Clinical features, diagnosis, and evaluation of gynecomastia in adults

INTRODUCTION — Gynecomastia, a benign proliferation of the glandular tissue of the male breast, is diagnosed on examination. Although it has been variably defined as breast tissue >0.5, >1, and >2 cm in diameter, a clinically useful definition of gynecomastia is palpable breast tissue that extends outside the area under the nipple and is ≥2 cm or as recent breast tissue growth (virtually always accompanied by tenderness) independent of size. Some boys and men are bothered by <2 cm of palpable nontender breast tissue whereas others are unperturbed by ≥2 cm of palpable nontender breast tissue. Many boys and men will report breast tenderness as bothersome or worrisome.

There are many causes of gynecomastia, but the pathophysiology is always an increase in the ratio of estrogen to androgen activity in the breast.

The clinical features and evaluation of gynecomastia will be reviewed here. Epidemiology, causes, pathogenesis, and management of gynecomastia and an overview of gynecomastia in children and adolescents are discussed separately. (See "Epidemiology, pathophysiology, and causes of gynecomastia" and "Management of gynecomastia" and "Breast masses in children and adolescents".)

CLINICAL FEATURES

Physical findings — In true gynecomastia, a ridge of glandular tissue will be felt that is reasonably symmetrical to the nipple-areolar complex. Breast glandular tissue can usually be detected when the size exceeds 0.5 cm in diameter. There are four typical features on examination: the glandular tissue is centrally located, symmetrical in shape, usually bilateral, and tender to palpation (during the early, growth phase) (figure 1).

A study of 506 adolescent and adult males presenting to emergency departments with trauma who underwent a chest computed tomography (CT) scan showed that some breast glandular tissues in males is a normal finding with 90^th, 95^th, and 97.5^th percentiles of normal breast tissue being 2.2, 2.6, and 3.6 cm, respectively [1]. Therefore, breast glandular tissue that is <2 cm should be considered a normal finding, but palpable enlargement ≥2 cm is gynecomastia.

Although gynecomastia is usually bilateral, it is often asymmetric, and some patients present with unilateral enlargement. One side may enlarge weeks to months before the other [2].

Symptoms — Most gynecomastia is discovered incidentally on physical examination, but adolescents commonly experience painful, tender gynecomastia. In contrast, gynecomastia-associated pain is usually not severe in adults, and most men are asymptomatic. Varying degrees of tenderness and nipple sensitivity with rubbing against a shirt are more common than pain. However, severe symptoms in men are a potential indication for earlier therapeutic intervention, even though these symptoms are usually self-limited, because fibrotic changes begin to develop after 6 to 12 months. (See "Gynecomastia in children and adolescents" and "Management of gynecomastia", section on 'Initial management'.)

Imaging features — We recommend against breast imaging unless there is concern for possible breast cancer (new onset or rapid growth of a unilateral, nontender, and/or fixed mass that is eccentric to an areola). The mammographic features of gynecomastia are described as "a fan-shaped density emanating from the nipple, gradually blending into surrounding fat" [3]. It may have extensions into surrounding fat and an appearance similar to that of a heterogeneously dense female breast.

The usual imaging studies are mammography and ultrasound. Mammography is difficult to perform for men with gynecomastia <4 cm. Both imaging modalities have good sensitivity and specificity for detection of breast malignancy, but mammography is more sensitive, and ultrasonography is more specific [4].

Histology — We do not perform biopsy and histologic examination unless the physical examination and imaging show signs of malignancy. Histologic studies show that the glandular changes in the breast are the same regardless of etiology, and the extent of glandular proliferation depends upon the intensity and duration of the growth stimulation. The histologic picture changes from the growth phase to the late fibrotic phase.

●Early florid stage of gynecomastia – The early or florid stage of gynecomastia, is generally present for the first six months after onset, and it is typically associated with breast pain and/or tenderness [5-8]. There is extensive ductal epithelial hyperplasia, proliferation and lengthening of the ducts, an increase in the stromal and periductal connective tissue, and proliferation of periductal inflammatory cells and edema and stromal fibroblastic proliferation (picture 1A-B).

●Late fibrotic stage – After 12 or more months, the breast tissue evolves into the late or quiescent, fibrotic stage. There is a slight increase in the number of ducts, with marked dilatation of the ducts and little or no epithelial cell proliferation. There is also an increase in the amount of stroma, stromal fibrosis, and a disappearance of the inflammatory reaction. Pain and tenderness are uncommon during this stage.

●When is medical therapy useful? – Medical therapy might be useful in the acute, florid stage. It is unlikely that any medical therapy will cause significant regression in the late fibrotic stage. (See "Management of gynecomastia".)

DIAGNOSIS

Examination — The diagnosis of gynecomastia is made on physical examination as a palpable mass of tissue at least 0.5 cm in diameter underlying the nipple. (See 'History and examination' below.) (figure 1).

The examiner places his or her thumb and forefinger or the fingers of each hand on each side of the breast and slowly brings them together (figure 1) [9]. For men with large breasts, the authors recommend having the man lie recumbent with hands resting behind his head. Gynecomastia is felt as a concentric, rubbery-to-firm mobile disk of tissue located directly beneath the areolar area. The disk can be "flipped up" to locate the edge of the rubbery tissue. Feeling an edge of rubbery tissue at the interface of normal and glandular tissue confirms the presence of gynecomastia.

Differential diagnosis

Pseudogynecomastia — Gynecomastia must be distinguished from pseudogynecomastia (lipomastia) that is due to an increase in breast fat, not glandular tissue. These patients have diffuse breast enlargement without any subareolar glandular tissue. When examining the patient with pseudogynecomastia, the fingers will not meet any resistance until they reach the nipple. There is no discrete rubbery mass and no palpable disc edge in pseudogynecomastia (figure 1) [9]. Areas of body fat (eg, abdominal flanks or anterior axillary fold) may be used as comparators.

Breast cancer — Gynecomastia must be differentiated from other causes of breast masses, most importantly, breast cancer. Gynecomastia can be distinguished from breast cancer by physical examination. Breast cancers are typically unilateral, nontender, hard and immobile masses that are found eccentric to the nipple-areolar complex. In addition, they are firm-to-hard in texture and may be associated with skin dimpling, nipple discharge, and ipsilateral axillary lymphadenopathy (algorithm 1).

We perform mammography or breast ultrasonography in the patient with unilateral breast enlargement where there is uncertainty whether the palpable, nonfat tissue represents gynecomastia or another lesion. If uncertainty persists, we suggest referral to a surgeon with experience in managing male breast cancer and other breast lesions (eg, neurofibroma, dermoid cyst, hematoma).

Men with Klinefelter syndrome with a hard, immobile breast mass deserve careful attention because they have a 20- to 60-fold increase in breast cancer risk compared with normal men. Although the relative risk is increased, their absolute risk of breast cancer is still considerably lower than it is in women. Therefore, we do not suggest routine mammographic screening for men with Klinefelter syndrome. (See "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome' and "Breast cancer in men", section on 'Epidemiology and risk factors'.)

EVALUATION TO DETERMINE CAUSE — When gynecomastia has been diagnosed, the combination of a careful history, physical examination, and a few diagnostic tests allows one to identify the cause in most patients [9]. Unilateral gynecomastia should be evaluated in the same fashion as bilateral gynecomastia. The causes of gynecomastia are shown in the tables and reviewed separately (table 1 and table 2). (See "Epidemiology, pathophysiology, and causes of gynecomastia".)

History and examination — Additional evaluation includes reviewing all medications, over-the-counter drugs (including testosterone precursors), dietary supplements, and herbal products that can cause gynecomastia (table 2). (See "Epidemiology, pathophysiology, and causes of gynecomastia".)

Improvement in gynecomastia after discontinuation or substitution of a drug for one to several months suggests, but does not prove, that the drug was responsible.

In adolescent boys, breast enlargement is almost always due to pubertal gynecomastia that will resolve spontaneously in most cases.

The patient should be asked about symptoms of liver and kidney disease, as well as overt hyperthyroidism (eg, weight loss and palpitations) and hypogonadism (eg, decreased libido and muscle strength).

In addition to the breast examination (see 'Physical findings' above) to make the diagnosis of gynecomastia, the history and physical examination should focus on the following:

●Symptoms and signs of liver and kidney disease, as well as thyrotoxicosis (eg, weight loss, tachycardia, goiter, tremor, lid lag, or exophthalmos). The patient should evaluated for signs that suggest hypogonadism (eg, small testes (typically ≤4 cc each) that suggest Klinefelter syndrome]). (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Chest findings' and "Overview of the clinical manifestations of hyperthyroidism in adults", section on 'Genitourinary' and "Clinical features and diagnosis of male hypogonadism", section on 'Physical findings'.)

●An abdominal mass might suggest adrenocortical carcinoma, and a testicular mass or increase in testicular size might indicate a neoplasm. If any of these conditions are found, it is the likely cause of the gynecomastia. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Clinical presentation' and "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Clinical manifestations'.)

Biochemical testing

●Total testosterone – We measure a morning serum total testosterone concentration between 8 and 10 AM in all adult men who present for evaluation of gynecomastia [10].

In males with incidentally discovered asymptomatic, nontender gynecomastia, we do not perform additional testing, as it has low diagnostic yield. The most likely cause of gynecomastia in this setting is idiopathic, and in males with chronic fibrotic gynecomastia the underlying etiology is likely to have remitted [11-13]. In contrast, for males with new-onset gynecomastia and evidence of a known pathologic conditions such as cirrhosis, chronic kidney disease, or hyperthyroidism (table 1), we perform disease-appropriate testing.

●If initial total T is low – Because new onset of gynecomastia is a symptom of hypogonadism and the biochemical findings of male hypogonadism increase starting typically by age 35 years, we measure a fasting morning serum total testosterone concentration in all adult men who present for evaluation of gynecomastia [10,14]. If it is low, then it should be repeated at least once between 8 and 10 AM, in addition to a free or bioavailable testosterone and gonadotropins luteinizing hormone (LH), and follicle stimulating hormone (FSH).

●Men with obesity or type 2 diabetes mellitus – In men with obesity or type 2 diabetes mellitus, we also measure sex hormone-binding globulin (SHBG) level which is typically low, resulting in a low total testosterone. A male with low SHBG and total testosterone levels but with a normal hypothalamic-pituitary-testicular axis will have normal free testosterone and normal LH concentrations. (See "Clinical features and diagnosis of male hypogonadism", section on 'Effect of abnormal SHBG' and "Approach to older males with low testosterone".)

●High hCG, suppressed LH – If the serum testosterone is normal or elevated and serum LH is suppressed below the lower limit of normal, then serum concentrations of human chorionic gonadotropin (hCG; measured by an assay that detects all forms of hCG and its beta subunit [15]) should be measured (algorithm 1).

An elevated hCG plus a suppressed LH concentration suggest a testicular or extragonadal germ cell tumor.

●High serum estradiol and suppressed LH – If the serum testosterone and LH are suppressed below the lower limit of normal, then serum estradiol should be measured. A high serum estradiol plus a suppressed LH concentration should prompt further evaluation for a testicular tumor (Leydig or Sertoli cell) or adrenal tumor (algorithm 1).

●Thyrotoxicosis – Gynecomastia associated with a mild elevation of serum estradiol and a normal LH is a common laboratory finding and does not indicate a tumor that secretes hCG or estradiol. Gynecomastia due to thyroid hormone is almost always clinically evident with symptoms and signs of thyrotoxicosis. However, thyrotoxicosis is associated with a usual pattern of high-normal or elevated serum FSH and LH, high or high-normal serum total testosterone, high serum SHBG, and low or low-normal free serum testosterone (algorithm 1) [16,17]. This pattern is due to increased (thyroxine-induced) aromatization of testosterone to estradiol; increased estradiol increases serum SHBG and lowers free testosterone.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Gynecomastia (male breast development) (The Basics)")

●Beyond the Basics topics (see "Patient education: Gynecomastia (breast enlargement in males) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Gynecomastia, a benign proliferation of the glandular tissue of the male breast, is caused by an increase in the ratio of estrogen to androgen activity. A clinically useful definition of gynecomastia is palpable breast tissue that extends outside the area under the nipple and is ≥2 cm, or as recent breast tissue growth (virtually always accompanied by tenderness) independent of size. (See 'Introduction' above.)

●Clinical features – Most gynecomastia is discovered incidentally on physical examination, but adolescents commonly experience painful, tender gynecomastia. Gynecomastia can usually be detected when the size of the glandular tissue exceeds 0.5 cm in diameter, but virtually always when the size of the glandular tissue exceeds 2 cm in diameter. There are four typical features on examination: the glandular tissue is centrally located, symmetrical in shape, usually bilateral, and tender to palpation (during the early growth phase) (figure 1). (See 'Clinical features' above.)

Histologic studies show that the glandular changes in the breast are the same regardless of etiology, and the extent of glandular proliferation depends upon the intensity and duration of the growth stimulation. The histologic picture changes from the growth phase to the late fibrotic phase. (See 'Histology' above.)

●Diagnosis – The diagnosis of gynecomastia is made on physical examination as a palpable mass of tissue of 2 cm or more, usually underlying the nipple. Breast glandular tissue that is nontender and 2 to 4 cm is a frequent finding in the normal population, and this finding does not generally require diagnostic evaluation. Of note, some individuals are bothered by <2 cm of palpable breast tissue while others are not bothered by >2 cm of palpable breast tissue that is nontender. The examination is performed by placing the thumb and forefinger on each side of the breast and slowly bringing them together (figure 1 and algorithm 1). (See 'Diagnosis' above.)

●Differential diagnosis

•Pseudogynecomastia – Gynecomastia needs to be distinguished from pseudogynecomastia (lipomastia, diffuse breast enlargement without any glandular tissue). When examining the patient with pseudogynecomastia, the fingers will not meet any resistance until they reach the nipple. There is no discrete mass (figure 1). (See 'Pseudogynecomastia' above.)

•Breast cancer – Breast cancers are typically unilateral, nontender, and often fixed masses found eccentric to the nipple-areolar complex. They are firm-to-hard in texture and may be associated with skin dimpling, nipple discharge, and regional lymphadenopathy (algorithm 1). If the differentiation cannot be made by physical examination, mammography or ultrasonography should be done. (See 'Breast cancer' above.)

●Evaluation to determine cause – Once gynecomastia has been diagnosed, the combination of a careful history, physical examination, and a few diagnostic tests allows one to identify the cause of gynecomastia in most patients (algorithm 1) [9].

Unilateral gynecomastia should be evaluated in the same fashion as bilateral gynecomastia. The causes of gynecomastia are shown in the tables and reviewed separately (table 1 and table 2). (See 'Evaluation to determine cause' above and "Epidemiology, pathophysiology, and causes of gynecomastia".)