Temporal relationships between hormone receptor binding and biological responses inthe uterus: Studies with short- and long-acting derivatives of estriol

The temporal relationships between hormone receptor binding and early and late biological responses in the uterus were examined using estriol (E₃), a weak estrogen, and several morelong acting estriol derivatives, namely ethinyl estriol (EE₃) (estriol cyclopentyl ether (E₃CPE), and ethinyl estriol)cyclopentyl ether (EE₃CPE). Dose-response curves) of 3‐day uterotrophic assays indicate that biological potency follows the order EE₃CPE (EE3 or estradiol) E₃ CPE > E₃ After a single injection of 5 μg of compound, E₃ elicits the early uterotrophic responses (increased uterine wet weight and 2‐deoxyglucose phosphorylation at 2‐6 h) but gives only weak stimulation of later uterotrophic responses (enhanced rates of 2‐deoxyglucose phosphorylation at 20‐24 h and increased DNA synthesis rate and uterine weight (over a 72 h period). E₃, EE₃ and estradiol all elicit a rapid (maximal by 1/2ȁ1 h) uptake of receptor into the nucleus and show an equivalent wet weight response at 3 h. After E₃ nuclear receptor levels and uterine weight decline rapidly; however, after (EE)3 estradiol, nuclear receptor levels decline less rapidly remaining at least two-fold above the control until 24ȁ48 h, and uterine weight also remains elevated for at least 48ȁ72 h. EE3 CPE elicits both the early (4 h) and later (20‐24 h) waves ofglucose metabolism, shows a prolonged effect on DNA synthesis rate, and shows the most dramatic andprolonged (beyond 72 h) maintenance of elevated uterine weight and high nuclear receptor (beyond 24 h).