Central and Peripheral Action of Estradiol and Catecholestrogens Administered at Low Concentration by Constant Infusion*

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Abstract
Endocrine, behavioral, and biochemical changes were produced in ovariectomized adult rats by administration of estradiol by Alzet minipump infusion and compared with the effects produced by 2-hydroxyestrone, 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2). Variables measured included LH release, lordosis behavior, hypothalamic and hypophysial levels of cytosol progestin receptors, and glucose-6-phosphate dehydrogenase (G6PDH) activity in the uterus and pituitary. An increase in uterine, but not pituitary, G6PDH activity was observed at the lowest rate of estradiol infusion (0.001 μg/h). The critical infusion rate to produce several other effects, including the activation of sexual receptivity and of cytosol progestin receptors, was 0.0025 μg/h. A higher rate of infusion of estradiol (0.01 μg/h) was needed to suppress tonic LH secretion and to induce cyclic LH surges as well as to increase hypophysial G6PDH activity significantly. At this rate of infusion, the serum concentration of estradiol approximated that of intact rats at proestrus. The increase in uterine wet weight and in G6PDH activity observed at an infusion rate of estradiol of 0.001 μg/h and the occurrence of sexual receptivity at 0.0025 μg/h demonstrate the efficacy of this mode of steroid hormone administration. Constant infusions of 2-OHE2 (1 μg/h) or 4-OHE2 (0.1 μg/h) produced similar behavioral and gonadotropin responses in ovariectomized rats as did the 0.01 μg/h infusion of estradiol. However, the activity of uterine G6PDH activity was lower in groups treated with the catecholestrogens than in the group treated with estradiol. Cell nuclear estrogen receptor occupation was also assessed for each of these treatments in limbic brain, pituitary, and uterus. Estradiol, 2-OHE2, and 4-OHE2 all produced comparable levels of estrogen receptor occupation in all three tissues when given at doses indicated above. In contrast, infusions of 2-hydroxyestrone at 1 μg/h had little influence on behavior, gonadotropin release, uterine growth, and G6PDH activity. Furthermore, this catecholestrogen failed to elevate cell nuclear estrogen receptor occupation above control levels in these tissues. These results demonstrate the efficacy of low doses of estradiol and its 2- and 4-hydroxylated derivatives infused by osmotic minipumps. They also show that peripherally administered catecholestrogens or their metabolites reach target tissues and are translocated to the nucleus like estradiol. Finally, the observations that similar levels of nuclear estrogen receptor occupation produced by estradiol, 2-OHE2, and 4-OHE2 infusions give similar behavioral and neuroendocrine responses argue in favor of a similar mode of action of these three steroids. (Endocrinology108: 1848, 1981)