Gynecomastia 

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.)

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.)

Gynecomastia results from an altered estrogen-androgen balance, in favor of estrogen, or from increased breast sensitivity to a normal circulating estrogen level.^[1] 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, 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.^[2]

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.^{[3, 4]} Physiologic gynecomastia is seen in newborn infants, pubescent adolescents,^{[5, 6]} and elderly individuals.

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.^{[7, 8]} 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.^[1]

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.^[9]

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)^[1]
• 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.^[1]
• 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.^[10]

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).^{[11, 12]}

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.^[13]

Antiandrogen/inhibitors of androgen synthesis are as follows:

• Cyproterone acetate
• Flutamide, bicalutamide, nilutamide
• Finasteride, dutasteride
• 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)
• 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.^[3]

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%

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,^{[5, 6]} 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]

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.