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   Table of Contents      
REVIEW ARTICLE
Year : 2016  |  Volume : 2  |  Issue : 2  |  Page : 69-75

Gynecomastia: A review of literature


Department of Radiotherapy, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India

Date of Web Publication19-May-2016

Correspondence Address:
Kishore Singh
Department of Radiotherapy, Maulana Azad Medical College, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2394-7438.182726

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  Abstract 

Gynecomastia is a benign enlargement of the male breast tissue, either due to the proliferation of glandular tissue or deposition of fat in breast tissue, usually caused by imbalance of estrogen and androgen hormones in body. Gynecomastia has a trimodal age distribution and begins as a small lump beneath the nipple which may be tender. Gynecomastia is usually benign but may be a cause of embarrassment for some. Evaluation of gynecomastia is performed with an aim at diagnosing the cause for the same. Individual treatment requirements can range from simple reassurance to medical treatment or even surgery depending on the etiology.

Keywords: Drug-induced breast enlargement, gynecomastia, hormonal imbalance, male breast


How to cite this article:
Arya R, Rathi AK, Singh K, Srivastava A, Panda D, Parida SN, Jha A, Kumar Y. Gynecomastia: A review of literature. MAMC J Med Sci 2016;2:69-75

How to cite this URL:
Arya R, Rathi AK, Singh K, Srivastava A, Panda D, Parida SN, Jha A, Kumar Y. Gynecomastia: A review of literature. MAMC J Med Sci [serial online] 2016 [cited 2019 Aug 25];2:69-75. Available from: http://www.mamcjms.in/text.asp?2016/2/2/69/182726


  Introduction Top


Gynecomastia is a benign enlargement of the male breast tissue. Gynae means “woman” and mastos means “breast” in Greek. It can be defined as the presence of >2 cm of palpable, firm, subareolar gland and ductal breast tissue.[1] Gynecomastia is common and is thought to be present in at least a third of men in the course of their lifetime.[2] True gynecomastia refers to enlarged glandular tissue rather than deposition of fat tissue. Enlargement of breast due to deposition of fat in the breast area is known as pseudogynecomastia. True gynecomastia is typically a rubbery or firm mound of tissue that is concentric with the nipple-areolar complex (NAC). This is to be distinguished from pseudogynecomastia, which lacks presence of such a disk of tissue, as it is an increase in subareolar fat without enlargement of the breast glandular component.

Gynecomastia is present in 60–90% of newborns and usually resolves spontaneously within a few weeks.[3] Most pubertal boys develop gynecomastia, and by the age of 14 years, 60% of boys have gynecomastia.[4] But this also resolves in most cases within a few months and by the 19 years of age, the prevalence is 5–15% only. Beyond the pubertal age, gynecomastia is present in 33–41% of normal men aged 25–45 years and in 55–60% of men over the age of 50 years.[5],[6] Most of these men are asymptomatic and are unaware that they have breast tissue. Gynecomastia is strongly correlated with the presence of obesity.[6] In an unselected group of hospitalized men, gynecomastia was found in 12% or less of men with body mass index below 19 kg/m 2, while over 80% of men with body mass index above 25 kg/m 2 had gynecomastia. Gynecomastia has been found in 45–50% of men in autopsy studies.[7]


  Causes of Gynecomastia Top


Physiological

Neonatal: This is the result of maternal estrogen and the gynecomastia resolves after a few weeks.

Pubertal: This is common around the age of 14, may be unilateral and tender. It resolves spontaneously within 1–2 years. It may be due to the relatively delayed testosterone surge with relation to estrogen at puberty, or due to a temporary increase in aromatase activity.

Involutional: As age advances there occurs decrease in testosterone level which gives rise to gynecomastia in elderly persons.[8],[9]

There are numerous causes of Gynecomastia mainly attributed to drugs or due to various pathological conditions [Table 1] and [Table 2]
Table 1: Pathological Causes of Gynecomastia

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Table 2: Drugs causing Gynecomastia

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Lack of testosterone: Congenital absence of testes - There are low levels of testosterone with normal estradiol levels, and patients experience severe gynecomastia, androgen resistance, klinefelter syndrome (XXY syndrome) is associated with gynecomastia in 80% of cases. Men with Klinefelter syndrome have an increased risk of breast cancer (risk is increased up to 20 times that of other patients with gynecomastia), viral orchitis, castration, renal disease and dialysis

Increased estrogen levels: These may be due to testicular tumors (e.g. Leydig's cell tumor) which secrete estradiol, tumors producing human chorionic gonadotropin (hCG): Choriocarcinoma, other neoplasms include: Lung cancer, gastric carcinoma, renal cell carcinoma and hepatoma, adrenocortical tumors, and lymphoma, hermaphroditism, congenital adrenal hyperplasia (high androgens and estrogens), liver disease or cirrhosis: Malnourishment and re-feeding syndrome, hyperthyroidism, obesity, extreme stress, aromatase excess syndrome

Drug-induced: Several drugs have been implicated. Inhibitors of testosterone synthesis: e.g. metronidazole, ketoconazole, spironolactone, gonadotropin releasing hormone agonists such as leuprolide and goserelin, Inhibitors of testosterone action: Cyproterone, flutamide, bicalutamide, finasteride, dutasteride, H2 receptor antagonists, proton pump inhibitors, and marijuana, Androgens causing high estrogen levels: Anabolic steroids, excessive testosterone replacement therapy, Medications which increase prolactin levels: Antipsychotics, tricyclic antidepressants, metoclopramide, and verapamil, Antiretrovirals: The exact mechanism by which antiretrovirals cause gynecomastia is unknown. It often presents as unilateral and tender gynecomastia. Efavirenz has been implicated and stopping it results in resolution of gynecomastia, Others: Amiodarone, isoniazid, methyldopa, diazepam, calcium-channel blockers, angiotensin-converting enzyme inhibitors, alcohol, amphetamines, growth hormone, isoniazide, theophylline, and heroin.

Miscelleneous causes: Long-term type 1 diabetes mellitus, chronic illness, spinal cord injury, and trauma, Idiopathic: No obvious cause found in 25% of cases, It is not always clear what causes gynecomastia during mid to late life. Still as age advances, blood testosterone levels decline and the hormone balance changes, favoring an increased level of estrogen. These factors probably conspire to account for most cases of “idiopathic” gynecomastia.

Commonly three types of gynecomastia have been described. The variety of gynecomastia is usually related to the duration of the disorder.[23] Florid type: Characterized by an increase in ductal tissue and vascularity. A variable amount of fat tends to be mixed in with the ductal tissue, Fibrous type: It has more stromal fibrosis and few ducts, Intermediate type: It is a mixture of these two.

Florid gynecomastia is usually seen when the duration is 4 months or less. The fibrous type is usually present after duration of 1 year. The intermediate type is thought to be a progression from florid to fibrous and is usually seen between 4 months and 12 months.[23]

Grading

Gynecomastia shows a gradation of clinical types that range from simple areolar protrusion to breasts with a female appearance. The main clinical features characterizing gynecomastia are breast swelling, increased areolar diameter, presence of an anomalous inframammary fold, glandular ptosis, and skin redundancy. This clinical classification is simple and stringent and takes into account the different relationships between the structural components of the breast, in particular, the inframammary fold and NAC, which is the watershed between mild forms and serious forms [Table 3].
Table 3: Clinical Classification of Gynecomastia

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Sign and symptoms

Gynecomastia is usually bilateral, but patients may present with asymmetrical or unilateral findings and has a rubbery to firm feel on palpation.

Palpation usually demonstrates a palpable, tender, firm, mobile, disc-like mound of tissues that is not as hard as breast cancer and is located centrally under the NAC. It is important to distinguish it from malignancy.

When palpable masses are unilateral, hard, fixed, peripheral to the nipple, and associated with nipple discharge, skin changes or lymphadenopathy, breast cancer should be suspected, and thorough evaluation is recommended.

Red flags that increase suspicion of breast cancer in men are unilateral enlargement, hard or irregular breast tissue, rapidly enlarging, recent onset, fixed mass with or without nipple or skin abnormalities, painful, size >5 cm, axillary lymphadenopathy.

Work up

History

A detailed history helps with special emphasis on Onset and duration of breast enlargement, associated symptoms (e.g., pain), sexual functioning, drug history/abuse, e.g., anabolic steroids, alcohol, heroin, and marijuana is very important, family history of gynecomastia has been elicited in 58% of patients with persistent pubertal gynecomastia, weight change, symptoms of hyperthyroidism.

Physical examination

Breast examination: Enlargement of breast tissue may represent adipose tissue (pseudogynecomastia) or true proliferation of breast tissue. This can be examined by pinching breast tissue between the thumb and forefinger-true proliferation can be felt as a distinct disc of tissue under the skin.

Any evidence of liver disease or renal impairment - e.g., palmar erythema, bruising, spider nevi, hepatomegaly etc., should be noticed.

Evidence to suggest lack of testosterone is hairless shiny skin, decreased testicular size, testicular masses, and tenor of voice.

Presence or absence of any sexual characteristics, signs of hyperthyroidism, or Cushing's syndrome.

Anthropometric measurements (e.g., body mass index) may also be helpful because obesity can be associated with increased peripheral conversion of androgens to estrogens and is associated with a higher prevalence of gynecomastia.

The presence of varicocele has also been strongly associated with gynecomastia.

Laboratory work up

Investigations should be performed on a clinical basis according to the history and examination. Blood tests are not indicated in those with fatty breast enlargement, physiological pubertal or senile changes, an identified drug cause, or in a clinically apparent cancer.

Recommended laboratory investigations to find the underlying cause of gynecomastia include:

Liver enzymes: Aspartate transaminase and alanine transaminase to rule out liver disease.

Serum creatinine: To determine any renal abnormality is present or not.

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 hCG, or serum dehydroepiandrosterone. Serum testosterone levels (free and total), estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) may also be evaluated to determine if hypogonadism may be the cause of gynecomastia.[10]

Chromosomal karyotyping may need to be considered in klinefelter syndrome.

Imaging

Ultrasonography (USG) or mammography of breasts in all cases of suspicious or unilateral breast enlargement should be considered. Mammography is the method of choice for radiologic examination for male breast tissue in the diagnosis of gynecomastia when breast cancer is suspected.[10],[11] However, since breast cancer is a rare cause of breast tissue enlargement in men, mammography is rarely needed.[12]

USG of testes: If there is any abnormality on examination, or if there is a raised beta-hCG or alpha-fetoprotein.

Abdominal computed tomography/USG: If a tumor of the adrenal glands or the testes is thought to be responsible for the gynecomastia.

Chest X-ray: If lung lesion is suspected.

Biopsy

Core needle biopsy must be performed for those with suspicious clinical or radiological findings. Biopsy will provide a definitive diagnosis.

Early histologic features include: Proliferation and lengthening of the ducts, increase in connective tissue, increase in inflammation and swelling surrounding the ducts. Increase in fibroblasts in the connective tissue.[8]

Chronic gynecomastia may show: Increased connective tissue fibrosis. An increase in the number of ducts. Less inflammation than in the acute stage of gynecomastia. Increased subareolar fat. Hyalinization of the stroma.[11]

Excisional biopsy

When surgery is performed for treatment of gynecomastia, the gland is routinely sent for pathological examination to confirm the diagnosis and to rule out any evidence of malignancy. 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.[14]

Differential diagnosis

Breast cancer, benign lesion (dermoid, cysts, lipomas, sebaceous cysts, lymphoplasmocytic inflammation, ductal ectasia, hematomas, and fat necrosis).[13]

Treatment

Treatment of gynecomastia is not always necessary. It depends upon its cause, duration, and severity and whether it causes pain or discomfort. Since transient gynecomastia occurs during puberty, generally resolves on its own without treatment within 3 years in 90% of cases, no active treatment is required. However, breasts > 4 cm in diameter may not completely regress. If medications are the cause of gynecomastia, stopping the offending drug can be effective in reducing gynecomastia. Treatment of any underlying medical conditions is also important. Both medications and surgery have been successfully used to treat gynecomastia.

Surgery

Surgery is preferred over medical treatment when the patient has been suffering from gynecomastia of more than 2 years duration. The aims of surgery are: (a) To eliminate painful breast tissue. (b) To restore the patient's chest to acceptable cosmetic shape.[27] The most commonly used technique is subcutaneous mastectomy that involves direct resection of the glandular tissue using a peri-areolar or trans-areolar approach, with or without liposuction.[11] Liposuction alone may be sufficient if breast enlargement is purely due to excess fatty tissue without substantial glandular hypertrophy.[11] More extensive surgery, including skin resection is required for patients with marked gynecomastia and those who develop excessive sagging of the breast tissue (with weight loss).[11] The first reported surgical treatment of gynecomastia was by Paulus Aegineta who used a lunate incision below the breast or, for larger breasts, two converging lunate incisions to enable the excision of excess skin.[41] Such extra-areolar skin incisions with their unsightly scars continued to be used until Webster described a surgery with a semicircular intra-areolar incision in 1946,[42] which has become the standard procedure for excision of gynecomastia. In the present time, surgical procedure most frequently used is liposuction. Liposuction/lipoplasty (“fat modeling”) is most effective treatment as it is associated with few sequelae. In this procedure, a narrow cannula is inserted in breast tissue and used to vacuum adipose tissue after that cannula pushed and pulled to break all adipocytes and suctioning them out. This procedure is known as suction-assisted liposuction. There are many other techniques of liposuction:

Tumescent technique/wet techniques: It is the most common type of liposuction. It involves injecting a large amount (3 times the volume of fat) of medicated solution (mixture of lidocaine and epinephrine) into the areas before the fat is removed. The lidocaine is the only anesthesia needed for the procedure and epinephrine in the solution helps reduce the loss of blood and swelling from the surgery due to vasoconstriction. This is longer and time taking procedure.

Super wet technique: It is similar to tumescent liposuction, but the difference is amount of fluid injected is equal to the amount of fat to be removed. As comparison to wet technique, it is less time taking but the disadvantage is, it requires sedation with an IV or general anesthesia.

Ultrasound-assisted liposuction (UAL):[29] This procedure takes longer time than the super-wet technique. In this procedure, ultrasonic vibrations are used to liquefy fat cells and then vacuumed out. It is of two types external and internal. UAL is used along with the tumescent technique in follow-up procedures for better precision.

Endoscopic-assisted subcutaneous mastectomy:[30] It is associated with smaller scars and greater patient satisfaction

Vacuum-assisted biopsy device (VABD): Originally VABD was introduced as a diagnostic tool for radiologically-guided, vacuum-assisted, breast biopsies but now it has proven beneficial to the treatment of gynecomastia.[43]

During this procedure, different type of incision is given like hemicircumareolar or periareolar incision to preserve the nipple.[28]

Reduction mammoplasty is considered for patients with macromastia or long-standing gynecomastia or in persons in whom medical therapy has failed.[16] It is also considered for cosmetic reasons (and for accompanying psychosocial reasons).[17],[18],[19] If surgery is necessary for patients with pseudogynecomastia, liposuction may be warranted.

A Chinese study indicated that endoscopic subcutaneous mastectomy, without skin excision, could be an effective treatment for gynecomastia.[5] In a report on the procedure's use in 65 patients (125 breasts) with gynecomastia, Grade II or III, the authors stated that only a few operative complications occurred, including 2 cases of partial nipple necrosis and 1 case of subcutaneous hydrops. They also reported that postsurgical chest contour was satisfactory in all patients and that no recurrences were seen during the 3–36 months follow-up period.

Complications of surgery include sloughing of tissue due to a compromised blood supply, contour irregularity, hematoma or seroma formation, and permanent numbness in the nipple-areolar area, doughnut deformity, nipple necrosis, nipple flattening [31] and, therefore, should be performed by surgeons with appropriate experience.

Medical

A major factor that should influence the initial choice of therapy for gynecomastia is the duration of the disease (gynecomastia). It is unlikely that any medical therapy will result in significant regression in the late fibrotic stage (a duration of 12 months or longer) of gynecomastia. As a result, medical therapies if used should be tried early in the course of the disease. In general, two types of medications have shown promise for the management of gynecomastia.

Testosterone replacement: This therapy has been effective in older men with low levels of testosterone, but it was not proved to be effective for men who have normal levels of the male hormone.

Selective estrogen receptor modulators (SERMs): SERMs are tamoxifen and raloxifene can help reduce the amount of breast tissue, although they are not able to entirely eliminate the problem. These medications are most often used for severe or painful gynecomastia conditions that may be the cause of gynecomastia. With the administration of clomiphene, an antiestrogen approximately 50% of patients achieve partial reduction in breast size, and approximately 20% of patients note complete resolution.[15] Adverse effects are rare and include visual problems, rashes, and nausea.

Tamoxifen, as an estrogen antagonist is effective for recent onset and tender gynecomastia.[20] Up to 80% of patients report partial to complete resolution after tamoxifen therapy.

Nausea and epigastric discomfort are the main adverse effects due to tamoxifen.

Other drug used is danazol, a synthetic derivative of testosterone and inhibits pituitary secretion of LH and FSH, which decreases estrogen synthesis from the testicles.

Treatments for gynecomastia have not been extensively studied, so data showing their effectiveness are limited. No drugs have yet been approved by the U.S. Food and Drug Administration for treatment of gynecomastia but several authors have reported efficacy of the same. Tamoxifen, in two randomized double-blind studies [32] involving a total of 16 patients with idiopathic gynecomastia led to a statistically significant reduction in breast pain and size, without significant side effects at a dosage of 10 mg twice a day. In two studies,[33] involving patients who developed gynecomastia following treatment for prostatic cancer, tamoxifen was shown to be an effective treatment. Based on the data above and the overall safety of the drug it is not unreasonable to try a 3-month course of tamoxifen therapy in patients with painful gynecomastia of recent onset. Boccardo et al.[35] demonstrated a significant difference in gynecomastia in patients with prostate cancer who were randomized to three groups: (i) 20 mg of tamoxifen (four of 37; 10% developed gynecomastia), (ii) placebo (29 of 40; 73% developed gynecomastia), (iii) 1 mg of anastrozole (18 of 35; 51% developed gynecomastia). Breast pain was significantly less in the tamoxifen group. In a randomized, double-blind study, danazol was found to significantly reduce breast tenderness and size compared with placebo.[34]

Radiotherapy

Radiation therapy is effective for prevention, as well as treatment of gynecomastia, caused by androgen ablation in patients of prostate cancer. Radiation therapy is more effective if given prophylactically before administration of hormone therapy. However, it has been used with some success in managing painful gynecomastia. Current National Institute of Clinical Excellence Guidelines (February 2008) state that “men starting long-term bicalutamide 150 mg monotherapy (<6 months) should receive prophylactic radiotherapy to both breast buds within the 1st month of treatment”. A single fraction of 8 Gy using orthovoltage or electron beam radiotherapy is recommended.[40]

In 2003, Widmark et al.[36] conducted the largest randomized trial on the use of radiation therapy for prevention of gynecomastia (n = 253) and found a reduction of gynecomastia rates from 71–28% when radiation therapy was given. For the treatment of existing gynecomastia, radiation therapy resulted in improvement or resolution of gynecomastia in 33% of treated patients, with 39% experiencing improvement or resolution of breast pain.[21]

Prophylactic and symptomatic radiotherapy is widely used in the German speaking countries, but patient numbers are small. The clinical results indicate that radiotherapy is a highly effective and well-tolerated treatment. Doses have ranged from 10 to 20 Gy in 2–5 fractions.[22] All of which are well tolerated with mild skin erythema being the main adverse effect. It is believed that the potential risk of radiation-induced skin or breast cancer is low, although long-term data are minimal.[37]

German Cooperative Group on Radiotherapy of Benign Diseases sent a standardized questionnaire to 294 Radiotherapy institutions. The questionnaires inquired about patient numbers, indications, Radiotherapy (RT) technique, dose, and available treatment results. Moreover, the participants were asked whether they were interested in participating in a prospective study.

From a total of 294 institutions, 146 replies were received, of which 141 offered radiotherapy for gynecomastia. Seven of those reported prophylactic RT only, whereas 129 perform both preventive and symptomatic RT. In 110 of 137 departments, a maximum of 20 patients was treated per year. Electron beams (76%) were used most often, while 24% of patients received photon beams or orthovoltage X-rays. Total doses were up to 20 Gy for prophylactic and up to 40 Gy for therapeutic radiotherapy. Results were reported by 19 departments: Prevention of gynecomastia was observed in 60–100% of patients. Only 13 institutions observed side effects.[38] Post-anti-androgenic chemotherapy when patient develop established gynecomastia and/or breast pain low-dose radiotherapy can also be efficacious for the treatment (used to treat prostate cancer; 36). In a recent study by Perdona et al.[39] gynecomastia persisted in 17 of 50 (34%) patients postirradiation compared with 35 of 50 patients (69%) in whom gynecomastia resolved. Radiotherapy is effective and well-tolerated and adverse events are breast or nipple erythema and skin irritation that is mild and short-lived.

Prevention

Gynecomastia related to medical conditions can be prevented by appropriate therapeutic interventions or by avoidance of the incriminated agent. When age-related hormonal fluctuations result in gynecomastia, it is not avoidable prophylactically. When administering long-term hormonal therapy to prostate cancer patients, prophylactic irradiation of bilateral breasts can prevent subsequent development of gynecomastia. In such patients, prophylactic administration of tamoxifen too has proven efficacious.

Outlook

Fortunately, in many cases, gynecomastia resolves spontaneously without the need for specific treatment. Medical and surgical treatments can be effective for persistent gynecomastia. Typically, gynecomastia is itself not malignant, but men with gynecomastia have an increased risk (about five-fold) for developing male breast cancer when compared with the general population. It is likely that the hormonal changes that produce gynecomastia in adult men also increase their risk of developing breast cancer. This is a commonly diagnosed entity and awareness to diagnose and treat it appropriately is warranted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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