Gynecomastia

Updated: Feb 14, 2022
  • Author: George Ansstas, MD; Chief Editor: George T Griffing, MD  more...
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Overview

Practice Essentials

Gynecomastia is a benign enlargement of the male breast (usually bilateral but sometimes unilateral) resulting from a proliferation of the glandular component of the breast (see the image below). It is defined clinically by the presence of a rubbery or firm mass extending concentrically from the nipples. Gynecomastia should be differentiated from pseudogynecomastia (lipomastia), which is characterized by fat deposition without glandular proliferation.

Adolescent gynecomastia. Adolescent gynecomastia.

Signs and symptoms

A thorough history should be obtained that addresses the following:

  • Age of onset and duration of the condition

  • Any recent changes in nipple size and any pain or discharge from the nipples

  • History of mumps, testicular trauma, alcohol use, or drug use

  • Family history of gynecomastia

  • History of sexual dysfunction, infertility, or hypogonadism

Physical examination should include the following:

  • Thorough examination of the breasts, with attention to size and consistency

  • Assessment for any nipple discharge or axillary lymphadenopathy

  • Testing to differentiate between true gynecomastia and pseudogynecomastia

  • Assessment of glandular tissue

  • Examination of the testicles, with attention to size and consistency, as well as nodules or asymmetry

  • Observation of any signs of feminization

  • Checking for any stigmata of chronic liver disease, thyroid disease, or renal disease

Hematoma, lipoma, male sexual dysfunction, and neurofibroma can be included in the differential diagnosis.

See Clinical Presentation for more detail.

Diagnosis

Patients with physiologic gynecomastia do not require further evaluation. Similarly, asymptomatic and pubertal gynecomastia do not require further tests and should be reevaluated in 6 months. Further evaluation is necessary in the following situations:

  • Breast size greater than 5 cm (macromastia)

  • A lump that is tender, of recent onset, progressive, or of unknown duration

  • Signs of malignancy (eg, hard or fixed lymph nodes or positive lymph node findings)

Laboratory tests that may be considered include the following:

  • Serum chemistry panel

  • Free or total testosterone, luteinizing hormone (LH), estradiol, and dehydroepiandrosterone sulfate levels

  • Thyroid-stimulating hormone (TSH) and free thyroxine levels

Imaging studies that may be helpful include the following:

  • Mammography: Indicated if one or more features of breast cancer are apparent upon clinical examination, [1] followed by fine-needle aspiration or breast biopsy as appropriate [2, 3]

  • Testicular ultrasonography: Indicated if the serum estradiol level is elevated and the clinical examination findings suggest the possibility of a testicular neoplasm

  • Breast ultrasonography (though the positive predictive value of imaging in males is low [4] )

  • CT: Gynecomastia is often reported on CT scans

See Workup for more detail.

Management

General management considerations are as follows:

  • As a rule, no treatment is required for physiologic gynecomastia

  • Pubertal gynecomastia resolves spontaneously within several weeks to 3 years in most patients; breasts larger than 4 cm in diameter may not regress completely

  • Identifying and managing an underlying primary disorder often alleviates breast enlargement

  • For patients with idiopathic gynecomastia or with residual gynecomastia after treatment of the primary cause, medical or surgical treatment may be considered.

  • If medical therapies are used, they should be tried early in the condition’s course

Pharmacologic agents used to treat gynecomastia include the following:

  • Clomiphene

  • Tamoxifen

  • Danazol (less frequently used)

Surgical approaches that may be considered include the following:

  • Reduction mammoplasty: Considered in cases of macromastia, long-standing gynecomastia, or failed medical therapy, as well as for cosmetic reasons

  • More extensive plastic surgery: May be considered in cases of marked gynecomastia or excessive sagging of the breast tissue from weight loss

  • Endoscopic subcutaneous mastectomy, without skin excision [5]

Surgical complications may include the following:

  • Sloughing of tissue due to a compromised blood supply

  • Contour irregularity

  • Hematoma or seroma formation

  • Permanent numbness in the nipple-areolar area

See Treatment and Medication for more detail.

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Background

Gynecomastia is a benign enlargement of the male breast resulting from a proliferation of the glandular component of the breast (see the image below). Gynecomastia is defined clinically by the presence of a rubbery or firm mass extending concentrically from the nipples. Although the condition is usually bilateral, it can be unilateral. The condition known as pseudogynecomastia, or lipomastia, is characterized by fat deposition without glandular proliferation. (See Etiology, Presentation, and Workup.)

Adolescent gynecomastia. Adolescent gynecomastia.

Patient education

Reassure patients with physiologic gynecomastia regarding the benign nature of their condition, and inform them that most cases spontaneously resolve. (See Prognosis.)

Counsel patients regarding the various treatment modalities available for gynecomastia, and highlight the risks, adverse effects, success rates, and benefits of each modality. For patient education information, see the Men's Health Center. (See Treatment and Medication.)

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Etiology

Gynecomastia results from an altered estrogen-androgen balance, in favor of estrogen, or from increased breast sensitivity to a normal circulating estrogen level. [6] The imbalance is between the stimulatory effect of estrogen and the inhibitory effect of androgen. (The normal production ratio of testosterone to estrogen is approximately 100:1; the normal ratio of testosterone to estrogen in the circulation is approximately 300:1.)

Estrogens induce ductal epithelial hyperplasia, [7] ductal elongation and branching, proliferation of the periductal fibroblasts, and an increase in vascularity. The histologic picture is similar in male and female breast tissue after exposure to estrogen. [8]

Estrogen production in males results mainly from the peripheral conversion of androgens (testosterone and androstenedione) to estradiol and estrone, which occurs through the action of the enzyme aromatase (mainly in muscle, skin, and adipose tissue). The testes secrete only 6-10 mg of estradiol and 2.5 mg of estrone per day. Since this only comprises a small fraction of estrogens in circulation (ie, 15% of estradiol and 5% of estrone), the remainder of estrogen in males is derived from the extraglandular aromatization of testosterone and androstenedione to estradiol and estrone. Thus, any cause of estrogen excess from overproduction to peripheral aromatization of androgens can initiate the cascade to breast development.

Increased estrogen production and/or action can occur at the testicular level or at the periphery and is characterized as follows:

  • From the testes - Can be due to testicular tumors or to ectopic production of human chorionic gonadotropin (hCG), as is reported with carcinoma of lung, kidney, gastrointestinal (GI) tract, and extragonadal germ cell tumors

  • From peripheral conversion - Can be due to increased substrate or increased activity of aromatase, as in chronic liver disease, malnutrition, hyperthyroidism, adrenal tumors, and familial gynecomastia

Gynecomastia can be physiologic or pathologic. [9, 10] Physiologic gynecomastia is seen in newborn infants, pubescent adolescents, [11, 12] and elderly individuals.

A study by Reinehr et al of pubertal boys indicated that those with gynecomastia have a significantly higher estradiol/testosterone ratio than do those with pseudogynecomastia and healthy controls without breast enlargement, the median ratios being 22, 12, and 18, respectively. In addition, a significantly lower testosterone concentration was found in boys with gynecomastia than in the other two groups. [13]

Gynecomastia in adults is often multifactorial. Increased aromatization of testosterone to estradiol and the gradual decrease of testosterone production in the aging testes most often account for gynecomastia in adult males. Older men are also more likely to take medications associated with gynecomastia than are younger men.

Rarely, hyperprolactinemia may lead to gynecomastia through its effects on the hypothalamus to cause central hypogonadism. [14, 15] Prolactin has also been reported to decrease androgen receptors and increase estrogen and progesterone receptors in breast cancer cells, which can lead to male gynecomastia. Prolactin itself stimulates milk production in breast tissue that has been primed by estrogen and progesterone, but it does not directly cause gynecomastia itself.

Pathologic gynecomastia

Pathologic gynecomastia can be caused by an increase in the production and/or action of estrogen, by a decrease in the production and/or action of testosterone accompanied by increased aromatization and high estrogen, or by drug use. However, gynecomastia can also be idiopathic. [6]

Pathologic decrease of androgen or increase of estrogen can be illustrated as following:

Decreased androgen action

  • Decreased production

  • Increased sex-hormone binding globulin (SHBG) – binds testosterone > estrogen favoring greater peripheral estrogen action

  • Androgen receptor antagonism

Increased estrogen action

  • Increased aromatization of androgens to estrogens

  • Increased androgenic precursors (dehydroepiandrosterone [DHEA] and androstenedione)

  • Increased SHBG – binds testosterone > estrogen favoring greater peripheral estrogen action

  • Estrogen receptor agonism

Conditions that result in primary or secondary hypogonadism can lead to gynecomastia in different mechanisms. Primary hypogonadism can be related to a congenital abnormality such as Klinefelter syndrome, an enzymatic defect in testosterone biosynthesis, infection, infiltrative disorders, testicular trauma, or aging. The associated reduction in testosterone production leads to a decrease in the serum testosterone concentration and a compensatory rise in leuteinizing hormone (LH) release. The excess LH results in enhanced Leydig cell stimulation with inhibition of the 17,20-lyase and 17-hydroxylase activities and increased aromatization of testosterone to estradiol; the net effect is an increase in estradiol relative to testosterone secretion. [16]

Secondary hypogonadism due to a hypothalamic or pituitary abnormality may also be associated with gynecomastia. In these patients, the production of LH is deficient, resulting in a low testosterone production rate and low estradiol production from the testes. However, the adrenal cortex continues to produce estrogen precursors that are aromatized in extraglandular tissue; the result is an estrogen/androgen imbalance.

The following are some of the conditions associated with gynecomastia:

  • Klinefelter syndrome

  • Congenital anorchia

  • Testicular trauma

  • Viral orchitis

  • Kallmann syndrome: A form of hypogonadotropic hypogonadism, Kallmann syndrome is usually associated with varying degrees of abnormality in olfactory perception; this results from the defective migration of gonadotropin-releasing hormone–secreting cells (which co-migrate with the cells of the olfactory epithelium) during embryogenesis.

  • Pituitary tumors or abnormalities such as the ones that lead to either hypersecretion or hyposecretion of LH

  • Malignancies that increase the serum level of hCG (eg, large cell lung cancer, gastric carcinoma, renal cell carcinoma, hepatoma) [6]

  • Renal failure: Men with end-stage renal disease may have reduced testosterone and elevated gonadotropin values. This apparent primary testicular failure may then lead to increased breast development. [6]

  • Hyperthyroidism: Gynecomastia seen with hyperthyroidism is due to increased aromatase activity and increased levels of SHBG. SHBG binds androgens more avidly than estrogen, allowing for higher free levels to act on peripheral tissues such as the breast.

  • Malnutrition: Gynecomastia seen with malnutrition and starvation is probably due to reduced gonadotropin and testosterone levels relative to estrogen and may worsen with refeeding, owing to a rise in estradiol production that outpaces the increases in gonadotropin and testosterone.

  • Environmental pollutants: The most likely mechanism is through estrogen receptor binding and activation.

  • Androgen insensitivity syndrome

  • Aromatase excess syndrome: Familial prepubertal gynecomastia is a rare autosomal dominant inherited disorder that results in an excess estrogen state due to increased aromatase activity. This disorder appears to be due to heterozygous inversion or polymorphisms of the P450 aromatase gene. The phenotypic picture was described in an 8-year-old boy with accelerated growth and bone maturation with severe feminization and gynecomastia due to high rate conversion of plasma androstenedione to estrone. [17]

Various drugs are implicated in gynecomastia and can be classified into categories (although drugs in the same class do not all cause gynecomastia to the same extent). [18, 19, 20]

Of note, the pathophysiologic mechanism for some drugs, such as estrogens or antiandrogens, is quite clear. However, for others such as spironolactone, the mechanism is more complex. Spironolactone can increase the aromatization of testosterone to estradiol, decrease testosterone production by the testes, increasing the rate of testosterone clearance by displacing it from SHBG, and also binding to androgen receptors leading to gynecomastia through estrogen/testosterone imbalance. Another example is tea tree oil, which possesses weak estrogenic and antiandrogenic activities that may contribute to an imbalance in estrogen and androgen pathway signaling. Estrogenic or antiandrogenic activities have been reported for other essential oils and some of their monoterpene constituents. [21]

Antiandrogen/inhibitors of androgen synthesis are as follows:

  • Cyproterone acetate

  • Flutamide, bicalutamide, nilutamide

  • Finasteride, dutasteride: A study by Hagberg et al indicated that dutasteride carries a greater risk of gynecomastia than does finasteride [22]

  • Ketoconazole

  • Spironolactone

  • Tea tree oil

Cancer/chemotherapeutic drugs are as follows:

  • Alkylating agents

  • Methotrexate

  • Vinca alkaloids

  • Imatinib

Cardiac and antihypertensive medications are as follows:

  • Calcium channel blockers (verapamil, nifedipine, diltiazem)

  • ACE Inhibitors (captopril, enalapril)

  • Digoxin

  • Alpha-blockers

  • Amiodarone

  • Methyldopa

  • Reserpine

  • Nitrates

Hormones are as follows:

  • Androgens

  • Anabolic steroids

  • Estrogens

  • Growth hormones

  • Chorionic gonadotropin

Psychoactive drugs are as follows:

  • Haloperidol

  • Diazepam

  • Tricyclic antidepressants

  • Haloperidol

  • Phenothiazines

Drugs for infectious diseases are as follows:

  • Antiretroviral therapy for HIV/AIDS (eg, indinavir) [23, 24]

  • Isoniazid

  • Ethionamide

  • Griseofulvin

  • Minocycline

  • Metronidazole

  • Ketoconazole

Drugs of abuse are as follows:

  • Amphetamines

  • Heroin

  • Methadone

  • Alcohol

  • Marijuana

Others are as follows:

  • Theophylline

  • Omeprazole

  • Auranofin

  • Diethylpropion

  • Domperidone

  • Penicillamine

  • Sulindac

  • Heparin

  • Methotrexate

Drugs can also be stratified depending on the evidence that supports their association with gynecomastia, as follows:

  • Probable - Estrogenlike or estrogen receptor binders, verapamil with relative risk (RR) of 9.7, spironolactone (RR of 9.3), cimetidine (RR of 7.2), finasteride, and ketoconazole

  • Possible - Digoxin (RR of 2.7), nifedipine (RR of 2.9), cytotoxic agents, and marijuana

  • Uncertain (reported but could be coincidental) - Nitrates, alfa-blockers, and diazepam

A study by Den Hond et al on the effects of pollutants on sexual maturation indicated that higher blood levels of lead increased the risk of gynecomastia in the study's subjects, while higher serum levels of hexachlorobenzene decreased the risk. The report involved 1679 adolescents, aged 14-15 years. The mechanism of gynecomastia is thought to be through estrogen receptor binding and activation. [9]

Estimates suggest the following etiologies in males seeking medical attention for gynecomastia:

  • Persistent pubertal gynecomastia - 25%

  • Drugs - 10-25%

  • No detectable abnormality - 25%

  • Cirrhosis or malnutrition - 8%

  • Primary hypogonadism - 8%

  • Testicular tumors - 3%

  • Secondary hypogonadism - 2%

  • Hyperthyroidism - 1.5%

  • Chronic renal insufficiency - 1%

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Epidemiology

Occurrence in the United States

Gynecomastia is the most common reason for male breast evaluation. The condition is common in infancy and adolescence, as well as in middle-aged to older adult males. One estimate is that 60-90% of infants have transient gynecomastia due to the high estrogen state of pregnancy.

The next peak of occurrence is during puberty, [11, 12] with a prevalence ranging from 4-69%. Some reports have shown a transient increase in estradiol concentration at the onset of puberty in boys who develop gynecomastia. Pubertal gynecomastia usually has an onset in boys aged 10-12 years. It generally regresses within 18 months, and persistence is uncommon in men older than 17 years. The third peak occurs in older men, with a prevalence of 24-65%. [#Clinical]

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Prognosis

Other than the associated risk of breast cancer, gynecomastia does not cause any long-term complications. In approximately 90% of cases, pubertal gynecomastia resolves within a period of months to several years. However, macromastia seldom resolves completely and often requires surgery.

Gynecomastia that occurs secondary to an underlying, treatable cause (eg, drug-induced gynecomastia) usually responds to treatment or removal of the primary cause. Men with Klinefelter syndrome have a 10- to 20-fold increased risk for breast cancer.

Research has indicated that the psychological effects of gynecomastia can include depression, anxiety, disordered eating, body dissatisfaction, and reduced self-esteem. [25]

A study by Sir et al suggested that gynecomastia can impinge on male sexual function. The study, which included 47 patients and 30 healthy controls, found that, as evaluated with the International Index of Erectile Function (IIEF), scores for erectile function, orgasmic function, and intercourse satisfaction were significantly lower in patients with gynecomastia than in the control group. However, the gynecomastia patients had a significantly higher mean IIEF desire score than did the controls. The study also found that hormone profiles (serum free triiodothyronine [T3], free thyroxine [T4], thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH], prolactin, estradiol, total testosterone, free testosterone, luteinizing hormone, and dehydroepiandrosterone sulfate [DHEA-SO4]) for the gynecomastia patients were similar to those of the controls, with the exception of FSH and free T3, which were significantly lower. [26]

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