Digoxin-Estradiol-17β Interaction: A Study of Uteiotropic Effects in Rats

The uterotropic effects of digoxin and concurrent digoxin and estradiol-17P treatments were studied in rats. Digoxin in a low-dose range (10-200 M.g/kg) was found to have weak uterotropic effects at both 6 and 30 hr after injection. The uterotropic activity of digoxin was at best 3% that of estradiol. At a high-dose range (1,000-4,000 l-ig/kg), digoxin had almost no uterotropic effects. The 6-hr uterotropic effects of moderate doses of estradiol were inhibited at both of these 2 vastly different dosages of digoxin. The inhibition observed with digoxin at the low-dose range is thought to represent the end result of hormone receptor competition whereas the inhibition with digoxin at the high-dose range is probably related to the effects of digitalis toxicity on uterine metabolism. It is concluded that digoxin has weak uterotropic activity, that digoxin may compete with estradiol for hormone receptor sites, and that toxic doses of digoxin can inhibit the uterotropic activity of estradiol. {Endocrinology 90: 843, 1972) HPHREE clinical findings in patients taking •*• digitalis—gynecomastia in elderly men ( 1 6), marked cornification of the vaginal squamous epithelium (4), and decreased urinary gonadotropins (5) in postmenopausal women—have suggested that digitalis exerts estrogen-like effects. However, these clinical studies have often been marred by the presence of various diseases and by administration of drugs. Little attention has been given to these observations in the laboratory. Scott and Read (6) reported that digoxin, 2 mg/kg, had uterotropic effects in oophorectomized rats; however, only five rats were given this treatment and no quantitative data were presented. Britsch and Azar (7) reported cornification of vaginal squamous epithelium in mice (18 g median weight) given 0.18 mg of digitoxin in 6 injections over an 18day period. However, only 13 mice, distributed among four different treatment groups, survived this experiment. In both studies, large doses were used. The mechanism of digitalis estrogenicity is unexplored. Chemically, both digoxin and estradiol have a steroid nucleus but digoxin lacks an aromatic A ring (8) (Fig. 1). If digoxin acts as a weak estrogen, it might antagonize the uterotropic effects of a stronger estrogen by competing for binding sites on uterine estrogen receptor proteins (9-11). Since estrogen priming has been Received September 21, 1971. This investigation was supported in part by Research Grant AM-S628 from the National Institutes of Health, Public Health Service. shown to protect dogs and rabbits against digitalis-induced arrhythmias (12,13), such inhibition would be of additional interest in that a similar competition for binding sites could occur in the myocardium The purpose of this study was to verify the estrogenicity of digoxin and to investigate the possible competitive effects between digoxin and estradiol. Materials and Methods Sprague-Dawley female rats, 21-23-days-old (3449 g), were used for these studies. All injections were given sc. Sesame oil was used for estradiol-173 (henceforth referred to as estradiol) injections; isotonic saline was used for digoxin (parenteral Lanoxin, Burroughs Wellcome & Co., Inc.). The digoxin doses ranged from 0.04-160 ng/dose or approximately 10-4,000 ng/kg. Either one injection of digoxin or saline was given or both digoxin and estradiol injections were given within 1 min of each other. The animals were killed at 6 or 30 hr after injection. The 6-hr uterine weight