Gynecomastia: incidence, causes and treatment

Abstract

Gynecomastia is a benign proliferation of glandular tissue of the breast in males. It is common during three phases in the age distribution curve: the neonatal period, puberty and senescence. An imbalance between estrogen and androgen action at the level of breast tissue is believed to be the underlying pathophysiology. Initial steps in the clinical evaluation involve differentiating it from pseudogynecomastia and ruling out male breast carcinoma. A selective laboratory and radiological work-up should follow to identify the underlying cause. Pubertal gynecomastia resolves spontaneously in the majority of adolescents, and hence reassurance and observation is regarded as the best approach. In adults with persistent painful gynecomastia, a short-term trial of medical therapy is an option that has shown good results. For chronic, bothersome gynecomastia, removal by plastic surgery is the treatment of choice.

Keywords::

• breast cancer
• estrogen
• gynecomastia
• puberty
• tamoxifen

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This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Review Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertendo; (4) view/print certificate.

Release date: 6 September 2011; Expiration date: 6 September 2012

Learning objectives

Upon completion of this activity, participants will be able to:

• • Distinguish when gynecomastia is usually diagnosed during the lifespan of males

• • Diagnose gynecomastia and its causes effectively

• • Evaluate treatment options for gynecomastia

• • Assess means to prevent gynecomastia

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Fnu Deepinder, MD

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.

Disclosure: Fnu Deepinder has disclosed no relevant financial relationships.

Glenn D Braunstein, MD

Chairman, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.

Disclosure: Glenn D Braunstein has disclosed no relevant financial relationships.

Incidence & prevalence

Gynecomastia is defined as a benign proliferation of glandular tissue of the breast in males, resulting in a concentric enlargement of one or both breasts. It is frequent during three phases in the age distribution curve: the neonatal period, pubertal period and senescence [1]. The prevalence of asymptomatic gynecomastia in neonates is estimated to be between 60 and 90% [2]. The second physiological peak of occurrence is at puberty between the ages of 10 and 16 years. Approximately 50–60% of adolescents have been estimated to have gynecomastia based upon early literature [3–5]. However, a recently published large population-based cross-sectional study involving 6200 males 1–19 years of age has demonstrated the prevalence of gynecomastia to be approximately 4% in the age group of 10–19 years [6]. Variation in reported prevalence across the studies could be attributed to differences in the size of palpable breast tissue used to define gynecomastia, sample size and selection, and ethnic and regional differences. Gynecomastia is believed to be a mid-puberty event as it is more frequent in boys with pubic hair Tanner stage three and four [6]. There have been a number of conflicting study reports in the literature regarding the association of BMI with gynecomastia. While several investigators demonstrated that boys with gynecomastia are heavier [3–5], others have found that boys with pubertal gynecomastia are shorter, leaner and have a lower BMI [6,7]. The last peak in incidence of gynecomastia is seen in men 50–85 years of age, and the reported prevalence is up to 70%. The frequency of bilateral gynecomastia is more common than unilateral gynecomastia [8,9]. The reported prevalence of unilateral gynecomastia is approximately 35–45% [6,7].

Histology

Histologically, painful and tender gynecomastia of recent onset generally shows hyperplasia of ductal epithelium, infiltration of the periductal tissue with inflammatory cells and increased subareolar fat. However, as gynecomastia becomes long-standing, dilated ducts with periductal fibrosis and stromal hyalinization are seen on histological examination [10,11].

Causes & pathophysiology of gynecomastia

Gynecomastia is a complex process resulting from many hormonal changes in the body. Estrogens strongly stimulate and androgens weakly inhibit mammary gland growth. The imbalance between estrogen actions relative to androgen action at the level of breast tissue is believed to be the main etiology. Various hypotheses have been put forth by a number of investigators explaining the etiology of gynecomastia, including: elevated estrogen levels; lowered free testosterone; abnormal testosterone-to-estrogen ratio; increased peripheral conversion of testosterone to estrogens by higher aromatase activity in periglandular fat and stroma; lower dehydroepiandrosterone sulfate-to-estrogen ratio; and altered local action or breast tissue sensitivity [1,12,13]. However, for most patients, the etiology still remains unclear.

Estrogens are known to bind less avidly to sex hormone-binding globulin (SHBG) than androgens such as testosterone. As a result, various drugs may displace relatively more estrogens than testosterone from SHBG, thus altering the estrogen/testosterone equilibrium in the body in favor of the former. Likewise, systemic conditions, such as hyperthyroidism and chronic liver disease, which result in increased concentration of SHBG lead to decreased bioavailable testosterone relative to free estrogens [1]. Various medications and environmental agents, including those with androgen antagonist or estrogen receptor agonist properties, are also known to cause gynecomastia. Box 1 summarizes the major known causes of gynecomastia [1,13–15] and Box 2 lists the drugs of common use implicated in the development of gynecomastia [13–15]. Many of the drug associations have been based on anecdotal reports or small series, but have not been subjected to rigorous cause–effect analysis.

Evaluation of a patient with gynecomastia

Initial steps in the clinical evaluation of a patient presenting with enlarged breast tissue are to differentiate true gynecomastia from pseudogynecomastia and rule out male breast carcinoma. Pseudo-gynecomastia is characterized by increased subareolar fat without enlargement of the glandular component of breast. By contrast, a palpable button of firm or rubbery breast tissue concentric with the nipple–areolar complex is felt in patients with true gynecomastia. Breast carcinoma is usually hard and located outside of the nipple–areolar complex, and may be associated with skin dimpling, nipple retraction, bleeding or discharge, and lymphadenopathy. It is also more likely to be unilateral as compared with gynecomastia, which frequently affects breast tissue of both sides. In case of any doubts clinically, diagnostic mammogram or ultrasound can be ordered to differentiate between gynecomastia and breast cancer [1]. Mammography has 90% sensitivity and specificity for distinguishing between benign and malignant lesions; however, the positive predictive value for malignancy is just 55%, primarily owing to the low overall prevalence of breast carcinoma in males [16]. If radiological investigations are suspicious or equivocal for malignancy, fine-needle aspiration or core biopsy is the next step in the diagnostic work-up [17].

Once the diagnosis of gynecomastia is established, it is essential to carry out a careful history and physical examination to identify any underlying cause, such as those mentioned in Box 1. It is also important to review the complete medication list, including any over-the-counter or herbal products that may be associated with gynecomastia (Box 2). A clear temporal association with a drug known to cause gynecomastia can obviate the need for expensive investigations. A recent study has also suggested gynecomastia to be more common in adolescent boys with left-sided varicocele [6]. Kumanov et al. reported that in 10–13-year-old adolescents, gynecomastia was significantly positively correlated with varicocele, with an adjusted odds ratio of 2.1 (95% CI: 1.1–4.1; p = 0.03). The results may have clinical significance as varicocele may be associated with a progressive decline in testicular function [6]. In cases of adult gynecomastia with no apparent cause, laboratory investigations should be performed, the extent of which remains controversial owing to the low overall likelihood of finding a pathological abnormality, especially in patients with longstanding asymptomatic gynecomastia. Patients with recent onset of gynecomastia associated with breast pain and tenderness should undergo diagnostic evaluation involving liver, renal and thyroid function tests to rule out any associated systemic medical condition. In addition, a limited hormonal work-up including blood testosterone, luteinizing hormone (LH), human chorionic gonadotrophin (hCG) and estradiol levels should be carried out.

Owing to the circadian variations in secretion, serum samples for total testosterone determination should be obtained in the early morning between 7:00 and 9:00 a.m. [18]. The measurement of free testosterone (free T) should be considered when alterations in SHBG are expected. In order to determine free T reliably, equilibrium dialysis or ultrafiltration techniques are required. These methods are complicated and not routinely recommended at present. However, a simple and reliable method for clinical practice is the estimation of free T from the levels of total testosterone and SHBG using a standard equation. Calculated free T correlates well with free T estimated by equilibrium dialysis [19,20].

Low testosterone and elevated LH serum levels represent primary testicular failure. In cases with low testosterone and low or inappropriately normal LH, it is important to determine prolactin, thyroid-stimulating hormone and free thyroxine levels. If hyperprolactinemia is discovered and secondary causes are ruled out or prolactin levels are >150 ng/dl, a gadolinium-enhanced MRI with special attention to the hypothalamus and pituitary regions is indicated to rule out prolactinoma or any space-occupying lesion in the sella turcica [18]. Similarly, in a patient with hypogonadotropic hypogonadism, a total testosterone level of less than 150 ng/dl (5.2 nmol/l) should prompt a pituitary–hypothalamic MRI to exclude a pituitary tumor. However, it is important to keep in mind that although prolactin elevation can cause fullness in the breasts and mild galactorrhea in patients whose breasts have been stimulated by estrogens and progesterone, it does not lead to true gynecomastia directly.

In complete and partial forms of androgen insensitivity, serum testosterone and LH levels are usually elevated and estradiol is usually higher than in normal males. High estradiol with decreased LH suggests either estrogen-secreting Leydig or Sertoli cell tumors, or adrenal neoplasm. Testicular ultrasound and adrenal imaging are needed to differentiate between the two. If the hCG is found to be increased in the initial set of laboratories, a search for gonadal or extragonadal germ cell tumors or a hCG-secreting nontrophoblastic neoplasm should be undertaken. If all testing is unrevealing, idiopathic gynecomastia is diagnosed [1].

Treatment

Pubertal gynecomastia

Pubertal gynecomastia is generally a transient phenomenon and resolves spontaneously in more than 90% of cases within 3 years. Therefore, reassurance and observation is regarded as the best approach for this asymptomatic and self-limiting condition [7]. Unfortunately, pubertal gynecomastia may have a negative impact on self esteem in adolescent boys and can lead to decreased participation in social activities and depression. When there is significant tenderness or psychosocial morbidity, pharmacological agents can be tried. In a few published reports, the selective estrogen receptor antagonist tamoxifen has been shown to be safe and effective in reducing the size of glandular tissue in persistent pubertal gynecomastia. Lawrence et al. demonstrated a decrease in breast size in 20 out of 22 patients with use of tamoxifen, with 40% showing greater than 50% size reduction. In the same study, the selective estrogen receptor modulator raloxifene achieved an impressive 86% response rate of more than 50% reduction in breast size [21]. Similarly, Derman et al. showed reduction in pain and breast size in all of the 37 boys administered 20 mg per day of tamoxifen [22]. However, despite these positive encouraging results, the studies are difficult to interpret because of the small sample size and absence of a placebo-treated control arm. The experience with aromatase inhibitor anastrozole has been disappointing in persistent pubertal gynecomastia and is not recommended at present [23]. A recent study suggested that it is efficacious in gynecomastia of less than 1 year duration. Anastrazole at doses of 1 mg per day for 6 months reduced breast area by approximately 63% and breast volume by 57% in 42 boys of mean age 13 years with mean gynecomastia duration of 7 months. However, there was no control arm in this trial and pubertal gynecomastia is usually a transient event [24]. It is unclear as to why aromatase inhibitors have not been very successful in the management of gynecomastia. This could be due to the fact that excessive aromatization of androgens to estrogens is not the only cause of relative or absolute excess of estrogens levels in such patients. Very rarely, plastic surgery may be considered in those boys who fail medical therapy. It might be associated with complications such as scarring, skin retraction and hyperesthesia, and gynecomastia may recur postoperatively [25].

Gynecomastia in adults

In the majority of men with asymptomatic gynecomastia, treatment is generally not required. In those experiencing pain, tenderness or embarrassment, treatment of the underlying identifiable cause can enable partial or full recovery. Likewise, if the gynecomastia is found to be drug induced, improvement is usually apparent within a month of discontinuing the offending medication. However, if the gynecomastia is long-standing, that is, more than 1 year, it is unlikely to resolve completely either spontaneously or with medical treatment owing to the presence of dense fibrous tissue. In such cases, subcutaneous surgical mastectomy or liposuction may be considered. Subcutaneous mastectomy involves resection of glandular tissue using a periareolar or transareolar approach with or without liposuction. Liposuction alone may be sufficient in cases of pseudogynecomastia where breast enlargement is primarily due to excess subareolar fat tissue [1,26].

Medical therapy is most useful during the painful phase of gynecomastia. Testosterone replacement can be used to improve gynecomastia secondary to hypogonadism. Topical preparations are preferable as they lead to more steady-state levels of testosterone in the body as compared with the injectable forms, which can worsen breast enlargement by aromatizing to estradiol. In recent years, anti-estrogens have been increasingly used empirically for symptomatic gynecomastia. Tamoxifen given orally at doses of 20 mg daily for up to 3 months has been shown to be effective in a number of randomized and nonrandomized trials demonstrating up to 80% partial improvement and 60% complete regression. Alagaratnam found 80% complete resolution of gynecomastia in Chinese men treated with tamoxifen for a median duration of 2 months [27]. Anastrozole has been shown to reverse testosterone-induced gynecomastia in two hypogonadal men [28].

Prevention

Anti-androgen therapy for prostate cancer results in high incidence of gynecomastia. Tamoxifen has been shown to prevent much of the gynecomastia in such patients in randomized double-blind placebo-controlled trials. The incidence of gynecomastia in men receiving bicalcutamide therapy for prostate cancer was found to be 10, 50 and 73% in those receiving prophylactic tamoxifen, anastrozole and placebo, respectively [29]. In a similar trial, the combined incidence of gynecomastia and mastalgia was 12% in those who received 3 months therapy with tamoxifen as compared with 64% with anastrozole and 70% with placebo [30]. Tamoxifen has also been demonstrated to be superior to prophylactic breast radiation therapy in the prevention of bicalcutamide-induced gynecomastia [31].

Expert commentary

Gynecomastia is a relatively common presenting complaint at the primary care and endocrine clinics. First and foremost, palpable glandular tissue needs to be differentiated from pseudogynecomastia by careful physical examination using pincer movement with thumb and forefinger while the patient is lying flat on his back with his hands clasped beneath his head. Once a diagnosis of true gynecomastia is established, a thorough history and physical examination should be performed to identify any reversible causes, including any drugs or herbal products. In adults with symptomatic gynecomastia with no apparent cause, limited hormonal testing should be conducted as the yield of work-up is quite poor. Breast imaging may be considered when signs and symptoms suggest breast cancer or the presence of BRCA-2 mutation is suspected from the family history.

For pubertal gynecomastia, reassurance and follow-up is the best approach as it is a transient phenomenon in most adolescents. In adults with painful gynecomastia, a trial of tamoxifen can be attempted at doses of 20 mg per day orally for up to 3 months. In patients who are likely to respond to tamoxifen, improvement is usually seen within 1 month. The overall response rate to tamoxifen has varied from 50–80% in the published literature, and the reported side effects are few. There are currently insufficient data to recommend the use of raloxifene, although it did show some encouraging results in small studies. The experience with aromatase inhibitors has been largely disappointing so far. In case of long-standing gynecomastia of more than 1 year in duration, medical therapy is usually futile, and surgical removal of breast glandular tissue can be offered to those who are symptomatic or bothered by their appearance.

Five-year view

It is important to note that none of the selective estrogen receptor modulators are approved by the US FDA for the prevention or treatment of gynecomastia. Further studies with a better study design and adequate sample size are needed to conclusively establish the role of tamoxifen and raloxifen in the management of symptomatic gynecomastia. Having a placebo-treated control arm with adequate follow-up is essential in such trials to evaluate true efficacy of the medication studied, as spontaneous regression of breast tissue is quite common.

Box 1. Causes of gynecomastia.

Idiopathic

Drug induced

Increased serum estrogen

• • Increased endogenous production

  – Leydig or Sertoli cell tumors

  – Eutopic or ectopic human chorionic gonadotrophin-secreting tumors

  – Adrenocortical tumors

• • Higher aromatization

  – Aging

  – Obesity

  – Hyperthyroidism

  – Liver disease

  – Familial or sporadic aromatase excess syndrome

  – Klinefelter’s syndrome

  – Testicular tumors

  – Adrenal tumors

  – Refeeding after starvation

• • Exogenous sources

  – Topical estrogen creams

  – Oral estrogen ingestion

• • Displacement of estrogen from sex hormone-binding globulin

  – Medications such as spironolactone and ketoconazole

• • Decreased estrogen metabolism

  – Cirrhosis

Decreased testosterone synthesis

• • Primary gonadal failure

  – Trauma

  – Radiation

  – Drugs

  – Orchitis

  – Klinefelter’s syndrome

  – Congenital anorchia

• • Secondary hypogonadism

  – Hypothalamic diseases

  – Pituitary failure

  – Kallmann syndrome

• • Decreased androgen action

  – Androgen receptor defect

  – Anti-androgen drugs

Miscellaneous

• • Chronic renal failure

• • Liver disease

• • HIV

• • Chronic illness

• • Enhanced breast tissue sensitivity

• • Environmental agents

  – Embalming agents

  – Lavender and tea tree oils

  – Phenothrin in delousing agents

Box 2. Common drugs associated with gynecomastia^†.

Hormones

• • Aromatizable androgens

• • hCG

• • Estrogens

• • Human growth hormone

• • Anabolic steroids

• • GnRH agonists/antagonists

Anti-androgens

• • Flutamide, bicalcutamide

• • Finasteride, dutasteride

• • Spironolactone

Antibiotics

• • Isoniazid

• • Ketoconazole

• • Metronidazole

Anti-ulcer medications

• • Cimetidine, rantidine

• • Proton pump inhibitors

Chemotherapeutic medications

• • Alkylating agents

• • Methotrexate

• • Vinca alkaloids

Cardiovascular medications

• • Digitoxin

• • Verapamil, diltiazem, nifedipine

• • Amiodarone

• • Captopril, enalapril

Psychoactive medications

• • Diazepam

• • Antipsychotics

• • Antidepressants

Drugs of abuse

• • Marijuana

• • Alcohol

• • Amphetamines

• • Heroin, methadone

Others

• • Metoclopramide

• • Phenytoin

• • HIV medications (protease inhibitors)

• • Statins

• • Theophylline

Key issues

• • Gynecomastia is benign proliferation of glandular tissue of the breast in males.

• • The reported prevalence varies in adolescents from 4 to 60%, depending on the diagnostic criteria and population studied.

• • The imbalance between estrogen and androgen action at the level of breast tissue is believed to be the main etiology.

• • A careful history and physical examination should be performed to establish the diagnosis of true gynecomastia and identify an underlying cause, including drugs or over-the-counter products known to be associated with the development of gynecomastia.

• • In cases of adult gynecomastia with no apparent cause, laboratory investigations should involve liver, renal and thyroid function tests and a limited hormonal work-up including testosterone, luteinizing hormone, human chorionic gonadotrophin and estradiol levels.

• • Mammography is reserved for cases suspected to have breast cancer or BRCA-2 mutation.

• • Although no medication is currently approved by the US FDA for either the prevention or treatment of gynecomastia, a trial of tamoxifen can be attempted at doses of 20 mg per day orally for up to 3 months for patients with painful gynecomastia.

• • For gynecomastia of more than 1 year in duration, surgical removal of breast glandular tissue is an option, usually with good cosmetic results.

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Gynecomastia: incidence, causes & treatment

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1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
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1. You are seeing a 68-year-old man who complains of bilateral breast enlargement with some pain for 15 months. He also has multiple other chronic illnesses and takes seven different medications daily. You consider whether this patient might have gynecomastia.

When is gynecomastia most commonly diagnosed?

• □ A Puberty, early adulthood and after age 65

• □ B Neonatal period, puberty and ages 50–85 years

• □ C Neonatal period, early childhood and puberty

• □ D Early childhood, puberty and early adulthood

2. Which of the following factors should you consider in the evaluation of this patient with gynecomastia?

• □ A Gynecomastia is characterized by firm or rubbery breast tissue concentric with the nipple–areolar complex

• □ B The positive predictive value of mammography for malignancy exceeds 90%

• □ C A thorough laboratory investigation is necessary, even if the patient uses medications that promote gynecomastia

• □ D Equilibrium dialysis should always be used to measure serum levels of free testosterone

3. What else should you consider regarding treatment of the patient in question 1?

• □ A His gynecomastia should spontaneously resolve soon

• □ B Liposuction is not a valid treatment option

• □ C Medical therapy is only useful in established asymptomatic disease

• □ D Testosterone therapy can improve gynecomastia in cases of hypogonadism

4. What should you consider regarding the prevention of gynecomastia among patients like the individual in question 1?

• □ A Stopping metoprolol may reduce his risk for gynecomastia

• □ B Stopping omeprazole may reduce his risk for gynecomastia

• □ C Anastrozole is more effective than tamoxifen in the prevention of gynecomastia

• □ D Radiation therapy is more effective than tamoxifen in the prevention of gynecomastia

Notes

^†Not all of these drugs have been shown to have a cause-and-effect relationship.

GnRH: Gonadotropin-releasing hormone; hCG: Human chorionic gonadotrophin.