Changes in the forward and reverse metabolism of aromatizable androgens during the development of large ovarian cysts in the pregnant rat.

Abstract

Twice-daily treatments with subovulatory doses of hCG result in the development of large ovarian cysts that possess the capacity to produce preovulatory amounts of estradiol (E2) in the presence of exogenous substrate (Biol Reprod 1991; 45:34-42). To determine the effects of prolonged stimulation by subovulatory doses of LH-like activity on the ability of ovarian follicles to produce aromatizable androgens and their metabolites and on the capacity of similar follicles to metabolize exogenous androstenedione (A4) and testosterone, pregnant rats were treated with either 0 (control), 1, or 3 IU hCG twice daily for 9 days, beginning on Day 13 of pregnancy. The largest follicles or cysts in the ovaries of these animals on Days 15, 17, 19, and 22 were incubated for 4 h in the presence of 1) medium alone, 2) 1 mM cAMP, 3) 800 ng/ml A4 with or without cAMP, or 4) 800 ng/ml testosterone with or without cAMP. In the presence or absence of cAMP, follicular incubates from controls displayed limited amounts of A4, testosterone, E2, estrone (E1), and 5alpha-reduced androgen accumulation compared to incubates from rats treated with hCG. By Day 22, follicular incubates from rats treated with 3 IU hCG contained more A4 than incubates from animals treated with 1 IU hCG. However, on each day tested, incubates from rats treated with 1 IU hCG displayed at least as much, and usually more, testosterone, E2, E1, and 5alpha-reduced androgens as did incubates from rats treated with 3 IU hCG. Follicles from rats treated with 3 IU hCG lost their ability to respond to cAMP with increased steroidogenesis. The capacity of follicles from controls and from rats treated with 3 IU hCG to metabolize exogenous A4 to testosterone, E2, and 5alpha-reduced androgens was maintained between 32 and 37 ng of steroid/4 h from Day 15 to Day 22, whereas the capacity of follicles from rats treated with 1 IU hCG to metabolize A4 ranged from 68 to 92 ng of steroid/4 h. Similar patterns for E2 and 5alpha-reduced steroid production were observed when exogenous testosterone was used as substrate. Follicles from all in vivo treatment groups displayed similar capacities to reverse-metabolize exogenous testosterone to A4 and E1 on Day 15 of pregnancy. This capacity increased dramatically, from 29 to 75 ng of steroid/4 h, between Days 15 and 17 for follicles from rats treated with 3 IU hCG. A similar increase was not observed for follicular incubates from rats treated with 1 IU hCG until Day 22 of pregnancy, and was never observed for follicles from controls. In summary, prolonged exposure to stimulation by subovulatory doses of LH-like activity differentially affects the forward and reverse metabolism of aromatizable androgens by ovarian cysts that are developing in the pregnant rat. The limited ability of large, hCG-induced cysts to forward-metabolize A4 and the apparent increased capacity of these follicles to reverse-metabolize testosterone to A4 indirectly support the notion that follicular 17-ketosteroid reductase and 17beta-hydroxysteroid dehydrogenase activities may be differentially regulated during the induction of ovarian cysts in response to prolonged stimulation by gonadotropins in the anovulatory environment of the pregnant rat.