PRACTICE RECOMMENDATIONS
• Examine enlarged male breasts to differentiate between true gynecomastia and pseudogynecomastia (seen with obesity) or a mass suggestive of tumor activity. C
• Ask patients about the use of medications associated with gynecomastia, such as some antihypertensives, antibiotics, psychotropic agents, or hormones. C
• Order renal function tests and measure levels of liver enzymes, testosterone, and other hormones when initial history and examination findings are insufficient for a diagnosis. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Harry J is a 57-year-old man who came to us for evaluation and management of hypertension. He also complained of chronic headaches. Our initial examination revealed a body mass index (BMI) of 29 kg/m2 and blood pressure (BP) of 150/100 mm Hg. The hypertension responded well to a combination of valsartan and hydrochlorothiazide. A few months later, he developed left breast soreness, as well as decreased libido. Examination revealed a round movable subareolar nodule 2 cm in diameter, with no associated skin changes or lymphadenopathy. Laboratory results were: total testosterone, 106 ng/dL (normal, 241-827); free testosterone, 23 pg/mL (47-244); thyroid-stimulating hormone (TSH), 2.222 mIU/mL (0.350-5.500); and prolactin, 102.7 ng/mL (2.1-17.7). Magnetic resonance imaging (MRI) of the brain revealed a nodular density <10 mm in the pituitary gland with minimal displacement of the stalk, consistent with a microadenoma.
Enlargement of the male breasts—gynecomastia—is caused by a benign proliferation of the ductal epithelium, due to a relative increase in the ratio of free estrogen to androgen locally in the breast. Gynecomastia of recent onset is often associated with pain and tenderness, as was the case with our patient.
Often self-limiting, age-related influences. Gynecomastia is common in newborns, during adolescence, and in old age.1 In both male and female newborns, maternal and placental estrogens induce bilateral proliferation of breast tissue. This resolves within a few weeks after birth. During the early stages of male puberty, there is a relative increase in estrogens derived mostly from peripheral aromatization of testicular and adrenal androgens. If gynecomastia results, it usually regresses spontaneously as testicular testosterone production increases in late puberty.2 Gynecomastia is also common in elderly men due to a decrease in testosterone production and an increase in sex hormone binding globulin (SHBG) that lowers free testosterone levels.
Deleterious contributing factors. Several other potential causes of gynecomastia exist (TABLE 1),3,4 and these can usually be identified with a systematic approach using a careful history, physical examination, and selected laboratory studies. Many medications are associated with gynecomastia (TABLE 2),5 one of the most common being spironolactone due to its antiandrogenic activity at the receptor level.5 Some drugs, although associated with gynecomastia, cannot be linked to a direct cause-and-effect mechanism. These factors are compounded in elderly, obese men who take medications such as spironolactone, known to cause gynecomastia.
TABLE 1
Causes of gynecomastia3,4
| Physiologic |
| Neonatal Adolescent Aging-related |
| Drug induced |
| Antiandrogens Antibiotics Antihypertensive agents GI agents Hormones Illicit drugs Psychiatric drugs |
| Decreased androgen production |
| Primary (testicular) hypogonadism Secondary (central) hypogonadism |
| Decreased androgen effect or synthesis |
| Androgen insensitivity syndrome 5α-Reductase deficiency 17-β-Hydroxysteroid dehydrogenase deficiency |
| Increased estrogen production |
| Adrenal tumor Testicular tumor hCG-secreting tumor Familial aromatase excess syndrome |
| Other |
| Liver disease Thyrotoxicosis Obesity Renal disease Malnutrition |
| GI, gastrointestinal; hCG, human chorionic gonadotropin. |
TABLE 2
Drugs associated with gynecomastia5
| Antiandrogens | Bicalutamide, flutamide, finasteride, spironolactone |
| Antibiotics | Isoniazid, ketoconazole, metronidazole |
| Antihypertensive agents | Amlodipine, diltiazem, nifedipine, verapamil, captopril, enalapril |
| GI agents | Cimetidine, ranitidine, omeprazole |
| Hormones | Anabolic steroids, estrogens, hCG, growth hormone, GnRH agonists |
| Illicit drugs, alcohol | Marijuana, methadone |
| Psychiatric drugs | Psychotropic agents, tricyclic antidepressants |
| Other | Antiretroviral agents, digitalis, fibrates, methotrexate, statins |
| GI, gastrointestinal; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin. | |
A patient’s medical history may reveal chronic conditions associated with gynecomastia. Such disorders include cirrhosis, hyperthyroidism, malnutrition, and chronic kidney disease. Rarely, gynecomastia can be a manifestation of a testicular, adrenal, or other neoplasm.
Despite a thorough evaluation, no detectable abnormality is found initially in 25% of gynecomastia cases.6 Close observation and monitoring is necessary in such instances, to ensure the earliest possible identification of the underlying cause and initiation of appropriate medical or surgical therapy.
First steps in the clinical evaluation
In cases of male breast enlargement, first determine whether you are dealing with true gynecomastia or “pseudogynecomastia,” which involves increased fat deposits typically seen in obese individuals.3 In cases of pseudogynecomastia, the tissue is uniformly enlarged and soft, with the same consistency as adipose tissue.
In about half of the cases of gynecomastia, the condition is bilateral.3 It is characteristically a rubbery or firm mass concentric with the nipple-areolar complex.
Clues to look for in the history. When examination suggests true gynecomastia, conduct a focused history to determine if medications or other substances might be causing the problem. (See “A case where drug therapy was to blame”) Some plant-derived oils used as skin care products have also been associated with gynecomastia due to weak estrogenic or anti-androgenic activity.7