Drugs That Can Cause Gynecomastia

In you're male, and are unfamiliar with the term gynecomastia, it might be time for you to make its acquaintance.

Glenn Braunstein, chairman of medicine at Cedars-Sinai Medical Center in Los Angeles and author of a 2007 article on the condition in the New England Journal of Medicine titled, rather unsurprisingly, "Gynecomastia," said that almost 50% of men will experience the disorder in their lives. [To avoid undue anxiety, let me say here and now that this is not a dangerous condition, and a number of studies suggest it will eventually resolve on its own in up to 80% of the cases, depending on cause.]

Just to get the terminology down: Gyne refers to female and mastia the breast. Gynecomastia (enlarged male breasts) is a disease that affects men, involving excess growth of the tissue in the male breast.

It results from an imbalance between androgen, a male sex hormone, such as testosterone, and the female hormone, estrogen. Estrogen is the hormone responsible for stimulating female sexual characteristics. In an imbalance between the sex hormones with estrogen predominating, men will develop breasts.

There are natural and disease-related causes, from weight gain to tumors to kidney disease or thyroid dysfunction. More germane to our topic is a less well-known cause--a side effect of certain drugs.  Medication-induced gynecomastia may account for as much as  20% to 25% of the incidences (Benbo & Carlson 2004).

Certain classes of medications pose a higher risk than others.

Antibiotics

A number of antibiotics--although by no means all--can cause gynecomastia. Some antibiotics, such as ketoconazole (Nizoral, Nizoral, Extina, Xolegel) and metronidazole (Flagyl) both work to inhibit the production of testosterone.

Although gynecomastia is generally rare in response to anti-tuberculosis treatments, two drugs have been associated with it.

A case report of a 38-year-old man who developed painful gynecomastia in response to ethionamide (Trecator) was published just this year. When the drug was stopped the growth was reversed, but when it was reintroduced, the gynecomastia reappeared.

Additionally, Isoniazid (Niazid), an antibiotic used to fight tuberculosis, has appeared several times in the clinical research in relation to gynecomastia, beginning as early as a report from France published in 1953 (see for example Lee et al 2009, Garg 2009, Monsoor et al 2009). Despite the fact that each case resolved itself upon stopping the medication, scientists still do not know the mechanism by which isoniazid causes male breast enlargement.

Treatments for prostate cancer

Anti-androgens, or drugs that inhibit the production of androgens, are often used to treat prostate enlargement or cancer. It is these androgens that create male characteristics, like muscle size, deep voice, or hair growth.

Hormonal antiandrogen therapy for prostate cancer is a serious risk factor for gynecomastia. The theory behind prostate cancer treatments is that testosterone stimulates the growth of the cancerous cells. Therefore, of necessity, the goal in treating this cancer with hormone treatments is to decrease the amount of androgens in the system, blocking their effects on the cancerous growth. In doing so, however, they decrease the overall amount of effective male hormone in the system.

The antiandrogen therapy includes in its mix estrogens (diethylstilbestrol), nonsteroidal antiandrogens (bicalutamide [Casodex], flutamide [Eulexin]), and steroidal antiandrogens (e.g. cyproterone [Androcur and Cyprostat]).Cyproterone and flutamide both block androgen production in peripheral tissues. Together with the added estrogen, this brew wreaks enough havoc hormonally that up to 50% of men receiving it develop gynecomastia (Dobs & Darkes 2005). In fact, two outlier studies found 79% of participants developed male breasts, in one case in response to flutamide (Chang et al 1996), and the other in response to nilutamide (Nilandron) (Decensi et al 1991). Most studies of prostate cancer treatments reported significantly lower incidences, however.

Proton pump inhibitors

Proton pump inhibitors reduce the secretion of stomach acid and are therefore used to treat gastric reflux disease and ulcers. A number of them have male breast development as an adverse side effect.

Well-known anti-ulcer drugs cimetidine (Tagamet), ranitidine (Zantac), misoprostol (Cytotec) and omeprazole (Prilosec) have all been documented to cause gynecomastia.

Researchers Luis Alberto Garcia Rodriguez and Hershel Jick, affiliated with the Boston Collaborative Drug Surveillance of Program at Boston University Medical Centre, studied 81,535 men between the ages of 25-84 years who took at least one of the anti-ulcers during the study period.

They found that the relative risk of users of cimetedine to non-users for developing the symptom was 7.2, 2.0 for misoprostol, a low 0.6 for omeprazole, and 2.6 for ranitidine. Men who took over 1000 mg a day of cimetedine had over 40 times the risk of developing gynecomastia compared with non-users.

All four of the medications stimulate the pituitary to secrete more prolactin, which is the hormone stimulating milk production--along with breast development--in women. Prolactin is additionally responsible for causing hypogonadism, where the testes produce little or no testosterone. It is a one-two punch.

Certain psychiatric medications

Certain antipsychotics, antidepressants, and anti-anxiety medications cause gynecomastia, although the mechanisms are not certain.

Antipsychotics block dopamine, that famous neurotransmitter involved in regulating the brain's reward and pleasure centers. Dopamine also plays an important role in sexual function.  It is already believed that by blocking the dopamine, the antipsychotics are responsible for a decrease in sex drive. At one and the same time, though, they lead to increased prolactin from the pituitary, which, again, leads to breast development.

Particular offenders in increasing prolactin levels are older antipsychotic haloperidol (Haldol) and new atypical antipsychotic risperidone (Risperdal), while most of the other second-generation antipsychotics (Seroquel, Abilify, Clozaril, Geodon) have a smaller effect.

Tricyclic antidepressants, more in fashion before the Prozac heralded the arrival of the SSRIs, can also cause male breast growth. It is believed that they, too, stimulate prolactin production.

Even anti-anxiety medications, particularly diazepam (best known as Valium) pose a risk factor. Gynecomastia is believed to result from a change in the balance between testosterone and estrogen hormone, although in many incidences the exact mechanism stimulating this imbalance are unclear (Jelenkovic & Macukanovic-Golubovic 2005). (See also Moerck & Magelund 1979, Bergman et al 1981, Llop 1994.)

Cardiac and antihypertensive agents

Antihypertensives are drugs that reduce high blood pressure, or hypertension.

Calcium channel blockers are the most common culprits among the antihypertensives in causing gynecomastia.

Calcium channel blockers prevent calcium from entering cells of the heart and blood vessel walls, resulting in lower blood pressure.

It is not fully known how the blockers induce the growth, except in the case of verapamil (Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Covera-HS), which has been reported to cause increased production of the hormone prolactin from the pituitary, with the resulting hypogonadism and breast development.

By 1988, the U.S. Food and Drug Administration had already received 31 reports of gynecomastia occurring after the use of calcium channel blockers.

Cardiac drug Dixogin (Digitalis), used to treat congestive heart failure and heart rhythm problems, actually mimics the action of estrogen, thereby encouraging breast growth.

ACE inhibitors are used for high blood pressure or congestive heart failure.  They widen the blood vessels, which increases blood flow, and decreases the amount of effort the heart needs to exert to pump blood through the body.

ACE inhibitors like captopril (Capoten), epleronone (Inspra) and enalapril (Vasotec) disrupt the balance of the sex hormones.

In 1988 Drs. HM Markusse and RH Meyboom reported the first documented case of gynecomastia associated with captopril. Seven months after initiating treatment the man developed a painful gynecomastia on his left side, and, upon discontinuation, both the pain and the enlargement disappeared within weeks.

In a 2003 study comparing the effectiveness of enalapril with epleronone for blood pressure control, one case of gynecomastia (2.5%) was reported due to eplerenone, and one (2.2%) to an eplerenone/analapril combination.

Despite this tendency on the part of eplerenone, Dr. Nancy J. Brown, from Vanderbilt University Medical Center, Nashville, TN, found in her study on the drug's safety and efficacy in patients with congestive heart failure, that eplerenone's tendency to cause gynecomastia was far less than that of antiandrogen drug, spironolactone (Aldactone), used to treat fluid retention in patients with congestive heart failure.

She found that "[r]ates of sex hormone–related side effects appear to be lower during treatment with eplerenone than with treatment with spironolactone. In controlled trials lasting 6 months or longer, the rates of gynecomastia. . . were 0.7%. . . By comparison, the rate of gynecomastia or mastodynia in men in the RALES trial, in which the mean time of follow-up was 24 months, was 10% and the rate of gynecomastia in men with essential hypertension treated with spironolactone has been reported as 6.9%."

Used to treat high blood pressure, spironolactone doesn't just work within the system to block the effect of androgens; it blocks the production of testosterone at the source, as well, thus doubling the ways in which gynecomastia might occur.

Finally, amiodarone (Cordarone, Pacerone) is used to treat life-threatening heart arrhythmias. Anontelli (1986) published a paper entirely devoted to the correlation between the drug and the the condition. Breast tissue growth is mentioned numerous times in connection with amiodarone throughout other literature on medication-caused gynecomastia.

A paper in the Cleveland Journal of Medicine in 2004 asserts clearly that amiodarone is associated with gynecomastia--but lists its mechanism for eliciting the symptom as "unknown."

HAART (highly active antiretroviral therapy)

HAART is a treatment for HIV involving a combination of anti-HIV drugs that decrease the amount of the HIV virus inside the patient's bloodstream.

Research has consistently found it to be a risk factor for gynecomastia.

Bernard M. Karnath, MD, associate professor of medicine, Department of Internal Medicine, University of Texas Medical Branch at Galveston, TX, wrote in his 2008 article, "Gynecomastia" of a study of 1304 HIV-infected men receiving HAART. In it 2.3% developed gynecomastia--but almost 75% of the causes resolved without treatment within the course of a year.

In a 2001 case summary of four HIV-infected patients taking HAART, the researchers found gynecomastia generally occurred three to seven months after the start of the regimen.

Combivir, one of the components of the HAART cocktail, has had many occurrences of gynecomastia as an adverse effect reported by users.

Roberto Manfredi and Leonardo Calza, doctors of infectious disease at the University of Bologna, studied nearly 1000 HIV patients, and determined, after observing the rates of development of gynecomastia, that "Gynecomastia is probably an underestimated problem in the setting of HAART."

Chemotherapy drugs

95% of a male's testosterone is produced in the testes by the Leydig cells.

Chemotherapy drugs, however, often do their work by killing off tumor cells--and a portion of healthy cells in the process (hence its name, cyto[cell]-toxic therapy). Chemotherapy causes Leydig cell damage, which leads to hypogonadism (where the sex glands produce few or no hormones).

A 1983 study followed 96 patients receiving chemotherapy for testicular cancer. Gynecomastia—accompanied by pain in the breasts--developed in 8% of the patients between 6 and 24 weeks after initiation of treatment. What was unusual in this case was that researchers found that survival rates were better for those who developed gynecomastia than for those who did not. In fact, they conclude, although "[g]ynecomastia may occur in adult males after cytotoxic therapy for testis cancer; such gynecomastia . . .may be a favorable prognostic sign."

Even beyond the chemotherapy itself, the treatment for the treatment can cause trouble. The strongest oral steroid avaialble, oxymetholone (Anadrol-50) is used to treat the anemia that results from the chemotherapy. Anadrol's own website writes, "Oxymetholone has been reported to produce gynecomastia in approx 50 % of it's [sic] users." The compound oxymetholone easily converts into estrogen inside the body, yielding a number of feminizing characteristics--among them, male breasts.

Aside from its usage with cancer patients, Anadrol is a commonly abused steroid for athletes, particularly body-builders. It is perhaps even more ironic then, that it is just these users who found their own 'antidote' for male breast growth--yet another cancer drug.

Tamoxifen (Nolvadex) is used with breast cancer patients, since it blocks estrogen receptors and prevents the estrogen from binding in the body. This same action will counteract the increase in body estrogen caused by oxymetholone and the subsequent breast development.

Others

Some additional drugs are known to cause gynecomastia, although the mechanism isn't always clear.

For example, in a well-meaning but misguided attempt to disinfect the surroundings of the Hatiain refugees in U.S. detention centers in 1981-2,  phenothrin (Sumithrin), a component of delousing agents, was a powerful enough antiandrogenic that it caused an outbreak of gynecomastia among the refugees.

Theophylline (Aerolate) is a drug used for asthma and COPD. A 1984 paper (Dardick) with a case study of the correlation between the drug and gynecomastia appears to be the first in the published literature, but others followed, including a thorough 2005 paper completely dedicated to the correlation by Vacque et al. Unfortunately for our purposes, it's in Spanish.

Finally, griseofulvin (Fulvicin) used to treat fungal skin infections like jock itch, athlete's foot, and ringworm, can also inhibit an enzyme that in turn inhibits production of androgen.

In almost all the cases discussed, the situation resolved itself once the offending medication was removed.  If that fails, because it is not a dangerous symptom, many men are content to let it be. However, if they have pain, or are psychologically discomfited by their larger breasts, men may turn to other avenues. There are no FDA-approved treatments for gynecomastia, but, as mentioned, tamoxifen has been found to be helpful. Others have tried testosterone therapy with moderate success. In the most extreme cases, men will elect to have breast reduction surgery.