Male mammal glandular tissue, under particular conditions, can proliferate and increase in volume. This phenomenon - benign and generally reversible - is named gynecomastia (from greek gyné, woman, and mastós breast).
Gynecomastia feels to touch like a rubbery mass extending concentrically under the areola and can affect one mammary gland only or both. This more or less pronounced volume-increase of the mammary glandular tissue can be associated with discomfort or pain. Sometimes adipose tissue accumulation at breast level can be mistaken for real gynecomastia. This condition, particularly frequent in overweight subjects, takes the name of pseudo-gynecomastia. Often gynecomastia and pseudo-gynecomastia are both present in the same subject at the same time.
Despite not being a health-threatening condition, gynecomastia can cause psychological distress due to physical-appearance alterations.
Etiology and pathogenesis
Mammary glandular tissue proliferation is physiologically stimulated by oestrogens and inhibited by androgens. Therefore, gynecomastia is generally caused by increased ratio of free-circulating oestrogens/androgens or altered effects of these hormones on their correspondent intracellular receptors in the mammary tissue.
The majority of gynecomastia cases are physiological in nature (neonatal, pubertal and senile gynecomastia). Sometimes gynecomastia can be idiopathic (about 25% of cases)1 or, more rarely, secondary to pathologies influencing the levels of circulating sexual hormones (i.e. testicular or adrenal neoplasias, hepatic cirrhosis, hyperthyroidism, hypogonadism, obesity, refeeding syndrome).2 In the end, a consistent part of gynecomastia cases, around 20%, is iatrogenic.1
Many drugs can cause gynecomastia (see Table 1) as much as several active principles, which have been associated to this condition.3 The active principles known for most frequently causing gynecomastia are exogenous oestrogens, anti-androgens, 5 alpha-reductase inhibitors, spironolactone and cimetidine.
Antiandrogens (such as bicalutamide and flutamide) can cause gynecomastia by antagonist action to testosterone and dihydrotestosterone on mammary glands. Besides – since endogenous androgens inhibit the negative feedback mechanism on the hypothalamus-pituitary-gonad axis – antiandrogens increase the levels of circulating testosterone which is converted at peripheral level into estradiol, therefore enhancing the oestrogen/androgen ratio. Usually gynecomastia appears during the first year of antiandrogens therapy for 40-70% of patients on long-term treatment.4
On the other hand, 5 alpha-reductase inhibitors (such as finasteride and dutasteride) act by preventing the conversion of testosterone into dihydrotestosterone. Consequently, the not-converted circulating testosterone is transformed into estradiol by aromatase and raises the oestrogens/androgens ratio. Gynecomastia risk then increases of 1-2% for treated patients.
Spironolactone, an aldosterone antagonist used for high blood pressure treatment, presents both anti-androgenic and oestrogenic activities. This drug can induce gynecomastia after one month only of treatment, with a dose-dependent incidence.3
Among the H2 histamine receptor blockers, cimetidine seems to be the active principle that most frequently can cause gynecomastia: a retrospective epidemiological study suggests a relative risk >7 for treated patients, strongly dose-dependent.
Other examples of drugs that can cause gynecomastia are protease inhibitors for antiretroviral therapy (such as saquinavir or lopinavir), antipsychotic (like haloperidol), several chemotherapy drugs (such as methotrexate or ciclophosfamide) and natural products which contain phytoestrogens (for example soya milk).4
The National Pharmacovigilance Network reports
Among the ADR reports collected by National Pharmacovigilance Network to date 31st December 2012, the majority of gynecomastia cases are due to drugs already known for causing this side effect (bicalutamide, dutasteride, flutamide, finasteride and the association furosemide/spironolactone). Periodically monitoring the Network, however, the Work Group for the analysis of signals (established by the Italian Medicines Agency) has identified gynecomastia cases associated to two drugs never linked before to the condition or not much documented yet: rosuvastatin and tamsulosin (respectively 4 and 7 reports).6
A deeper analysis has shown that gynecomastia is a rare adverse effect probably correlated to all HMG-CoA reductase inhibitors (i.e. statins). For tamsulosin, on the other hand, the effects on sexual hormones are unknown yet, as there are no other published cases. Signals from passive surveillance systems are not definitive proofs of cause-effect relationship between drug and event, but are useful instruments for early alerts on possible safety issues of commercialized drugs.
What to do in case of gynecomastia
In case of suspected drug-induced gynecomastia, it would be opportune considering a therapy discontinuation. In some cases, it could be helpful reducing the doses or substituting the suspected drug with another one belonging to the same class, but with a weaker association to gynecomastia.3
Mammography scan allows distinguishing with certainty between gynecomastia and pseudogynecomastia. On the other hand, laboratory tests are necessary for identifying other possible causes, checking the renal, hepatic and thyroid functions and the free-circulating hormones levels.2
Iatrogenic gynecomastia is generally reversible within 6 months or one year since its onset. If drug discontinuation is not enough or not possible (for example with anti-androgens), a therapy based on tamoxifene (20 mg daily) might be taken into consideration. In fact, despite not being approved for this indication, literature data suggest a response rate of 50-80% of cases, with detectable improvements from the first month of treatment.3 In the rare eventuality of both drug dechallenge and tamoxifene therapy being unsuccessful, it is possible to resort to surgery or radiotherapy, according to the patient’s needs.
Table 1 – List of drugs that can cause gynecomastia
|Drugs frequently causing gynecomastia1|
|Antiandrogens||Bicalutamide, flutamide, finasteride, dutasteride|
|Antiretroviral||Protease inhibitors (saquinavir, indinavir, nelfinavir, ritonavir, lopinavir), reverse transcriptase inhibitors (stavudine, zidovudine, lamivudine)|
|Environmental exposure||Phenothrin (antiparasitical)|
|Exogenous hormones||Oestrogens, prednisone (male teenagers)|
|Gastrointestinal drugs||H2 histamine receptor blockers (cimetidine)|
|Drugs possibly causing gynecomastia1|
|Antifungal||Ketoconazole (prolonged oral use)|
|Antihypertensive||Calcium channel blockers (amlodipine, diltiazem, felodipine, nifedipine, verapamil)|
|Antipsychotic (first generation)||Haloperidol, olanzapine, paliperidone (high doses), risperidone (high doses), ziprasidone|
|Chemotherapy drugs||Methotrexate, cyclophosphamide, carmustine, etoposide, cytarabine, melphalan, bleomycin, cisplatin, vincristine, procarbazine|
|Exogenous hormones||Androgens (athletes abuse)|
|Gastrointestinal drugs||Proton pump inhibitors (omeprazole)|
|Cardiovascular drugs||Phytoestrogens (soya-based products, high quantity)|
|Drugs rarely or very unlikely causing gynecomastia1|
|Miscellany||Amiodarone, amphetamine, aripiprazole, atorvastatin, captopril, cetirizine, clonidine, cyproterone acetate, dasatinib, diazepam, diethylstilbestrol, digoxin, domperidone, entecavir, ethanol, fenofibrate, fluoxetine, gabapentin, heroin, imatinib, lisinopril, loratadine, marijuana, methadone, metronidazole, misoprostol, MyTosterone®, paroxetine, penicillamine, phthalates, pravastatin, pregabalin, ranitidine, rosuvastatin, sulindac, sulpiride, sunitinib, theophylline, venlafaxine|
|Data from the National Pharmacovigilance Network (reports)2|
|Bicalutamide (44), dutasteride (31), flutamide (28), finasteride (26), furosemide/spironolactone (21), ranitidine (15), potassium (14), spironolactone (14), domperidone (12), lansoprazole (11), omeprazole (9), esomeprazole (7), tamsulosin (7), canrenone (6), risperidone (6), atorvastatin (5), rosuvastatin (4)|
|1 Contents adapted from Pharmacotherapy 2012;32:1123-40|
2 Drugs reported as suspected gynecomastia cause from at least 4 times. Active principles are listed by decreasing number of reports (in brackets). Data updated to 31/12/2012
CreVIF, Regional Centre for Drugs Evaluation and Information, Medical Sciences Dept,
Clinical and Experimental Pharmacology Unit, University of Bologna