Adolescent physiologic gynecomastia should resolve within six months to two years after onset. If symptoms persist after two years or past 17 years of age, further evaluation is indicated. Use of medications or substances associated with gynecomastia or other underlying illness may be a factor.
If no other etiology can be found and if the patient desires treatment, supplementation with testosterone, use of estrogen receptor—modifying agents, or referral for surgery to improve cosmesis is warranted.
After persistent pubertal gynecomastia, medication use and substance use are the most common causes of nonphysiologic gynecomastia. Agents associated with gynecomastia are listed in Table 2. Increases sex hormone—binding globulin concentration. Information from references 7 , and 9 through Additionally, lavender, tea tree oil, dong quai, and Tribulus terrestris an ingredient in performance-enhancing supplements have been linked to gynecomastia.
Anabolic steroid use often causes irreversible gynecomastia. The injection of exogenous testosterone inhibits natural production of testosterone, which cannot recover rapidly enough between steroid-injecting cycles to prevent estrogen predominance.
Attempts to prevent gynecomastia with the use of concomitant tamoxifen or other aromatase inhibitors may result in irreversible adverse effects. Liver injury may impair hepatic degradation of estrogens and increase levels of sex hormone—binding globulin that contribute to increased peripheral estrogens.
Patients with alcohol-related liver disease are at particular risk of gynecomastia because phytoestrogens in alcohol and the direct inhibition of testosterone production by ethanol further disrupt the estrogen-to-testosterone ratio. Gynecomastia may be the only presenting symptom in men with primary hypogonadism.
For example, one-half of men with Klinefelter syndrome have gynecomastia. Although testicular tumors are rare, approximately 10 percent of persons with testicular tumors present with gynecomastia alone. Adrenal tumors may secrete estrogen and estrogen precursors, causing a similar disruption in the estrogen-to-testosterone ratio.
These tumors can be detected by elevated serum dehydroepiandrosterone sulfate levels or increased urinary ketosteroid levels. Similarly, the presence of human chorionic gonadotropin hCG in serum can be used to detect hCG-secreting tumors that may include testicular germ cell, liver, gastric, or bronchogenic carcinomas. All of these tumors require surgical excision. Gynecomastia occurs in 10 to 40 percent of men with hyperthyroidism, although it is rarely the only symptom at presentation.
Hormonal dysfunction is common in men with renal failure because of overall suppression of testosterone production and direct testicular damage secondary to uremia. Conditions that impair absorption, such as ulcerative colitis and cystic fibrosis, may result in gynecomastia. Refeeding after prolonged malnutrition can also trigger breast tissue proliferation. Although malnutrition suppresses hormone production, refeeding helps resume production.
However, the liver lags in recovery and cannot fully degrade estrogens. Although obesity causes pseudogynecomastia a proliferation of adipose rather than glandular tissue , elevated weight is also associated with true gynecomastia.
New research suggests that leptin and aromatase activity associated with obesity contribute to increased circulating estrogens, causing gynecomastia. Other rare causes of gynecomastia include exposure to phthalates and lead, emotional stress, and repetitive mechanical stress causing unilateral symptoms.
Additionally, patients with human immunodeficiency virus infection may develop gynecomastia from the disease process or use of antiretroviral medications. No cause is found in 25 percent of patients who develop gynecomastia. Some patients with gynecomastia may present with breast pain, embarrassment, or fear of breast cancer.
In other patients, gynecomastia is discovered on routine physical examination and causes no emotional or physical distress. Understanding the patient's concerns can help direct treatment. The history should rule out other causes of breast enlargement, such as those listed in Table 3.
Symptoms that last longer than one to two years suggest nonphysiologic causes that require intervention for resolution. Nipple discharge; skin changes; rapidly enlarging, firm breast masses; coincident testicular masses; or systemic symptoms such as weight loss should raise concern. Information from references 31 through The physical examination should include evaluation of height and weight, and examination of the breasts, genitals, liver, lymph nodes, and thyroid.
Assessment of symmetry and consistency of breast tissue is critical on breast examination. Most commonly, gynecomastia is bilateral, although unilateral symptoms can occur and are usually left-sided. Palpable, firm glandular tissue in a concentric mass around the nipple areolar complex is most consistent with gynecomastia.
Increases in subareolar fat are more likely pseudogynecomastia, whereas hard, immobile masses should be considered breast carcinoma until proven otherwise. Similarly, masses associated with skin changes, nipple retraction, nipple discharge, or enlarged lymph nodes should raise concern for malignancy.
The history and physical examination should direct the laboratory and imaging workup Figure 1. Laboratory studies to investigate the underlying cause of gynecomastia should include measurement of hepatic transaminase, serum creatinine, and thyroid-stimulating hormone levels for all patients.
Levels of serum beta hCG, serum dehydroepiandrosterone sulfate, or urinary ketosteroid should be obtained to rule out testicular, adrenal, or other tumors when clinically suspected.
Likewise, total and free testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels define hormonal imbalances resulting from primary or secondary hypogonadism. Hyperprolactinemia is not common in patients with gynecomastia. Laboratory studies may be ordered using a stepwise approach guided by history and physical examination, but a diagnosis of physiologic gynecomastia should not be made until underlying etiologies have been excluded.
Recommendations for imaging studies are based mainly on case reports and expert opinion. Some studies have suggested routine testicular ultrasonography in men with gynecomastia to detect nonpalpable testicular tumors that were missed on clinical examination. Breast imaging should be guided by examination. Just as in women, mammography and breast ultrasonography may be useful in men if the physical examination raises suspicion for breast malignancy.
Fine-needle aspiration of masses for cytology should be pursued only if malignancy is suspected. Men with Klinefelter syndrome have a risk of breast cancer 16 to 30 times higher than other men. Even with a reassuring examination, men with gynecomastia and Klinefelter syndrome may require imaging.
Few patients with gynecomastia need treatment for cosmesis or analgesia. For patients with nonphysiologic gynecomastia, treatment is directed toward improving the underlying illness or discontinuing use of the contributing. Watchful waiting with biannual follow-up is appropriate for those with physiologic gynecomastia who are untroubled by symptoms and who have no features that suggest underlying disease or malignancy. Early treatment will maximize benefit in men with significant physical symptoms or emotional distress.
Medications are more effective if used as early as possible after symptoms are first noted, whereas surgery can be performed at any time with similar results. A number of medications have been used to treat gynecomastia. A retrospective chart review of men presenting to a breast clinic for gynecomastia found that only 13 of patients required medication for treatment. Patients were treated with 10 mg of tamoxifen per day for three months, and 10 of the 13 had resolution of pain and breast enlargement.
Gynecomastia is a common adverse effect of bicalutamide Casodex therapy that may prompt some men to discontinue prostate cancer treatment. Tamoxifen has been recommended as a preventive agent for gynecomastia in these patients. A double-blind study of men randomized to receive 20 mg of tamoxifen once per day with bicalutamide or bicalutamide alone found that after six months, gynecomastia and breast pain were significantly reduced in men who received tamoxifen 8. In a retrospective chart review of 38 patients in a pediatric endocrinology clinic, raloxifene Evista; 60 mg once per day for three to nine months reduced pubertal gynecomastia in 91 percent of patients, whereas tamoxifen 10 to 20 mg twice per day for three to nine months was effective in 86 percent of patients.
Dihydrotestosterone, danazol, and clomiphene Clomid have also been used to treat gynecomastia with varying success. Sansone A, et al. Gynecomastia and hormones. Jameson JL, et al. Disorders of the testes and male reproductive system. In: Harrison's Principles of Internal Medicine.
The McGraw-Hill Companies; Papadakis MA, et al. Endocrine disorders. McGraw-Hill Education; Merck Manual Professional Version. Mayo Clinic; Rasko YM, et al. Surgical management of gynecomastia: A review of the current insurance coverage criteria.
Plastic and Reconstructive Surgery. It has also been reported that LH and hCG reduce the concentration of androgen receptors in the skin. Findings of lobular structures in microscopic analysis on GM tissue are very rare. Progesterone appears to be required to form true glandular acini acting in synergy with insulin growth factor-1 IGF Another hormonal action that stimulates breast tissue in men is observed secondary to hyperprolactinemia.
GM is a multifactorial disease and many conditions may be associated with it. Table 2 outlines the various specific causes of GM. The hypertrophy may reach severe proportions, leading to an effeminate appearance in boys.
Such occurrences may alter self-perceptions, especially in the sexual sphere. Relative excess of serum levels of estrogens compared with androgens is implicated in the pathogenesis, due to estradiol production rising sooner than testosterone production. Some other factors may also interact, and usually there is concomitant elevation in serum IGF-1 concentrations. Interestingly, a family history has been elicited in more than half of the patients with persistent pubertal GM. Older men over the age of 65 years often present relative hypogonadism with a decline in plasma testosterone levels, elevation of SHBG and decrease in free testosterone.
Furthermore, there is progressive adiposity favoring peripheral aromatase activity. Benign testicular tumors Sertoli or Leydig cell tumors may secrete estradiol.
Secondary suppression of LH levels interferes negatively with testosterone synthesis. The elevated estrogen levels raise the serum concentration of SHBG, which preferentially binds testosterone, thereby lowering the free testosterone levels.
Choriocarcinoma and other germ cell tumors produce hCG and stimulate testicular cells Leydig to secrete estradiol, and furthermore, often cause GM. These tumors may be palpable or be detected only by means of ultrasound.
Other hCG secreting tumors of ectopic origin may lead to GM e. Adrenocortical tumors are generally large malignant types of neoplasia, with predominant incidence in young and middle-aged men. They are feminizing tumors with direct secretion of estrogens and steroid precursors, like androstenedione. The serum estrogen elevation also suppresses LH-mediated testosterone production. Severe hyperthyroidism increases serum SHBG. Primary gonadal failure as a result of testicular trauma, chemotherapy, mumps, orchitis and leprosy can cause GM by lowering the serum testosterone levels, inducing elevation of LH and stimulating the remaining Leydig cells to secrete estrogens.
The reason why the presence of an extra X chromosome is linked to GM is unclear. Findings of low testosterone levels with normal LH assays denote secondary testicular failure. It is noteworthy that men with long-standing type 1 diabetes may develop diabetic mastopathy, presenting hard diffuse enlargements of one or both breasts. Other endocrine-metabolic conditions related to the development of GM include metabolic syndrome, refeeding after severe starvation and substantial weight loss and functional hyperprolactinemia.
The chief sex hormone abnormalities in cases of liver cirrhosis are decreased serum testosterone levels and increased estradiol levels. The causes are probably multifactorial. Men with chronic renal failure are often hypogonadal, with defects in testicular steroidogenesis. Even though the mechanisms through which a long list of drugs can cause GM are not fully clear, they are derived from estrogen-like activities, stimulation of testicular production of estrogens, inhibition of testosterone synthesis or blockade of androgen action.
One of the medications most frequently associated with GM is the diuretic spironolactone, which is a competitive antagonist of aldosterone. Spironolactone also inhibits testosterone production in the testes, enhances the aromatization of testosterone to estradiol and binds to androgen receptors in some tissues, thereby acting as an antiandrogenic substance.
Androgen deprivation therapy for prostate cancer frequently presents GM as a side effect. Some illicit drugs, such as cocaine, heroin and amphetamines, and other abused drugs, are commonly associated with GM. Marijuana is believed to interfere with estrogen receptors and acts as a phytoestrogen. Doping with anabolic androgenic steroids, gonadotropins and growth hormones for power sports and weight training is rampant.
Table 3 outlines the common pharmaceutical products that may cause GM with prolonged use. So far, at least 20 clinical conditions and 30 medications have been implicated in relation to causing GM. Clinical evaluations on men with enlarged breast tissue have three phases: 1 making the diagnosis of true GM; 2 trying to find an etiological factor to further guide case management; and 3 classifying into severity grades. Differentiation of true GM from pseudogynecomastia local fat deposition alone and tumors is based on physical examination by means of inspection and palpation.
Initially, the patient must disrobe from the waist upwards, for inspection in a seated position: with the arms relaxed, with the arms raised, and with the hands pressed against the hips to contract the pectoral muscles. After palpation of the axillary nodes, the patient is asked to lie down in a supine position with his hands clasped beneath his head.
First, the examiner carefully flat-palpates with his fingers to detect glandular tissue, and then, with his thumb and forefinger separated, slowly brings the fingers together from either side of the breast. Patients with pseudogynecomastia do not show mound resistance of this nature, and no firm tissue is found.
Breast carcinoma usually consists of a unilateral hard irregular mass, located outside the areola and may be accompanied by skin dimpling, nipple retraction and axillary lymphadenopathy.
Other local problems, such as dermoid cysts, lymphangiomas, lipomas, post-trauma hematomas, neurofibromas and several benign tumors are usually easily distinguished.
Any lesion that is suspected to be malignant should be evaluated by means of core-needle or excisional biopsies. GM is clinically bilateral in approximately half of the patients. Ruling out the possible presence of breast carcinoma is paramount, particularly in adults with unilateral enlargements, family histories of breast cancer or Klinefelter syndrome. Mammography is the primary imaging method when there is any suspicion of cancer.
Sonography has been widely used in GM cases. It is important to recognize the various patterns of GM in order to avoid unnecessary worries. The typical findings include hypoechoic retroareolar masses nodular, poorly defined or flame-shaped , with increased anteroposterior depth at the nipple.
If differentiation between GM and breast carcinoma cannot be made on the basis of clinical and imaging findings, the patient should undergo percutaneous biopsy. Microscopically, GM is characterized by proliferation of the ductules, without terminal acini, in fibroconnective stroma Figure 1. In the early onset stage florid phase , there is extensive ductal hyperplasia; over time, the glandular elements become less prominent and fibrosis becomes the main finding fibrous phase.
Although it might be tempting to try to establish a correlation between etiological factors and histological appearance, no such correlation has ever been identified. The current wisdom is to endorse the concept that men with GM are not at high risk of breast cancer. A detailed history, with attention given to age, medications, duration and onset of breast enlargement, symptoms of tenderness or pain, recreational drug use and anabolic steroid use, is crucial.
The general physical examination may reveal signs of thyroid disease, hypogonadism or other conditions. Abdominal masses may be found in patients with adrenocortical carcinomas. The investigation should specifically pay attention both to the breasts and to the genitals. Further work-up includes screening laboratory tests and ultrasonography on the adrenal glands and testes.
However, in practical terms, even extensive testing is unlikely to reveal anything when there is no history or physical examination suggestive of an underlying pathological cause. Testosterone, free bioavailable testosterone and LH should be measured in the morning, since they have a circadian rhythm with the highest values in the early hours.
GM shows a gradation of clinical types that range from simple areolar protrusion to breasts with a female appearance. The main clinical features characterizing GM are breast swelling, increased areolar diameter, presence of an anomalous inframammary fold, glandular ptosis and skin redundancy.
There are several morphological classifications for GM. This classification takes into account the different relationships between the structural components of the breast, in particular the inframammary fold and nipple-areola complex NAC , which is the watershed between mild forms and serious forms. Based upon this classification, in a standing position we classify all types of GM into four grades of increasing severity from I to IV, as follows Figures 2 , 3 , 4 and 5 :.
If the GM is slight, without noteworthy psychological repercussion and the appropriate work-up does not reveal any underlying disease and only shows weight loss, reassurance and periodic follow-up visits every months are recommended.
Reassurance is widely regarded as the safest and most reasonable form of treatment, given that the condition is usually self-limiting and asymptomatic.
For mild enlargements in pubertal boys, the simplest therapeutic approach is verbal explanation and reassurance regarding the signs and symptoms. Reassurance should be based on full and authoritative explanations about the common transient hormonal imbalance at this age, the natural involution of the condition and the absence of later sexual and fertility effects. Although fibroglandular overgrowth may also be present, this is typically overwhelmed in obese boys by the surrounding fat accumulation.
For this reason and, equally as important, for other developmental and psychological reasons, a weight loss program diet and physical exercises should be the first-line treatment. If possible, any causative medications or anabolic agents should be immediately withdrawn. In these subjects no significant correlation was noted between breast tissue diameter and body mass index, presumably because the body mass index was increased owing to fluid retention.
The results could not be accounted for based on medications. Serum free testosterone concentrations were lower in the cirrhotic patients than in the controls 0. The total estrogen-free testosterone ratio was higher in cirrhotic patients
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