Androgen-uterine interactions: an assessment of androgen interaction with the testosterone- and estrogen-receptor systems and stimulation of uterine growth and progesterone-receptor synthesis

Abstract

This study investigates growth and the induction of progesterone-receptor synthesis in the immature (day 20--23) rat uterus after injection of different doses of 5 alpha-dihydrotestosterone (DHT) and testosterone (T) in long- and short acting injection vehicles. Moderate doses of T (300 microgram/day in saline for 3 days) elicit uterine growth (ca. 250% of control) that is abolished by concomitant injections of antiandrogen (1 mg flutamide/day or 8 mg DIMP/day) but is unaffected by injections of antiestrogens (60 microgram CI-628 or U11,100A/day). Uterine growth evoked by 17 beta-estradiol (3 microgram/day for 3 days) is, however, only antagonized with the antiestrogens but not antiandrogens. Experiments employing whole uteri in vitro indicate that the specific nuclear uptake of 10(-8) M [3H]T is markedly inhibited by the antiandrogens DIMP, flutamide, and the hydroxylated flutamide metabolite (LACT) [LACT greater than DIMP greater than FLUT] while the antiestrogens CI-628 and U11,100A are ineffective. In contrast, the specific nuclear uptake of 10(-8) M [3H]-estradiol is inhibited by only the antiestrogens and not antiandrogens. When very high (5 or 10 mg) doses of DHT Are administered in an oil-containing injection vehicle, nuclear translocation and cytoplasmic depletion of the estrogen receptor does occur and a uterotrophic response is elicited which is resistant to antagonism by antiandrogen. Likewise, the DHT-stimulated increase in progesterone-receptor content is not decreased by concomitant antiandrogen. Similar 5 or 10 mg doses of DHT, administered in a water-soluble dimethylsulfoxide vehicle, show little estrogen-receptor movement and the DHT-induced uterine growth and induction of progesterone-receptor synthesis is almost completely eliminated with antiandrogen. Regardless of the degree of uterine growth stimulation, however, the androgens are poor stimulators of uterine progesterone-receptor synthesis compared with estradiol. These results indicate that androgens may interact with both the androgen- and estrogen-receptor systems in the uterus in inducing uterine growth and that the nature of the cellular mechanism, i.e., whether the androgen- and/or estrogen-receptor system is involved, is dependent critically upon the in vivo dose of androgen and the mode of hormone administration.