gynecomastia gynecomastia gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. gynecomastia can cause significant psychological distress or unease. gynecomastiaadult male with significant gynecomastiapronunciation/ˌɡaɪnɪkoʊˈmæstiə, ˌdʒaɪ-, -kə-/ or /ɡaɪˈniːkəˌmæstiə, -koʊ-/ specialtyendocrinology, plastic surgeryusual onsetany agedurationusually up to 2 years, but can be lifelongcausesincreased estrogen/androgen ratio (physiologic, medications, chronic kidney disease, obesity, cirrhosis, malnutrition, certain cancers)diagnostic methodphysical exam, mammography (if indicated)differential diagnosispseudogynecomastia, breast cancertreatmentlifestyle modifications, aromatase inhibitors, serms, or surgery gynecomastia can be normal in newborn male babies due to exposure to estrogen from the mother, in adolescent boys going through puberty, in older men over age 50, and/or in obese men. most occurrences of gynecomastia do not require diagnostic tests. gynecomastia may be caused by abnormal hormone changes, any condition that leads to an increase in the ratio of estrogens/androgens such as liver disease, kidney failure, thyroid disease and some non-breast tumors. alcohol and some drugs can also cause breast enlargement. other causes may include klinefelter syndrome, metabolic dysfunction, or a natural decline in testosterone production. this may occur even if the levels of estrogens and androgens are both appropriate, but the ratio is altered. gynecomastia is the most common benign disorder of the male breast tissue and affects 35% of men, being most prevalent between the ages of 50 and 69. it is normal for up to 70% of adolescent boys to develop gynecomastia to some degree. of these, 75% resolve within two years of onset without treatment. if the condition does not resolve within 2 years, or if it causes embarrassment, pain or tenderness, treatment is warranted. medical treatment of gynecomastia that has persisted beyond two years is often ineffective. gynecomastia is different from "pseudogynecomastia", which is commonly present in men with obesity. medications such as aromatase inhibitors have been found to be effective and even in rare cases of gynecomastia from disorders such as aromatase excess syndrome or peutz–jeghers syndrome, but surgical removal of the excess tissue can be needed to correct the condition. in 2019, 24,123 male patients underwent the procedure in the united states, accounting for a 19% increase since 2000. definition gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogen and androgen. gynecomastia is different from "pseudogynecomastia", which is defined as an excess of skin and/or adipose tissue in the male breasts without the growth of true glandular breast tissue; this is commonly associated with obesity and can be ruled out by physical exam. signs and symptoms in gynecomastia there is always enlargement of one or both breasts, symmetrically or asymmetrically, in a man. a soft, compressible, and mobile mass of breast tissue is felt under the nipple and its surrounding skin in contrast to softer fatty tissue which is not associated with a mass. it may also be accompanied by breast tenderness or nipple sensitivity, which is commonly associated with gynecomastia observed in adolescents, typically early in development. gynecomastia that is painful, bothersome, rapidly-growing, associated with masses in other areas of the body, or persistent should be evaluated by a clinician for potential causes. dimpling of the skin, nipple discharge, and nipple retraction are not typical features of gynecomastia and may be associated with other disorders. milky discharge from the nipple is not a typical finding, but may be seen in a gynecomastic individual with a prolactin secreting tumor. an increase in the diameter of the areola and asymmetry of the chest are other possible signs of gynecomastia. gynecomastia has psychosocial implications that may be particularly challenging for adolescents who are experiencing physical maturation and self-identity formation, which includes body image disturbances, negative attitudes towards eating, self-esteem problems, social withdrawal, anxiety, and shame. men with gynecomastia may appear anxious or stressed due to concerns about its appearance and the possibility of having breast cancer. causes gynecomastia is thought to be caused by an altered ratio of estrogens to androgens mediated by an increase in estrogen action, a decrease in androgen action, or a combination of these two factors. estrogen and androgens have opposing actions on breast tissue: estrogens stimulate proliferation while androgens inhibit proliferation. the cause of gynecomastia is unknown in around 25% of cases. known causes can be physiologic (occurring normally) or non-physiologic due to underlying pathologies such as drug use, chronic disease, tumors, or malnutrition. physiologic physiologic or normal gynecomastia can occur at three timepoints in life: shortly after birth in both female and male infants, during puberty in adolescent males, and in older adults over the age of 60. newborns gynecomastia of boys going through puberty. 60-90% of male and female newborns may show breast development at birth or in the first weeks of life. during pregnancy, the placenta converts the androgenic hormones dehydroepiandrosterone (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 leak from the nipples. the temporary gynecomastia seen in newborn babies usually resolves after two or three weeks. adolescents hormonal imbalance (elevated ratio of estrogen to androgen) during early puberty, either due to decreased androgen production from the adrenals and/or increased conversion of androgens to estrogens, leads to transient gynecomastia in adolescent males. it can occur in up to 65% of adolescents as early as age 10 and peaks at ages 13 and 14. it is self-limited in 75-90% of adolescents and usually resolves spontaneously within 1 to 3 years as pubertal progression increases testosterone levels and cause regression of breast tissue. by age 17, only 10% of adolescent males have persistent gynecomastia. older adults 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 males. increased fatty tissue, a major site of aromatase activity, leads to increased conversion of androgenic hormones such as testosterone to estrogens. additionally, levels of sex hormone binding globulin (shbg) increase with age and bind with less affinity to estrogen than androgens. put together, the elevated ratio of estrogen to androgen leads to gynecomastia, also known as senile gynecomastia in this group. there is a 24-65% prevalence of senile gynecomastia in older males. drugs an exceptional case of extreme gynecomastia in a 63-year-old man, treated with the nonsteroidal antiandrogen flutamide for prostate cancer. (a) with flutamide; (b) after discontinuation of flutamide. more than 90% of cases of gynecomastia with nonsteroidal antiandrogens including flutamide are mild to moderate. about 10–25% of gynecomastia cases are estimated to result from the use of medications or exogenous chemicals. drugs can increase estrogen activity or increase the estrogen to androgen ratio through various mechanisms, such as binding to estrogen receptors, promoting estrogen synthesis, providing precursors that can be aromatized into estrogen, causing damage to the testes, inhibiting testosterone synthesis, inhibiting the action of androgens, or displacing estrogen from shbg. drugs with good evidence for association with gynecomastia include cimetidine, ketoconazole, gonadotropin-releasing hormone analogues, human growth hormone, human chorionic gonadotropin, 5α-reductase inhibitors such as finasteride and dutasteride, certain estrogens used for prostate cancer, and antiandrogens such as bicalutamide, flutamide, and spironolactone. drugs with fair evidence for association with gynecomastia include calcium channel blockers such as verapamil, amlodipine, and nifedipine; risperidone, olanzapine, anabolic steroids, alcohol, opioids, efavirenz, alkylating agents, and omeprazole. certain components of personal skin care products such as lavender or tea tree oil have been reported to cause prepubertal gynecomastia due to its estrogenic and anti-androgenic effects. certain dietary supplements such as dong quai and tribulus terrestris have also been associated with gynecomastia. refeeding gynecomastia malnutrition and significant loss of body fat suppress gonadotropin secretion, leading to hypogonadism. this is reversible when adequate nutrition resumes, where the return of gonadotropin secretion and gonadal function cause a transient imbalance of estrogen and androgen that mimics puberty, resulting in transient gynecomastia. this phenomenon, also known as refeeding gynecomastia, was first observed when men returning home from prison camps during world war ii developed gynecomastia after resuming a normal diet. similar to pubertal gynecomastia, refeeding gynecomastia resolves on its own in 1–2 years. chronic disease 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. additionally, gynecomastia has been observed in 50% of patients with chronic kidney disease undergoing dialysis. similar to the mechanism behind refeeding gynecomastia, dialysis allows patients with renal failure who were previously malnourished to expand their diets and regain weight. dialysis-associated gynecomastia resolves spontaneously within 1–2 years. 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 alcoholic drinks 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. a small proportion of male gynecomastia cases may be seen with rare inherited disorders such as spinal and bulbar muscular atrophy and the very rare aromatase excess syndrome. hypogonadism gynecomastia can be caused by absolute deficiency in androgen production due to primary or secondary hypogonadism. primary hypogonadism results when there is damage to the testes (due to radiation, chemotherapy, infections, trauma, etc), leading to impaired androgen production. it can also be caused by chromosomal abnormality seen in klinefelter syndrome, which is associated with gynecomastia in about 80% of cases. secondary hypogonadism results when there is damage to the hypothalamus or pituitary (due to radiation, chemotherapy, infection, trauma, etc), and similarly lead to impaired androgen production. the net effect is reduced androgen production while serum estrogen levels (from peripheral aromatization of androgens) remain unaffected. the lack of androgen-mediated inhibition of breast tissue proliferation combined with relative estrogen excess result in gynecomastia. tumors testicular tumors such as leydig cell tumors, sertoli cell tumors (such as in peutz–jeghers syndrome) and hcg-secreting choriocarcinoma may result in rapid-onset gynecomastia by causing excess production of estrogen. other tumors such as adrenal tumors, pituitary gland tumors (such as a prolactinoma), or lung cancer, 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 pathology: a large glandular mass of male breast tissue, surgically removed microscopic image showing gynecomastoid hyperplasia, the cellular changes seen in gynecomastia h&e stain the causes of common gynecomastia remain uncertain, but are thought to result from an imbalance between the actions of estrogen, which stimulates breast tissue growth, and androgens, which inhibit breast tissue growth. 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 breast tissue growth, estrogens indirectly decrease secretion of testosterone by suppressing luteinizing hormone secretion, resulting in decreased testicular secretion of testosterone. estrogen excess one of the main mechanisms for imbalance between estrogens and androgens is the overproduction of estrogens. a possible cause may be a neoplasm that originates from estrogen-secreting cells. tumors that produce hcg stimulate production of estradiol while reducing other testicular hormone production. obesity is another common cause of excess serum estrogens due to the presence of aromatase in peripheral tissue, which is a protein that converts androgens into estrogens. peutz-jeghers syndrome is a rare cause of testicular tumors that affect aromatase expression, which results in elevated serum estrogen levels. aromatase excess syndrome is a rare genetic disorder that leads to increased conversion of androgens to estrogens in the body. androgen deficiency 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 and gynecomastia, and has a higher risk of breast cancer in males