Activation of Androgens by Hydroxysteroid (17β) Dehydrogenase 1 in Vivo as a Cause of Prenatal Masculinization and Ovarian Benign Serous Cystadenomas

Abstract

Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) belong to the short-chain dehydrogenase/reductase family consisting of a diverse pool of enzymes with oxidoreductase activity. HSD17B enzymes catalyze the conversion between 17-keto and 17-hydroxy steroids, either activating or inactivating sex steroids. Previous studies have demonstrated a role for human HSD17B1 enzyme in estradiol (E2) biosynthesis both in gonads and extragonadal steroid target tissues and various estrogen-dependent diseases. In the present study, five transgenic (TG) mouse lines universally overexpressing human HSD17B1 were generated and characterized at fetal and adult ages, especially to study the enzyme function in vivo. Activity measurements in vivo indicated that in addition to activating estrone to E2, the enzyme is able to significantly reduce androstenedione to testosterone, and TG females presented increased testosterone concentration preceding birth. As a consequence, TG females suffered from several phenotypic features typical to enhanced fetal androgen exposure. Furthermore, the ovaries developed androgen-dependent ovarian benign serous cystadenomas at adulthood. Androgen dependency of the phenotypes was confirmed by rescuing them by antiandrogen treatment, or by transplanting wild-type ovaries to the TG females. In conclusion, the data evidently show that, in addition to activating estrone to E2, human HSD17B1 enhances androgen action in vivo. Thus, the relative amounts of androgenic and estrogenic substrates available partially determine the physiological function of the enzyme in vivo. The novel function observed for human HSD17B1 is likely to open new possibilities also for the use of HSD17B1-inhibitors as drugs against androgen-related dysfunctions in females.

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

“…Along with the significant androgenic activity of hHSD17B1 and with the increased foetal testosterone concentration, the TG female mice expressing hHSD17B1 ubiquitously presented with androgen-dependent phenotypic alterations, such as increased anogenital distance, suppressed nipple development, lack of vaginal opening and the combination of vagina with the urethra (Table 2). These alterations observed in the HSD17B1TG females were effectively rescued by prenatal anti-androgen (flutamide) treatment, further confirming the dependence of these phenotypes on androgens (Saloniemi et al 2007). Androgen receptor (AR) is expressed in both female and male reproductive tissues during development, and consequently, the female reproductive tract responds also to androgens (Bentvelsen et al 1995).…”

“…This suggested that the hHSD17B1 possesses considerable androgenic activity with the preference for estrogenic substrates. Accordingly, a significantly increased conversion of A-dione to testosterone was observed in both female and male HSD17B1TG mice, together with significantly increased testosterone concentration in foetal TG females (Saloniemi et al 2007). In summary, the data observed indicate that hHSD17B1 is not fully estrogen-specific but presents with significant androgenic activity.…”

“…after prenatal flutamide treatment (Miyata et al 2002, Foster & Harris 2005, or in the TG mice having an increased E 2 /testosterone ratio due to the expression of P450 aromatase (CYP19A1; Li et al 2002). Accordingly, prenatal flutamide treatment retained nipple development and rescued vaginal morphology in masculinised HSD17B1TG female mice (Saloniemi et al 2007. Interestingly, around the urethra of HSD17B1TG females, we identified an enlarged Skene's paraurethral gland, also referred to as the female prostate.…”

“…The female prostate has been reported to be present in several species and, similarly to the males, it has been shown to respond to androgens (Santos et al 2006). In HSD17B1TG females, flutamide treatment also suppressed the gland development (Saloniemi et al 2007). The fact that placental testosterone concentration was not increased indicated that elevated androgen exposure was not of maternal origin.…”

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

“…A recent 17b-HSD1 transgenic mouse study indicated that 17b-HSD1 is also capable of causing a significant amount of androgen activation in vivo, suggesting that 17b-HSD1 inhibitors may also have a role to play in women with diseases related to androgenic dysfunction (Saloniemi et al 2007). There are now many different groups working to find selective inhibitors of 17b-HSD1.…”