Gynecomastia final

716 American Family Physician www.aafp.org/afp Volume 85, Number 7 ◆ April 1, 2012

GynecomastiaGRETCHEN DICKSON, MD, MBA, University of Kansas School of Medicine, Wichita, Kansas

lthough the adult male breast con-tains minimal amounts of adipose

and glandular tissue, there is poten-tial 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 prolif-eration of glandular breast tissue.1

Physiologic GynecomastiaPhysiologic 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 estro-gens.2 Newborn gynecomastia, although concerning to parents, usually resolves spon-taneously within four weeks of birth. Chil-dren 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 experi-ence 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 gyne-comastia in adolescents.5-7 Adolescents may also experience nonphysiologic gynecomas-tia 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 war-ranted to ameliorate emotional distress.

Decreasing free testosterone levels may contribute to a final peak in gynecomas-tia incidence in men older than 50 years. Although older men are less likely to present for evaluation of gynecomastia than ado-lescents, a study of hospitalized men esti-mates that approximately 65 percent of men between 50 and 80 years of age experience some degree of gynecomastia.8

Nonphysiologic GynecomastiaNonphysiologic 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 sub-stances 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.

Gynecomastia is defined as benign proliferation of glandular breast tissue in men. Physiologic gynecomastia is common in newborns, adolescents, and older men. It is self-limited, but can be treated to minimize emotional distress and physical discomfort. Nonphysiologic gyne-comastia may be caused by chronic conditions (e.g., cirrhosis, hypogonadism, renal insuf-ficiency); use of medications, supplements, or illicit drugs; and, rarely, tumors. Discontinuing use of contributing medications and treating underlying disease are the mainstay of treat-ment. Medications, such as estrogen receptor modulators, and surgery have a role in treating gynecomastia in select patients. Treatment should be pursued early and should be directed by the patient. (Am Fam Physician. 2012;85(7):716-722. Copyright © 2012 American Academy of Family Physicians.)

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Gynecomastia

April 1, 2012 ◆ Volume 85, Number 7 www.aafp.org/afp American Family Physician 717

MEDICATIONS AND SUBSTANCES

After persistent pubertal gynecomastia, medication use and substance use are the most common causes of non-physiologic gynecomastia. Agents associated with gyne-comastia 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 Trib-ulus terrestris (an ingredient in performance-enhancing

supplements) have been linked to gynecomastia.15-17 Although soy consumption is thought to be safe, con-suming 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 vari-ability in marketed preparations.19

Anabolic steroid use often causes irreversible gyne-comastia. The injection of exogenous testosterone inhibits natural production of testosterone, which can-not recover rapidly enough between steroid-injecting cycles to prevent estrogen predominance. Attempts to prevent gynecomastia with the use of concomitant

Table 1. Causes of Gynecomastia

Cause Frequency (%)

Physiologic gynecomastia 25

Idiopathic or unknown cause 25

Medication or substance use (Table 2) 10 to 25

Cirrhosis 8

Primary hypogonadism

5α-reductase deficiency

Androgen insensitivity syndrome

Congenital anorchia

Hemochromatosis

Klinefelter syndrome

Testicular torsion

Testicular trauma

Viral orchitis

8

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

3

Secondary hypogonadism

Kallmann syndrome

2

Hyperthyroidism 2

Chronic renal insufficiency 1

Other

Familial gynecomastia

Human immunodeficiency virus

Malnutrition and disorders of impaired absorption (e.g., ulcerative colitis, cystic fibrosis)

6

hCG = human chorionic gonadotropin.

Adapted with permission from Derkacz M, Chmiel-Perzynska I, Nowa-kowski A. Gynecomastia—a difficult diagnostic problem. Endokrynol Pol. 2011;62(2):191, with additional information from reference 1.

Table 2. Mechanism of Effect of Agents Commonly Associated with Gynecomastia

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.

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 gyne-comastia.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 estrogen-to-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 gonadotro-pin (hCG) in serum can be used to detect hCG-secreting tumors that 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.

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 gyne-comastia in men.27 Dialysis improves malnutrition- associated gynecomastia, but only renal transplant effec-tively resolves nutritional and hormonal causes of gyne-comastia 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 sup-presses hormone production, refeeding helps resume production. However, the liver lags in recovery and can-not fully degrade estrogens.9 As the liver recovers, gyne-comastia usually resolves within one to two years after resumption of a balanced diet.

Although obesity causes pseudogynecomastia (a pro-liferation of adipose rather than glandular tissue), ele-vated weight is also associated with true gynecomastia. New research suggests that leptin and aromatase activity associated with obesity contribute to increased circulat-ing 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 Tes-ticular injury from illnesses (e.g., mumps orchitis), infil-trative processes (e.g., tuberculosis, hemochromatosis), or trauma may decrease testosterone production and lead to gynecomastia. Additionally, patients with human immunodeficiency virus infection may develop gyneco-mastia from the disease process or use of antiretroviral medications. No cause is found in 25 percent of patients who develop gynecomastia.7,30,31

DiagnosisSome 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 physi-cal 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,

No cause is found in 25 percent of patients who develop gynecomastia.


and illicit drugs. Symptoms that last longer than one to two years suggest nonphysiologic causes that require intervention for resolu-tion. Nipple discharge; skin changes; rapidly enlarging, firm breast masses; coincident tes-ticular masses; or systemic symptoms such as weight loss should raise concern.

The physical examination should include evaluation of height and weight, and exami-nation of the breasts, genitals, liver, lymph nodes, and thyroid. Assessment of symmetry and consistency of breast tissue is critical on breast examination. Most commonly, gyneco-mastia is bilateral, although unilateral symp-toms 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 pseudogy-necomastia, whereas hard, immobile masses should be considered breast carcinoma until proven otherwise. Similarly, masses associ-ated with skin changes, nipple retraction, nipple discharge, or enlarged lymph nodes should raise concern for malignancy.

DIAGNOSTIC TESTING

The history and physical examination should direct the laboratory and imaging workup (Figure 1). Laboratory studies to investigate the underlying cause of gyne-comastia should include measurement of hepatic transaminase, serum creatinine, and thyroid-stimulating hormone levels for all patients. Levels of serum beta hCG, serum dehydroepiandrosterone sulfate, or urinary 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-stimulating hormone levels define hormonal imbalances resulting from primary or secondary hypogonadism. Hyperprolactinemia is not common in patients with gyne-comastia. Laboratory studies may be ordered using a step-wise approach guided by history and physical examination, but a diagnosis of physiologic gynecomastia should not be made until underlying etiologies have been excluded.

Recommendations for imaging studies are based mainly on case reports and expert opinion. Some stud-ies have suggested routine testicular ultrasonogra-phy in men with gynecomastia to detect nonpalpable

testicular tumors that were missed on clinical examina-tion.34 However, a more widely advocated, conservative approach is to perform testicular ultrasonography only in those with palpable testicular masses, gynecomastia larger than 5 cm, or otherwise unexplained gynecomas-tia. Breast imaging should be guided by examination. Just as in women, mammography and breast ultrasonog-raphy may be useful in men if the physical examination raises suspicion for breast malignancy.35

Fine-needle aspiration of masses for cytology should be pursued only if malignancy is suspected. Men with Klinefelter syndrome have a risk of breast cancer 16 to

Table 3. Diagnoses in Men Referred for Imaging or Biopsy Because of Breast Enlargement

Diagnosis Frequency (%) Findings

Gynecomastia 63 to 93 Discrete, round, mobile mass under areola; usually bilateral

Pseudogynecomastia 5.4 Increased adipose rather than glandular tissue on examination

Breast cancer 1.4 to 2.9 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

Lipoma 0.9 to 2.9 Asymmetric breast enlargement

Sebaceous cyst 1.4 to 2 Drainage of material from site

Swelling feels closer to skin than a part of deeper tissue

Asymmetric breast enlargement

Mastitis 0.8 to 1.1 Systemic signs of infection

Fat necrosis 0.3 to 0.9 History of injury to the area may be present

May be a local swelling, not over nipple areolar complex


Dermoid cyst 0.9 Painless lump that may enlarge; may be anywhere in the breast

Hematoma 0.9 History of injury to the area may be present


Metastatic disease 0.8 History of cancer

Ductal ectasia 0.5 Nonspecific breast tenderness

Hamartoma 0.5 Solid mass; diagnosis made with pathologic examination

Lymphoplasmacytic inflammation

0.5 Diagnosis made on pathology specimen after removal of mass

Postsurgical changes

0.5 History of surgery

Information from references 31 through 33.

Gynecomastia


30 times higher than other men. Even with a reassuring examination, men with gynecomastia and Klinefelter syndrome may require imaging.7,36

TreatmentFew patients with gynecomastia need treatment for cos-mesis or analgesia.37 In a study on treatment for gyne-comastia, 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 gyne-comastia, treatment is directed toward improving the

underlying illness or discontinuing use of the contribut-ing. Watchful waiting with biannual follow-up is appro-priate for those with physiologic gynecomastia who are untroubled by symptoms and who have no features that suggest underlying disease or malignancy. Early treat-ment will maximize benefit in men with significant physical symptoms or emotional distress. Medications are more effective if used as early as possible after symp-toms are first noted, whereas surgery can be performed at any time with similar results.

A number of medications have been used to treat gyne-comastia. A retrospective chart review of men presenting

Diagnosis of Gynecomastia

Figure 1. Algorithm for the diagnosis of gynecomastia.

Patient presents with breast enlargement

Is the patient a newborn? Likely transplacental; should resolve within four weeks

Yes

Yes

Yes

No

No

No

Is the patient taking a medication or substance listed in Table 2?

Discontinue agent and monitor for resolution

Perform physical examination

Evidence of chronic disease? Treat underlying disease

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

Ultrasonography results normal

Consider exogenous estrogen use, stress, or underlying chronic disease as possible cause

High level of prolactin

Perform magnetic resonance imaging for pituitary adenoma

High level of human chorionic gonadotropin

Perform testicular ultrasonography for germ cell tumor

Low levels of luteinizing hormone and testosterone


High level of luteinizing hormone and low level of testosterone


All hormone levels normal

Idiopathic gynecomastia

Pseudogynecomastia

Recommend weight loss

Gynecomastia

Test hepatic function and measure creatinine and thyroid-stimulating hormone levels

Unremarkable examination

Provide reassurance

Breast mass that raises suspicion for malignancy

Perform mammography and breast ultrasonography with biopsy

Testicular mass

Perform testicular ultrasonography

Gynecomastia


to a breast clinic for gynecomastia found that only 13 of 220 patients required medication for treatment. Patients were treated with 10 mg of tamoxifen per day for three months, and 10 of the 13 had resolution of pain and breast enlargement.37 Although tamoxifen is thought to be an effective and safe treatment for physiologic, per-sistent pubertal, or idiopathic gynecomastia, two small double-blind, crossover trials found only modest benefit when compared with placebo.39,40

Gynecomastia is a common adverse effect of bicalu-tamide (Casodex) therapy that may prompt some men to discontinue prostate cancer treatment. Tamoxifen has been recommended as a preventive agent for gyne-comastia in these patients. A double-blind study of 282 men randomized to receive 20 mg of tamoxifen once per day with bicalutamide or bicalutamide alone found that after six months, gynecomastia and breast pain were significantly reduced in men who received tamoxifen (8.8 versus 96.7 percent in the control group).41 An Italian randomized controlled trial of 80 participants also found that 20 mg of tamoxifen once per week is as effective as 20 mg once per day.42

In a retrospective chart review of 38 patients in a pedi-atric endocrinology clinic, raloxifene (Evista; 60 mg once per day for three to nine months) reduced pubertal gynecomastia in 91 percent of patients, whereas tamoxi-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 of pubertal gynecomastia (i.e., self-limited), placebo- controlled trials are still needed. Dihydrotestosterone, danazol, and clomiphene (Clomid) have also been used to treat gynecomastia with varying success.

More studies are needed to assess the effectiveness of aromatase inhibitors, such as anastrozole (Arimidex; 1 mg per day). 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 par-ticipants demonstrated no statistically significant difference between anastrozole 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 to reduce breast tissue, and a number of techniques have been used.32,33,45 Longer duration of symptoms, higher-grade dis-ease, or inability to tolerate medications may prompt surgery as a first-line option.

However, unilateral symptoms, high-grade disease, and long duration of symptoms are also associated with more surgical complications.46

If pseudogynecomastia is suspected, no workup is needed, and the patient can be reassured that weight loss will lead to resolution of pseudogynecomastia and also be most beneficial for overall health.46 If necessary, lipo-suction procedures can reduce breast enlargement sec-ondary to subareolar fat accumulation.

The author thanks Anne Walling, MD, and Scott Moser, MD, for their assistance with this manuscript.

Data Sources: Essential Evidence Plus and PubMed were searched for relevant articles using the following search terms: gynecomastia, physi-ologic gynecomastia, and breast enlargement. Each term was searched individually and in conjunction with the following terms: males, men, diagnosis, treatment, and management. A search using the same words was also completed within http://www.guidelines.gov and the Cochrane collection. Search dates: December 10 to 25, 2010.

The Author

GRETCHEN DICKSON, MD, MBA, is director of the Family Medicine Clerk-ship, and assistant professor of family medicine at the University of Kansas School of Medicine in Wichita.

Address correspondence to Gretchen Dickson, MD, MBA, University of Kansas School of Medicine, 1010 N. Kansas, Wichita, KS 67214 (e-mail: [email protected]). Reprints are not available from the author.

Author disclosure: No relevant financial affiliations to disclose.

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence rating References

Discontinuing use of spironolactone (Aldactone) often results in regression of breast tissue within three months.

B 13, 14

Routine testicular ultrasonography should be considered in men with gynecomastia to detect nonpalpable testicular tumors that were missed on clinical examination.

C 34

Mammography and breast ultrasonography should be performed in men if the physical examination raises suspicion for breast cancer.

C 35

Tamoxifen and raloxifene (Evista) are effective for preventing and treating gynecomastia in men being treated for prostate cancer.

B 4, 37, 42

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

Gynecomastia


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39. Parker LN, Gray DR, Lai MK, Levin ER. Treatment of gynecomastia with tamoxifen: a double-blind crossover study. Metabolism. 1986;35(8): 705-708.

40. McDermott MT, Hofeldt FD, Kidd GS. Tamoxifen therapy for painful idiopathic gynecomastia. South Med J. 1990;83(11):1283-1285.

41. Fradet Y, Egerdie B, Andersen M, et al. Tamoxifen as prophylaxis for pre-vention 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.

42. Bedognetti D, Rubagotti A, Conti G, et al. An open, randomised, multi-centre, 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.

43. Mauras N, Bishop K, Merinbaum D, Emeribe U, Agbo F, Lowe E. Phar-macokinetics and pharmacodynamics of anastrozole in pubertal boys with recent-onset gynecomastia. J Clin Endocrinol Metab. 2009;94(8): 2975-2978.

44. Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2004;89(9): 4428-4433.

45. 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.

46. 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.

Mayo Clin Proc. • November 2009;84(11):1010-1015 • www.mayoclinicproceedings.com1010

Gynecomastia: PathoPhysioloGy, evaluation, and manaGement

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedingsa .

Gynecomastia: Pathophysiology, Evaluation, and Management

concise RevieW FoR clinicians

Ruth E. Johnson, MD, and M. Hassan Murad, MD, MPH

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 medi-cations. 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 pseudogyne-comastia by careful history taking and physical examination. A stepwise approach that includes imaging and laboratory testing to exclude neoplasms and endocrinopathies may facilitate cost-effective 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

From 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 Aero-space Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).

© 2009 Mayo Foundation for Medical Education and Research

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 is defined as benign proliferation of male breast glandular tissue.1 Asymptomatic gyne-

comastia is very common and has a trimodal age distri-bution, 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 symp-tomatic 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 treat-ment (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 gyne-comastia 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 evalua-tion may be cost-effective and reduce the associated patient anxiety. This article describes the pathophysiology and common mechanisms and causes of benign gynecomastia

and introduces a diagnostic algorithm to facilitate evalua-tion and management of symptomatic cases that present in primary care settings.

PATHOPHYSIOLOGY

The imbalance between estrogen action relative to an-drogen 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). Lev-els of free serum testosterone are decreased in patients with gonadal failure, which can be primary (Klinefelter syndrome, mumps orchitis, castration) or secondary (hy-pothalamic 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 gyneco-mastia 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 medica-tions (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 dehydroepiandrosterone-

Mayo Clin Proc. • November 2009;84(11):1010-1015 • www.mayoclinicproceedings.com 1011



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 rel-evant elements of which are presented in Table 1) often reveal that patients actually are presenting with pseu-dogynecomastia, which means accumulation of sub-areolar fat without real proliferation of glandular tissue. Examination of these patients reveals diffuse breast en-largement without a subareolar palpable nodule. These patients do not need additional work-up and only require reassurance. Gynecomastia is usually bilateral,3,9 but pa-tients may present with asymmetrical or unilateral find-ings. 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 unilat-eral, hard, fixed, peripheral to the nipple, and associated with nipple discharge, skin changes, or lymphadenopathy, breast cancer should be suspected and thorough evalua-tion 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 varico-celes has also been strongly associated with gynecomas-tia.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

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 supple-ments, particularly those containing phyto estrogen, may also cause gynecomastia.12

In one case series, history and physical examination de-tected a predisposing medical condition or causative medi-cation in 83% of cases of gynecomastia.13 All breast cancer cases in that series presented with a dominant mass on clini-cal examination or other signs suggestive of malignancy.

Diagnostic approach

After initial history and examination exclude pseudogy-necomastia and other obvious explanatory conditions, mammography can differentiate true gynecomastia from a mass that requires tissue sampling to exclude malig-nancy. 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 mammogra-phy 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 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

TABLE 2. Drugs Associated With Gynecomastiaa

Hormonesb Androgens, anabolic steroids, estrogens, estrogen agonists, and hCGAntiandrogens/ Bicalutamide, flutamide, nilutamide, inhibitors of cyproterone, and GRH agonists (leuprolide androgen synthesis and goserelin)Antibiotics Metronidazole, ketoconazole,b minocycline, isoniazidAntiulcer medications Cimetidine,b ranitidine, and omeprazoleChemotherapeutic Methotrexate, alkylating agents, and vinca agents alkaloidsCardiovascular drugs Digoxin,b ACEIs (eg, captopril and enalapril), calcium channel blockers (diltiazem, nifedipine, verapamil), amiodarone, methyldopa, spironolactone, reserpine, and minoxidilPsychoactive 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 = gonadotropin-releasing hormone; hCG = human chorionic gonadotropin; HIV = hu-man immunodeficiency virus.

b Denotes stronger association.Adapted from N Engl J Med.1




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 pi-tuitary, gonadal, and extragonadal endocrinopathies and neoplasms as seen in the stepwise algorithm depicted in the Figure. If all testing is unrevealing, idiopathic gyneco-mastia 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 re-view 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, lym-phoplasmacytic 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 frequen-cy 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 symptomat-ic proliferation of glandular tissue and tenderness resolves. If the appropriate work-up does not reveal considerable un-derlying 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, hyper-thyroidism) should be addressed. Most cases of pubertal gynecomastia usually resolve in less than a year.8 If gyne-comastia persists and is associated with pain or psycho-logical distress and if the patient wishes to pursue treat-ment, 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.

pharmacotherapy

Several pharmacological agents have been used to manip-ulate the hormonal imbalances thought to cause gyneco-mastia. 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 ta-moxifen for a median of 2 months with 36 months of fol-low-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 ralox-ifene) to treat 38 consecutive patients with persistent pu-bertal 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 ad-verse effects.17

Dihydrotestosterone, danazol, clomiphene, and aro-matase 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 bal-ance of their benefits and harms should be highlighted to candidate patients.

surgical correction

Surgery is the criterion standard treatment for gynecomas-tia. The most commonly used technique is subcutaneous mastectomy that involves the direct resection of the glandu-lar 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 com-plications.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 di-agnostic evaluation. Breast cancer is rare in males, repre-senting 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




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

Pseudogynecomastia or obvious causative drug

or condition

LFTs and calcium, creatine, and TSH assays

Treat underlying disease

Renal, hepatic, or thyroid disease

Image-guided or surgical biopsy as

neededMammography

Palpable scrotal mass

Provide assurance, remove/treat cause,

provide periodic follow-up

Testicular US

Suspect breast mass (hard, eccentric)Gynecomastia

Hormone testing (total and bioavailable T, E2, prolactin,

LH, hCG assays)

History and physical examination

↑hCG↓T + ↑LH ↓T + ↓LH↑Prl with or

without ↓T and normal or low LH

↑E2 and normal to low LH

Negative work-up

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

Adrenal neoplasm

Normal findings

Increased aromatase activity (obesity, adrenal or liver disease, thyrotoxicosis)Exogenous estrogens (eg, sex reassignment, phytoestrogens)

Evaluate for:Extragonadal germ cell tumors (bronchogenic, hepatic, renal)Nontrophoblastic hCG-secreting tumors


Testicular US MRI of the head Testicular US




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 sup-porting 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

CONCLUSION

The evaluation of gynecomastias can be complex. A step-wise 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 endocrinopa-thies. The etiology is usually benign.

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 gy-naecomastia in 954 young males and its relationship to somatometric param-eters. Ann Hum Biol. 1994;21(6):579-587. 3. Niewoehner CB, Nuttal FQ. Gynecomastia in a hospitalized male popu-lation. Am J Med. 1984;77(4):633-638. 4. Nordt CA, DiVasta AD. Gynecomastia in adolescents. Curr Opin Pe-diatr. 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 treat-ment strategies. Horm Res. 1997;48(3):95-102. 8. Biro FM, Lucky AW, Huster GA, Morrison JA. Hormonal studies and phys-ical maturation in adolescent gynecomastia. J Pediatr. 1990;116(3):450-455. 9. Kumanov P, Deepinder F, Robeva R, Tomova A, Li J, Agarwal A. Re-lationship 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 gynaeco-mastia in young adult males and factors associated with idiopathic gynaeco-mastia. 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 mam-mography 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 pre-liminary report. Clin Ther. 1987;9(5):483-487. 16. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Beneficial ef-fects 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 gy-necomastia. Int J Adolesc Med Health. 2003;15(4):359-363.

CME Questions About Gynecomastia

1. Which one of the following statements best describes a typical presentation of gynecomastia?

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

2. Which one of the following statements best describes the recommendations for gynecomastia evaluation?

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

18. Courtiss EH. Gynecomastia: analysis of 159 patients and current recom-mendations 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 endo-scope. J Laparoendosc Adv Surg Techniq A. 2008;18(3):433-437. 21. Handschin AE, Bietry D, Hüsler R, Banic A, Constantinescu M. Surgi-cal 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, consis-tency, and helpfulness: state-of-the-art clinical practice guidelines in endocri-nology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab. 2008 Mar;93(3):666-673. Epub 2008 Jan 2.




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 mayoclinicproceedings.com.

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