Samuel Walker Nickles
James S. Rosoff, MD
BASICS
DESCRIPTION
• Gynecomastia (GM) is benign enlargement of the male breast due to proliferation of ductal elements.
• Pseudogynecomastia/lipomastia is an increase in breast adipose tissue. This can be distinguished by careful physical exam of subareolar tissue and comparison to adjacent adipose tissue.
EPIDEMIOLOGY
Incidence (1)
Approximately 2,000 cases of male breast cancer are diagnosed in the United States annually
Prevalence
• 30–65% of men have palpable breast tissue and at autopsy 40–55% of men have histologic evidence of GM
• Age related: Asymptomatic GM is 60–90% in neonates, 50–60% in adolescents, and up to 70% in men aged 50–69 yr
RISK FACTORS
• Alcoholism
• Endocrinopathies
• Medications
• Obesity
• Renal failure
Genetics
• Klinefelter syndrome (47, XXY) is strongly associated with GM
• An increased risk of male breast cancer has been reported in families with a BRCA2 mutation
PATHOPHYSIOLOGY
• Male breast tissue has both androgen and estrogen receptors.
• Androgens inhibit breast development and estrogens stimulate it. GM develops when there is an imbalance of these two influences (ie, androgen deficiency or excess estrogen) or lack of tissue response to them.
ASSOCIATED CONDITIONS
• Prostate cancer
• Testicular tumors
• Cirrhosis
• Renal failure
GENERAL PREVENTION
With hormonally induced GM, prophylactic breast irradiation may reduce GM
DIAGNOSIS
HISTORY
• Age of patient and onset of symptoms (pubertal, GM of aging)
• Associated fevers or chills, breast trauma, nipple discharge
• Medical conditions (cirrhosis, chronic kidney disease, HIV, hyperthyroidism)
• Medications/drugs
• History of cryptorchidism
• Sexual history: Sexual maturation, changes in libido, erectile dysfunction, infertility
PHYSICAL EXAM
• General appearance, weight, amount of adipose tissue (contains aromatase capable of peripheral conversion of androgens to estrogen)
• Secondary sexual characteristics such as body hair distribution and phallus size
• Thyroid exam
• Breast exam: Special attention should be paid to distinguish true GM from pseudogynecomastia; unilateral vs. bilateral (if unilateral should be concerned for potential male breast cancer), firm and mobile vs. fixed, skin dimpling, any nipple discharge, palpation of axillary lymph nodes
• Genitourinary exam with special attention to the testicular exam
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Basic studies: Creatinine, LFTs, thyroid function tests, serum testosterone
• Further testing as needed:
– Serum estrogens (estradiol, estrone)
– LH, FSH, prolactin
– Tumor markers: AFP, β-hCG
– Adrenal androgens, serum DHEA, urinary 17-ketosteroids
Imaging
• Testicular US if abnormal tumor markers
• CT of the abdomen and pelvis/chest if abnormal levels of adrenal androgens
• Mammography if cancer suspected
Diagnostic Procedures/Surgery
Breast biopsy for suspected breast cancer
Pathologic Findings
• Proliferation of ductules embedded in a connective tissue stroma
• Over about 12 months, the breast tissue evolves into a quiescent stage, in which the amount of stroma and fibrosis increasesand the ductules become less prominent. glandular acini are rare (2)
DIFFERENTIAL DIAGNOSIS
• Physiologic GM: Normal in neonatal boys secondary to maternal estrogen exposure.
– Occurs in 60–90% of neonatal boys and resolves within several weeks after delivery.
– Pubertal GM results from the earlier rise of estrogens in early puberty. As the normal ratio of estrogen to testosterone is restored later in puberty the GM resolves.
– 50–70% of boys develop GM during puberty.
– 20% of men still have GM at 20 yr of age.
• GM of aging:
– The hypothalamic–pituitary–testis axis is variable in age-related decline. Some men will have elevated gonadotropins while others will be normal.
– Adiposity increases with age which leads to increasing peripheral conversion.
– Sex hormone–binding globulin (SHBG) levels rise with age and decreasing bioavailable testosterone.
– Medications may also play a part in GM in older men.
• Estrogen secreting tumors:
– Leydig cell tumors are rare tumors of the testis; 85–90% are benign, most are nonpalpable. Some Leydig cell tumors can directly secrete estradiol. This increases estrogen levels and inhibits LH secretion, suppressing testicular production of testosterone.
– Sertoli cell tumor: Converts androgens to estrogens leading to a direct increase in circulating levels of estrogens.
– Feminizing adrenal cortical tumors are generally malignant and poorly differentiated. These cancers directly secrete estrogens as well as steroid precursors that may be aromatized to estrogens in peripheral tissues. Increased estrogen suppresses LH-mediated production of testosterone as well.
• hCG-secreting tumor such as choriocarcinoma stimulates Leydig cells to preferentially secrete estradiol. Many HCG-secreting tumors also will take up steroid precursors such as DHEA and convert them to active estrogens.
• Increased peripheral aromatization to estrogens: Familial aromatase excess syndrome. The enzyme aromatase (P450 aroma or CYP19A1) catalyzes the conversion of steroid precursors to estrogens.
• Estrogen receptor agonists:
– Therapeutic administration of estrogens such as DES (diethylstilbestrol) may be used to treat men with prostate cancer and can lead to GM. Estrogens may also be used to stimulate breast development in male-to-female transsexuals.
– Unintentional exposure may occur transcutaneously by sexual intercourse with a partner that uses topical estrogen. Occupational exposure is also possible. Estrogens can be found in hair creams, embalming creams, and in the production of medicinal estrogen products.
– Marijuana smoke, digitoxin, testosterone, or other aromatizable androgens.
• Androgen deficiency or resistance:
– Primary or secondary hypogonadism: Testicular failure from any cause may result in GM. Testosterone deficiency leads to elevated LH, which increases estradiol production by remaining Leydig cells. Increased estrogens lead to elevated levels of SHBG, further decreasing free testosterone.
– Klinefelter syndrome is the most common genetic disorder associated with hypogonadism and infertility in men. GM is present in 50–70% of cases. Klinefelter syndrome is the only cause of GM with an established risk of breast cancer (20-fold increase).
– Defects in genes critical for testosterone production may also lead to decreased testosterone production.
• Androgen resistance disorders:
– In both partial and complete androgen insensitivity syndrome, cellular response to androgens is inadequate (elevated gonadotropins and increased serum testosterone) due to lack of negative feedback.
• Refeeding associated GM:
– Recognized after WWII when imprisoned men resumed normal diets and developed tender GM. Starvation is associated with hypogonadotrophic hypogonadism. With resumption of a healthy diet and regaining weight the hypothalamic–pituitary–testis axis returns to normal, resulting in transient estrogen excess. May also explain GM associated with several chronic diseases.
• Renal failure:
– Many men with chronic kidney disease develop GM upon initiation of hemodialysis. Before initiation of dialysis men are often nauseated, anorexic, and on protein-restricted diets. The pathogenesis is thought to be similar to refeeding GM.
• Cirrhosis:
– Studies have shown that the prevalence of GM in cirrhotics is no different than hospitalized age-matched controls. Hormonal changes in chronic liver disease may increase the risk of GM.
– Patients with cirrhosis have decreased clearance of androstenedione, which provides more substrate for peripheral conversion via aromatase.
– SHBG may also be increased, decreasing free testosterone.
– Alcohol has a direct toxic effect on gonadal function, and cirrhotics may have testicular atrophy and hypogonadism.
• Hyperthyroidism:
– 10–40% of men with thyrotoxicosis may have GM. Due to the increased peripheral conversion of androgens to estrogens. There is also an increase in SHBG in hyperthyroidism. Restoration of euthyroid state resolves associated GM in 1–2 wk.
• HIV:
– Multifactorial. Use of illicit drugs (heroin or marijuana) may also be seen in this group. Other chronic disease states may also be present such as Hep C, Hep B, and alcoholic liver disease. Some men on HAART therapy have hypogonadotropic hypogonadism.
• Diabetes Mellitus:
– Diabetic mastopathy presents as a discrete lump or diffuse nodularity. The lesions are composed of B-cell infiltration of mammary ducts and lobules with fibrosis and vasculitis. Can be seen in Hashimoto thyroiditis and lupus.
• Medications:
– Androgen deprivation therapy (ADT) in prostate cancer is often associated with breast pain, tenderness, and enlargement.
– Rates of GM in men treated with ADT vary depend on the type employed.
• Miscellaneous medications may be responsible for as much as 25% of new cases of GM in adults.
– Destruction of Leydig cells: Chemotherapy with cytotoxic agents.
– Decreased testosterone or DHT production: Spironolactone, ketoconazole, metronidazole, finasteride, dutasteride.
– Androgen receptor blocker: Flutamide, bicalutamide, nilutamide, cimetidine, marijuana, spironolactone.
– Increased serum prolactin: Antipsychotic agents, metoclopramide.
– Possible: Refeeding GM, isoniazid, digoxin.
– Unknown: HAART, human growth hormone, amiodarone, calcium channel blockers, amphetamines, diazepam, antidepressants (tricyclics and SSRIs).
• Breast cancer:
– Rare in men; symptoms are similar to those of female breast cancer.
– A hard fixed mass, ulceration, bloody nipple discharge, or lymphadenopathy should raise suspicion.
– Suspicious lesions should be biopsied.
– Except in the setting of Klinefelter syndrome, GM does not increase the risk of breast cancer.
TREATMENT
GENERAL MEASURES
Removal of the offending drug or exogenous source of estrogen if possible
MEDICATION
First Line
• SERMs have been used to block the effects of estrogen excess on breast tissue. Tamoxifen, 10 and 20 mg/d, for 3–9 mo with 90% resolution. Additionally, raloxifene and clomiphene citrate have also been used.
Second Line
• Aromatase inhibitors such as testolactone and anastrazole have been used but not proven as effective as tamoxifen.
• Testosterone replacement therapy in androgen-deficient men may result in partial regression of GM, especially if breast enlargement is of recent onset.
SURGERY/OTHER PROCEDURES
• With longstanding GM, or those that refuse medical treatment, cosmetic surgical excision and reconstruction may be performed
• Testicular cancer: Orchiectomy
• Adrenal tumors: Adrenalectomy
ADDITIONAL TREATMENT
Radiation Therapy
• Prophylactic breast irradiation has been used prior to initiation of estrogens or androgen blockade for blockade for prostate cancer patients
– Dose: 12 Gy in 2 fractions to 20 Gy in 5 fractions
Additional Therapies
Radioactive iodine ablation or propylthiouracil for hyperthyroidism
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Generally favorable prognosis.
• Patient main concerns: Ruling out breast cancer and cosmetic correction
COMPLICATIONS
Psychological stress
FOLLOW-UP
Patient Monitoring
No regular follow-up is necessary for patients who have physiologic GM and are untroubled by their symptoms and do not have symptoms suggestive of malignancy.
Patient Resources
N/A
REFERENCES
1. Braunstien GD. Gynecomastia. N Engl J Med. 1993;328:490–495.
2. Bembo SA, Carlson HE. Gynecomastia: Its features, and when and how to treat it.Cleveland Clinic Journal OF Medicine. 2004;(6):511–517.
3. Narula HS, Carleson HE. Gynecomastia. Endocinol Metab Clin North Am. 2007;36:497–519.
ADDITIONAL READING
Melmed S, et al. Williams Textbook of Endocrinology. Elsevier; Phialdephia, 2013;766–769, 1180–1181.
See Also (Topic, Algorithm, Media)
• Gynecomastia Algorithm 
• Gynecomastia Image 
• Infertile Male Syndrome
• Testis, Leydig Cell Tumor
• Testosterone, Decreased (Hypogonadism)
• XXY Syndrome (Klinefelter Syndrome)
CODES
ICD9
• 278.00 Obesity, unspecified
• 611.1 Hypertrophy of breast
• 758.7 Klinefelter’s syndrome
ICD10
• E66.9 Obesity, unspecified
• N62 Hypertrophy of breast
• Q98.4 Klinefelter syndrome, unspecified
CLINICAL/SURGICAL PEARLS
• Breast cancer is rare in males, representing <1% of all cases of breast cancer.
• Klinefelter syndrome is the only cause of gynecomastia with an established risk of breast cancer.