氢酶 3 型（HSD17B3）缺乏症会导致人类出现性发育障碍，受影响的男性出生时具有女性化的外生殖器，但在青春期会出现男性化。本研究中产生的 Hsd17b3 基因敲除（HSD17B3KO）小鼠表现出的激素紊乱与 HSD17B3 突变患者中观察到的相似。与受影响的人类一样，成年 HSD17B3KO 小鼠的血清 T 在正常范围内，而血清 A-二酮浓度显著增加。这导致血清 T/A-二酮比值明显降低，这是 HSD17B3 缺乏症患者的一个诊断特征。然而，与人类不同的是，雄性 HSD17B3KO 小鼠出生时具有正常的男性化表型，但青春期延迟。与当前的观点相反，来自 HSD17B3KO 小鼠的数据表明，循环 T 主要来源于睾丸，表明在缺乏 HSD17B3 的情况下存在强烈的代偿机制。HSD17B3KO 小鼠中没有睾丸恶性肿瘤的发生支持这样一种观点，即人类患者的睾丸肿瘤是由于伴随的隐睾症引起的。HSD17B3KO 小鼠还表现出莱迪希细胞成熟受损和成年后雄性化不足的迹象。缺乏 HSD17B3 的基因敲除小鼠和人类患者之间存在相同的激素紊乱，这使得当前的小鼠模型对于理解患者表型的机制以及 HSD17B3 缺乏症中的内分泌紊乱和代偿性类固醇生成机制具有重要价值。
