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

Warren N. Schmidt, Benita S. Katzenellenbogen

Research output: Contribution to journalArticle

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 5α-dihydrotestosterone (DHT) and testosterone (T) in long- and short-acting injection vehicles. Moderate doses of T (300 μ/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 μg CI-628 or U11,100A/day). Uterine growth evoked by 17β-estradiol (3 μg/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 > DIMP > 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.

Original languageEnglish (US)
Pages (from-to)91-108
Number of pages18
JournalMolecular and Cellular Endocrinology
Volume15
Issue number2
DOIs
StatePublished - Aug 1979

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Androgen Antagonists
Androgen Receptors
Progesterone Receptors
Estrogen Receptors
Androgens
Dihydrotestosterone
Estrogen Receptor Modulators
Flutamide
Growth
Nitromifene
Injections
Uterus
Estradiol
Metabolites
Dimethyl Sulfoxide
Testosterone
Rats
Oils
Hormones
Water

Keywords

  • antiandrogens
  • antiestrogens
  • dihydrotestosterone
  • uterus

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

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title = "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 5α-dihydrotestosterone (DHT) and testosterone (T) in long- and short-acting injection vehicles. Moderate doses of T (300 μ/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 μg CI-628 or U11,100A/day). Uterine growth evoked by 17β-estradiol (3 μg/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 > DIMP > 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.",
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T2 - An assessment of androgen interaction with the testosterone- and estrogen-receptor systems and stimulation of uterine growth and progesterone-receptor synthesis

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N2 - 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 5α-dihydrotestosterone (DHT) and testosterone (T) in long- and short-acting injection vehicles. Moderate doses of T (300 μ/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 μg CI-628 or U11,100A/day). Uterine growth evoked by 17β-estradiol (3 μg/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 > DIMP > 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.

AB - 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 5α-dihydrotestosterone (DHT) and testosterone (T) in long- and short-acting injection vehicles. Moderate doses of T (300 μ/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 μg CI-628 or U11,100A/day). Uterine growth evoked by 17β-estradiol (3 μg/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 > DIMP > 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.

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