Gynecomastia
Gynecomastia | |
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Pseudogynecomastia, breast cancer | |
Treatment | Lifestyle modifications, aromatase inhibitors, SERMs, or surgery |
Gynecomastia (also spelled gynaecomastia)
Gynecomastia can be normal in: newborn male babies, due to exposure to estrogen from the mother; adolescent boys going through
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.
Medications such as aromatase inhibitors have been found to be effective[15] and even in rare cases of gynecomastia from disorders such as aromatase excess syndrome or Peutz–Jeghers syndrome,[16] but surgical removal of the excess tissue can be needed to correct the condition.[17] In 2019, 24,123 male patients underwent the procedure in the United States, accounting for a 19% increase since 2000.[18]
Definition
Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in men due to the growth of
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
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.[25] Men with gynecomastia may appear anxious or stressed due to concerns about its appearance and the possibility of having breast cancer.[26][27]
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.[7] Estrogen and androgens have opposing actions on breast tissue: estrogens stimulate proliferation while androgens inhibit proliferation.[7][26] The cause of gynecomastia is unknown in around 25% of cases.[22][27] 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.[28]
Newborns
60-90% of male and female newborns may show breast development at birth or in the first weeks of life.
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.[31][32] 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.[31][26] By age 17, only 10% of adolescent males have persistent gynecomastia.[31]
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.[26] Additionally, levels of sex hormone binding globulin (SHBG) increase with age and bind with less affinity to estrogen than androgens.[28] Put together, the elevated ratio of estrogen to androgen leads to gynecomastia, also known as senile gynecomastia in this group.[26] There is a 24–65% prevalence of senile gynecomastia in older males.[26]
Non-physiologic
Drugs
About 10–25% of gynecomastia cases are estimated to result from the use of medications or exogenous chemicals.
Drugs with fair evidence for association with gynecomastia include
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.[43] 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.[43][7]
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.[27][44] 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.[7][26]
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;
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.[45][46]
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.[7] It can also be caused by chromosomal abnormality seen in Klinefelter syndrome, which is associated with gynecomastia in about 80% of cases.[43][26] 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.[7][28] The lack of androgen-mediated inhibition of breast tissue proliferation combined with relative estrogen excess result in gynecomastia.[7]
Tumors
Testicular tumors such as
Individuals with prostate cancer who are treated with androgen deprivation therapy may experience gynecomastia.[48]
Pathophysiology
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.[8][17] Breast prominence can result from enlargement of glandular breast tissue, chest adipose tissue (fat) and skin, and is typically a combination.[39] As in females, estrogen stimulates the growth of breast tissue in males.[7] 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.[7]
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.[49] Tumors that produce hCG stimulate production of estradiol while reducing other testicular hormone production.[50] 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.[50] Peutz-Jeghers syndrome is a rare cause of testicular tumors that affect aromatase expression, which results in elevated serum estrogen levels.[51] Aromatase excess syndrome is a rare genetic disorder that leads to increased conversion of androgens to estrogens in the body.
Androgen deficiency
Primary
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.[7][50] Conditions such as hyperthyroidism and chronic liver disease affect levels of SHBG, leading to symptomatic gynecomastia.[49]
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
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.[26] Potential causative agents include oral contraceptive pills, spironolactone, and anabolic steroids.[54]
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,[7] and increased levels of SHBG, which leads to decreased blood levels of free testosterone.[26] Around 10–40% of males with Graves' disease (a common form of hyperthyroidism) experience gynecomastia.[26] Increased conversion of testosterone to estrogen by increased aromatase activity,[7] 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.[26]
Estrogen excess | Androgen deficiency | Increased levels of sex hormone-binding globulin | Androgen resistance | Medications |
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Diagnosis
To diagnose gynecomastia, a thorough history and physical examination are obtained by a
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.
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,[27][55] lipoma, sebaceous cyst, dermoid cyst, hematoma, metastasis, ductal ectasia, fat necrosis, or a hamartoma are typically excluded before making the diagnosis.[27]
Imaging
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.[26] 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.[24][26] 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.[56]
Classification
The spectrum of gynecomastia severity has been categorized into a grading system:[57]
- 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.[58]
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.[7] 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.[7][17][59] Clomifene seems to be less effective than tamoxifen or raloxifene.[59] Tamoxifen may be used to treat gynecomastia in adults and of the medical treatments used, tamoxifen is the most effective.[60][61] 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.[17][62] Aromatase inhibitors (AIs) such as anastrozole have been used off-label for cases of gynecomastia occurring during puberty but are less effective than SERMs.[16][59]
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.[16] Androgens/anabolic steroids may be effective for gynecomastia.[59] 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.[59]
Surgery
If chronic gynecomastia does not respond to medical treatment, surgical removal of glandular breast tissue is usually required.[17] The American Board of Cosmetic Surgery reports surgery is the "most effective known treatment for gynecomastia."[63] 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.[64] In adolescent males, it is recommended that surgery is postponed until puberty is completed (penile and testicular development should reach Tanner scale Stage V).[64]
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.[57] 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.[18]
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.[65]
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.[66][67][68][69]
Prognosis
Gynecomastia itself is a benign finding. It does not confer a poor prognosis, for some patients with underlying pathologies such as
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.[5][9]
New cases of gynecomastia are common in three age populations: newborns, adolescents, and men older than 50 years.[57] 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.[26][27] During adolescence, on average 33 percent of males are estimated to exhibit signs of gynecomastia.[7] 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.[26][49]
The
History
The term gynaecomastia was coined by
Society and culture
Gynecomastia can result in psychological distress for those with the condition. Support groups exist to help improve the self-esteem of affected people.[69]
Moob, a
In 2019, a 12-person Philadelphia jury awarded $8 billion in punitive damages to plaintiffs tied to the use of
In Murray v. Janssen Pharmaceuticals, Murray was a Risperidone user who was prescribed the medication at age nine and developed male breasts. A jury decided in Murray's favor in November 2015 and awarded him $1.75 million. The $1.75 million jury verdict represented damages for "disfigurement and mental anguish," though it was later reduced to $680,000.[74] In the second portion of the bifurcated trial, the plaintiffs sought to prove that the companies knew and deliberately disregarded evidence that Risperidone could lead to gynecomastia in young males, and nonetheless promoted the medication off-label and released the medication into the open market for prescription and use by patients without disclosing the side effects.[74] The jury found for the plaintiffs in the second portion of the trial and awarded $8 billion in punitive damages. The amount was later reduced to $6.8 million by Judge Kenneth Powell Jr.[75]
Etymology
The term comes from Greek γυνή gyné (stem gynaik-) 'female' and μαστός mastós 'breast'.[3]
See also
References
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External links
- Media related to Gynecomastia at Wikimedia Commons