Estrogen agonistic and antagonistic action of 8 non-steroidal antiestrogens on progestin receptor induction in rat pituitary gland and uterus.

All 8 non-steroidal antiestrogens tested considerably increased progestin receptor concentration in the uterus and, to a lesser extent, in the pituitary of ovariectomized rats. However, the pituitary was more sensitive than the uterus to the estrogen antagonistic action of these compounds, in that monohydroxytamoxifen, LY 117,018, enclomiphene, nitromifen, nafoxidine and trans-tamoxifen completely blocked progestin receptor induction by estradiol benzoate. In these tissues the order of the in vitro binding affinity of antiestrogens to cytoplasmic estrogen receptors was not correlated with either their in vivo estrogen agonistic or antagonistic potency.

Estrogen induction of progestin receptors in pituitary, hypothalamic and uterine cytosol of androgenized female rats.

Female rats treated neonatally with a single dose (1.25 mg/animal) of testosterone propionate and ovariectomized when adult did not respond to a priming dose (20 micrograms/animal) of estradiol-17 beta 3-benzoate and subsequent application of progesterone (2.5 mg/animal) 72 h later with an afternoon surge of luteinizing hormone, which could be induced by the same hormonal regimen in neonatally oil-treated long-term ovariectomized female rats. However, both treatment groups responded equally well to the estrogen stimulus with an increase in cytosolic progestin receptors in hypothalamic and pituitary, as well as uterine tissue. It therefore seems unlikely that the observed loss of sensitivity of the gonadotropin release mechanism in neonatally androgenized, estrogen-primed female rats to a progesterone stimulus can be explained by a loss of progestin receptor induction capacity of estrogen/progestin target tissues involved in gonadotropin secretion.

Induction of cytosolic progestin binding sites by catecholestrogens in rat pituitary gland and uterus: different potencies of 2- and 4-hydroxyestradiol.

The ability of catecholestrogens to induce cytosolic progestin binding sites in the hypothalamus, pituitary gland, and uterus of ovariectomised-adrenalectomised rats was demonstrated by the increase in high-affinity [3H]promegestone binding sites (KD 1.39, 0.50, and 0.54 nM, respectively) following a single subcutaneous injection (26.4 micrograms/animal) of the 3.4-dibenzoate ester of 4-hydroxyestradiol. The affinity and the time course of induction of these binding sites were very similar to those after a single injection of an equivalent dose (20 micrograms/animal) of estradiol 3-benzoate, exhibiting maximal receptor levels after 44 h. Widely differing efficacies in the induction of progestin binding sites were observed between the dibenzoate esters of 2- and 4-hydroxyestradiol. 2-Hydroxyestradiol 2,3-dibenzoate was ineffective in the pituitary gland up to a dose of 132 micrograms/animal, whereas 4-hydroxyestradiol dibenzoate was equipotent to estradiol benzoate, showing a maximal induction of progestin binding sites at single doses in the range of 13.2-26.4 micrograms/animal (equivalent to 10-20 micrograms of estradiol benzoate). As compared to the pituitary gland, the uterus was much more sensitive to the systemic administration of estrogen benzoates. At single doses in the range of 1.32-6.6 micrograms/animal (equivalent to 1-5 micrograms of estradiol benzoate), 4-hydroxyestradiol dibenzoate induced maximal levels of progestin receptors, and even 2-hydroxyestradiol dibenzoate, when given at a high dose (132.4 micrograms/animal, equivalent to 100 micrograms of estradiol benzoate), produced a slight increase in progestin binding sites.

Estrogen responsiveness of progestin receptor induction in the pituitary, preoptic-hypothalamic brain and uterus of neonatally estrogenized female rats.

Female rats were defeminized by neonatal treatment with estradiol-17beta benzoate, moxestrol (RU 2858), monohydroxytamoxifen ICI 79,280) or the dibenzoate esters of the catecholestrogens, 2-hydroxyestradiol-17beta and 4-hydroxyestradiol-17beta. When ovariectomized as adults and primed with estradiol-17beta benzoate all these rats demonstrated a deficient luteinizing hormone response to progesterone administration. However, estrogen responsiveness of progestin receptor induction was unimpaired in both the pituitary gland, the preoptic-hypothalamic brain and the uterus.