Activation of androgens by hydroxysteroid (17beta) dehydrogenase 1 in vivo as a cause of prenatal masculinization and ovarian benign serous cystadenomas.
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.
Saloniemi
Taija
T
Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20144 Turku, Finland.
Lamminen
Tarja
T
Huhtinen
Kaisa
K
Welsh
Michelle
M
Saunders
Philippa
P
Kujari
Harry
H
Poutanen
Matti
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D018293:Cystadenoma, Serous / Q000201:enzymology* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics; D010053:Ovary / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014770:Virilism / Q000235:genetics*
D000728:Androgens; D013739:Testosterone; D000735:Androstenedione; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase