Evaluation of Gynecomastia
David M. Slovik
Gynecomastia is a benign proliferation of the glandular tissue of the male breast. It is to be distinguished from pseudogynecomastia with fat deposition but no glandular proliferation, which is often seen in obese men. Clinically, a rubbery or firm mass extends concentrically from the nipples. Some patients present out of fear of loss of masculinity or onset of breast cancer. Others may not have recognized the change and come to the physician at the suggestion of friends or family. Gynecomastia is common in infancy due to high in utero estrogen levels. It is also a normal transient physiologic event in up to 70% of pubertal boys. Prevalence in adult men older than age 50 years can be as high as 65%.
The primary physician must be able to recognize gynecomastia, differentiate it from malignancy, and initiate an evaluation to rule out important underlying medical causes that range from hormonally active neoplasms to cirrhosis and hyperthyroidism.
In most instances, the cause is benign, and the tasks are to allay fears and help the patient to decide about treatment.
Pathophysiology
Estradiol is the growth hormone of the breast. Gynecomastia represents a phenomenon of relative estradiol excess leading to the proliferation of breast tissue. Under normal circumstances, most estradiol in men is derived from the peripheral conversion of testosterone and adrenal estrone. The basic mechanisms of gynecomastia are a decrease in androgen production, an absolute increase in estrogen production, and an increased availability of estrogen precursors for peripheral conversion to estradiol. Blocking of androgen receptors and increased binding of androgen are additional modes of reduced androgen effect.
Reduced Androgen Production, Availability, and Receptor Blockade
A decrease in androgen production accounts for many cases seen in older men, particularly those with testicular endocrine failure due to cancer therapy and those taking the antifungal agent ketoconazole. Over 50% of men with prostate cancer will develop gynecomastia
if they receive androgen deprivation therapy. Androgen availability is reduced in both hyperthyroidism and cirrhosis through an increase in sex hormone-binding globulin, which enhances the binding of testosterone relative to estradiol and decreases free testosterone. Blockade of androgen receptors accounts for the gynecomastia associated with use of spironolactone, cimetidine, flutamide, and perhaps marijuana. Cocaine use is also associated with gynecomastia, but the mechanism is unclear. Some over-the-counter skin products have weak antiandrogen properties.
if they receive androgen deprivation therapy. Androgen availability is reduced in both hyperthyroidism and cirrhosis through an increase in sex hormone-binding globulin, which enhances the binding of testosterone relative to estradiol and decreases free testosterone. Blockade of androgen receptors accounts for the gynecomastia associated with use of spironolactone, cimetidine, flutamide, and perhaps marijuana. Cocaine use is also associated with gynecomastia, but the mechanism is unclear. Some over-the-counter skin products have weak antiandrogen properties.
Increased Estrogen Production
Age-related increases in adipose tissue increase extraglandular aromatization of testosterone to estradiol and androstenedione to estrone. Increased estrogen production may also be seen with Klinefelter syndrome, adrenal carcinomas, tumors producing ectopic human chorionic gonadotropin (hCG), and Leydig cell tumors of the testes. Tumors that produce hCG stimulate the testicular production of estradiol. Teratomas of the testes and carcinomas of the lung, pancreas, and colon are known sources of ectopic hCG. The transient gynecomastia of puberty represents a brief physiologic increase in testicular estrogen secretion and lasts 1 to 2 years before receding. Gynecomastia seen with malnutrition and starvation is probably due to reduced gonadotropin and testosterone levels relative to estrogen and may worsen with refeeding due to a rise in gonadotropins and estradiol production that outpaces the increases in gonadotropin and testosterone.
Increased Estrogen Precursor Availability
Increased estrogen precursor availability is the mechanism of gynecomastia in patients who have androgen-secreting tumors or congestive heart failure or who use exogenous androgen (which leads to an increased conversion of testosterone and androstenedione to estradiol and estrone). This effect has also been documented with the use of androstenedione, the popular “natural” sex hormone precursor supplement taken by body builders and adolescents. Hyperthyroidism causes an increased peripheral conversion of testosterone to estrogen precursors. Much of the conversion takes place in fatty tissue. An exogenous estrogen effect is seen with the use of digitalis and synthetic estrogens. Ketoconazole and spironolactone cause a release of free estrogen by displacement from sex hormone-binding globulin.
Clinical Presentations
The most noticeable feature is an increase in breast tissue. Although usually bilateral, gynecomastia is unilateral in one third of cases. Idiopathic and drug-induced gynecomastia is typically unilateral, whereas in pubertal and hormonal cases, the changes are often bilateral. It may be that asymmetry is a more accurate description than unilateral enlargement, based on the prevalence of bilaterally histologic but not clinically evident gynecomastia in autopsy series. Tenderness may also be noted in one third of patients, but actual pain is less frequent. Enlargement is usually central and symmetric, although it is occasionally eccentric.
A few distinctive clinical presentations are worth noting: In Klinefelter syndrome, gynecomastia develops around puberty in a patient with long limbs, small and firm testes, infertility, and normal or deficient secondary sex features. In cirrhosis, patients present with loss of libido, loss of body hair, and testicular atrophy (see Chapter 71). In hyperthyroidism, they may present with weight loss, tachycardia, and goiter.
Recovery from malnutrition or serious chronic illnesses (severe heart failure, renal failure, liver failure) leads to a picture resembling a second puberty with a rise in gonadotropins and development of transient gynecomastia.
Carcinoma of the male breast is distinct from gynecomastia; it is characterized by a unilateral, eccentrically located firm, often fixed mass in association with axillary lymphadenopathy. Male breast cancer is rare; it is generally not more frequent in patients with gynecomastia, although the incidence in patients with Klinefelter syndrome is higher.
The differential diagnosis can be organized by underlying pathophysiology (Table 99-1). It can also be considered in terms of age of presentation. In healthy pubertal boys, transient physiologic gynecomastia is the most likely explanation. Testicular or adrenal tumors are rare in this age group, but Klinefelter syndrome may account for a number of cases. In adult men, alcohol-related liver disease and drugs predominate, with the list including estrogens, androgens, androstenedione, spironolactone, digitalis preparations, angiotensin converting enzyme (ACE) inhibitors, calciumchannel blockers, flutamide, ketoconazole, cimetidine, alcohol, and marijuana. The association also exists but is more tenuous with use of phenothiazines, amphetamines, reserpine, methyldopa, isoniazid, tricyclic antidepressants, phenytoin, and heroin. In one series, 22% of patients had a history of taking a drug associated with gynecomastia, and 26% had alcoholic liver disease.
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