11-Oxyandrogens from the viewpoint of pediatric endocrinology

Abstract

11-Oxyandrogens, such as 11-ketotestosterone (11-KT), 11-ketodihydrotestosterone (11-KDHT), 11β-hydroxytestosterone (11-OHT), 11β-hydroxyandrostenedione (11-OHA4), and 11-KA4, are newly specified human androgens. These 11-oxyandrogens are present in the cord blood and placenta, as well as in the blood of men and women of various ages, and are produced primarily in the adrenal gland. Accumulating evidence suggests that these steroids contribute to androgen excess in patients with 21-hydroxylase deficiency or polycystic ovary syndrome. More importantly, unlike classic androgens, 11-oxyandrogens produced in maternal tumors can pass through the placenta without being converted into estrogens, and cause severe virilization of female fetuses. Thus, overproduction of 11-oxyandrogens represents a new mechanism of 46,XX disorders of sex development. On the other hand, the physiological roles of 11-oxyandrogens remain to be clarified. This mini-review introduces the current understanding of 11-oxyandrogens, from the perspective of pediatric endocrinology.

Keywords: 11-oxygenated C19 steroid; 11-ketotestosterone; 11-oxygenated androgen; disorders of sex development (DSD); fetus.

Fig. 1.

Steroidogenic pathways to classic androgens and 11-oxyandrogens. Classic androgens and 11-oxyandrogens are shown in double- and thick-lined boxes, respectively. Estrogens are indicated by broken-lined boxes. 17OH-P5, 17-hydroxy pregnanolone; 17-OHP, 17-hydroxy progesterone; DHEA-S, dehydroepiandrosterone sulfate; DHEA, dehydroepiandrosterone; A4, androstenedione; E1, estrone; T, testosterone, DHT, dihydrotestosterone; E2, estradiol; 11-OHA4, 11β-hydroxyandrostenedione; 11-OHT, 11β-hydroxytestosterone; 11-OHDHT, 11β-hydroxydihydrotestosterone; 11-KA4, 11-ketoandrostenedione; 11-KT, 11-ketotestosterone; 11-KDHT, 11-ketodihydrotestosterone. HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; CYP21A2, cytochrome P450 21A2; SULT2A1, sulfotransferase 2A1; CYP17A1, cytochrome P450 17A1; HSD17B2, 17β-hydroxysteroid dehydrogenase type 2; HSD17B1/3, 17β-hydroxysteroid dehydrogenase type 1/3; AKR1C3 (HSD17B5), aldo-keto reductase 1C3; CYP19A1, cytochrome P450 19A1 (aromatase); SRD5A1/2, 5α-reductase type 1/2; CYP11B1, cytochrome P450 11B1; HSD11B1, 11β-hydroxysteroid dehydrogenase type 1; HSD11B2, 11β-hydroxysteroid dehydrogenase type 2.

Fig. 2.

Schematic of maternal-fetal transfer of 11-oxyandrogens. Classic androgens are unlikely to pass through the placenta because they are converted into estrogens by placental aromatase. However, 11-oxyandrogens can be transferred from maternal circulation to the fetus, because they are non-aromatizable steroids. T, testosterone; A4, androstenedione; 11-KA4, 11-ketoandrostenedione; 11-KT, 11-ketotestosterone; E1, estrone; E2, estradiol.