(20–50 times higher than males without the disorder). secondary 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. increased levels of sex hormone-binding globulin estrogens can increase blood levels of the protein sex hormone-binding globulin (shbg), which binds free testosterone (the active form) more strongly than estrogen, leading to decreased action of testosterone in male breast tissue. conditions such as hyperthyroidism and chronic liver disease affect levels of shbg, leading to symptomatic gynecomastia. androgen resistance dysfunction in the androgen receptor prevents the effects of testosterone from acting on its target tissues. androgen insensitivity syndromes result from the different degrees of resistance to the effects of androgens, and can cause external genitalia that may not be aligned with the genotype of the individual's sex chromosomes. complete androgen insensitivity syndrome results in the failure to develop external genitalia such as the penis and scrotum along with development of breasts in an individual with testes. partial androgen insensitivity syndrome may result in a variety of presentations. minimal androgen insensitivity syndrome may present as gynecomastia in adolescence and may additionally be associated with infertility. medications 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. potential causative agents include oral contraceptive pills, spironolactone, and anabolic steroids. 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 secondary 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. chronic disease individuals who have cirrhosis or chronic liver disease may develop gynecomastia for several reasons. those diagnosed with cirrhosis 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. around 10–40% of males 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. estrogen excess androgen deficiency increased levels of sex hormone-binding globulin androgen resistance medications tumors (testicular, choriocarcinoma, adrenal, pituitary gland, lung) peutz-jeghers syndrome aromatase excess syndrome obesity aging primary hypogonadism (klinefelter's syndrome) secondary hypogonadism hyperthyroidism (grave's disease) cirrhosis androgen insensitivity syndromes oral contraceptives calcium channel blockers cimetidine ketoconazole gonadotropin-releasing hormone analogues human growth hormone human chorionic gonadotropin 5α-reductase inhibitors antiantrogens 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 sex 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. diagnosis of men with breast enlargement can be evaluated using an algorithm. a review of the medications or 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. if these initial laboratory tests fail to uncover the cause of gynecomastia, then additional tests to evaluate for an underlying hormonal balance due to hypogonadism or a testicular tumor should be checked including total and free levels of testosterone, luteinizing hormone, follicle stimulating hormone, estradiol, serum beta human chorionic gonadotropin (β-hcg), and prolactin. high levels of prolactin are uncommon in people with gynecomastia. if β-hcg levels are abnormally high, then ultrasound of the testicles should be performed to check for signs of a hormone-secreting testicular tumor. markers of testicular, adrenal, or other tumors such as urinary 17-ketosteroid or serum dehydroepiandrosterone may also be checked if there is evidence of hormonal imbalance on physical examination. if this evaluation does not reveal the cause of gynecomastia, then it is considered to be idiopathic gynecomastia (of unclear cause). differential diagnosis while there can be many potential causes of male patients that present with increased breast tissue, differential diagnoses are most concerning for gynecomastia, pseudogynecomastia, and breast cancer (which is rare in men). other potential causes of male breast enlargement such as mastitis, lipoma, sebaceous cyst, dermoid cyst, hematoma, metastasis, ductal ectasia, fat necrosis, or a hamartoma are typically excluded before making the diagnosis. 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. if a mass/lump is felt during a physical exam some features of the lump that would point to malignancy would be painless, non moveable (fixed), irregularly shaped, and skin changes. mammography is rarely indicated for men since breast cancer is an unlikely diagnosis. 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 gynecomastoid hyperplasia - low magnification 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: grade i: minor enlargement, no skin excess grade ii: moderate enlargement, no skin excess grade iii: moderate enlargement, skin excess grade iv: marked enlargement, skin excess treatment if the gynecomastia doesn't resolve on its own in two years, then medical treatment is necessary. the options are medication or surgical intervention. medication gynecomastia can respond well to medical treatment although it is usually only effective when done within the first two years after the start of male breast enlargement. selective estrogen receptor modulators (serms) such as tamoxifen, raloxifene, and clomifene may be beneficial in the treatment of gynecomastia but are not approved by the food and drug administration for use in gynecomastia. clomifene seems to be less effective than tamoxifen or raloxifene. tamoxifen may be used to treat gynecomastia in adults and of the medical treatments used, tamoxifen is the most effective. recent studies have shown that treatment with tamoxifen may represent a safe and effective mode of treatment in cases of cosmetically disturbing or painful gynecomastia. aromatase inhibitors (ais) such as anastrozole have been used off-label for cases of gynecomastia occurring during puberty but are less effective than serms. 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. androgens/anabolic steroids may be effective for gynecomastia. testosterone itself may not be suitable to treat gynecomastia as it can be aromatized into estradiol, but nonaromatizable androgens like topical androstanolone (dihydrotestosterone) can be useful. surgery male with asymmetrical gynecomastia, before and after excision of the gland and liposuction of the waist if chronic gynecomastia does not respond to medical treatment, surgical removal of glandular breast tissue is usually required. the american board of cosmetic surgery reports surgery is the "most effective known treatment for gynecomastia." surgical treatment should be considered if the gynecomastia persists for more than 12 months, causes distress (ie physical discomfort or psychological distress), and is in the fibrotic stage. in adolescent males, it is recommended that surgery is postponed until puberty is completed (penile and testicular development should reach tanner scale stage v). 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. in 2019, 24,123 male patients underwent surgical treatment for gynecomastia in the united states, accounting for a 19% increase since 2000. thirty-five percent of those patients were between the ages of 20 and 29, and 60% were younger than age 29 at the time of the operation. at an average surgeon's fee of $4,123, gynecomastia surgery was also the 11th most costly male cosmetic surgery of 2019. others 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. in the united states, 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 itself is a benign finding. it does not confer a poor prognosis, for some patients with underlying pathologies such as testicular cancer the prognosis may be worse. 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, depression or shame. epidemiology gynecomastia is the most common benign disorder of the male breast tissue and affects 35 percent of men, being most prevalent between the ages of 50 and 69. new cases of gynecomastia are common in three age populations: newborns, adolescents, and men older than 50 years. newborn gynecomastia occurs in about 60–90 percent of male babies and most cases resolve on their own in about 2–3 weeks after delivery. during adolescence, on average 33 percent of males are estimated to exhibit signs of gynecomastia. gynecomastia in older men is estimated to be present in 24–65 percent of men between the ages of 50 and 80. estimates on asymptomatic gynecomastia is about up to 70% in men aged 50 to 69 years. 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 fairly common but has been a recent decline. in 2020, there were over 18,000 procedures of this type performed in the united states which is down 11% compared to in 2019. history the term gynaecomastia was coined by galen. he also recognised glandular enlargement of the male breast; however, this wasn't a condition of gynaecomastia according to him. a surgical procedure for treatment of gynaecomastia was described by albucasis in his second book of kitab al-tasrif. society and culture gynecomastia can result in psychological distress for those with the condition. support