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Gynecomastia final

  1. 1. 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 gynecomastia may be caused by chronic conditions (e.g., cirrhosis, hypogonadism, renal insufficiency); use of medications, supplements, or illicit drugs; and, rarely, tumors. Discontinuing use of contributing medications and treating underlying disease are the mainstay of treatment. 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: A handout on this topic is available at http://family A lthough the adult male breast contains minimal amounts of adipose and glandular tissue, there is potential for proliferation if estrogen or progesterone levels increase. Gynecomastia, which can be physiologic or nonphysiologic, occurs when the estrogen-to-testosterone ratio in men is disrupted, leading to proliferation of glandular breast tissue.1 Physiologic Gynecomastia Physiologic gynecomastia has a trimodal age distribution, with incidence peaking in newborns, adolescents, and men older than 50 years. Up to 90 percent of newborn boys have palpable breast tissue secondary to transplacental transfer of maternal estrogens.2 Newborn gynecomastia, although concerning to parents, usually resolves spontaneously within four weeks of birth. Children with symptoms that persist after their first birthday should be examined further; they may be at risk of persistent pubertal gynecomastia. One-half of adolescent males will experience gynecomastia, with typical onset at 13 to 14 years of age, or Tanner stage 3 or 4.3,4 An increase in estradiol concentration, lagging free testosterone production, and increased tissue sensitivity to normal male levels of estrogen are possible causes of gynecomastia in adolescents.5-7 Adolescents may also experience nonphysiologic gynecomastia as the result of substance, supplement, or medication use, or from the unmasking of genetic conditions with delay of expected pubertal development. Although adolescent physiologic gynecomastia often resolves spontaneously, intervention may be warranted to ameliorate emotional distress. Decreasing free testosterone levels may contribute to a final peak in gynecomastia incidence in men older than 50 years. Although older men are less likely to present for evaluation of gynecomastia than adolescents, a study of hospitalized men estimates that approximately 65 percent of men between 50 and 80 years of age experience some degree of gynecomastia.8 Nonphysiologic Gynecomastia Nonphysiologic gynecomastia can occur at any age as a result of a number of medical conditions, medication use, or substance use. Common causes of nonphysiologic gynecomastia are listed in Table 1.1,9 PERSISTENT PUBERTAL GYNECOMASTIA Adolescent physiologic gynecomastia should resolve within six months to two years after onset. If symptoms persist after two years or past 17 years of age, further evaluation is indicated. Use of medications or substances associated with gynecomastia or other underlying illness may be a factor. If no other etiology can be found and if the patient desires treatment, supplementation with testosterone, use of estrogen receptor– modifying agents, or referral for surgery to improve cosmesis is warranted. Downloaded from the American Family Physician Web site at Copyright © 2012 American Academy of Family Physicians. For the private, noncommer- 716  American one individual user of the Web site. All other rights reserved. Contact for copyright questions and/orNumber 7 requests. 1, 2012 Volume 85, permission April cial use of Family Physician ◆
  2. 2. Gynecomastia Table 1. Causes of Gynecomastia Table 2. Mechanism of Effect of Agents Commonly Associated with Gynecomastia Cause Frequency (%) Physiologic gynecomastia Idiopathic or unknown cause Medication or substance use (Table 2) Cirrhosis Primary hypogonadism 5α-reductase deficiency Androgen insensitivity syndrome Congenital anorchia Hemochromatosis Klinefelter syndrome Testicular torsion Testicular trauma Viral orchitis Tumors Adrenal tumors Gastric carcinoma producing hCG Large cell lung cancer producing hCG Pituitary tumors Renal cell carcinoma producing hCG Testicular tumors, particularly Leydig or Sertoli cell tumors Secondary hypogonadism Kallmann syndrome Hyperthyroidism Chronic renal insufficiency Other Familial gynecomastia Human immunodeficiency virus Malnutrition and disorders of impaired absorption (e.g., ulcerative colitis, cystic fibrosis) 25 25 10 to 25 8 8 3 2 2 1 6 hCG = human chorionic gonadotropin. Adapted with permission from Derkacz M, Chmiel-Perzynska I, Nowakowski A. Gynecomastia—a difficult diagnostic problem. Endokrynol Pol. 2011;62(2):191, with additional information from reference 1. Antiandrogenic properties Alkylating agents Bicalutamide (Casodex) Cimetidine (Tagamet) Cisplatin Flutamide Isoniazid Ketoconazole Marijuana Methotrexate Metronidazole (Flagyl) Omeprazole (Prilosec) Penicillamine (Cuprimine) Ranitidine (Zantac) Spironolactone (Aldactone) Vinca alkaloids Estrogenic properties Anabolic steroids Diazepam (Valium) Digoxin Estrogen agonists Estrogens Gonadotropin-releasing hormone agonists Human chorionic gonadotropins Phenytoin (Dilantin) Phytoestrogens Increases metabolism of androgens Alcohol Increases sex hormone– binding globulin concentration Diazepam Phenytoin Induces hyperprolactinemia Haloperidol Metoclopramide (Reglan) Phenothiazines Unknown mechanism Amiodarone Amlodipine (Norvasc) Amphetamines Angiotensin-converting enzyme inhibitors Antiretroviral agents Atorvastatin (Lipitor) Didanosine (Videx) Diltiazem Etomidate (Amidate) Fenofibrate (Tricor) Finasteride Fluoxetine (Prozac) Heroin Methadone Methyldopa Minocycline (Minocin) Minoxidil Mirtazapine (Remeron) Nifedipine (Procardia) Nilutamide (Nilandron) Paroxetine (Paxil) Reserpine Risperidone (Risperdal) Rosuvastatin (Crestor) Sulindac (Clinoril) Theophylline Tricyclic antidepressants Venlafaxine (Effexor) Verapamil 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 nonphysiologic gynecomastia. Agents associated with gynecomastia are listed in Table 2.7,9-11 Common contributors include antipsychotics, antiretrovirals, and prostate cancer therapies with long-term use.12 Spironolactone (Aldactone) also has high propensity to cause gynecomastia, although other mineralocorticoid receptor antagonists, such as eplerenone (Inspra), have not produced similar effects.13,14 Discontinuing use of the contributing agent often results in regression of breast tissue within three months. Additionally, lavender, tea tree oil, dong quai, and Tribulus terrestris (an ingredient in performance-enhancing April 1, 2012 ◆ Volume 85, Number 7 supplements) have been linked to gynecomastia.15-17 Although soy consumption is thought to be safe, consuming more than 300 mg per day has been reported to cause gynecomastia.18 All supplement use in patients with gynecomastia should be scrutinized given the variability in marketed preparations.19 Anabolic steroid use often causes irreversible gynecomastia. The injection of exogenous testosterone inhibits natural production of testosterone, which cannot recover rapidly enough between steroid-injecting cycles to prevent estrogen predominance. Attempts to prevent gynecomastia with the use of concomitant American Family Physician 717
  3. 3. Gynecomastia tamoxifen or other aromatase inhibitors may result in irreversible adverse effects.20 Use of marijuana, heroin, or amphetamines also may contribute to irreversible gynecomastia.10,11 CIRRHOSIS Liver injury may impair hepatic degradation of estrogens and increase levels of sex hormone–binding globulin that contribute to increased peripheral estrogens. Patients with alcohol-related liver disease are at particular risk of gynecomastia because phytoestrogens in alcohol and the direct inhibition of testosterone production by ethanol further disrupt the estrogen-to-testosterone ratio. PRIMARY HYPOGONADISM Gynecomastia may be the only presenting symptom in men with primary hypogonadism. For example, one-half of men with Klinefelter syndrome have gynecomastia.21 Suspicion for primary hypogonadism is warranted in any adolescent with persistent pubertal gynecomastia. TUMORS Although testicular tumors are rare, approximately 10 percent of persons with testicular tumors present with gynecomastia alone.22,23 In a study of 175 men who were referred to a breast surgeon for evaluation of gynecomastia, a testicular tumor was diagnosed in 3 percent.23 Leydig cell tumors, although often benign, are prone to cause gynecomastia because they secrete estradiol. Adrenal tumors may secrete estrogen and estrogen precursors, causing a similar disruption in the estrogento-testosterone ratio. These tumors can be detected by elevated serum dehydroepiandrosterone sulfate levels or increased urinary 17-ketosteroid levels. Similarly, the presence of human chorionic gonadotroNo cause is found pin (hCG) in serum can in 25 percent of be used to detect hCGpatients who develop secreting tumors that gynecomastia. may include testicular germ cell, liver, gastric, or bronchogenic carcinomas. All of these tumors require surgical excision. HYPERTHYROIDISM Gynecomastia occurs in 10 to 40 percent of men with hyperthyroidism, although it is rarely the only symptom at presentation.24,25 Restoration of euthyroid state will resolve gynecomastia in one to two months. 718  American Family Physician CHRONIC RENAL INSUFFICIENCY Hormonal dysfunction is common in men with renal failure because of overall suppression of testosterone production and direct testicular damage secondary to uremia.26 Malnutrition occurs in up to 40 percent of patients with renal failure; this may contribute to gynecomastia in men.27 Dialysis improves malnutritionassociated gynecomastia, but only renal transplant effectively resolves nutritional and hormonal causes of gynecomastia in those with renal failure. OTHER Conditions that impair absorption, such as ulcerative colitis and cystic fibrosis, may result in gynecomastia. Refeeding after prolonged malnutrition can also trigger breast tissue proliferation. Although malnutrition suppresses hormone production, refeeding helps resume production. However, the liver lags in recovery and cannot fully degrade estrogens.9 As the liver recovers, gynecomastia usually resolves within one to two years after resumption of a balanced diet. Although obesity causes pseudogynecomastia (a proliferation of adipose rather than glandular tissue), elevated weight is also associated with true gynecomastia. New research suggests that leptin and aromatase activity associated with obesity contribute to increased circulating estrogens, causing gynecomastia.28 Other rare causes of gynecomastia include exposure to phthalates and lead, emotional stress, and repetitive mechanical stress causing unilateral symptoms.29-31 Testicular injury from illnesses (e.g., mumps orchitis), infiltrative processes (e.g., tuberculosis, hemochromatosis), or trauma may decrease testosterone production and lead to gynecomastia. Additionally, patients with human immunodeficiency virus infection may develop gynecomastia from the disease process or use of antiretroviral medications. No cause is found in 25 percent of patients who develop gynecomastia.7,30,31 Diagnosis Some patients with gynecomastia may present with breast pain, embarrassment, or fear of breast cancer. In other patients, gynecomastia is discovered on routine physical examination and causes no emotional or physical distress. Understanding the patient’s concerns can help direct treatment. HISTORY AND PHYSICAL EXAMINATION The history should rule out other causes of breast enlargement, such as those listed in Table 3.31-33 Physicians should review patients’ use of medications, supplements, Volume 85, Number 7 ◆ April 1, 2012
  4. 4. Table 3. Diagnoses in Men Referred for Imaging or Biopsy Because of Breast Enlargement Diagnosis and illicit drugs. Symptoms that last longer than one to two years suggest nonphysiologic causes that require intervention for resolution. Nipple discharge; skin changes; rapidly enlarging, firm breast masses; coincident testicular masses; or systemic symptoms such as weight loss should raise concern. The physical examination should include evaluation of height and weight, and examination of the breasts, genitals, liver, lymph nodes, and thyroid. Assessment of symmetry and consistency of breast tissue is critical on breast examination. Most commonly, gynecomastia is bilateral, although unilateral symptoms can occur and are usually left-sided. Palpable, firm glandular tissue in a concentric mass around the nipple areolar complex is most consistent with gynecomastia. Increases in subareolar fat are more likely pseudogynecomastia, whereas hard, immobile masses should be considered breast carcinoma until proven otherwise. Similarly, masses associated with skin changes, nipple retraction, nipple discharge, or enlarged lymph nodes should raise concern for malignancy. Frequency (%) Findings Gynecomastia 63 to 93 Pseudogynecomastia 5.4 Breast cancer 1.4 to 2.9 Lipoma Sebaceous cyst 0.9 to 2.9 1.4 to 2 Mastitis Fat necrosis 0.8 to 1.1 0.3 to 0.9 Dermoid cyst 0.9 Hematoma 0.9 Discrete, round, mobile mass under areola; usually bilateral Increased adipose rather than glandular tissue on examination Patient falls outside of age range for physiologic gynecomastia Bloody nipple discharge Axillary lymphadenopathy Nonpainful mass (pain more common in gynecomastia) Often unilateral Personal history of malignancy Asymmetric breast enlargement Drainage of material from site Swelling feels closer to skin than a part of deeper tissue Asymmetric breast enlargement Systemic signs of infection History of injury to the area may be present May be a local swelling, not over nipple areolar complex Asymmetric breast enlargement Painless lump that may enlarge; may be anywhere in the breast History of injury to the area may be present Asymmetric breast enlargement History of cancer Nonspecific breast tenderness Solid mass; diagnosis made with pathologic examination Diagnosis made on pathology specimen after removal of mass History of surgery DIAGNOSTIC TESTING The history and physical examination Metastatic disease 0.8 should direct the laboratory and imaging Ductal ectasia 0.5 workup (Figure 1). Laboratory studies to Hamartoma 0.5 investigate the underlying cause of gyneLymphoplasmacytic 0.5 comastia should include measurement of inflammation hepatic transaminase, serum creatinine, and Postsurgical 0.5 thyroid-stimulating hormone levels for all changes patients. Levels of serum beta hCG, serum dehydroepiandrosterone sulfate, or urinary Information from references 31 through 33. 17-ketosteroid should be obtained to rule out testicular, adrenal, or other tumors when clinically suspected. Likewise, total and free testosterone, estradiol, luteinizing hormone, and follicle- testicular tumors that were missed on clinical examinastimulating hormone levels define hormonal imbalances tion.34 However, a more widely advocated, conservative resulting from primary or secondary hypogonadism. approach is to perform testicular ultrasonography only Hyperprolactinemia is not common in patients with gyne- in those with palpable testicular masses, gynecomastia comastia. Laboratory studies may be ordered using a step- larger than 5 cm, or otherwise unexplained gynecomaswise approach guided by history and physical examination, tia. Breast imaging should be guided by examination. but a diagnosis of physiologic gynecomastia should not be Just as in women, mammography and breast ultrasonogmade until underlying etiologies have been excluded. raphy may be useful in men if the physical examination Recommendations for imaging studies are based raises suspicion for breast malignancy.35 mainly on case reports and expert opinion. Some studFine-needle aspiration of masses for cytology should ies have suggested routine testicular ultrasonogra- be pursued only if malignancy is suspected. Men with phy in men with gynecomastia to detect nonpalpable Klinefelter syndrome have a risk of breast cancer 16 to April 1, 2012 ◆ Volume 85, Number 7 American Family Physician 719
  5. 5. Gynecomastia Diagnosis of Gynecomastia Patient presents with breast enlargement Yes Is the patient a newborn? Likely transplacental; should resolve within four weeks No Yes Is the patient taking a medication or substance listed in Table 2? Discontinue agent and monitor for resolution No Perform physical examination Testicular mass Perform testicular ultrasonography Gynecomastia Breast mass that raises suspicion for malignancy Unremarkable examination Perform mammography and breast ultrasonography with biopsy Provide reassurance Pseudogynecomastia Test hepatic function and measure creatinine and thyroidstimulating hormone levels Evidence of chronic disease? Recommend weight loss Yes Treat underlying disease No Measure serum human chorionic gonadotropin, dehydroepiandrosterone, luteinizing hormone, follicle-stimulating hormone, estradiol, testosterone, and prolactin levels High level of estradiol and low level of luteinizing hormone Perform testicular ultrasonography High level of prolactin Perform magnetic resonance imaging for pituitary adenoma High level of human chorionic gonadotropin Low levels of luteinizing hormone and testosterone Perform testicular ultrasonography for germ cell tumor Secondary hypogonadism High level of luteinizing hormone and low level of testosterone Primary hypogonadism All hormone levels normal Idiopathic gynecomastia Ultrasonography results normal Consider exogenous estrogen use, stress, or underlying chronic disease as possible cause Figure 1. Algorithm for the diagnosis of gynecomastia. 30 times higher than other men. Even with a reassuring examination, men with gynecomastia and Klinefelter syndrome may require imaging.7,36 Treatment Few patients with gynecomastia need treatment for cosmesis or analgesia.37 In a study on treatment for gynecomastia, about one-half of men were not significantly bothered by symptoms.38 Pain is more common in patients with gynecomastia that is rapidly progressive or of recent onset. For patients with nonphysiologic gynecomastia, treatment is directed toward improving the 720  American Family Physician underlying illness or discontinuing use of the contributing. Watchful waiting with biannual follow-up is appropriate for those with physiologic gynecomastia who are untroubled by symptoms and who have no features that suggest underlying disease or malignancy. Early treatment will maximize benefit in men with significant physical symptoms or emotional distress. Medications are more effective if used as early as possible after symptoms are first noted, whereas surgery can be performed at any time with similar results. A number of medications have been used to treat gynecomastia. A retrospective chart review of men presenting Volume 85, Number 7 ◆ April 1, 2012
  6. 6. Gynecomastia SORT: KEY RECOMMENDATIONS FOR PRACTICE Clinical recommendation Evidence rating References More studies are needed to assess the effectiveness of aromatase inhibitors, such as anastrozole (Arimidex; 1 mg per day). C 34 One trial of 42 pubertal boys demonstrated a 57 percent reduction in breast volume with anastrozole treatment.43 However, a randomized controlled trial of 80 parC 35 ticipants demonstrated no statistically significant difference between anastrozole B 4, 37, 42 and placebo in the percentage of patients with greater than 50 percent breast volume reduction at three months.44 Surgery can be performed at any time A = consistent, good-quality patient-oriented evidence; B = inconsistent or limitedto reduce breast tissue, and a number of quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence techniques have been used.32,33,45 Longer rating system, go to duration of symptoms, higher-grade disease, or inability to tolerate medications may prompt surgery as a first-line option. to a breast clinic for gynecomastia found that only 13 of However, unilateral symptoms, high-grade disease, and 220 patients required medication for treatment. Patients long duration of symptoms are also associated with more were treated with 10 mg of tamoxifen per day for three surgical complications.46 months, and 10 of the 13 had resolution of pain and If pseudogynecomastia is suspected, no workup is breast enlargement.37 Although tamoxifen is thought to needed, and the patient can be reassured that weight loss be an effective and safe treatment for physiologic, per- will lead to resolution of pseudogynecomastia and also sistent pubertal, or idiopathic gynecomastia, two small be most beneficial for overall health.46 If necessary, lipodouble-blind, crossover trials found only modest benefit suction procedures can reduce breast enlargement secwhen compared with placebo.39,40 ondary to subareolar fat accumulation. Gynecomastia is a common adverse effect of bicalu- The author thanks Anne Walling, MD, and Scott Moser, MD, for their tamide (Casodex) therapy that may prompt some men assistance with this manuscript. to discontinue prostate cancer treatment. Tamoxifen Data Sources: Essential Evidence Plus and PubMed were searched for has been recommended as a preventive agent for gyne- relevant articles using the following search terms: gynecomastia, physicomastia in these patients. A double-blind study of ologic gynecomastia, and breast enlargement. Each term was searched 282 men randomized to receive 20 mg of tamoxifen once individually and in conjunction with the following terms: males, men, diagnosis, treatment, and management. A search using the same words per day with bicalutamide or bicalutamide alone found was also completed within and the Cochrane that after six months, gynecomastia and breast pain were collection. Search dates: December 10 to 25, 2010. significantly reduced in men who received tamoxifen (8.8 versus 96.7 percent in the control group).41 An Italian The Author randomized controlled trial of 80 participants also found that 20 mg of tamoxifen once per week is as effective as GRETCHEN DICKSON, MD, MBA, is director of the Family Medicine Clerkship, and assistant professor of family medicine at the University of Kansas 20 mg once per day.42 School of Medicine in Wichita. In a retrospective chart review of 38 patients in a pediAddress correspondence to Gretchen Dickson, MD, MBA, University of atric endocrinology clinic, raloxifene (Evista; 60 mg Kansas School of Medicine, 1010 N. Kansas, Wichita, KS 67214 (e-mail: once per day for three to nine months) reduced pubertal Reprints are not available from the author. gynecomastia in 91 percent of patients, whereas tamoxi- Author disclosure: No relevant financial affiliations to disclose. fen (10 to 20 mg twice per day for three to nine months) was effective in 86 percent of patients.4 However, there was no control group, and given the natural history REFERENCES of pubertal gynecomastia (i.e., self-limited), placebo- 1. Braunstein GD. Clinical practice. Gynecomastia. N Engl J Med. 2007; 357(12):1229-1237. controlled trials are still needed. Dihydrotestosterone, 2. McKiernan JF, Hull D. Breast development in the newborn. Arch Dis danazol, and clomiphene (Clomid) have also been used Child. 1981;56(7):525-529. to treat gynecomastia with varying success. 3. Georgiadis E, Papandreou L, Evangelopoulou C, et al. Incidence of Discontinuing use of spironolactone (Aldactone) often results in regression of breast tissue within three months. Routine testicular ultrasonography should be considered in men with gynecomastia to detect nonpalpable testicular tumors that were missed on clinical examination. Mammography and breast ultrasonography should be performed in men if the physical examination raises suspicion for breast cancer. Tamoxifen and raloxifene (Evista) are effective for preventing and treating gynecomastia in men being treated for prostate cancer. April 1, 2012 ◆ Volume 85, Number 7 B 13, 14 American Family Physician 721
  7. 7. Gynecomastia gynaecomastia in 954 young males and its relationship to somatometric parameters. Ann Hum Biol. 1994;21(6):579-587. 2 7. Mehrotra R, Kopple JD. Nutritional management of maintenance dialysis patients: why aren’t we doing better? Annu Rev Nutr. 2001;21:343-379. 4. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr. 2004;145(1):71-76. 2 8. Dundar B, Dundar N, Erci T, Bober E, Büyükgebiz A. Leptin levels in boys with pubertal gynecomastia. J Pediatr Endocrinol Metab. 2005;18(10): 929-934. 5. Biro FM, Lucky AW, Huster GA, Morrison JA. Hormonal studies and physical maturation in adolescent gynecomastia. J Pediatr. 1990;116(3): 450-455. 2 9. Spyropoulou G, Karamatsoukis S, Foroglou P. Unilateral pseudogynecomastia: an occupational hazard in manual metal-pressing factories? Aesthetic Plast Surg. 2011;35(2):270-273. 6. LaFranchi SH, Parlow AF, Lippe BM, Coyotupa J, Kaplan SA. Pubertal gynecomastia and transient elevation of serum estradiol level. Am J Dis Child. 1975;129(8):927-931. 3 0. Durmaz E, Ozmert EN, Erkekoglu P, et al. Plasma phthalate levels in pubertal gynecomastia. Pediatrics. 2010;125(1):e122-e129. 7. Braunstein GD. Gynecomastia. N Engl J Med. 1993;328(7):490-495. 8. Niewoehner CB, Nuttal FQ. Gynecomastia in a hospitalized male population. Am J Med. 1984;77(4):633-638. 9. Derkacz M, Chmiel-Perzynska I, Nowakowski A. Gynecomastia—a difficult diagnostic problem. Endokrynol Pol. 2011;62(2):190-202. 1 0. Thompson DF, Carter JR. Drug-induced gynecomastia. Pharmacotherapy. 1993;13(1):37-45. 1. Eckman A, Dobs A. Drug-induced gynecomastia. Expert Opin Drug Saf. 1 2008;7(6):691-702. 1 2. Roke Y, van Harten PN, Boot AM, Buitelaar JK. Antipsychotic medication in children and adolescents: a descriptive review of the effects on prolactin level and associated side effects. J Child Adolesc Psychopharmacol. 2009;19(4):403-414. 3 1. Den Hond E, Dhooge W, Bruckers L, et al. Internal exposures to pollutants and sexual maturation in Flemish adolescents. J Expo Sci Environ Epidemiol. 2011;21(3):224-233. 3 2. Laituri CA, Garey CL, Ostlie DJ, St Peter SD, Gittes GK, Snyder CL. Treatment of adolescent gynecomastia. J Pediatr Surg. 2010;45(3):650-654. 3 3. Rho YK, Kim BJ, Kim MN, Kang KS, Han HJ. Laser lipolysis with pulsed 1064 nm Nd:YAG laser for the treatment of gynecomastia. Int J Dermatol. 2009;48(12):1353-1359. 3 4. Kolitsas N, Tsambalas S, Dimitriadis F, et al. Gynecomastia as a first clinical sign of nonseminomatous germ cell tumor. Urol Int. 2011;87(2): 248-250. 3 5. Muñoz Carrasco R, Alvarez Benito M, Muñoz Gomariz E, Raya Povedano JL, Martínez Paredes M. Mammography and ultrasound in the evaluation of male breast disease. Eur Radiol. 2010;20(12):2797-2805. 1 3. Engbaek M, Hjerrild M, Hallas J, Jacobsen IA. The effect of low-dose spironolactone on resistant hypertension. J Am Soc Hypertens. 2010; 4(6):290-294. 3 6. Brinton LA, Carreon JD, Gierach GL, McGlynn KA, Gridley G. Etiologic factors for male breast cancer in the U.S. Veterans Affairs medical care system database. Breast Cancer Res Treat. 2010;119(1):185-192. 1 4. McKenna C, Burch J, Suekarran S, et al. A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure. Health Technol Assess. 2010;14(24):1-162. 3 7. Hanavadi S, Banerjee D, Monypenny IJ, Mansel RE. The role of tamoxifen in the management of gynaecomastia. Breast. 2006;15(2):276-280. 1 5. Henley DV, Lipson N, Korach KS, Bloch CA. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med. 2007;356(5):479-485. 3 8. Ozen H, Akyol F, Toktas G, et al. Is prophylactic breast radiotherapy necessary in all patients with prostate cancer and gynecomastia and/or breast pain? J Urol. 2010;184(2):519-524. 1 6. Goh SY, Loh KC. Gynaecomastia and the herbal tonic “Dong Quai”. Singapore Med J. 2001;42(3):115-116. 3 9. Parker LN, Gray DR, Lai MK, Levin ER. Treatment of gynecomastia with tamoxifen: a double-blind crossover study. Metabolism. 1986;35(8): 705-708. 7. Jameel JK, Kneeshaw PJ, Rao VS, Drew PJ. Gynaecomastia and the plant 1 product “Tribulis terrestris.” Breast. 2004;13(5):428-430. 4 0. McDermott MT, Hofeldt FD, Kidd GS. Tamoxifen therapy for painful idiopathic gynecomastia. South Med J. 1990;83(11):1283-1285. 1 8. Messina M. Soybean isoflavone exposure does not have feminizing effects on men: a critical examination of the clinical evidence. Fertil Steril. 2010;93(7):2095-2104. 4 1. Fradet Y, Egerdie B, Andersen M, et al. Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: a randomised, placebo-controlled, dose-response study. Eur Urol. 2007;52(1):106-114. 1 9. Toorians AW, Boyee TF, De Rooy J, Stolker LA, Hoogenboom RL. Gynaecomastia linked to the intake of a herbal supplement fortified with diethylstillbestrol. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2010;27(7):917-925. 2 0. Basaria S. Androgen abuse in athletes: detection and consequences. J Clin Endocrinol Metab. 2010;95(4):1533-1543. 2 1. Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006;1:42. 2 2. Harris M, Rizvi S, Hindmarsh J, Bryan R. Testicular tumour presenting as gynaecomastia. BMJ. 2006;332(7545):837. 2 3. Daniels IR, Layer GT. Testicular tumours presenting as gynaecomastia. Eur J Surg Oncol. 2003;29(5):437-439. 2 4. Muthusamy E. Hyperthyroidism with gynaecomastia, galactorrhoea and periodic paralysis. Singapore Med J. 1991;32(5):371-372. 2 5. Becker KL, Winnacker JL, Matthews MJ, Higgins GA Jr. Gynecomastia and hyperthyroidism. An endocrine and histological investigation. J Clin Endocrinol Metab. 1968;28(2):277-285. 2 6. Iglesias P, Carrero JJ, Díez JJ. Gonadal dysfunction in men with chronic kidney disease: clinical features, prognostic implications and therapeutic options. J Nephrol. 2012;25(1):31-42. 722  American Family Physician 4 2. Bedognetti D, Rubagotti A, Conti G, et al. An open, randomised, multicentre, phase 3 trial comparing the efficacy of two tamoxifen schedules in preventing gynaecomastia induced by bicalutamide monotherapy in prostate cancer patients. Eur Urol. 2010;57(2):238-245. 4 3. Mauras N, Bishop K, Merinbaum D, Emeribe U, Agbo F, Lowe E. Pharmacokinetics and pharmacodynamics of anastrozole in pubertal boys with recent-onset gynecomastia. J Clin Endocrinol Metab. 2009;94(8): 2975-2978. 4 4. Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, doubleblind, placebo-controlled trial. J Clin Endocrinol Metab. 2004;89(9): 4428-4433. 4 5. Cigna E, Tarallo M, Fino P, De Santo L, Scuderi N. Surgical correction of gynecomastia in thin patients. Aesthetic Plast Surg. 2011;35(4):439-445. 4 6. Colombo-Benkmann M, Buse B, Stern J, Herfarth C. Indications for and results of surgical therapy for male gynecomastia. Am J Surg. 1999;178 (1):60-63. Volume 85, Number 7 ◆ April 1, 2012
  8. 8. CONCISE REVIEW FOR CLINICIANS Gynecomastia: Pathophysiology, Evaluation, and Management Gynecomastia: Pathophysiology, Evaluation, and Management Ruth E. Johnson, MD, and M. Hassan Murad, MD, MPH On completion of this article, you should be able to: (1) recognize the different mechanisms and causative medications and conditions associated with gynecomastia, (2) demonstrate the ability to conduct a stepwise diagnostic approach to evaluate and diagnose most cases of gynecomastia, and (3) identify the available treatments for gynecomastia and assist patients in the process of decision making about treatment. Gynecomastia, defined as benign proliferation of male breast glandular tissue, is usually caused by increased estrogen activity, decreased testosterone activity, or the use of numerous medications. Although a fairly common presentation in the primary care setting and mostly of benign etiology, it can cause patients considerable anxiety. The initial step is to rule out pseudogynecomastia by careful history taking and physical examination. A stepwise approach that includes imaging and laboratory testing to exclude neoplasms and endocrinopathies may facilitate costeffective diagnosis. If results of all studies are normal, idiopathic gynecomastia is diagnosed. The evidence in this area is mainly of observational nature and lower quality. Mayo Clin Proc. 2009;84(11):1010-1015 G ynecomastia is defined as benign proliferation of male breast glandular tissue.1 Asymptomatic gynecomastia is very common and has a trimodal age distribution, occurring in neonatal, pubertal, and elderly males. The prevalence of asymptomatic gynecomastia is 60% to 90% in neonates, 50% to 60% in adolescents, and up to 70% in men aged 50 to 69 years.2-5 Prevalence of symptomatic gynecomastia is markedly lower. A screening for gynecomastia in 214 hospitalized adult men aged 27 to 92 years revealed that 65% had gynecomastia, defined in this study as nodule size greater than 2 cm; however, none of them were symptomatic.3 Variation in reported prevalence across studies is attributed to variations in the size of the palpable breast tissue used to define gynecomastia and to population characteristics such as age and setting of treatment (primary care vs referral clinics). The evaluation and management perspectives presented in this article do not pertain to physiologic neonatal and adolescent cases but rather to symptomatic adults who are concerned and seek evaluation and treatment. Although breast cancer is rare in men, those with gynecomastia often become anxious and seek medical attention, making this presentation fairly common in primary care settings. Diagnostic evaluation of these cases can be costly and involves laboratory and radiographic testing; therefore, a diagnostic algorithm that facilitates step-by-step evaluation may be cost-effective and reduce the associated patient anxiety. This article describes the pathophysiology and common mechanisms and causes of benign gynecomastia 1010 Mayo Clin Proc. • and introduces a diagnostic algorithm to facilitate evaluation and management of symptomatic cases that present in primary care settings. PATHOPHYSIOLOGY The imbalance between estrogen action relative to androgen action at the breast tissue level appears to be the main etiology of gynecomastia.6 Elevated serum estrogen levels may be a result of estrogen-secreting neoplasms or their precursors (eg, Leydig or Sertoli cell tumors, human chorionic gonadotropin [hCG]­ producing tumors, and – adrenocortical tumors) but more commonly are caused by increased extragonadal conversion of androgens to estrogens by tissue aromatase (as occurs in obesity). Levels of free serum testosterone are decreased in patients with gonadal failure, which can be primary (Klinefelter syndrome, mumps orchitis, castration) or secondary (hypothalamic and pituitary disease). Androgen resistance syndromes due to impaired activity of enzymes involved in the biosynthesis of testosterone can also be associated with gynecomastia.7 The balance between free testosterone and estrogen is also affected by serum levels of sex hormone–binding globulin, which is the proposed mechanism of gynecomastia in certain conditions, such as hyperthyroidism, chronic liver disease, and the use of some medications such as spironolactone.1 Receptors of androgens can also have genetic defects or become blocked by certain medications (eg, bicalutamide, used in the treatment of prostate cancer), and the receptors of estrogens can be activated by certain medications or environmental exposures.1 Of note, patients with pubertal gynecomastia have normal levels of serum estradiol, testosterone, and dehydroepiandrosteroneFrom the Division of Preventive, Occupational and Aerospace Medicine, Mayo Clinic, Rochester, MN. Individual reprints of this article are not available. Address correspondence to M. Hassan Murad, MD, MPH, Division of Preventive, Occupational and Aerospace Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (murad. © 2009 Mayo Foundation for Medical Education and Research November 2009;84(11):1010-1015 • For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  9. 9. Gynecomastia: Pathophysiology, Evaluation, and Management TABLE 1. Elements of Patient History and Physical Examination Relevant for Evaluation of Gynecomastia History Duration of symptoms Localized symptoms, such as a palpable mass, breast tenderness or enlargement, and nipple discharge History of an undescended testis, mumps, or liver or kidney disease Detailed history of medications, supplements, illicit drugs, anabolic steroids History of coping with potential distress caused by breast condition Physical examination Height, weight Signs of feminization, current Tanner stage Stigmata of liver disease Breast and overlying skin Regional lymph nodes Thyroid Scrotum sulfate and a normal estrogen-testosterone ratio. However, free testosterone levels in these patients are lower than those of controls without gynecomastia.8 Eventually, the exposure to the hormonal imbalance leads to proliferation of glandular tissues, ie, ductal hyperplasia. CLINICAL MANIFESTATIONS AND DIAGNOSIS Careful history taking and physical examination (the relevant elements of which are presented in Table 1) often reveal that patients actually are presenting with pseu­ dogynecomastia, which means accumulation of subareolar fat without real proliferation of glandular tissue. Examination of these patients reveals diffuse breast enlargement without a subareolar palpable nodule. These patients do not need additional work-up and only require reassurance. Gynecomastia is usually bilateral,3,9 but patients may present with asymmetrical or unilateral findings. Palpation usually demonstrates a palpable, tender, firm, mobile, disclike mound of tissues1,4 that is not as hard as breast cancer and is located centrally under the nipple-areolar complex. When palpable masses are unilateral, hard, fixed, peripheral to the nipple, and associated with nipple discharge, skin changes, or lymphadenopathy, breast cancer should be suspected and thorough evaluation is recommended. Anthropometric measurements (eg, body mass index) may also be helpful because obesity can be associated with increased peripheral conversion of androgens to estrogens and is associated with a higher prevalence of gynecomastia.3,10 The presence of varicoceles has also been strongly associated with gynecomastia.9 A family history of gynecomastia has been elicited in 58% of patients with persistent pubertal gynecomastia. History may also reveal a clear and temporal association Mayo Clin Proc. • with a causative drug and obviate the need for extensive and costly evaluation. If the association with a drug is unclear, then evaluation is recommended. Table 2 depicts the numerous medications that have been associated with gynecomastia. It has also been associated with the use of alcohol and illicit drugs, such as marijuana, heroin, methadone, and amphetamines.4 Several herbal supplements, particularly those containing phyto­ strogen, may e also cause gynecomastia.12 In one case series, history and physical examination detected a predisposing medical condition or causative medication in 83% of cases of gynecomastia.13 All breast cancer cases in that series presented with a dominant mass on clinical examination or other signs suggestive of malignancy. Diagnostic Approach After initial history and examination exclude pseudogynecomastia and other obvious explanatory conditions, mammography can differentiate true gynecomastia from a mass that requires tissue sampling to exclude malignancy. Mammography was found to be fairly accurate in distinguishing between malignant and benign male breast diseases and can substantially reduce the need for biopsies. The sensitivity and specificity of mammography for benign and malignant breast conditions exceed 90%; however, the positive predictive value for malignant conditions is low (55%) because of the low prevalence of malignancy in patients presenting with gynecomastia.14 TABLE 2. Drugs Associated With Gynecomastiaa Hormonesb Androgens, anabolic steroids, estrogens, estrogen agonists, and hCG Antiandrogens/ Bicalutamide, flutamide, nilutamide, inhibitors of cyproterone, and GRH agonists (leuprolide androgen synthesis and goserelin) Antibiotics Metronidazole, ketoconazole,b minocycline, isoniazid Antiulcer medications Cimetidine,b ranitidine, and omeprazole Chemotherapeutic Methotrexate, alkylating agents, and vinca agents alkaloids Cardiovascular drugs Digoxin,b ACEIs (eg, captopril and enalapril), calcium channel blockers (diltiazem, nifedipine, verapamil), amiodarone, methyldopa, spironolactone, reserpine, and minoxidil Psychoactive agents Anxiolytic agents (eg, diazepam), tricyclic antidepressants, phenothiazines, haloperidol, and atypical antipsychotic agents Miscellaneous Antiretroviral therapy for HIV, metoclopramide, penicillamine, phenytoin, sulindac, and theophylline a ACEI = angiotensin-converting enzyme inhibitor; GRH = gonadotropinreleasing hormone; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus. b Denotes stronger association. Adapted from N Engl J Med.1 November 2009;84(11):1010-1015 • For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a 1011
  10. 10. Gynecomastia: Pathophysiology, Evaluation, and Management Imaging of the scrotum is only recommended if palpable masses are present. Laboratory investigations are pursued in cases of true gynecomastia without clear explanation. Liver, kidney, and thyroid function tests exclude the respective medical conditions. Hormonal testing measures levels of total and bioavailable testosterone, estradiol, prolactin, luteinizing hormone, and hCG, and its findings can direct toward pituitary, gonadal, and extragonadal endocrinopathies and neoplasms as seen in the stepwise algorithm depicted in the Figure. If all testing is unrevealing, idiopathic gynecomastia is diagnosed. Differential Diagnosis The differential diagnosis of a palpable breast mass in a male patient includes pseudogynecomastia, gynecomastia, breast cancer, and numerous other benign conditions. A review of all mammographic findings for men for a period of 5 years at Mayo Clinic in Jacksonville, FL, revealed a 1% rate of malignancy. Most cases were due to benign causes; of these, gynecomastia represented 62%, with other causes including lipomas, dermoid cysts, sebaceous cysts, lymphoplasmacytic inflammation, ductal ectasia, hematomas, and fat necrosis.13 In contrast, the differential diagnosis of gynecomastia per se, as demonstrated in a series of young adult patients with gynecomastia aged 19 through 29 years, includes idiopathic gynecomastia (58%), hypogonadism (25%), hyperprolactinemia (9%), chronic liver disease (4%), and drug-induced gynecomastia (4%).10 The frequency distribution of these etiologies is imprecise because of the small number of cases reported in the literature and may vary widely across publications and practice settings. MANAGEMENT AND PROGNOSIS Overall, gynecomastia is a benign condition and is usually self-limited. Over time, fibrotic tissue replaces symptomatic proliferation of glandular tissue and tenderness resolves. If the appropriate work-up does not reveal considerable underlying pathology, reassurance and periodic follow-up are recommended. Although evidence is lacking to support a recommendation for follow-up intervals, 6 months seems reasonable. Causative medications should be withdrawn or the underlying causative medical conditions (eg, hyperthyroidism) should be addressed. Most cases of pubertal gynecomastia usually resolve in less than a year.8 If gynecomastia persists and is associated with pain or psychological distress and if the patient wishes to pursue treatment, pharmacological and surgical options are available. Pharmacotherapy is likely beneficial if implemented early before fibrous tissue replaces glandular tissue, whereas surgery can be performed at any time. 1012 Mayo Clin Proc. • Pharmacotherapy Several pharmacological agents have been used to manipulate the hormonal imbalances thought to cause gynecomastia. However, the studies that evaluated their efficacy were in general small and uncontrolled, making inference challenging. Estrogen receptor modifiers appear to be fairly safe and beneficial. Alagaratnam15 treated 61 Chinese men with tamoxifen for a median of 2 months with 36 months of follow-up, demonstrating an 84% rate of complete regression of breast swelling. Lawrence et al16 used a 3- to 9-month course of estrogen receptor modifiers (tamoxifen or raloxifene) to treat 38 consecutive patients with persistent pubertal gynecomastia and demonstrated a mean reduction in breast nodule diameter of 2.1 cm with no serious adverse effects. Similar results were reported in another case series of 37 patients who used tamoxifen; reductions in pain and nodule size were seen in all patients without long-term adverse effects.17 Dihydrotestosterone, danazol, clomiphene, and aromatase inhibitors such as testolactone and anastrozole may also have benefit but are less commonly studied and used.4 Overall, the use of all these drugs is supported by a very low quality of evidence, and the uncertainty about the balance of their benefits and harms should be highlighted to candidate patients. Surgical Correction Surgery is the criterion standard treatment for gynecomastia. The most commonly used technique is subcutaneous mastectomy that involves the direct resection of the glandular tissue using a periareolar or transareolar approach with or without associated liposuction. Liposuction alone may be sufficient if breast enlargement is purely due to excess fatty tissue without substantial glandular hypertrophy.18 Skin resection is needed for more advanced cases. In general, surgical treatment produces good cosmesis and is well tolerated. Newer, less invasive techniques that require minimal surgical incision have recently emerged and may offer faster recovery and lower rates of local complications.18-20 Histologic analysis is recommended in true gynecomastia corrections because unexpected histologic findings such as spindle-cell hemangioendothelioma and papilloma may occur in 3% of cases.21 Patients with gynecomastia have a favorable prognosis. These patients present with 2 main concerns: ruling out breast cancer and cosmetic correction. The first concern is adequately addressed by following the appropriate diagnostic evaluation. Breast cancer is rare in males, representing less than 1% of all cases of breast cancer; only 1% of mammograms in men reveal breast cancer.13 Therefore, the decision to treat and the choice of treatment should be November 2009;84(11):1010-1015 • For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  11. 11. Gynecomastia: Pathophysiology, Evaluation, and Management Pseudogynecomastia or obvious causative drug or condition History and physical examination Gynecomastia LFTs and calcium, creatine, and TSH assays Palpable scrotal mass Provide assurance, remove/treat cause, provide periodic follow-up Testicular US Suspect breast mass (hard, eccentric) Renal, hepatic, or thyroid disease Image-guided or surgical biopsy as needed Mammography Treat underlying disease Hormone testing (total and bioavailable T, E2, prolactin, LH, hCG assays) ↓T + ↑LH ↓T + ↓LH ↑hCG ↑Prl with or without ↓T and normal or low LH ↑E2 and normal to low LH Negative work-up Primary hypogonadism Secondary hypogonadism Testicular US MRI of the head Testicular US Idiopathic gynecomastia Testicular germ cell tumor Normal findings Pituitary adenoma, empty sella, or mass panhypopituitarism Mass (Leydig or Sertoli cell tumor) Normal findings CT of the abdomen Evaluate for: Extragonadal germ cell tumors (bronchogenic, hepatic, renal) Nontrophoblastic hCG-secreting tumors Adrenal neoplasm Normal findings Increased aromatase activity (obesity, adrenal or liver disease, thyrotoxicosis) Exogenous estrogens (eg, sex reassignment, phytoestrogens) FIGURE. Diagnostic algorithm for gynecomastia. CT = computed tomography; E2 = estradiol; hCG = human chorionic gonadotropin; LFT = liver function test; LH = luteinizing hormone; Prl = prolactin; T = testosterone; TSH = thyroid-stimulating hormone; US = ultrasonography. Adapted from N Engl J Med.11 Mayo Clin Proc. • November 2009;84(11):1010-1015 • For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a 1013
  12. 12. Gynecomastia: Pathophysiology, Evaluation, and Management based on the degree to which this condition has affected the quality of life and mental health of patients and on their desire for cosmetic correction. The body of research supporting the diagnostic approach and treatment strategies for gynecomastia consists of expert opinion, case series, and observational studies; hence, the evidence is considered to be of low to very low quality. By acknowledging this low quality of evidence when discussing testing and treatment options with patients, physicians allow room in the process of decision making for consideration of other factors, such as resources, availability of services, and patients’ values and preferences.22 18. Courtiss EH. Gynecomastia: analysis of 159 patients and current recommendations for treatment. Plast Reconstr Surg. 1987;79(5):740-753. 19. Prado AC, Castillo PF. Minimal surgical access to treat gynecomastia with the use of a power-assisted arthroscopic-endoscopic cartilage shaver. Plast Reconstr Surg. 2005;115(3):939-942. 20. Zhu J, Huang J. Surgical management of gynecomastia under endoscope. J Laparoendosc Adv Surg Techniq A. 2008;18(3):433-437. 21. Handschin AE, Bietry D, Hüsler R, Banic A, Constantinescu M. Surgical management of gynecomastia—a 10-year analysis. World J Surg. 2008; 32(1):38-44. 22. Swiglo BA, Murad MH, Schünemann HJ, et al. A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab. 2008 Mar;93(3):666-673. Epub 2008 Jan 2. CME Questions About Gynecomastia CONCLUSION The evaluation of gynecomastias can be complex. A stepwise approach that starts with careful history taking and physical examination may obviate the need for extensive work-up. Subsequent selective imaging and laboratory testing help exclude possible neoplasms and endocrinopathies. The etiology is usually benign. 1. Which one of the following statements best describes a typical presentation of gynecomastia? References 1. Braunstein GD. Gynecomastia. N Engl J Med. 2007;357(12):1229-1237. 2. Georgiadis E, Papandreou L, Evangelopoulou C, et al. Incidence of gynaecomastia in 954 young males and its relationship to somatometric parameters. Ann Hum Biol. 1994;21(6):579-587. 3. Niewoehner CB, Nuttal FQ. Gynecomastia in a hospitalized male population. Am J Med. 1984;77(4):633-638. 4. Nordt CA, DiVasta AD. Gynecomastia in adolescents. Curr Opin Pediatr. 2008;20(4):375-382. 5. McKiernan JF, Hull D. Breast development in the newborn. Arch Dis Child. 1981;56(7):525-529. 6. Braunstein GD. Aromatase and gynecomastia. Endocr Relat Cancer. 1999; 6(2):315-324. 7. Mathur R, Braunstein GD. Gynecomastia: pathomechanisms and treatment strategies. Horm Res. 1997;48(3):95-102. 8. Biro FM, Lucky AW, Huster GA, Morrison JA. Hormonal studies and physical maturation in adolescent gynecomastia. J Pediatr. 1990;116(3):450-455. 9. Kumanov P, Deepinder F, Robeva R, Tomova A, Li J, Agarwal A. Relationship of adolescent gynecomastia with varicocele and somatometric parameters: a cross-sectional study in 6200 healthy boys. J Adolesc Health. 2007;41(2):126-131. 10. Ersöz H, Onde ME, Terekeci H, Kurtoglu S, Tor H. Causes of gynaecomastia in young adult males and factors associated with idiopathic gynaecomastia. Int J Androl. 2002;25(5):312-316. 11. Braunstein GD. Gynecomastia. N Engl J Med. 1993;328(7):490-495. 12. Braunstein GD. Environmental gynecomastia [editorial]. Endocr Pract. 2008;14(4):409-410. 13. Hines SL, Tan WW, Yasrebi M, DePeri ER, Perez EA. The role of mammography in male patients with breast symptoms. Mayo Clin Proc. 2007;82(3): 297-300. 14. Evans GF, Anthony T, Turnage RH, et al. The diagnostic accuracy of mammography in the evaluation of male breast disease [published correction appears in Am J Surg. 2001;181(6):579]. Am J Surg. 2001;181:96-100. 15. Alagaratnam TT. Idiopathic gynecomastia treated with tamoxifen: a preliminary report. Clin Ther. 1987;9(5):483-487. 16. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr. 2004;145(1):71-76. 17. Derman O, Kanbur NO, Kutluk T. Tamoxifen treatment for pubertal gynecomastia. Int J Adolesc Med Health. 2003;15(4):359-363. 2. Which one of the following statements best describes the recommendations for gynecomastia evaluation? 1014 Mayo Clin Proc. • a. Unilateral peripheral mass b. Painless bilateral hard and fixed masses c. A mass associated with nipple discharge d. Bilateral painful masses in an anxious adolescent e. Bilateral masses with minimal axillary lymphadenopathy a. Diagnostic work-up for gynecomastia is recommended if initial history and findings on examination do not reveal an obvious cause b. Any case of gynecomastia requires laboratory tests and imaging to rule out endocrinopathies and malignancies c. A disclike mound of tissue just beneath the nipple-areolar complex is a feature of malignancy d. Breast pain is a sign of malignancy e. Mammography is recommended to rule out pseudogynecomastia 3. Which one of the following statements best describes the interpretation of laboratory results in patients with gynecomastia? a. Elevated luteinizing hormone and low testosterone levels suggest secondary hypogonadism b. Elevated levels of prolactin are common in gynecomastia and do not require additional evaluation c. Elevated levels of human chorionic gonadotropin (hCG) and normal findings on testicular ultrasonography indicate the need for evaluation for extragonadal hCG-secreting tumors d. Elevated estradiol levels with normal findings on testicular ultrasonography do not require additional work-up e. If results on all laboratory testing are normal, pseudogynecomastia is diagnosed November 2009;84(11):1010-1015 • For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  13. 13. Gynecomastia: Pathophysiology, Evaluation, and Management 4. Which one of the following statements best describes the available pharmacological agents for gynecomastia? a. Randomized trials have shown estrogen receptor modifiers to be safe and effective b. Tamoxifen is effective but produces serious adverse effects c. Tamoxifen treatment reduces the future risk of developing breast cancer d. Pharmacotherapy is most effective when instituted early e. Tamoxifen reduces breast size but is unlikely to resolve breast pain 5. Which one of the following statements best describes the surgical options available to treat gynecomastia? a. Surgical therapy for gynecomastia is the criterion standard for treatment of patients interested in cosmesis b. Liposuction is very effective for most cases of gynecomastia c. Mastectomy with axillary dissection is the treatment of choice for gynecomastia d. The newer endoscopic approach is only appropriate when the breast is enlarged primarily as a result of fat accumulation e. Resection of glandular tissue is always recommended because of the increased risk of neoplastic transformation of benign gynecomastia This activity was designated for 1 AMA PRA Category 1 Credit(s).™ Because the Concise Review for Clinicians contributions are now a CME activity, the answers to the questions will no longer be published in the print journal. For CME credit and the answers, see the link on our Web site at Mayo Clin Proc. • November 2009;84(11):1010-1015 • For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a 1015