Androgen-Uterine Interaction: Nuclear Translocation of the Estrogen Receptor and Induction of the Synthesis of the Uterine-Induced Protein (IP) by High Concentrations of Androgens in Vitro but not in Vivo

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Abstract
High concentration of androgens in vitro [10-6 and 10-7 M 5.alpha.-dihydrotestosterone (DHT) and testosterone (T)] translocate the estrogen receptor from the cytoplasmic to the nuclear fraction of the immature rat uterus, and the androgen translocated sites are capable of eliciting the synthesis of the specific uterine induced protein (IP), formerly attributed to estrogenic compounds only. The magnitude of receptor translocation and IP synthesis induction is related to the concentration of androgen, and, at equal concentrations, DHT is more effective than T. Competitive protein-binding assays with cell-free uterine cytosol indicate that DHT and T bind with barely detectable affinity to the cytosol estrogen receptor [relative binding ability about 0.001% that of estradiol (E2)] and radioactive E2 uptake into whole uterus after pretreatment with androgens indicates that the androgen-translocated nuclear sites are readily filled by E2. DHT and T translocate the estrogen receptor to the nucleus in vitro, and the salt-extracted nuclear receptor is present as a 5 S (transformed) receptor; concentrations of DHT and T that effect translocation are unable to elicit the heat-activated transformation of the estrogen receptor in cell-free cytosol under conditions in which low concentrations of E2 fully transform the receptor. Under in vivo conditions, high levels of androgens (5-2000 .mu.g DHT or T) do not evoke any detectable translocation of the estrogen receptor and do not elicit any IP synthesis induction although uterine weight is increased (> 200 .mu.g androgen) in long-term (2-3 day) assays. The analysis of androgen uptake and metabolism indicates that 500 .mu.g or higher doses of DHT or T in vivo result in uterine concentrations of unmetabolized DHT or T equal to those seen after exposure to 5 .times. 10-7-1 .times. 10-6 M DHT or T in vitro. Under conditions where in vivo and in vitro tissue uptake of androgen is equivalent, in vivo androgens are unable to affect the estrogen receptor system as is seen in vitro. The in vitro and in vivo effects of androgens on the uterus probably are clearly different, and the action of androgens on the uterus in vivo are probably not directly mediated through the estrogen receptor system.