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

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Author Manuscript Published OnlineFirst on February 24, 2012; DOI: 10.1158/1078-0432.CCR-11-1389 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

REVISION 2 Molecular Pathways: Digoxin use and estrogen-sensitive cancers: risks and possible therapeutic implications

Invited review

Robert J. Biggar Department of Epidemiology Research Statens Serum Institut Copenhagen, Denmark

Running Title: Digoxin and estrogen-sensitive cancer risk

Address for correspondence:

Robert J. Biggar, MD

Department of Epidemiology Research, Statens Serum Institut

Artillerivej 5, 2300 Copenhagen, Denmark

Email: [email protected]

Phone: (45) 3268 3722

The author declares no conflict of interest. The study was a review requiring no ethical approval.

All work is original and not submitted for consideration elsewhere.

Abstract: 199 words; Text: 2,177 words; Tables: 0; Figures: 1; References: 66.

Key words:

Digoxin, digitalis, estrogen, spironolactone, gynecomastia, breast cancer, uterus cancer, endometrial cancer, ovary cancer, ovarian cancer, cervical cancer, prostate cancer, estrogen receptors, tamoxifen, aromatase inhibitors

Key words not in abstract:

Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 24, 2012; DOI: 10.1158/1078-0432.CCR-11-1389 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Endometrial cancer, ovarian cancer, cervical cancer, digitalis, gynecomastia Abstract

Digoxin, a phyto-estrogen, binds with estrogen receptors (ERs) and can cause gynecomastia.

Among women currently using digoxin, breast and uterus cancers incidences are significantly

increased (approximate risk ratios: 1.3 to 1.5). Both cancers are often estrogen-sensitive. In

contrast, ovary and cervix cancers are relatively estrogen-insensitive, and incidence is unaffected

by digoxin exposure. When digoxin use stops, incidence rapidly reverts to that in non-uses.

These patterns parallel those of estrogen, suggesting that digoxin works via ER-stimulated proliferation of ductal/acinar cells, accelerating the growth of nascent cancers. Also consistent

with an estrogenic effect, men using digoxin have a small but significant reduction in prostate

cancer (risk ratio: 0.76). Other estrogen-like drugs, particularly spironolactone, should be

investigated for similar effects. The effect of digoxin use in women being treated for breast

cancer or in survivors is unknown. Women with estrogen-sensitive cancers on adjuvant therapy

may take tamoxifen, which blocks ERs. However, post-menopausal patients may use aromatase

inhibitors, which block estrogen production while leaving ERs susceptible to digoxin. If adverse

effects are found, tamoxifen may be preferred over aromatase inhibitors in patients receiving

estrogen-mimicking drugs. Alternatively, other cardiotropic drugs might be considered in

women with or at high risk of developing estrogen-sensitive cancers.

BACKGROUND

Digitalis, a medicinal extract of the plant foxglove, has a powerful inotropic effect on cardiac

muscle. Chemically, two forms are used as medications in patients with heart disease, digoxin

and, less commonly, digitoxin. Both forms are phyto-estrogens, or plant estrogens. Recent

studies have shown that use of digoxin significantly increases the risk of breast and uterus cancer1-3. Both cancers are often estrogen-sensitive. In contrast, no changes in risk were seen

for two ovary and cervix3 cancers, both relatively estrogen-insensitive.

Chemistry and physiology

The principal effect of digitalis drugs is to inhibit the sodium-potassium pump, which regulates the flux of ions across the cell membrane, calcium being of particular importance in cardiac conditions4. However, the basic structure of digitalis compounds is similar to that of estradiol,

the principal estrogen (Figure 1). Several studies have indicated that digitalis drugs have the

capacity to bind to estrogen receptors (ERs), although with less affinity than estrogen itself5,6.

Stimulation of ERs induces proliferation of ductal and acinar tissue. Thus, it is not surprising that chronic use of digitalis induces gynecomastia in men7,8, just as will estrogen excess in men.

The effect on female breast tissue is likely similar, although enlargement would be less

noticeable.

Estrogen and cancer risk

The vast literature on estrogen use and cancer risks in women is beyond the scope of this review.

Briefly, exogenous estrogens given as menopausal hormone therapy have been documented to

increase the incidence of breast cancer in many studies see reference 9, particularly when given with

progestins10. Generally, breast cancer incidence increases soon after initial exposure remained

above expected levels for the duration of use, possibly increasing slightly over time. However,

when estrogen exposure ceases, the incidence of breast cancer promptly declines as well. This

pattern is consistent with a pathway in which current use of estrogen accelerates the growth of

nascent breast cancers rather than inducing them de novo11. Similarly, for the uterus, both

hyperplasia12 and endometrial cancer incidence13 increase with estrogen use, an effect decreased by including progestins in the formulation of hormone therapy. For ovary cancer, there appears to be a slight increase in risk with estrogen use14-16 but not to the risk ratios seen with breast

cancer. Use seems not to impact cervical cancer risk17.

Digitalis and cancer risk

The potential for digitalis to increase cancer risk was appreciated decades ago. Three studies

specifically examined this hypothesis, all concluding there was no significant increase in risk18-

20. However, in each study, the point estimate of incidence was increased about 30% above non-

users. With hindsight, there was inadequate power to detect low risks with statistical confidence,

given their limited size. In two case-control studies, men with breast cancer were significantly

more likely (2-fold) to use digitalis than expected21,22. These studies ignored or dismissed the

importance of these associations.

Recently, two studies in Denmark re-examined breast cancer risk in women using digoxin1,2, the only digitalis drug in the Danish formulary. Using large datasets, both studies reached similar conclusions: the risk was significantly increased. In a regional case/control study1, women with

breast cancer (N=324 cases) had an odds ratio of 1.30 (95% confidence interval (CI) 1.14-1.48)

for being a current digoxin user compared to non-users (N=2,546). The association was robust

even after adjustment for prior exposure to menopausal hormone therapy and was not

confounded by indications for use of hormonal therapy. In a nationwide cohort, risk was

examined in 2.1 million women (25.5 million person-years of follow-up through 2008;

N=49,016 breast cancers). Digoxin exposure was obtained through a national prescription

database28 initiated in 1995. The breast cancer incidence rate ratio was 1.39 (95% CI: 1.32-1.46)

in women currently using digoxin, compared to exact age- and calendar-year-adjusted non-using

women. Incidence increased within the first year of digoxin use and continued for the duration

of exposure. Risk in continuing users was high in the first year of exposure, and then dropped to

a nadir at 3 years before rising again. Rate ratio for ER+ (1.35) and untested (1.51) breast cancers

were significantly increased, but for ER- breast cancers (1.20), confidence intervals included

unity. In former users, incidence declined significantly below expected levels in the first year

but rose to expected levels thereafter.

The sodium-potassium pump regulates the transport of a variety of products across the cell

membrane4, providing alternative pathways by which digoxin might affect cancer risk. To

evaluate if the digoxin-associated risk was likely mediated through its effect on ERs, the

incidences of cancers of corpus uteri (uterus), ovary and uterine cervix were compared in

digoxin-exposed and never-exposed women3. Uterus cancers are predominately estrogen-

6 sensitive ER+ endometrial cancers, whereas ovarian and cervix cancer are relatively estrogen- insensitive (with uncommon exceptions). The incidence rate ratio of uterus cancers was increased 1.48-fold (95% CI: 1.32-1.65) in current digoxin users. In contrast, risks of ovary and cervix cancers were not increased in current digoxin users (1.06; 0.92-1.22 and 1.00; 0.79-1.25, respectively). Furthermore, the higher risk of uterus cancer decreased when use of digoxin use ended.

Risk factors for uterus cancer23 include obesity, a potentially confounding risk factor because it is shared with cardiovascular disease. However, endometrial cancer risk is decreased in smokers24, and furthermore, no association was seen between uterus cancer and drugs used for angina3, which argues against the digoxin effect being related to shared risk factors for cardiovascular disease. That current digoxin increased the risk of only the estrogen-sensitive 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.

Estrogen retards the growth on prostate cancer. By analogy, so might digoxin. In drug screening, digoxin was found to be among the most potent of commonly used drugs in inhibiting growth of prostate cancer cell lines25. In the same study, the investigators examined risk in men using digoxin, finding a lower prostate cancer incidence (0.76 (95% CI: 0.61–0.95) compared to non-users25. Further studies are needed to confirm this result, but the result is consistent with digoxin exerting an estrogenic effect.

CLINICAL-TRANSLATIONAL ADVANCES

Other estrogen-mimicking drugs

Other common drugs resemble estrogen. Of most interest is spironolactone, a synthetic 17-

lactone steroid used as a potassium-sparing diuretic in patients with heart failure, cirrhosis,

hypertension and primary aldosteronism, often for prolonged periods26. Spironolactone binds to

and inhibits aldosterone receptors but also to ERs6. Functionally, it is an estrogen agonist27, but

it may also interfere with estrogen metabolism28. Gynecomastia is a common side effect,

occurring in 10% with conventional doses and up to 50% with high doses)29-30. In case reports

patients on spironolactone have been reported to have developed breast cancer31-34, but with

common cancers, case reports have limited value. In one small case-control study (N=302

women with breast cancer), no significant association with spironolactone use was observed35.

This finding should be re-examined in a study with more power. Both digoxin and spironolactone may be used together in patients with heart disease, complicating analysis.

However, this possibility also raises the prospect of overlapping stimulatory effects on breast tissue cells and perhaps even higher risks.

One clue to an estrogenic drug effect might be an association of the drug with gynecomastia.

However, gynecomastia may have different causes. Estrogen acts directly on ductal or acinar tissue. Presumably, digoxin and possibly spironolactone act similarly. However, gynecomastia may also occur indirectly, via prolactin release from the pituitary7. Antipsychotic and rauwolfia

drugs can cause gynecomastia by blocking dopamine and alpha-adrenergic receptor sites in the

hypothalamus (e.g., phenothiazine derivatives, and opiate derivatives) or by depleting pituitary

catecholamine (e.g., reserpine)7. In the 1980s, considerable concern was raised about reserpine

and breast cancer risk, but the association was inconclusivee.g.,36. In recent years the risk has

been dismissed as unimportant37 but despite this, reserpine is no longer widely used. A review of neuroleptic drugs found no increase in breast cancer risk38. Chemically, these drugs differ from

estrogen. With pituitary-induced gynecomastia, galactorrhea may occur7, suggesting that

ductal/acinar cells may differentiate further with hypothalamic/pituitary stimulation than with

estrogen, which might affect differentiation and malignant potential. Finally, drugs such as

cimetidine, a commonly used H2-receptor antagonist, and some (but not all) other anti-ulcer

drugs used to control gastric acidity, may interfere with estrogen metabolism39 and chronic use

has been associated with gynecomastia40. However, but two studies found no association

between cimetidine and breast cancer41,42.

Dietary and over-the-counter phyto-estrogen formulations are sometimes taken for menopausal

symptoms. Compared to prescription medications, they are used in much weaker preparations

and often taken only episodically. There is little evidence they are effective as menopausal

therapy43 but also no evidence that they affect breast44 or uterus cancer risk45.

Public health impact

Despite concern about increasing the risk of breast cancer, digital drugs have important roles in

patient care. Any reconsideration of their use would likely conclude that the benefits of digoxin

for heart disease outweigh the cancer risks. Digoxin use is primarily in the elderly, and hence

this discussion largely concerns post-menopausal breast cancer risk in older women. In

approximately 350,000 Danish women > 70 years old, breast and uterus cancer annual

incidences are approximately 350 and 90 per 100,000 per year, respectively (data from the

Danish Cancer Registry46). The higher rate ratios for breast and uterus cancers apply only to

2.2% of these women currently using digoxin (data from the Danish Register of Medicinal

Products Statistics23). Thus, in 100,000 women >70 years old, 2200 women would be current

digoxin users, among whom approximately 11 breast (8 expected, based on non-users) and 3

uterus (2 expected) cancers would be observed. The net cancer increase is therefore about 3

breast and 1 uterus cancer cases per 100,000 elderly women per year. While this is only 1% of

all breast cancers in this age group, women using digoxin remain at increased risk for every year

of digoxin use.

Digoxin use in women with cancer

The above presentation focused on cancer incidence. A further concern is the use of digoxin in

women with a history of estrogen-sensitive cancers. Most physicians consider exogenous

estrogen contraindicated in such patients but an absolute prohibition remains controversiale.g. 47-

48. Digoxin use in women with estrogen-sensitive cancers has not been rigorously examined.

While incidence risk is increased with digoxin exposure, this increase may not translate to risk of

death from breast cancer. Mortality from cancer is similar in women who develop breast cancer

while on estrogens and those not on estrogen49-50. Perhaps better medical surveillance is

provided or possibly the biology of the cancers differs. If digoxin-cancer patterns of mortality

parallel those of estrogen, as might be predicted, there may be no direct impact on mortality from

breast cancer, but even so, having both breast cancer and heart disease is likely to cause

increased mortality overall. Similar considerations likely apply to uterus cancer.

Complicating any analysis will be the use of adjuvant therapy, in particular tamoxifen.

Tamoxifen and other drugs of its type bind to the ER with complex results. They inhibit

attachment of estrogen on ductal and acinar cells51 and thus could also block digoxin effect on

mammary tissue. However, effects of different drugs within this class vary. In particular,

tamoxifen increases the proliferation of endometrial cells and increases the risk of endometrial

cancer and sarcomas of the uterus, whereas other drugs in the same class apparently do not52-53.

In recently years, aromatase inhibitors, a different class of drug, have become widely used in the treatment of post menopausal patients. These agents block estrogen production but leave the

ERs unaffected and without competition by natural estrogens54. Thus, digoxin would have full

license to interact with the ER and stimulate proliferation, assuming its effect is mediated

through ER binding. If digoxin use is shown to affect breast cancer prognosis adversely, then

use of tamoxifen as adjunct therapy might be considered.

In conflict with concern about an increasing risk, some investigators hypothesize digoxin might

benefit women with breast cancer. In vitro, it inhibits cell adhesion or proliferation in breast cancer cell cultures55,56 and several different molecular pathways have been porposede.g,57-58.

One retrospective study (32 women on digoxin with mortality as the outcome) suggested it might

be beneficial59. Regarding cell culture systems, drug doses may be well in excess of those physiologically tolerated by human subjects and hence toxic both to cells and the patient.

However, estrogen itself, at very high doses, can also inhibit breast cancer cell lines in vitro60.

Summary

Current digoxin use increases the incidence of estrogen-dependent breast and uterus cancers, with rate ratios reverting to the null when exposure stops. Since only current use increases the incidence, the mechanism may be that of a promoter, i.e., digoxin enhancing proliferation of nascent tumors rather than inducing new tumors. On theoretical grounds (and anecdotal data), other estrogen-mimicking drugs may have similar effects. Of particular concern are the potassium-sparing diuretics. Despite cancer risks, the use of digital drugs may be medically indicated because their cardiac benefits likely exceed cancer risks. However, the impact of digoxin use on women with active estrogen-sensitive cancers has yet to be evaluated. It is possible that digoxin, and perhaps other estrogen-mimicking drugs, could affect extant breast and uterus cancers adversely. Physicians treating women with existing cancers may wish to consider using alternative therapies, where possible, and should be especially alert to possible breast or uterus cancer symptoms when digoxin use is clinically indicated.

Acknowledgements: Dr. Louise Brinton, National Cancer Institute, Bethesda, MD and Prof.

Niels Kroman, Rigshospitalet, Copenhagen, Denmark provided helpful comments on this manuscript. Support for this paper was provided by the Danish Cancer Society (Kræftens

Bekæmpelse, Grant number R40-A1857-11-S2)) without restriction its contents or any role in the

decision to submit.

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Figure 1. Speculation concerning the pathogenesis by which estrogen and estrogenic compounds might affect estrogen-sensitive tissues, including nascent cancer cells.

Molecular Pathways: Digoxin use and the estrogen-sensitive cancers: risks and possible therapeutic implications

Robert J Biggar

Clin Cancer Res Published OnlineFirst February 24, 2012.

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