Gynecomastia

Signs and symptoms

The classic feature of gynecomastia is male breast enlargement with soft, compressible, and mobile subcutaneous chest tissue palpated under the areola of the nipple in contrast to softer fatty tissue. This enlargement may occur on one side or both. Dimpling of the skin and nipple retraction are not typical features of gynecomastia. Milky discharge from the nipple is also not a typical finding, but may be seen in a gynecomastic individual with a prolactin secreting tumor. Males with gynecomastia may appear anxious or stressed due to concerns about the possibility of having breast cancer. An increase in the diameter of the areola and asymmetry of chest tissue are other possible signs of gynecomastia.

Causes

Gynecomastia is thought to be caused by an altered ratio of estrogens to androgens mediated by an increase in estrogen production, a decrease in androgen production, or a combination of these two factors. Estrogen acts as a growth hormone to increase the size of male breast tissue. The cause of gynecomastia is unknown in around 25% of cases. Drugs are estimated to cause 10–25% of cases of gynecomastia.

Certain health problems in men such as liver disease, kidney failure or low testosterone can cause breast growth in men. Drugs and liver disease are the most common cause in adults. Other medications such as methadone, aldosterone antagonists (spironolactone & epelerenone), HIV medication, cancer chemotherapy, hormone treatment for prostate cancer, heartburn and ulcer medications, calcium channel blockers, antifungal medications such as ketoconazole, antibiotics such as metronidazole, tricyclic antidepressants such as amitriptyline, herbals such as lavender, tea tree oil, and dong quai are also known to cause gynecomastia. Phenothrin, an insecticide, possesses antiandrogen activity, and has been associated with gynecomastia.

Physiologic

Many newborn infants of both sexes show breast development at birth or in the first weeks of life. During pregnancy, the placenta converts the androgenic hormones DHEA and DHEA sulfate to the estrogenic hormones estrone and estradiol, respectively; after these estrogens are produced by the placenta, they are transferred into the baby's circulation thereby leading to temporary gynecomastia in the baby. In some infants neonatal milk (also known as "witch's milk") can be secreted. The temporary gynecomastia seen in newborn babies usually resolves after two or three weeks.

Gynecomastia in adolescents usually starts between the ages of ten and twelve and commonly goes away after eighteen months.

Declining testosterone levels and an increase in the level of subcutaneous fatty tissue seen as part of the normal aging process can lead to gynecomastia in older men. This is also known as senile gynecomastia. Increased fatty tissue in these men leads to increased conversion of androgenic hormones such as testosterone to estrogens.

When the human body is deprived of adequate nutrition, testosterone levels drop while the adrenal glands continue to produce estrogens thereby causing a hormonal imbalance. Gynecomastia can also occur once normal nutrition is restarted (this is known as refeeding gynecomastia).

A small proportion of male gynecomastia cases may be inherited due to the very rare aromatase excess syndrome inherited in an autosomal dominant manner.

Non-physiologic

Approximately 10–25% of cases are estimated to result from the use of medications. This is known as non-physiologic gynecomastia. Medications known to cause gynecomastia include ketoconazole, cimetidine, gonadotropin-releasing hormone analogues, human growth hormone, human chorionic gonadotropin, 5α-reductase inhibitors such as finasteride and dutasteride, estrogens such as those used in transgender women and men with prostate cancer, and antiandrogens such as bicalutamide, flutamide, and spironolactone,. Medications that are probably associated with gynecomastia include calcium channel blockers such as verapamil, amlodipine, and nifedipine; risperidone, anabolic steroids, alcohol, opioids, efavirenz, alkylating agents, and omeprazole. Certain components of personal care products such as lavender or tea tree oil and certain supplements such as dong quai and Tribulus terrestris have been associated with gynecomastia.

Chronic disease

Patients with kidney failure are often malnourished, which may contribute to gynecomastia development. Dialysis may attenuate malnutrition of kidney failure. Additionally, many kidney failure patients experience a hormonal imbalance due to the suppression of testosterone production and testicular damage from high levels of urea also known as uremia-associated hypogonadism.

In individuals with liver failure or cirrhosis, the liver's ability to properly metabolize hormones such as estrogen may be impaired. Additionally, those with alcoholic liver disease are further put at risk for development of gynecomastia; ethanol may directly disrupt the synthesis of testosterone and the presence of phytoestrogens in alcohol may also contribute to a higher estrogen to testosterone ratio. Conditions that can cause malabsorption such as cystic fibrosis or ulcerative colitis may also produce gynecomastia.

Tumors

Testicular tumors such as Leydig cell tumors or Sertoli cell tumors (such as in Peutz-Jeghers syndrome) or hCG-secreting choriocarcinoma may result in gynecomastia. Other tumors such as adrenocortical tumors, pituitary gland tumors (such as a prolactinoma), or bronchogenic carcinoma, can produce hormones that alter the male–female hormone balance and cause gynecomastia.

Individuals with prostate cancer who are treated with androgen deprivation therapy may experience gynecomastia.

Pathophysiology

The causes of common gynecomastia remain uncertain, but are thought to result from an imbalance between the actions of estrogen and androgens at the breast tissue. Breast prominence can result from enlargement of glandular breast tissue, chest adipose tissue (fat) and skin, and is typically a combination. As in females, estrogen stimulates the growth of breast tissue in males. In addition to directly stimulating male breast tissue growth, estrogens indirectly decrease secretion of testosterone by suppressing luteinizing hormone secretion resulting in decreased testicular secretion of testosterone. Furthermore, estrogens can increase blood levels of the protein sex hormone binding globulin (SHBG), which binds free testosterone (the active form) leading to decreased action of testosterone in male breast tissue.

Adolescent gynecomastia is caused by the faster rise in estradiol than testosterone seen during early puberty. However, this skewed estrogen/androgen ratio is normally corrected with the expected increase in testosterone seen later in puberty. Another mechanism through which gynecomastia may occur is a defect in the function of androgen receptors in male breast tissue even if the level of androgen hormones in the blood is normal. In rare cases, the gynecomastia persists throughout puberty and such cases are often associated with a family history of a similar occurrence.

Primary hypogonadism (indicating an intrinsic problem with the testes in males) leads to decreased testosterone synthesis and increased conversion of testosterone to estradiol potentially leading to a gynecomastic appearance. Klinefelter syndrome is a notable example of a disorder that causes hypogonadism, gynecomastia, and has a higher risk of breast cancer in males (20-50 times higher than males without the disorder). Central hypogonadism (indicating a problem with the brain) leads to decreased production and release of luteinizing hormone (LH) (a stimulatory signal for endogenous steroid hormone synthesis) which leads to decreased production of testosterone and estradiol in the testes.

Individuals who have cirrhosis or chronic liver disease may develop gynecomastia for several reasons. Cirrhotics tend to have increased secretion of the androgenic hormone androstenedione from the adrenal glands, increased conversion of this hormone into various types of estrogen, and increased levels of SHBG, which leads to decreased blood levels of free testosterone. Approximately 10-40% of individuals with Graves disease (a common form of hyperthyroidism) experience gynecomastia. Increased conversion of testosterone to estrogen by increased aromatase activity, increased levels of SHBG and increased production of testosterone and estradiol by the testes due to elevated levels of LH cause the gynecomastia. Proper treatment of the hyperthyroidism can lead to the resolution of the gynecomastia.

Medications are known to cause gynecomastia through several different mechanisms. These mechanisms include increasing estrogen levels, mimicking estrogen, decreasing levels of testosterone or other androgens, blocking androgen receptors, increasing prolactin levels, or through unidentified means. High levels of prolactin in the blood (which may occur as a result of certain tumors or as a side effect of certain medications) has been associated with gynecomastia. A high level of prolactin in the blood can inhibit the release of gonadotropin releasing hormone and therefore cause central hypogonadism. Receptors for prolactin and other hormones including insulin-like growth factor 1, insulin-like growth factor 2, luteinizing hormone, progesterone, and human chorionic gonadotropin have been found in male breast tissue, but the impact of these various hormones on gynecomastia development is not well understood.

Diagnosis

To diagnose gynecomastia, a thorough history and physical examination are obtained by a physician. Important aspects of the physical examination include evaluation of the male breast tissue with palpation to evaluate for breast cancer and pseudogynecomastia (male breast tissue enlargement solely due to excess fatty tissue), evaluation of penile size and development, evaluation of testicular development and an assessment for masses that raise suspicion for testicular cancer, and proper development of secondary sexual characteristics such as the amount and distribution of pubic and underarm hair. Gynecomastia usually presents with bilateral involvement of the breast tissue but may occur unilaterally as well.

A review of the medications or illegal substances an individual takes may reveal the cause of gynecomastia. Recommended laboratory investigations to find the underlying cause of gynecomastia include tests for aspartate transaminase and alanine transaminase to rule out liver disease, serum creatinine to determine if kidney damage is present, and thyroid-stimulating hormone levels to evaluate for hyperthyroidism. Additional tests that may be considered are markers of testicular, adrenal, or other tumors such as urinary 17-ketosteroid, serum beta human chorionic gonadotropin, or serum dehydroepiandrosterone. Serum testosterone levels (free and total), estradiol, luteinizing hormone, and follicle stimulating hormone may also be evaluated to determine if hypogonadism may be the cause of gynecomastia.

Differential diagnosis

Other causes of male breast enlargement such as mastitis, breast cancer, pseudogynecomastia, lipoma, sebaceous cyst, dermoid cyst, hematoma, metastasis, ductal ectasia, fat necrosis, or a hamartoma are typically excluded before making the diagnosis. Another condition that may be confused with gynecomastia is enlargement of the pectoralis muscles.

Imaging

Mammography is the method of choice for radiologic examination of male breast tissue in the diagnosis of gynecomastia when breast cancer is suspected on physical examination. However, since breast cancer is a rare cause of breast tissue enlargement in men, mammography is rarely needed. If mammography is performed and does not reveal findings suggestive of breast cancer, further imaging is not typically necessary. If a tumor of the adrenal glands or the testes is thought to be responsible for the gynecomastia, ultrasound examination of these structures may be performed.

Histology

Early histological features expected to be seen on examination of gynecomastic tissue attained by fine-needle aspiration biopsy include the following: proliferation and lengthening of the ducts, an increase in connective tissue, an increase in inflammation and swelling surrounding the ducts, and an increase in fibroblasts in the connective tissue. Chronic gynecomastia may show different histological features such as increased connective tissue fibrosis, an increase in the number of ducts, less inflammation than in the acute stage of gynecomastia, increased subareolar fat, and hyalinization of the stroma. When surgery is performed, the gland is routinely sent to the lab to confirm the presence of gynecomastia and to check for tumors under a microscope. The utility of pathologic examination of breast tissue removed from male adolescent gynecomastia patients has recently been questioned due to the rarity of breast cancer in this population.

Classification

The spectrum of gynecomastia severity has been categorized into a grading system:

Treatment

Mild cases of gynecomastia in adolescence may be treated with advice on lifestyle habits such as proper diet and exercise with reassurance. In more severe cases, medical treatment may be tried including surgical intervention.

Medication

Medical treatment of gynecomastia is most effective when done within the first two years after the start of male breast enlargement. Selective estrogen receptor modulators (SERMs) such as tamoxifen or raloxifene may be beneficial in the treatment of gynecomastia but are not approved by the Food and Drug Administration for use in gynecomastia. Tamoxifen may be used for painful gynecomastia in adults. Aromatase inhibitors (AIs) have been used off-label for cases of gynecomastia occurring during puberty. A few cases of gynecomastia caused by the rare disorders aromatase excess syndrome and Peutz-Jeghers syndrome have responded to treatment with AIs such as anastrozole.

Surgery

If chronic gynecomastia is treated, surgical removal of glandular breast tissue is usually required. Surgical approaches to the treatment of gynecomastia include subcutaneous mastectomy, liposuction-assisted mastectomy, laser-assisted liposuction, and laser-lipolysis without liposuction. Complications of mastectomy may include hematoma, surgical wound infection, breast asymmetry, changes in sensation in the breast, necrosis of the areola or nipple, seroma, noticeable or painful scars, and contour deformities.

Other

Radiation therapy and tamoxifen have been shown to help prevent gynecomastia and breast pain from developing in prostate cancer patients who will be receiving androgen deprivation therapy. The efficacy of these treatments is limited once gynecomastia has occurred and are therefore most effective when used prophylactically.

Many insurance companies deny coverage for surgery for gynecomastia treatment or male breast reduction on the basis that it is a cosmetic procedure.

Prognosis

Gynecomastia is not physically harmful, but in some cases it may be an indicator of other more serious underlying conditions, such as testicular cancer. The glandular tissue typically grows under the influence of hormonal stimulation and is often tender or painful. Furthermore, gynecomastia frequently presents social and psychological difficulties such as low self-esteem or shame for the sufferer. Weight loss can alter the condition in cases triggered by obesity, but losing weight will not reduce the glandular component and patients cannot target areas for weight loss. Massive weight loss can result in sagging chest tissue known as chest ptosis.

Epidemiology

Gynecomastia is the most common benign disorder of the male breast tissue. New cases of gynecomastia are common in three age populations: newborns, adolescents, and men older than 50 years old. Newborn gynecomastia occurs in about 60-90% of male babies and most cases resolve on their own. During adolescence, up to 70% of males are estimated to exhibit signs of gynecomastia. Senile gynecomastia is estimated to be present in 24-65% of men between the ages of fifty and eighty.

The prevalence of gynecomastia in men may have increased in recent years, but the epidemiology of the disorder is not fully understood. The use of anabolic steroids and exposure to chemicals that mimic estrogen in cosmetic products, organochlorine pesticides, and industrial chemicals have been suggested as possible factors driving this increase. According to the American Society of Plastic Surgeons, breast reduction surgeries to correct gynecomastia are becoming increasingly common. In 2006, there were 14,000 procedures of this type performed in the United States alone.

Society and culture

Gynecomastia can result in psychological distress for those with the condition. Common derogatory terms for gynecomastia include "moobs" (for man boobs) and "bitch tits". Support groups exist to help improve the self-esteem of affected individuals.