Gynecomastia GRETCHEN DICKSON, MD, MBA, University of Kansas School of Medicine, Wichita, Kansas Gynecomastia is defined as benign proliferation of glandular breast tissue in men. Physiologic gynecomastia is common in newborns, adolescents, and older men. It is self-limited, but can be treated to minimize emotional distress and physical discomfort. Nonphysiologic gyne- comastia may be caused by chronic conditions (e.g., cirrhosis, hypogonadism, renal insuf- ficiency); use of medications, supplements, or illicit drugs; and, rarely, tumors. Discontinuing use of contributing medications and treating underlying disease are the mainstay of treat- ment. Medications, such as estrogen receptor modulators, and surgery have a role in treating gynecomastia in select patients. Treatment should be pursued early and should be directed by the patient. (Am Fam Physician. 2012;85(7):716-722. Copyright © 2012 American Academy of Family Physicians.) ▲ Patient information: lthough the adult male breast con- of genetic conditions with delay of expected A handout on this topic is tains minimal amounts of adipose pubertal development. Although adolescent available at http://family doctor.org/080.xml. and glandular tissue, there is poten- physiologic gynecomastia often resolves tial for proliferation if estrogen or spontaneously, intervention may be war- A progesterone levels increase. Gynecomastia, ranted to ameliorate emotional distress. which can be physiologic or nonphysiologic, Decreasing free testosterone levels may occurs when the estrogen-to-testosterone contribute to a final peak in gynecomas- ratio in men is disrupted, leading to prolif- tia incidence in men older than 50 years. eration of glandular breast tissue.1 Although older men are less likely to present for evaluation of gynecomastia than ado- Physiologic Gynecomastia lescents, a study of hospitalized men esti- Physiologic gynecomastia has a trimodal mates that approximately 65 percent of men age distribution, with incidence peaking in between 50 and 80 years of age experience newborns, adolescents, and men older than some degree of gynecomastia.8 50 years. Up to 90 percent of newborn boys have palpable breast tissue secondary to Nonphysiologic Gynecomastia transplacental transfer of maternal estro- Nonphysiologic gynecomastia can occur at gens.2 Newborn gynecomastia, although any age as a result of a number of medical concerning to parents, usually resolves spon- conditions, medication use, or substance taneously within four weeks of birth. Chil- use. Common causes of nonphysiologic dren with symptoms that persist after their gynecomastia are listed in Table 1.1,9 first birthday should be examined further; they may be at risk of persistent pubertal PERSISTENT PUBERTAL GYNECOMASTIA gynecomastia. Adolescent physiologic gynecomastia should One-half of adolescent males will experi- resolve within six months to two years after ence gynecomastia, with typical onset at 13 onset. If symptoms persist after two years to 14 years of age, or Tanner stage 3 or 4.3,4 or past 17 years of age, further evaluation An increase in estradiol concentration, is indicated. Use of medications or sub- lagging free testosterone production, and stances associated with gynecomastia or increased tissue sensitivity to normal male other underlying illness may be a factor. If levels of estrogen are possible causes of gyne- no other etiology can be found and if the comastia in adolescents.5-7 Adolescents may patient desires treatment, supplementation also experience nonphysiologic gynecomas- with testosterone, use of estrogen receptor– tia as the result of substance, supplement, modifying agents, or referral for surgery to or medication use, or from the unmasking improve cosmesis is warranted. Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2012 American Academy of Family Physicians. For the private, noncommer- 716 Americancial use of oneFamily individual Physician user of the Web site. All other rights reserved.www.aafp.org/afp Contact [email protected] for copyright questionsVolume and/or 85, Number permission 7 requests.◆ April 1, 2012 Gynecomastia Table 1. Causes of Gynecomastia Table 2. Mechanism of Effect of Agents Commonly Associated with Gynecomastia Cause Frequency (%) Antiandrogenic Induces hyperprolactinemia Physiologic gynecomastia 25 properties Haloperidol Idiopathic or unknown cause 25 Alkylating agents Metoclopramide (Reglan) Medication or substance use (Table 2) 10 to 25 Bicalutamide (Casodex) Phenothiazines Cirrhosis 8 Cimetidine (Tagamet) Unknown mechanism Primary hypogonadism 8 Cisplatin Amiodarone 5α-reductase deficiency Flutamide Amlodipine (Norvasc) Androgen insensitivity syndrome Isoniazid Amphetamines Congenital anorchia Ketoconazole Angiotensin-converting Hemochromatosis Marijuana enzyme inhibitors Klinefelter syndrome Methotrexate Antiretroviral agents Testicular torsion Metronidazole (Flagyl) Atorvastatin (Lipitor) Testicular trauma Omeprazole (Prilosec) Didanosine (Videx) Viral orchitis Penicillamine (Cuprimine) Diltiazem Tumors 3 Ranitidine (Zantac) Etomidate (Amidate) Adrenal tumors Spironolactone (Aldactone) Fenofibrate (Tricor) Gastric carcinoma producing hCG Vinca alkaloids Finasteride Large cell lung cancer producing hCG Estrogenic properties Fluoxetine (Prozac) Pituitary tumors Anabolic steroids Heroin Renal cell carcinoma producing hCG Diazepam (Valium) Methadone Testicular tumors, particularly Leydig or Digoxin Methyldopa Sertoli cell tumors Estrogen agonists Minocycline (Minocin) Secondary hypogonadism 2 Estrogens Minoxidil Kallmann syndrome Gonadotropin-releasing Mirtazapine (Remeron) Hyperthyroidism 2 hormone agonists Nifedipine (Procardia) Chronic renal insufficiency 1 Human chorionic Nilutamide (Nilandron) Other 6 gonadotropins Paroxetine (Paxil) Familial gynecomastia Phenytoin (Dilantin) Reserpine Human immunodeficiency virus Phytoestrogens Risperidone (Risperdal) Malnutrition and disorders of impaired Increases metabolism Rosuvastatin (Crestor) absorption (e.g., ulcerative colitis, of androgens Sulindac (Clinoril) cystic fibrosis) Alcohol Theophylline Increases sex hormone– hCG = human chorionic gonadotropin. binding globulin Tricyclic antidepressants Adapted with permission from Derkacz M, Chmiel-Perzynska I, Nowa- concentration Venlafaxine (Effexor) kowski A. Gynecomastia—a difficult diagnostic problem. Endokrynol Diazepam Verapamil Pol. 2011;62(2):191, with additional information from reference 1. Phenytoin Information from references 7, and 9 through 11. MEDICATIONS AND SUBSTANCES After persistent pubertal gynecomastia, medication use and substance use are the most common causes of non- supplements) have been linked to gynecomastia.15-17 physiologic gynecomastia. Agents associated with gyne- Although soy consumption is thought to be safe, con- comastia are listed in Table 2.7,9-11 Common contributors suming more than 300 mg per day has been reported include antipsychotics, antiretrovirals, and prostate cancer to cause gynecomastia.18 All supplement use in patients therapies with long-term use.12 Spironolactone (Aldactone) with gynecomastia should be scrutinized given the vari- also has high propensity to cause gynecomastia, although ability in marketed preparations.19 other mineralocorticoid receptor antagonists, such as Anabolic steroid use often causes irreversible gyne- eplerenone (Inspra), have not produced similar effects.13,14 comastia. The injection of exogenous testosterone Discontinuing use of the contributing agent often results inhibits natural production of testosterone, which can- in regression of breast tissue within three months. not recover rapidly enough between steroid-injecting Additionally, lavender, tea tree oil, dong quai, and Trib- cycles to prevent estrogen predominance. Attempts ulus terrestris (an ingredient in performance-enhancing to prevent gynecomastia with the use of concomitant April 1, 2012 ◆ Volume 85, Number 7 www.aafp.org/afp American Family Physician 717 Gynecomastia tamoxifen or other aromatase inhibitors may result in CHRONIC RENAL INSUFFICIENCY irreversible adverse effects.20 Use of marijuana, heroin, Hormonal dysfunction is common in men with renal or amphetamines also may contribute to irreversible failure because of overall suppression of testosterone gynecomastia.10,11 production and direct testicular damage secondary to uremia.26 Malnutrition occurs in up to 40 percent of CIRRHOSIS patients with renal failure; this may contribute to gyne- Liver injury may impair hepatic degradation of estrogens comastia in men.27 Dialysis improves malnutrition- and increase levels of sex hormone–binding globulin that associated gynecomastia, but only renal transplant effec- contribute to increased peripheral estrogens. Patients tively resolves nutritional and hormonal causes of gyne- with alcohol-related liver disease are at particular risk of comastia in those with renal failure. gynecomastia because phytoestrogens in alcohol and the direct inhibition of testosterone production by ethanol OTHER further disrupt the estrogen-to-testosterone ratio. Conditions that impair absorption, such as ulcerative colitis and cystic fibrosis, may result in gynecomastia. PRIMARY HYPOGONADISM Refeeding after prolonged malnutrition can also trigger Gynecomastia may be the only presenting symptom breast tissue proliferation. Although malnutrition sup- in men with primary hypogonadism. For example, presses hormone production, refeeding helps resume one-half of men with Klinefelter syndrome have gyne- production.