REVIEW SHIRLEY A. BEMBO, MD HAROLD E. CARLSON, MD CME Division of Endocrinology, Diabetes, and Professor, Department of Medicine, and CREDIT Metabolism, State University of New York Head, Division of Endocrinology, Diabetes, at Stony Brook and Metabolism, State University of New York at Stony Brook Gynecomastia: Its features, and when and how to treat it ■ ABSTRACT YNECOMASTIA (enlargement of the male G breast) is usually benign. Yet, it causes Gynecomastia is common, being present in 30% to 50% much anxiety, psychosocial discomfort, and of healthy men. A general medical history and careful fear of breast cancer. physical examination with particular attention to features In this article we briefly review the causes suggestive of breast cancer often suffice for evaluation in of gynecomastia, the key features to look for in patients without symptoms or those with incidentally the history and the physical examination, who discovered breast enlargement. Men with recent-onset needs a more detailed evaluation, and when gynecomastia or mastodynia need a more detailed and how to treat this condition. evaluation, including selected laboratory tests to search ■ for an underlying cause. Treatment depends on the cause PREVALENCE AND OCCURRENCE and may include observation, withdrawal of an offending Gynecomastia is common. In two case series, drug, therapy of an underlying disease, giving androgen palpable breast tissue was detected on physical or antiestrogen drugs, or plastic surgery. examination in 36% of healthy younger adult men, 57% of healthy older men,1 and more ■ KEY POINTS than 70% of hospitalized elderly men.2 In autopsy studies, its prevalence was as high as Gynecomastia is probably not associated with an 55%.3 increased risk of breast cancer, except in Klinefelter Gynecomastia has three peaks of occur- syndrome. rence during the life span: The neonatal period. An estimated 60% Most cases of gynecomastia result from an imbalance to 90% of infants have transient gynecomastia between estrogenic (stimulatory) and androgenic due to transplacental transfer of maternal (inhibitory) effects on the breast. estrogens. It usually regresses completely by the end of the first year. Drug-induced gynecomastia accounts for 20% to 25% of Puberty. Gynecomastia may occur in 48% cases. Even with detailed evaluation, there is no to 64% of boys at puberty. It may first appear as identifiable cause in about 25% of cases. early as 10 years of age, with a peak onset between ages 13 and 14, followed by a decline in late teenage years. Late in life. The highest prevalence is among men ages 50 to 80.1,2 ■ HISTOLOGY Histologic studies reveal a proliferation of duc- This paper discusses therapies that are experimental or are not approved by the US Food and tules embedded in a connective tissue stroma; Drug Administration for the use under discussion. glandular acini are rare. In the early or florid CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 6 JUNE 2004 511 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. GYNECOMASTIA BEMBO AND CARLSON stage, ductal hyperplasia and proliferation are important. These may include excessive local extensive while the stroma is loose and ede- production of estrogen due to increased aro- matous. matase activity, decreased estrogen degrada- Usually, over about 12 months, the breast tion, or changes in androgen or estrogen tissue evolves into a quiescent stage, in which receptors.5 the amount of stroma and fibrosis increases Hyperprolactinemia is not believed to play and the ductules become less prominent. This a direct role in gynecomastia, although pro- distinction seems to be unimportant diagnos- lactin receptors have recently been demon- tically, as these microscopic findings are the strated in gynecomastia tissue.8 Most patients same regardless of the cause of the gynecomas- with gynecomastia have normal serum pro- tia.3,4 lactin levels.9 Moreover, not all patients with hyperprolactinemia have gynecomastia. ■ CLINICAL CHARACTERISTICS Elevated prolactin levels may, however, sup- press gonadotropin release, producing sec- Pseudogynecomastia (fatty breasts) is common ondary hypogonadism, which then contributes in obese men and needs to be differentiated to the development of gynecomastia. from true gynecomastia. In true gynecomastia, there may be a button of firm subareolar tissue, Absolute estrogen excess or there may be a more diffuse collection of Exogenous estrogens. The simplest fibroglandular tissue that resembles that of the mechanism underlying gynecomastia is female breast, and which may be difficult to absolute estrogen excess, as with the use of distinguish from simple adiposity. Comparing diethylstilbestrol in the treatment of advanced the subareolar tissue with the anterior axillary prostatic carcinoma.6 Cases have also resulted fold or other subcutaneous tissue may help in from unintended exposure to exogenous estro- differentiating true gynecomastia from gens in vaginal creams and hair lotions.10,11 pseudogynecomastia.5 Leydig cell tumors are rare testicular Although commonly bilateral and sym- tumors that secrete estradiol; about 90% are Gynecomastia metric, gynecomastia of any cause may be uni- benign. Most patients are young to middle- is present in lateral or asymmetric. Unilateral gynecomas- aged.12,13 The increased serum estradiol level tia seems to be more common on the left side.4 suppresses pituitary luteinizing hormone one third to Gynecomastia is often asymptomatic and (LH), leading to decreased serum testosterone. one half of may be an incidental finding on routine exam- Elevated serum estradiol also stimulates the ination, but breast pain or tenderness may be production of sex hormone-binding globulin healthy men present, particularly if the onset of the condi- (SHBG), which preferentially binds testos- tion is recent. terone, leading to decreased free testosterone Breast cancer accounts for only 0.2% of all with normal or elevated free estradiol. Leydig malignancies in men,5 and generally presents cell tumors are small and, in some cases, non- as a unilateral firm mass, often eccentric in palpable. If they are nonpalpable, testicular location rather than centered beneath the are- sonography or thermography may be needed ola. Skin dimpling, nipple retraction, nipple to detect them. Treatment remains surgical. discharge, and axillary lymphadenopathy may Estrogen-producing adrenal tumors, be seen. although rare, are usually malignant and are often quite large when discovered.14 In about ■ AN IMBALANCE OF ESTROGENS one half of cases, there is a palpable abdomi- OVER ANDROGENS nal mass. They tend to secrete large amounts of estrogen precursors such as androstene- Estrogens stimulate breast tissue growth, dione, dehydroepiandrosterone (DHEA), and whereas androgens inhibit it.6,7 Most cases of DHEA sulfate, and some directly produce gynecomastia appear to result from an imbal- estradiol and estrone.15 Two thirds of patients ance between estrogenic and androgenic have elevations of urinary 17-ketosteroids, effects on the breast. and some have elevated serum DHEA sulfate, Local tissue factors in the breast may be both of which are useful tumor markers. 512 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 6 JUNE 2004 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. Tumors producing chorionic gonado- chromosome plays a role in the development tropin. The placental hormone human chori- of breast cancer is uncertain, although some onic gonadotropin (hCG) is similar to LH in studies suggest it; a plausible mechanism is both its structure and its action on the testis. that expression of genes on the noninactivat- Thus, elevated serum levels of hCG dispro- ed portions of the second X chromosome facil- portionately stimulate normal Leydig cells of itates the development of the cancer. the testis to secrete increased amounts of Fibroblasts from patients with the XXY geno- estradiol. In addition, many hCG-secreting type have also been shown to have an tumors can take up estrogen precursors from increased rate of transformation after expo- the circulation and aromatize them into sure to simian virus 40. active estrogens. Secondary hypogonadism. Although less A variety of tumors can secrete hCG, common, gynecomastia may also be a conse- including testicular germ cell tumors and quence of androgen deficiency in secondary bronchogenic, liver, and gastric carcino- hypogonadism due to partial hypopituitarism. mas.13 Measurement of serum beta-hCG by In this situation, peripheral aromatization of immunoassay is used for diagnosis. Normal adrenal androgens to estrogens remains unaf- men have undetectable serum levels of hCG fected and maintains normal serum estrogen in commercially available assays. levels. Puberty. Gynecomastia develops in about Relative estrogen excess two thirds of boys during puberty. There are Aging seems to be associated with pro- periods during puberty when the balance of gressive testicular dysfunction, with low or sex hormone secretion favors estrogen,12 low-normal serum testosterone levels and, in despite an increase in androgen production. some cases, elevated LH.16 Total and free This ratio returns to more normal adult values serum estradiol concentrations remain nor- as puberty advances. The condition is usually mal. The exact mechanism of testicular failure asymptomatic and self-limited and regresses remains unknown. spontaneously after about 2 years.