Evaluation and treatment of gynecomastia
Janis F. Neuman
Family physicians frequently encounter patients with gynecomastia, a condition characterized by proliferation of the glandular component of the male breast. Patients may present with a painful breast lump, or the condition may be an incidental finding on a routine physical examination. Gynecomastia may be the source of significant anxiety and embarrassment for both patients and their families.
The challenge for the primary care physician is to determine whether the proliferation of glandular breast tissue is due to a physiologic or pathologic process. In most patients, gynecomastia is related to puberty or is idiopathic. These patients require only reassurance. However, gynecomastia has a broad range of causes, some of them very serious (Table 1). It is therefore important to identify cost-effective diagnostic strategies for evaluating and managing gynecomastia. This article focuses on the physiology, diagnosis and treatment of this clinical finding.
Causes of Gynecomastia
Adrenal disorders Tumor
Other Chronic disease
Liver disease, cirrhosis
Nervous system damage Familial Idiopathic
Gynecomastia is the most common variant condition of the male breast. In obese patients, it may be caused by fat deposition. However, in true gynecomastia, ropy breast tissue is present.
Proliferation of breast tissue is a frequent finding in male adolescents. In one series, gynecomastia (defined as the presence of breast tissue 0.5 cm in diameter) was found in 38 percent of 10- to 16-year-old boys. The condition was found in 65 percent of 14-year-old boys and in 14 percent of 16-year-old boys. In general surveys of sexual development,[2,3] gynecomastia was noted in only 10 percent of male adolescents 12 to 17 years of age, reflecting, the significant number of cases that resolve by age 17.
Gynecomastia is also a common finding in normal adult men. In one study, the incidence of any degree of gynecomastia in adult men varied significantly, from 36 percent in young military recruits to 57 percent in men over 50 years old, suggesting that the condition may become more common with age. Based on histologic evidence in autopsy studies,[5,6] the incidence of gynecomastia in adults may range from 4 to 40 percent.
ESTROGEN AND ANDROGEN LEVELS
Gynecomastia results from the effect of an altered estrogen-androgen balance on breast tissue or from the increased sensitivity of breast tissue to a normal estrogen level.
Testosterone is the primary androgenic hormone in men. Most testosterone is produced by the testes; only 5 percent is produced by the adrenal gland via androstenedione. Two thirds of circulating testosterone is bound to sex hormone binding globulin (SHBG). The active androgenic hormone is dihydrotestosterone, which is produced peripherally from testosterone at the target site of action in receptor-positive tissue.
Circulating testosterone and androstenedione are converted to estrogens, primarily estrone and estradiol, by peripheral aromatization in adipose tissue, muscle and skin. Estradiol is also produced by the testicular Leydig’s cells under the direct stimulation of luteinizing hormone (LH) from the pituitary gland. Glandular breast tissue is highly sensitive to estrone, and any changes in the estrogen-androgen ratio may cause gynecomastia. Estradiol binds directly to breast tissue receptors and activates estrogenic target genes, resulting in breast tissue growth (Figure 1).
Breast tissue is present in 60 to 90 percent of newborns during the first three weeks of life. The tissue is usually located bilaterally, but it may be present on only one side. The breast tissue results from high estrogen levels in the fetoplacental unit. Neonatal gynecomastia usually resolves by the time infants are four months old.
Pubertal gynecomastia follows the onset of sexual development by six months. Sexual development should be evident in the findings of pubic hair, pigmentation of the scrotal skin and enlargement of the testes (3 cm in length and 8 mL in volume).
In about 75 percent of cases, gynecomastia is bilateral, with the breasts enlarging concurrently or sequentially. If the condition is bilateral, the breasts are commonly affected to different degrees. The breast tissue resembles the early stage of the female breast bud (female Tanner stage 2). Pubertal gynecomastia often regresses spontaneously in six months; 75 percent of cases resolve within two years of onset, and 90 percent resolve within three years of onset.
Macrogynecomastia is defined as a breast tissue of more than 5 cm in diameter and dome-shaped, such that the areola and the nipple form a mound above the level of the breast (female Tanner stage 4). Since macrogynecomastia may be pathologic or physiologic, rapid diagnosis and treatment are essential. Glandular tissue of more than 4 cm in diameter is unlikely to regress spontaneously.
The incidence of gynecomastia increases with age. In men, aging leads to progressive primary testicular failure, an increase in body fat and an increase in the estrogen-androgen ratio. All of these changes may lead to physiologic gynecomastia.
Of all cases of gynecomastia, 25 percent are idiopathic or related to aging, 25 percent are classified as persistent pubertal gynecomastia, 10 to 15 percent are caused by drugs, 10 percent are secondary to liver disease and nutritional problems, and 10 percent are caused by primary hypogonadism. The remaining cases are due to testicular neoplasms (3 percent), secondary hypogonadism or renal disease.
When assessing a patient with gynecomastia, the physician should look for potentially treatable or life-threatening conditions. In the adolescent, it is important to distinguish pubertal from pathologic gynecomastia (Table 2). Pathologic gynecomastia is associated with both androgen deficiency and estrogen excess. Both causes may be associated with medications, endocrinopathy, tumors, chronic diseases, familial disorders and miscellaneous other conditions.
Features Distinguishing Pubertal Gynecomastia
from Pathologic Gynecomastia
Feature Pubertal gynecomastia Pathologic gynecomastia
Onset Age of 10 to 18 years Age younger than 10
Causative drugs None Positive history of
Family history Transient gynecomastia Permanent gynecomastia
Chronic illness None Liver or renal disease,
Genital disease None Orchitis, testicular
Puberty onset Normal and before Precocious or after
Physical Well nourished, testes Malnourished, goiter,
examination enlarged, Tanner small or
findings stage 2 to 4 asymmetric testes,
Breast mass Disc centered beneath Hard, asymmetric mass
Adapted from Mahoney CP. Adolescent gynecomastia. Differential diagnosis and
management. Pediatr Clin North Am 1990;37:1389-404. Used with permission.
If the free testosterone and LH levels are normal, the diagnosis is idiopathic gynecomastia. This condition is characterized by mild or transient derangement of the estrogen-androgen ratio, an increased sensitivity of br-east tissue to normal endogenous levels of estrogen or a familial defect in aromatase activity.
A normal free testosterone level excludes hypogonadism. If the free testosterone level is repeatedly low and the LH level is elevated, the diagnosis of primary hypogonadism is confirmed.
A decreased free testosterone level and a low or inappropriately normal LH level confirm the presence of secondary hypogonadism. If the free testosterone level is decreased and the LH level is low or inappropriately normal, the prolactin level is measured, even in the absence of galactorrhea, to exclude prolactinoma.
If the pr-olactin level is elevated, the thyroid-stimulating hormone (TSH) level should be measured to exclude the possibility of hyperthyroidism or hypothyroidism. If the TSH level is normal, magnetic resonance imaging (MRI) may be appropriate, but only if the patient is symptomatic and has evidence of androgen deficiency, such as impotence. An elevated TSH level indicates hypothyroidism, and a low TSH level indicates hyperthyroidism. These two conditions are usually apparent on physical examination.
Small prolactinomas that are not causing clinically significant symptoms do not require treatment. If appropriate, the patient should be referred to an endocrinologist for further evaluation.
An elevated or normal testosterone level and an inappropriately elevated LH level require further investigation. This combination usually represents androgen insensitivity syndrome if feminization is present, but an Lh-secreting tumor is another possibility. Androgen-receptor resistance syndromes due to receptor insensitivity to normal testosterone levels elevate the LH level because of missing feedback inhibition, which increases testosterone production.
If the LH level is markedly elevated, the HCG level should be measured to distinguish an HCG-producing testicular germ cell tumor (choriocarcinoma, embryonal cell carcinoma, seminoma, teratoma or mixed tumor) from a primary nontrophoblastic malignancy (giant cell lung carcinoma, gastric carcinoma, hepatocellular carcinoma, renal cell cancer or extragonadal germ cell tumor).
If the HCG level is elevated, testicular ultrasonography should be performed. If no testicular tumor is found, a chest radiograph and computed tomography (CT) or MRI of the abdomen and pelvis (focusing on the liver and the adrenal glands) should be obtained to exclude nontesticular HCG production. If testicular ultrasonography reveals a testicular tumor, the alpha-fetoprotein level is measured, and the patient is referred for surgery. An elevated alpha-fetoprotein level confirms the presence of a germ cell tumor.
In addition to free testosterone and LH levels, serum estradiol and dehydroepiandrosterone sulfate (DHEAS) levels should be measured in patients with clinical evidence of undermasculinization and feminization. An elevated estradiol level suggests an estrogen-producing testicular tumor, such as Leydig or Sertoli cell tumor. Patients with these tumors have a decreased LH level and a normal DHEAS level. In such cases, testicular ultrasonography is indicated. If a tumor is found, the patient should be referred for surgery. If the sonogram is normal, the gynecomastia is idiopathic or can be attributed to increased aromatase activity.
An elevated estradiol level, a decreased LH level and an increased DHEAS level indicate adrenal production of hormone precursors and metabolites. Most adrenal feminizing tumors are malignant, and all are large enough to be seen with adrenal CT or MRI studies. Adrenal tumors may also increase glucocorticoid and mineralocorticoid levels. Normal adrenal CT or MRI studies indicate that the gynecomastia is idiopathic or is caused by increased aromatase activity.
Liver and renal function tests should be ordered if an abnormality is suspected and the findings of the history or physical examination suggest an underlying abnormality.
In determining if and how a patient with gynecomastia is to be managed or treated, the benefits, risks and costs of the possible treatment options must be analyzed. When deciding on treatment, the physician also needs to consider pain, and cosmetic and psychogenic factors. In 90 percent of cases, adolescent pubertal gynecomastia with a tissue diameter of less than 4 cm disappears in three years without treatment and in six months with treatment.
The choice of treatment is guided by the evaluation and the final diagnosis. Gynecomastia generally develops because of minor hormone imbalances or medication effects, and it has no serious consequences. Treatment of the underlying disorder often results in regression of gynecomastia, especially if the tissue proliferation is of recent onset. If gynecomastia is related to a medication or other drug exposure, the patient should discontinue using that agent. Then the patient should be followed to see if the condition resolves.
Treatment of underlying neoplasms results in regression of gynecomastia in only 44 percent of affected patients. Gynecomastia regresses in an even lower percentage of patients if the neoplasm is malignant. The condition persists because of fibrotic changes, not because of an ongoing endocrine abnormality.
If gynecomastia has been present for more than one year, it probably cannot be reversed by medical treatment, regardless of the cause. Therefore, prompt diagnosis and treatment are extremely important.
Documented hypogonadal disorders should be treated with testosterone replacement in an initial dosage of 200 mg monthly, administered by injection. If the testosterone level is normal, low-dose injections, starting at 50 mg of testosterone per month, may be given to alter the estrogen-androgen ratio. The effect of this treatment varies. Dihydrotestosterone heptanoate would be the preferred agent for injection, because it is not peripherally aromatized; however, this hormone is not yet commercially available in the United States.
Gynecomastia can be treated with the antiestrogens tamoxifen (Nolvadex) and clomiphene (Clomid, Serophene). Tamoxifen competes with estrogen at receptor sites in breast tissue. This drug is especially effective if the tissue is tender, small in size and new. The tamoxifen dosage is 10 to 20 mg twice daily. In young patients with gynecomastia, the reported efficacy rates for clomiphene range from 42 to 95 percent.[25,26] Clomiphene is given in a dosage of 50 to 100 mg per day for one to six months, based on the patient’s response.
Danazol (Danocrine), a weak androgen, inhibits pituitary secretion of LH and FSH, thereby decreasing testicular production of estrogen. One study in adults found that danazol, 200 mg twice daily for three months, decreased gynecomastia and associated breast tenderness considerably in adult patients. In another study, testolactone, an aromatase inhibitor not yet available in the United States, was found to be less effective than tamoxifen in treating pubertal gynecomastia.
Gynecomastia may cause considerable psychologic distress, especially in adolescents who are struggling with issues relating to sexual identity and self-image. If neither reassurance nor medical treatment is successful, surgery should be considered. While suction lipectomy removes fat, it is ineffective in removing the glandular tissue associated with gynecomastia. Reduction mammoplasty with breast tissue removal is effective and produces good cosmetic results.
Surgery is often required for macrogynecomastia. This condition may respond to hormonal treatment if the breast tissue disc is less than 6 cm in diameter and the enlargement has been present for less than four years. If the breast disc is more than 6 cm in diameter and gynecomastia has been present for more than four years, surgery is required.
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JANIS F. NELTMAN, m.d. is program director of the Kaiser Permanente Family Practice Residency Program at Kaiser Permanente Medical Center, Fontana, Calif. A graduate of the University of Southern California School of Medicine, Los Angeles, Dr. Neuman completed a family practice residency at Kaiser Permanente Medical Center, Fontana.
COPYRIGHT 1997 American Academy of Family PhysiciansGynecomastia is a proliferation of the glandular component of the male breast. Causes include altered estrogen-androgen levels, aging, puberty, chronic disease, tumors and drugs. The physician must determine whether the condition has a physiologic or pathologic cause. Pubertal gynecomastia is generally physiologic and regresses without treatment. The likelihood of pathology is increased in patients over 26 years of age who present with new-onset gynecomastia. A thorough history, a complete physical examination and an appropriate clinical evaluation facilitate the prompt diagnosis and treatment of this condition.
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