RU 16117, an orally active estriol-like weak estrogen

RU 16117, the 11 alpha-methoxy derivative of ethynyl estradiol, is an orally active weak estrogen potentially effective in the treatment of estrogen-deficiency in postmenopausal women (climacteric symptoms and severe osteoporosis). Biochemical studies have shown that RU 16117, like estriol, possesses the properties characteristic of a partial estrogen agonist/antagonist. RU 16117 binds to the cytosol estrogen receptor (ER) to form a complex which dissociates much faster than the estradiol complex. This explains its lower nuclear uptake. Furthermore, the nuclear RU 16117 complex also dissociates faster than the estradiol complex. Consequently, although low doses of RU 16117 can induce the majority of the effects of estradiol (increased polymerase A and B activities, cytosol ER replenishment, progestin receptor induction, increased uterine weight), these effects are long-lived only if the dose is considerably increased or if the compound is administered repeatedly or continuously. Since RU 16117 transiently occupies available estrogen binding sites, it can prevent the full response of estradiol. Thus, under appropriate kinetic conditions, it acts as an estrogen antagonist on the above parameters and also on DMBA-induced mammary tumors in the rat. At a daily dose of 24 micrograms for a period of 4 weeks RU 16117 led to 65% reduction in the number of already-established tumors. RU 16117 inhibits basal gonadotropin secretion and decreases the LH response to LHRH. Injection of 5 micrograms s.c. to the rat in estrus markedly inhibited the spontaneous peaks of LH, FSH and PRL measured on the afternoon of expected proestrus. Low doses which block ovulation by 100% had no detectable effect on vaginal cornification, thus suggesting a greater sensitivity at the hypothalamo-pituitary level.(ABSTRACT TRUNCATED AT 400 WORDS)