At presentation, all patients require a thorough history and physical exam. Particular attention should be given to medications, drug and alcohol abuse, as well as other chemical exposures. Symptoms of underlying systemic illness, such as hyperthyroidism, liver disease, or renal failure should be sought. Furthermore, the clinician must recall neoplasm as a possible etiology and should establish the duration and timing of breast development. Obviously, rapid breast growth that has occurred recently is more concerning than chronic gynecomastia. Additionally, the clinician should inquire about fertility, erectile dysfunction and libido to rule out hypogonadism, either primary or secondary, as a potential cause.
In our experience, the breast examination is best performed with the patient supine and with the examiner palpating from the periphery to the areola. The glandular mass should be measured in diameter. Gynecomastia is diagnosed by finding subareolar breast tissue of 2 cm in diameter or greater. Malignancy is suspected if an immobile firm mass is found on physical examination. Skin dimpling, nipple retraction or discharge, and axillary lymphadenopathy further support malignancy as a possible diagnosis.
A thorough testicular exam is essential. Bilaterally small testes imply testicular failure, while asymmetric testes or a testicular mass suggest the possibility of neoplasm. Visual field impairment may suggest pituitary disease. Physical findings of underlying systemic conditions such as thyrotoxicosis, HIV disease, liver, or kidney failure should also be assessed.
All patients who present with gynecomastia should have serum testosterone, estradiol, LH and HCG measured (Fig 2). Further testing should be tailored according to the history, physical examination and the results of these initial tests. An elevated HCG or a markedly elevated serum estradiol suggests neoplasm and a testicular ultrasound is warranted to identify a testicular tumor, keeping in mind, however, other non-testicular tumors can also secrete HCG. A low testosterone level, with an elevated LH and normal to high estrogen level indicates primary hypogonadism. If the history suggests Klinefelter's Syndrome, then a karyotype should be performed for definitive diagnosis. Low testosterone, low LH and normal estradiol levels imply secondary hypogonadism, and hypothalamic or pituitary causes should be sought. If testosterone, LH and estradiol levels are all elevated, then the diagnosis of androgen resistance should be entertained. Liver, kidney and thyroid function should be assessed if the physical examination suggests liver failure, kidney failure, or hyperthyroidism, respectively. Furthermore, if examination of breast tissue suggests malignancy, a biopsy should be performed. This is of particular importance in patients with Klinefelter's syndrome, who have an increased risk of breast cancer.
Treatment of the underlying endocrinologic or systemic disease that has caused gynecomastia is mandatory. Testicular tumors, such as Leydig cell, Sertoli cell or granulosa cell tumors should be surgically removed. In addition to surgery, germ cell tumors are further managed with chemotherapy involving cisplatin, bleomycin and either vinblastine or etoposide (42, 19). Should underlying thyrotoxicosis, renal or hepatic failure be discovered, appropriate therapy should be initiated. Medications that cause gynecomastia should also be discontinued whenever possible based on their role in management of the underlying condition. Of course, if a breast biopsy indicates malignancy, then mastectomy should be performed.
If no pathologic abnormality is detected, then appropriate treatment is close observation. A careful breast exam should be done initially every 3 months until the gynecomastia regresses or stabilizes, after which a breast exam can be performed yearly. It is important to remember that some cases of pubertal gynecomastia may resolve spontaneously.
If the gynecomastia is severe, does not resolve, and does not have a treatable underlying cause, some medical therapies may be attempted. There are 3 classes of medical treatment for gynecomastia: androgens (testosterone, dihydrotestosterone, danazol), anti-estrogens (clomiphene citrate, tamoxifen) and aromatase inhibitors such as testolactone. Testosterone treatment of hypogonadal men with gynecomastia often fails to produce breast regression once gynecomastia is established. Unfortunately, testosterone treatment may actually produce the side effect of gynecomastia by being aromatized to estradiol. Thus, although testosterone is used to treat hypogonadism, its use to specifically counteract gynecomastia is limited (53). Dihydrotestosterone, a non-aromatizable androgen, has been used in patients with prolonged pubertal gynecomastia with good response rates (27). Since dihydrotestosterone is given either intramuscularly or percutaneously, this may restrict its usefulness. Danazol, a weak androgen that inhibits gonadotropin secretion, resulting in decreased serum testosterone levels, has been studied in a prospective placebo-controlled trial, whereby gynecomastia resolved in 23 percent of the patients, as opposed to 12 percent of the patients on placebo (25). The dose used for gynecomastia is 200 mg orally twice daily. Unfortunately, undesirable side effects including edema, acne, and cramps have limited its use (33). Investigators have reported a 64 percent response rate with 100 mg/day of clomiphene citrate, a weak estrogen and moderate antiestrogen (29). Lower doses of clomiphene have shown varied results, indicating that higher doses may need to be administered, if clomiphene is to be attempted. Tamoxifen, also an antiestrogen, has been studied in 2 randomized, double-blind studies in which a statistically significant regression in breast size was achieved, although complete regression was not documented (1). One study compared tamoxifen with danazol in the treatment of gynecomastia. Although patients taking tamoxifen had a greater response with complete resolution in 78 percent of patients treated with tamoxifen, as compared to only a 40 percent response in the danazol-treated group, the relapse rate was higher for the tamoxifen group (52). Although complete breast regression may not be achieved and a chance of recurrence exists with therapy, tamoxifen, due to relatively lower side effect profile, may be a more reasonable choice when compared to the other therapies. If used, tamoxifen should be given at a dose of 10 mg twice a day for at least 3 months (33). An aromatase inhibitor, testolactone, has also been studied in an uncontrolled trial with promising effects (57). Further studies must be performed on this drug before any recommendations can be established on its usefulness in the treatment of gynecomastia. Newer aromatase inhibitors such as anastrozole and letrozole may have therapeutic potential (35, 43), but recent randomized, double-blind, placebo-controlled trials have not confirmed its efficacy. In a study involving patients receiving bicalutamide therapy for prostate cancer, only Tamoxifen, but not anastrozole, significantly reduced the incidence of gynecomastia/breast pain when used prophylactically and therapeutically (6, 46). In another study with pubertal gynecomastia, no significant difference was demonstrated between the anastrozole and placebo groups in patients suffering from pubertal gynecomastia (41).
When medical therapy is ineffective, particularly in cases of longstanding gynecomastia, or when the gynecomastia interferes with the patient's activities of daily living, or when there is suspicion of malignancy of breast, then surgical therapy is appropriate. This includes removal of glandular tissue coupled with liposuction, if needed. In our experience, uses of delicate cosmetic surgical techniques are warranted to prevent unsightly scarring.