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)