sign in sign up
<<
Home , Gynecomastia

REVIEW

SHIRLEY A. BEMBO, MD HAROLD E. CARLSON, MD CME Division of , 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 ) 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 . 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 palpable breast tissue was detected on physical or drugs, or plastic . 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. . It usually regresses completely by the end of the first year. Drug-induced gynecomastia accounts for 20% to 25% of . 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 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 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 levels may, however, sup- press gonadotropin release, producing sec- Pseudogynecomastia (fatty ) is common ondary , 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 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 ; 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 one third to Gynecomastia is often asymptomatic and (LH), leading to decreased serum . one half of may be an incidental finding on routine exam- Elevated serum estradiol also stimulates the ination, but 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. dimpling, 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 nal mass. They tend to secrete large amounts of estrogen precursors such as androstene- Estrogens stimulate breast tissue growth, dione, (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 .15 Two thirds of patients ance between estrogenic and androgenic have elevations of urinary 17-, 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 in secondary bronchogenic, liver, and gastric carcino- hypogonadism due to partial hypopituitarism. mas.13 Measurement of serum beta-hCG by In this situation, peripheral 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. Aging is also associated with accumula- Refeeding gynecomastia was first noted in Gynecomastia tion of , which maintains nor- World War II, when men liberated from prison in puberty is mal serum estrogen levels, since adipose tissue camps developed gynecomastia within a few is an important site of aromatization of andro- weeks of resuming an adequate diet; the con- usually gens to estrogens. dition persisted for about 1 to 2 years and then asymptomatic Primary hypogonadism from any cause regressed spontaneously. The mechanism is (eg, mumps orchitis, trauma, cytotoxic not known but may be similar to that of puber- and regresses chemotherapy) is commonly associated with tal gynecomastia.5 Significant and spontaneously gynecomastia. Several factors may contribute are often accompanied by hypo- to an altered estrogen-to-androgen ratio. First, gonadism, due to decreased gonadotropin levels of total and free testosterone decrease. secretion. With , gonadotropin Second, the resulting increase in serum LH secretion and gonadal function return to nor- stimulates the enzyme in testicular mal, resulting in a “second puberty.” Leydig cells to produce more estrogen. In Renal failure and dialysis. Men with addition, peripheral aromatization of the chronic renal failure have a variety of hor- adrenal androgen to estro- monal abnormalities, including low levels of gen remains unaffected. serum testosterone, raised estradiol and LH is associated with levels, and modest increases in serum pro- gynecomastia in about 80% of Klinefelter lactin. The hormonal abnormalities are often cases, perhaps due to primary hypogonadism. reversed with renal transplantation but are It is the only cause of gynecomastia that clear- not altered by dialysis.12 ly carries an increased risk of breast cancer— Dialysis-associated gynecomastia may be 10-fold to 20-fold greater than normal.13 pathogenetically similar to refeeding gyneco- Klinefelter patients typically carry an mastia. Before dialysis, renal failure patients extra X chromosome. Whether the extra X must follow restricted diets, often are anorec-

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 6 JUNE 2004 513 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. GYNECOMASTIA BEMBO AND CARLSON

T ABLE 1 Drugs that can cause gynecomastia

DRUG MECHANISM Unknown Calcium channel blockers Unknown (diltiazem, , ) Central nervous system agents Unknown (amphetamines, diazepam, , phenytoin, reserpine, tricyclic antidepressants) Androgen receptor antagonism Cytotoxic agents Primary hypogonadism due to Leydig cell damage (alkylating agents, vincristine, nitrosoureas, methotrexate) Androgen receptor antagonism Hormones Androgens Aromatization to estrogens; other mechanisms? Estrogens Direct stimulation of the breast Human chorionic gonadotropin Stimulation of testicular Leydig cell estrogen secretion Possibly refeeding , Inhibition of testosterone synthesis Marijuana Androgen receptor antagonism D-penicillamine Unknown Phenothiazines Elevated serum prolactin Androgen receptor antagonism; at high doses, interference with testosterone biosynthesis Theophylline Unknown

Drug-induced tic, and tend to lose weight. With dialysis, diet roidism.5 Breast enlargement usually resolves gynecomastia is liberalized and patients often regain weight. after the euthyroid state is restored. Dialysis-associated gynecomastia has been Stressful life events were linked to may account reported to improve spontaneously after 1 to 2 episodes of transient gynecomastia in a report for up to 25% years. of five cases.17 Increased serum cortisol and of the liver, especially alcoholic estradiol levels with decreased serum testos- of all cases cirrhosis, is commonly associated with terone were found during the stressful episode gynecomastia. A number of factors may (though all measurements were within normal explain this link: can inhibit the limits). It was proposed that the adrenal hypothalamic-pituitary-testicular axis, leading glands might increase their secretion of estro- to low serum testosterone levels; peripheral gen precursors in response to stress. aromatization of androgens to estrogens increases in ; SHBG levels are Drugs and gynecomastia often elevated, causing a further decrease in Drug-induced gynecomastia is common and free testosterone levels; and some alcoholic may account for 20% to 25% of cases.15 beverages contain that may Mechanisms that have been reported include contribute to relative estrogen excess.5,12 direct action of estrogens or estrogen-like sub- . Gynecomastia has stances, enhancement of testicular production been reported in 10% to 40% of men with of estrogens, and inhibition of testosterone hyperthyroidism. SHBG is often increased in synthesis or action (TABLE 1). hyperthyroidism, resulting in high normal or Therapeutic doses of testosterone can be elevated total serum testosterone and peripherally aromatized to estrogen, which decreased free testosterone levels. Peripheral may result in gynecomastia, but other mecha- conversion of androgens to estrogens by aro- nisms may be involved, since nonaromatizable matase may also be enhanced in hyperthy- androgens such as or dihy-

514 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. Breast enlargement

Evidence of cancer? No Yes

Equivocal Biopsy

Negative Positive Recent onset or symptomatic? Yes No Positive If general exam is normal, Drug history Drug-induced reassurance and observation Negative

Yes Recent initiation Dialysis-induced of dialysis No

Yes Pubertal? Pubertal (reassure that it will regress No with time)

Yes Weight loss and Refeeding recent gain? gynecomastia No

Screen for hyperthyroidism, hypogonadism, liver disease, tumors

FROM CARLSON HE. GYNECOMASTIA. IN: MORLEY JE, KORENMAN SG, EDITORS. ENDOCRINOLOGY AND METABOLISM IN THE ELDERLY. BOSTON: BLACKWELL SCIENTIFIC PUBLICATIONS INC, 1992. REPRODUCED BY PERMISSION OF THE PUBLISHER.

FIGURE 1 Diagnostic approach to the evaluation of male breast enlargement drotestosterone may also cause gynecomastia. healthy man with asymptomatic, incidental- Some drugs can cause gynecomastia ly discovered gynecomastia should not be through multiple mechanisms. For example, subjected to an exhaustive endocrine evalua- spironolactone, in addition to being an andro- tion. gen receptor antagonist, may also interfere The breasts should be examined in detail, with testosterone biosynthesis.18 However, however, to rule out the likelihood of breast the mechanisms by which many drugs cause cancer, and if the findings are suspicious, fine gynecomastia are still not known. needle aspiration or excisional biopsy should be done (FIGURE 1). Ultrasonography or mam- ■ DIAGNOSTIC EVALUATION mography may be helpful in evaluating men at high risk, such as those with Klinefelter Since palpable breast tissue is so prevalent in syndrome. the normal male population, an otherwise Men with recent-onset breast enlarge-

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 6 JUNE 2004 515 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. GYNECOMASTIA BEMBO AND CARLSON

T ABLE 2 ■ TREATMENT

Diagnostic evaluation of gynecomastia Treatment of gynecomastia depends on the History underlying cause. If it is drug-induced, it may Duration of breast enlargement regress if the offending medication is stopped. Presence of breast pain or tenderness Similarly, breast enlargement following cyto- Drug history (prescription, over-the-counter, occupational, toxic chemotherapy may also resolve sponta- or recreational) Sexual functioning neously. Changes in virilization Treatment of hyperthyroidism and surgi- Changes in weight cal removal of testicular, adrenal, or other Symptoms of hyperthyroidism causative tumors may lead to regression. In Physical examination patients with hypogonadism, treatment with Thyroid and signs of thyroid hormone excess testosterone may produce regression by pro- Breast examination, suspicious findings suggestive viding androgen and suppressing LH-stimulat- of malignancy ed estradiol secretion. Abdominal examination for possible adrenal mass or hepatomegaly Pubertal gynecomastia usually eventu- Examination of genitalia, testicular size, testicular mass ally resolves naturally, as does breast Degree of virilization: body hair, voice, muscles enlargement associated with dialysis or Laboratory evaluation refeeding. Serum Liver enzymes Drug treatment Thyroid-stimulating hormone, free thyroxine Even with exhaustive evaluation, no underly- Serum total and free or bioavailable testosterone, luteinizing ing cause is identifiable in about 25% of hormone, follicle-stimulating hormone, estradiol, prolactin 15 Beta-human chorionic gonadotropin patients. In these cases, no treatment is nec- Serum dehydroepiandrosterone sulfate or urinary essary, unless the condition causes pain, 17-ketosteroids embarrassment, or psychological discomfort. In these patients, drug therapy may be tried. Options include (clomiphene, ), androgens (danazol), and aro- ment or who present with breast pain and ten- matase inhibitors. derness require a more detailed evaluation to Clomiphene has been tried mainly in search for a possible underlying cause (TABLE 2). uncontrolled studies, in which it had variable Laboratory screening should include efficacy.19 measurements of: Tamoxifen, in an uncontrolled study, • Thyroid function resulted in complete regression of gynecomas- • Liver enzymes tia in 70% of cases.20 • Serum creatinine Danazol is a weak androgen that inhibits • Serum total and free or bioavailable pituitary secretion of LH and FSH. In a ran- testosterone, estradiol, LH, follicle-stimu- domized, double-blind study, danazol signifi- lating hormone (FSH), and prolactin cantly reduced breast tenderness and size com- • Serum beta-hCG pared with placebo.21 In a head-to-head study, • Serum DHEA-sulfate or urinary 17-keto- 78% of patients receiving tamoxifen 20 mg steroids (may be added if a feminizing daily showed complete regression of gyneco- is part of the differential mastia vs 40% in patients receiving danazol diagnosis). 400 mg daily.22 Imaging studies should not be ordered , an , unless clinical signs or laboratory results dic- was tried in a small uncontrolled study in tate them. Imaging studies may include testic- patients with pubertal gynecomastia, with ular sonography or thermography, computed good results.19 There have been no studies tomography of the adrenal glands, magnetic of the newer aromatase inhibitors resonance imaging of the sella turcica, and or in the treatment of gyneco- mammography. mastia.

516 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. should be limited to only 6 Several studies have shown that prophylactic months. When gynecomastia has been breast irradiation is effective in preventing present for more than 2 years, medical gynecomastia and mastodynia in patients with therapy may no longer be effective, and scheduled to receive estrogen surgery may be the only useful treatment. or therapy.23 The usual method is to remove the glandu- lar tissue through a periareolar incision Surgery with or without suction lipectomy. Results Due to limited experience and unknown are cosmetically unsatisfactory in up to long-term side effects, trials of medical 50% of patients, however.24

■ REFERENCES duction from an . J Endocrinol Invest 1994; 1. Nuttall FQ. Gynecomastia as a physical finding in normal men. J Clin 17:275–278. Endocrinol Metab 1979; 48:338–340. 15. Braunstein GD. Gynecomastia. N Engl J Med 1993; 328:490–495. 2. Niewoehner CB, Nuttall FQ. Gynecomastia in a hospitalized male 16. Gray A, Feldman HA, McKinley JB, et al. Age, disease, and changing population. Am J Med 1984; 77:633–638. sex hormone levels in middle-aged men: results of the Massachusetts 3. Andersen JA, Gram JB. Male breast at autopsy. Acta Pathol Microbiol male aging study. J Clin Endocrinol Metab 1991; 73:1016–1025. Immunol Scand (Sect A) 1982; 90:191–197. 17. Gooren LJG, Daantje CRE. Psychological stress as a cause of intermit- 4. Bannayan GA, Hajdu SI. Gynecomastia: clinicopathologic study of tent gynecomastia. Horm Metab Res 1986; 18:424. 351 cases. Am J Clin Pathol 1972; 57:431–437. 18. Loriaux DL, Menard R, Taylor A, Pita JC, Santen R. Spironolactone 5. Carlson HE. Gynecomastia. In: Morley JE, Korenman SG, editors. and endocrine dysfunction. Ann Intern Med 1976; 85:630–636. Endocrinology and Metabolism in the Elderly. Boston: Blackwell 19. Zachmann M, Eiholzer U, Muritano M, et al. Treatment of pubertal Scientific Publications Inc, 1992:294–307. gynecomastia with testolactone. Acta Endocrinol Supp (Copenh) 6. Moore GF, Wattenberg CA, Rose DK. Breast changes due to diethyl- 1986; 279:218–224. . JAMA 1945; 127:60–62. 20. Parker LN, Gray DR, Lai MK, et al. Treatment of gynecomastia with 7. Ando S, DeAmicis F, Rago V, et al. Breast cancer: from estrogen to tamoxifen: a double-blind crossover study. Metabolism 1986; androgen receptor. Mol Cell Endocrinol 2002; 193:121–128. 35:705–708. 8. Mertani HC, Garcia-Caballero T, Lambert A, et al. Cellular expression 21. Jones DJ, Holt SD, Surtees P, et al. A comparison of danazol and of and prolactin receptors in human breast disor- placebo in the treatment of adult idiopathic gynecomastia: results of ders. Int J Cancer 1998; 79:202–211. a prospective study in 55 patients. Ann R Coll Surg Engl 1990; 9. Turkington RW. Serum prolactin levels in patients with gynecomastia. 72:296–298. J Clin Endocrinol Metab 1972; 34:62–66. 22. Ting AC, Chow LW, Leung YF. Comparison of tamoxifen with danazol 10. DeRaimondo CV, Roach AC, Meador CK. Gynecomastia from expo- in the management of idiopathic gynecomastia. Am Surg 2000; sure to vaginal estrogen cream. N Engl J Med 1980; 302:1089–1090. 66:38–40. 11. Gottswinter JM, Korth-Schutz S, Ziegler R. Gynecomastia caused by 23. Picker AP. The safety and tolerability of low-dose irradiation for the estrogen containing hair lotion. J Endocrinol Invest 1984; 7:383–386. management of antiandrogen monotherapy. Lancet Oncol 2003; 12. Hershkovitz E, Leiberman E. Gynecomastia: a review. The 4:30–36. Endocrinologist 2002; 12:321–332. 24. Daniels IR, Layer GT. Gynecomastia. Eur J Surg 2001; 167:885–892. 13. Korenman SG. The endocrinology of the abnormal male breast. Ann NY Acad Sci 1986; 464:400–408. ADDRESS: Shirley A. Bembo, MD, Division of Endocrinology and 14. Zayed A, Stock JL, Liepman MK, et al. Feminization as a result of Metabolism, Health Sciences Center, T15 Room 060, Stony Brook both peripheral conversion of androgens and direct estrogen pro- University, Stony Brook, NY 11794-8154.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 6 JUNE 2004 517 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission.