Digoxin use and the risk of cancers of the corpus uteri, ovary and cervix

Abstract

Digoxin is a phyto-estrogen capable of inducing hormonal effects. Use has been associated with increased risk of breast cancer, an estrogen-sensitive malignancy. The incidence of corpus uteri (uterus) cancer is also strongly increased with exposure to estrogens. Therefore, we evaluated whether digoxin use might also increase its incidence. In all women in Denmark, we identified digoxin users from 1995 through 2008 using a nationwide pharmacy registry system. Cancer occurrence was obtained from Danish Cancer Registry. Relative risk was determined using incidence risk ratios (RR) and 95% confidence intervals (CIs) relative to non-users after adjustment for age-and calendar-time. For ovarian and cervical cancers, RRs in users and non-users were similarly evaluated, these cancers representing gynecological cancers with weak or no associations to estrogen exposure. Of 2.1 million women, 104,648 (4.9%) had digoxin exposure and 137,493 6.5% had exposure to angina drugs but not digoxin during the study period. For uterus cancer, the RR was increased in current digoxin users (1.48, 95% CI: 1.32-1.65; N 5 350). Incidence was marginally increased in former users. For ovary and cervix cancers, RRs in current digoxin users were 1.06 (95% CI: 0.92-1.22; N 5 207) and 1.00 (95% CI: 0.79-1.25; N 5 81), respectively. We examined risks in women using angina drugs but not digoxin to determine whether being under cardiac care affected risk. Among women using angina drugs only, RRs for uterus, ovary or cervix cancers were not statistically significant. We conclude that women currently using digoxin, a phyto-estrogen, have an increased risk of developing uterus cancers.Digoxin is an inotropic drug widely used in the management of cardiac problems, especially in the elderly. While its principal effect is on the Na þ K þ pump, 1 it is a phyto-estrogen capable of binding to estrogen receptors. 2,3 Recent studies in Denmark have found that breast cancer risk is increased about 30-40% in women currently using digoxin, 4,5 the effect being greatest on estrogen receptor positive cancers. 5 Risk of cancer of the corpus uteri (endometrium) is also increased by exogenous estrogen exposure when exposure is not opposed by progestins. [6][7][8] We hypothesized that the risk of this cancer would be increased in current digoxin users, analogous to its effects in breast cancer. Finding risk to be increased would have important clinical implications for the use of digoxin in women. It would also add further evidence that the mechanism by which digoxin affects cancer risk is likely attributable to the estrogenic effect of digoxin.To examine the hypothesis, we examined relative risks of three gynecological cancers in users of digoxin: cancer of the corpus uteri (hereafter called uterus cancer) to those of ovary and uterine cervix (hereafter called cervix) cancers. These three cancers were chosen as study end points because they are reasonably common and all are related to reproductive organs. In contrast to uterus cancer, neither ovary nor cervix cancer...

Digoxin use and risk of invasive breast cancer: evidence from the Nurses’ Health Study and meta-analysis

“…Furthermore, digoxin is associated with higher incidence of male breast cancer [42, 43], and lower incidence of prostate cancer [44], both of which are consistent with estrogenic effects on the respective tissues of origin [45, 46]. Perhaps the most compelling evidence comes from another Danish study, which showed a positive association between digoxin use and incidence of uterine cancer (an estrogen-sensitive malignancy), but null associations with incident cancers of the ovary and cervix (which are not strongly affected by estrogen) [47]. …”

Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

“…Risk factors for uterus cancer include obesity (24), a potentially confounding risk factor because it is shared with cardiovascular disease. However, endometrial cancer risk is decreased in smokers (24), and furthermore, no association was seen between uterus cancer and drugs used for angina (3), which argues against the digoxin effect being related to shared risk factors for cardiovascular disease. That current digoxin increased the risk of only the estrogensensitive cancers of the breast and uterus, both approximately 1.3-to 1.5-fold, but not ovary or cervix cancer, supports a mechanism mediated by its effect on the ERs.…”

“…Both forms are phyto-estrogens, or plant estrogens. Recent studies have shown that use of digoxin significantly increases the risk of breast and uterus cancer (1)(2)(3). Both cancers are often estrogen sensitive.…”

Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

“…Early animal studies indicate that digoxin may bind to estrogen receptors (ER) [1] and have estrogenic effects. In support of this digoxin is a recognized cause of gynecomastia [3], and digoxin use has been associated with increased risk of estrogen-sensitive cancers such as uterus cancer [4].…”