Androgen-uterine interactions: an assessment of androgen interaction with the testosterone- and estrogen-receptor systems and stimulation of uterine growth and progesterone-receptor synthesis.
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.
D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D009929:Organ Size; D010797:Phthalimides / Q000494:pharmacology; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011987:Receptors, Steroid / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects* / Q000254:growth & development
D000726:Androgen Antagonists; D004965:Estrogen Antagonists; D007555:Isoxazoles; D010797:Phthalimides; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide