Gynecomastia

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Practice Essentials

Gynecomastia is a benign enlargement of the male breast (usually bilateral but sometimes unilateral) resulting from a proliferation of the glandular component of the breast (see the image below). It is defined clinically by the presence of a rubbery or firm mass extending concentrically from the nipples. Gynecomastia should be differentiated from pseudogynecomastia (lipomastia), which is characterized by fat deposition without glandular proliferation.



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Adolescent gynecomastia.

Signs and symptoms

A thorough history should be obtained that addresses the following:

Physical examination should include the following:

Hematoma, lipoma, male sexual dysfunction, and neurofibroma can be included in the differential diagnosis.

See Clinical Presentation for more detail.

Diagnosis

Patients with physiologic gynecomastia do not require further evaluation. Similarly, asymptomatic and pubertal gynecomastia do not require further tests and should be reevaluated in 6 months. Further evaluation is necessary in the following situations:

Laboratory tests that may be considered include the following:

Imaging studies that may be helpful include the following:

See Workup for more detail.

Management

General management considerations are as follows:

Pharmacologic agents used to treat gynecomastia include the following:

Surgical approaches that may be considered include the following:

Surgical complications may include the following:

See Treatment and Medication for more detail.

Background

Gynecomastia is a benign enlargement of the male breast resulting from a proliferation of the glandular component of the breast (see the image below). Gynecomastia is defined clinically by the presence of a rubbery or firm mass extending concentrically from the nipples. Although the condition is usually bilateral, it can be unilateral. The condition known as pseudogynecomastia, or lipomastia, is characterized by fat deposition without glandular proliferation. (See Etiology, Presentation, and Workup.)



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Adolescent gynecomastia.

Patient education

Reassure patients with physiologic gynecomastia regarding the benign nature of their condition, and inform them that most cases spontaneously resolve. (See Prognosis.)

Counsel patients regarding the various treatment modalities available for gynecomastia, and highlight the risks, adverse effects, success rates, and benefits of each modality. For patient education information, see the Men's Health Center. (See Treatment and Medication.)

Etiology

Gynecomastia results from an altered estrogen-androgen balance, in favor of estrogen, or from increased breast sensitivity to a normal circulating estrogen level.[6] The imbalance is between the stimulatory effect of estrogen and the inhibitory effect of androgen. (The normal production ratio of testosterone to estrogen is approximately 100:1; the normal ratio of testosterone to estrogen in the circulation is approximately 300:1.)

Estrogens induce ductal epithelial hyperplasia,[7] ductal elongation and branching, proliferation of the periductal fibroblasts, and an increase in vascularity. The histologic picture is similar in male and female breast tissue after exposure to estrogen.[8]

Estrogen production in males results mainly from the peripheral conversion of androgens (testosterone and androstenedione) to estradiol and estrone, which occurs through the action of the enzyme aromatase (mainly in muscle, skin, and adipose tissue). The testes secrete only 6-10 mg of estradiol and 2.5 mg of estrone per day. Since this only comprises a small fraction of estrogens in circulation (ie, 15% of estradiol and 5% of estrone), the remainder of estrogen in males is derived from the extraglandular aromatization of testosterone and androstenedione to estradiol and estrone. Thus, any cause of estrogen excess from overproduction to peripheral aromatization of androgens can initiate the cascade to breast development.

Increased estrogen production and/or action can occur at the testicular level or at the periphery and is characterized as follows:

Gynecomastia can be physiologic or pathologic.[9, 10] Physiologic gynecomastia is seen in newborn infants, pubescent adolescents,[11, 12] and elderly individuals.

Gynecomastia in adults is often multifactorial. Increased aromatization of testosterone to estradiol and the gradual decrease of testosterone production in the aging testes most often account for gynecomastia in adult males. Older men are also more likely to take medications associated with gynecomastia than are younger men.

Rarely, hyperprolactinemia may lead to gynecomastia through its effects on the hypothalamus to cause central hypogonadism.[13, 14] Prolactin has also been reported to decrease androgen receptors and increase estrogen and progesterone receptors in breast cancer cells, which can lead to male gynecomastia. Prolactin itself stimulates milk production in breast tissue that has been primed by estrogen and progesterone, but it does not directly cause gynecomastia itself.

Pathologic gynecomastia

Pathologic gynecomastia can be caused by an increase in the production and/or action of estrogen, by a decrease in the production and/or action of testosterone accompanied by increased aromatization and high estrogen, or by drug use. However, gynecomastia can also be idiopathic.[6]

Pathologic decrease of androgen or increase of estrogen can be illustrated as following:

Decreased androgen action

Increased estrogen action

Conditions that result in primary or secondary hypogonadism can lead to gynecomastia in different mechanisms. Primary hypogonadism can be related to a congenital abnormality such as Klinefelter syndrome, an enzymatic defect in testosterone biosynthesis, infection, infiltrative disorders, testicular trauma, or aging. The associated reduction in testosterone production leads to a decrease in the serum testosterone concentration and a compensatory rise in leuteinizing hormone (LH) release. The excess LH results in enhanced Leydig cell stimulation with inhibition of the 17,20-lyase and 17-hydroxylase activities and increased aromatization of testosterone to estradiol; the net effect is an increase in estradiol relative to testosterone secretion.[15]

Secondary hypogonadism due to a hypothalamic or pituitary abnormality may also be associated with gynecomastia. In these patients, the production of LH is deficient, resulting in a low testosterone production rate and low estradiol production from the testes. However, the adrenal cortex continues to produce estrogen precursors that are aromatized in extraglandular tissue; the result is an estrogen/androgen imbalance.

The following are some of the conditions associated with gynecomastia:

Various drugs are implicated in gynecomastia and can be classified into categories (although drugs in the same class do not all cause gynecomastia to the same extent).[17, 18, 19]

Of note, the pathophysiologic mechanism for some drugs, such as estrogens or antiandrogens, is quite clear. However, for others such as spironolactone, the mechanism is more complex. Spironolactone can increase the aromatization of testosterone to estradiol, decrease testosterone production by the testes, increasing the rate of testosterone clearance by displacing it from SHBG, and also binding to androgen receptors leading to gynecomastia through estrogen/testosterone imbalance. Another example is tea tree oil, which possesses weak estrogenic and antiandrogenic activities that may contribute to an imbalance in estrogen and androgen pathway signaling. Estrogenic or antiandrogenic activities have been reported for other essential oils and some of their monoterpene constituents.[20]

Antiandrogen/inhibitors of androgen synthesis are as follows:

Cancer/chemotherapeutic drugs are as follows:

Cardiac and antihypertensive medications are as follows:

Hormones are as follows:

Psychoactive drugs are as follows:

Drugs for infectious diseases are as follows:

Drugs of abuse are as follows:

Others are as follows:

Drugs can also be stratified depending on the evidence that supports their association with gynecomastia, as follows:

A study by Den Hond et al on the effects of pollutants on sexual maturation indicated that higher blood levels of lead increased the risk of gynecomastia in the study's subjects, while higher serum levels of hexachlorobenzene decreased the risk. The report involved 1679 adolescents, aged 14-15 years. The mechanism of gynecomastia is thought to be through estrogen receptor binding and activation.[9]

Estimates suggest the following etiologies in males seeking medical attention for gynecomastia:

Epidemiology

Occurrence in the United States

Gynecomastia is the most common reason for male breast evaluation. The condition is common in infancy and adolescence, as well as in middle-aged to older adult males. One estimate is that 60-90% of infants have transient gynecomastia due to the high estrogen state of pregnancy.

The next peak of occurrence is during puberty,[11, 12] with a prevalence ranging from 4-69%. Some reports have shown a transient increase in estradiol concentration at the onset of puberty in boys who develop gynecomastia. Pubertal gynecomastia usually has an onset in boys aged 10-12 years. It generally regresses within 18 months, and persistence is uncommon in men older than 17 years. The third peak occurs in older men, with a prevalence of 24-65%. [#Clinical]

Prognosis

Other than the associated risk of breast cancer, gynecomastia does not cause any long-term complications. In approximately 90% of cases, pubertal gynecomastia resolves within a period of months to several years. However, macromastia seldom resolves completely and often requires surgery.

Gynecomastia that occurs secondary to an underlying, treatable cause (eg, drug-induced gynecomastia) usually responds to treatment or removal of the primary cause. Men with Klinefelter syndrome have a 10- to 20-fold increased risk for breast cancer.

Research has indicated that the psychological effects of gynecomastia can include depression, anxiety, disordered eating, body dissatisfaction, and reduced self-esteem.[24]

A study by Sir et al suggested that gynecomastia can impinge on male sexual function. The study, which included 47 patients and 30 healthy controls, found that, as evaluated with the International Index of Erectile Function (IIEF), scores for erectile function, orgasmic function, and intercourse satisfaction were significantly lower in patients with gynecomastia than in the control group. However, the gynecomastia patients had a significantly higher mean IIEF desire score than did the controls. The study also found that hormone profiles (serum free triiodothyronine [T3], free thyroxine [T4], thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH], prolactin, estradiol, total testosterone, free testosterone, luteinizing hormone, and dehydroepiandrosterone sulfate [DHEA-SO4]) for the gynecomastia patients were similar to those of the controls, with the exception of FSH and free T3, which were significantly lower.[25]

History

A thorough history is essential to evaluate the causes of gynecomastia. The following should be included:

Gynecomastia is often reported on CT scans. The image below illustrates bilateral gynecomastia in a 72-year-old man with an esophageal cancer. Prominent areolae with dense subareolar ductal tissue are seen. This can be a normal finding in 50% of men at autopsy.



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Prominent areolae with dense subareolar ductal tissue.

Pseudogynecomastia

In pseudogynecomastia, a condition that occurs in obese men, there is only fat deposition, found in the subareolar area. This is not pathologic or physiologic. Patients with pseudogynecomastia typically have bilateral deposition of fat, and, over time, these deposits do not change in shape or size unless a significant increase in aromatization occurs in the fatty tissue, leading to true gynecomastia. A careful history may reveal that the lesions have remained unchanged over a span of several years. If mammography demonstrates no evidence of malignancy, a treatment option would be observation alone.

Physical Examination

Perform a thorough examination of the breasts, noting their size and consistency. In addition, determine the presence of any nipple discharge or axillary lymphadenopathy.

Differentiate between true gynecomastia and pseudogynecomastia. These 2 entities may be distinguished by having the patient lie on his back with his hands behind his head. The examiner then places a thumb on each side of the breast and slowly brings the thumbs together. In true gynecomastia, a ridge of glandular tissue will be felt that is symmetrical to the nipple-areolar complex. With pseudogynecomastia, the fingers will not meet until they reach the nipple.

Also note the following in gynecomastia:

Note that hematoma, lipoma, male sexual dysfunction, and neurofibroma can be included in the differential diagnosis of gynecomastia.

Approach Considerations

Patients with physiologic gynecomastia do not require further evaluation. Similarly, asymptomatic and pubertal gynecomastia do not require further tests and should be reevaluated in 6 months. Further evaluation is necessary in patients with the following:

A serum chemistry panel may be helpful in evaluating for renal or liver disease. Free or total testosterone, luteinizing hormone (LH), estradiol, and dehydroepiandrosterone sulfate levels are used to evaluate a patient with possible feminization syndrome. Obtain thyroid-stimulating hormone (TSH) and free thyroxine levels if hyperthyroidism is suspected.

Imaging studies

Order a mammogram if 1 or more features of breast cancer are apparent upon clinical examination.[1] This can be followed by fine-needle aspiration or breast biopsy, as the case merits.[2, 3]

Obtain a testicular ultrasonogram if the serum estradiol level is elevated and the clinical examination findings suggest the possibility of a testicular neoplasm.

Breast imaging, through mammography or ultrasonography, may be controversial, because gynecomastia is much more common than male breast cancer. The positive predictive value of imaging in males is 55% using mammography and 17% using ultrasonography.[4]  However, a study by Telegrafo et al in which ultrasonography was used to diagnosis and classify gynecomastia found the same results as when mammography was used, suggesting that ultrasonography can be employed as a primary imaging modality for determining the presence of gynecomastia and categorizing its shape.[26]

Histologic findings

Characteristic findings include proliferation of ductules and stroma (consisting of connective-tissue elements such as fibroblasts, collagen, and myofibroblasts) and occasional acini. Gynecomastia of short duration consists of a prominent ductular component with loose stroma. Long-standing gynecomastia consists of dense stroma with few ductules.

Vascular findings

Ramadan et al, assessing breast vascularity in 54 male patients, aged 11-27 years, with gynecomastia, concluded that vascular structures ought to be considered a component of gynecomastia. Using ultrasonographic scanning, the authors found a strong correlation between the progression of breast development and that of arterial and venous blood flow.[27]

Approach Considerations

Generally, no treatment is required for physiologic gynecomastia. Pubertal gynecomastia resolves spontaneously within several weeks to 3 years in approximately 90% of patients. Breasts greater than 4 cm in diameter may not completely regress.

Identifying and managing an underlying primary disorder often alleviates breast enlargement.[28] If hypogonadism (primary or secondary) is the cause of gynecomastia, parenteral or transdermal testosterone replacement therapy is instituted. However, testosterone does have the potential to exacerbate gynecomastia through the aromatization of the exogenous hormone into estradiol.

For patients with idiopathic gynecomastia or with residual gynecomastia after treatment of the primary cause, medical or surgical treatment may be considered.

A major factor that should influence the initial choice of therapy for gynecomastia is the condition’s duration. It is unlikely that any medical therapy will result in significant regression in the late fibrotic stage (a duration of 12mo or longer) of gynecomastia. As a result, medical therapies, if used, should be tried early in the condition's course. The diagram below is a suggested treatment approach for patients presenting with breast enlargement.



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Suggested algorithm for the management of gynecomastia.

A study by Innocenti et al suggested that the reason patients undergo gynecomastia surgery and their level of satisfaction with the operation vary with body type. The report involved adult patients classified according to one of three different body types—high muscle mass, normal, or overweight—who were treated with subcutaneous mastectomy. The investigators found that the primary reason patients with normal body type underwent surgery was emotional distress owing to a feminine appearance. In contrast, most of those with high muscle mass wanted the operation because unsatisfactory contouring of the pectoralis area had damaged their self-confidence, while the majority of patients in the overweight group underwent surgery because they looked upon gynecomastia as a weight disorder. The study also found that patients with normal body type had higher levels of satisfaction with their surgical outcomes than did members of the other two groups.[29]

Pharmacologic Therapy

With the administration of clomiphene,[30] an antiestrogen, approximately 50% of patients achieve partial reduction in breast size, and approximately 20% of patients note complete resolution. Adverse effects, while rare, include visual problems, rash, and nausea.

Tamoxifen, an estrogen antagonist, is effective for recent-onset and tender gynecomastia.[31] Up to 80% of patients report partial to complete resolution. Nausea and epigastric discomfort are the main adverse effects.[32]

Other drugs used, albeit less frequently, include danazol.[33] Danazol, a synthetic derivative of testosterone, inhibits pituitary secretion of LH and follicle-stimulating hormone (FSH), which decreases estrogen synthesis from the testicles.

Breast Surgery

Reduction mammoplasty is considered for patients with macromastia or long-standing gynecomastia or in persons in whom medical therapy has failed.[6] It is also considered for cosmetic reasons (and for accompanying psychosocial reasons).[34, 35, 36, 37, 38, 39, 40, 41, 42, 43]

More extensive plastic surgery may be required in patients with marked gynecomastia or who have developed excessive sagging of the breast tissue due to weight loss. If surgery is necessary for patients with pseudogynecomastia, liposuction may be warranted.

A retrospective study by Zavlin et al found the prevalence of gynecomastia surgery complications in pediatric and adult patients to be low, with 30-day surgical complication rates of 3.9% and 1.9%, respectively, and 30-day medical complication rates of 0.0% and 0.3%, respectively. The investigators also found that the mean operative time for pediatric patients (111.3 minutes) was almost double that for adults (56.7 minutes).[44]

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 IIB 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- to 36-month 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.

Medication Summary

Clomiphene,[30] an antiestrogen, can be administered on a trial basis at a dose of 50-100 mg per day for up to 6 months. Approximately 50% of patients achieve partial reduction in breast size, and approximately 20% of patients note complete resolution. Adverse effects, while rare, include visual problems, rash, and nausea.

Tamoxifen, an estrogen antagonist, is effective for recent-onset and tender gynecomastia when used in doses of 10-20 mg twice daily.[31] Up to 80% of patients report partial to complete resolution. Tamoxifen is typically used for 3 months before referral to a surgeon. Nausea and epigastric discomfort are the main adverse effects.[32]

Other, less frequently used drugs include danazol.[33] Danazol, a synthetic derivative of testosterone, inhibits pituitary secretion of LH and follicle-stimulating hormone (FSH), which decreases estrogen synthesis from the testicles. The dose used for gynecomastia is 200mg twice daily. Complete resolution of breast enlargement has been reported in 23% of cases. Adverse effects include weight gain, acne, muscle cramps, fluid retention, nausea, and abnormal liver function test results.

Testosterone (Androderm, AndroGel, Axiron, Testim)

Clinical Context:  Testosterone is the predominant male sex hormone used for replacement therapy in male hypogonadism.

Danazol

Clinical Context:  Danazol is a synthetic steroid analog with strong antigonadotropic activity (it inhibits LH and FSH) and weak androgenic action.

Class Summary

Androgens suppress pituitary release of gonadotropic hormones.

These agents are used to inhibit the effects of estrogen.[6, 30, 31, 32, 33, 45]

Clomiphene (Clomid, Serophene)

Clinical Context:  Clomiphene stimulates the release of pituitary gonadotropins.

Tamoxifen

Clinical Context:  Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex that decreases deoxyribonucleic acid (DNA) synthesis and inhibits estrogen effects.

Class Summary

Selective estrogen receptor modulators inhibit estrogen effects.

What is gynecomastia?What should be the focus of history in the evaluation of gynecomastia?What should be included in the physical exam of gynecomastia?Which conditions should be included in the differential diagnoses of gynecomastia?Which factors necessitate further evaluation of gynecomastia?Which lab tests are performed in the evaluation of gynecomastia?What is the role of imaging studies in the evaluation of gynecomastia?What are the treatment options for gynecomastia?Which medications are used in the treatment of gynecomastia?What is the role of surgery in the treatment of gynecomastia?What are possible complications from surgery treatment of gynecomastia?What is gynecomastia?What should be included in patient education about gynecomastia?What is the pathogenesis of gynecomastia?How does estrogen contribute to the development of gynecomastia?What are the characteristics of increased estrogen production resulting in gynecomastia?In which age groups is physiologic gynecomastia most likely to occur?Which factors causes gynecomastia in adults?What is the role of hyperprolactinemia in the etiology of gynecomastia?What are the causes of pathologic gynecomastia?What causes decreased androgen action in pathologic gynecomastia?What causes increased estrogen action in pathologic gynecomastia?What is the role of hypogonadism in the etiology of gynecomastia?Which conditions may cause gynecomastia?What is the role of drugs in the etiology of gynecomastia?Which antiandrogen medications may cause gynecomastia?Which chemotherapy agents may cause gynecomastia?Which cardiac medications may cause gynecomastia?Which hormonal medications may cause gynecomastia?Which psychoactive agents may cause gynecomastia?Which medications used to treat infectious diseases may cause gynecomastia?Which drugs of abuse may cause gynecomastia?Which medications may cause gynecomastia?How are drugs stratified as etiologic agents of gynecomastia?What are the most common etiologies of gynecomastia?What is the prevalence of gynecomastia in the US?What is the prognosis of gynecomastia?How well does gynecomastia respond to treatment?What are the psychological effects of gynecomastia?How does gynecomastia affect sexual function?What should be the focus of history for gynecomastia?What is the role of CT scans in the diagnosis of gynecomastia?How is pseudogynecomastia differentiated from gynecomastia?How is a breast exam conducted in the evaluation of gynecomastia?What should be the focus of the physical exam for gynecomastia?What are the differential diagnoses for Gynecomastia?What is included in the workup of gynecomastia?What is the role of lab studies in the evaluation of gynecomastia?What is the role of mammogram in the evaluation of gynecomastia?When is a testicular ultrasound indicated in the treatment of gynecomastia?What is the role of imaging in the evaluation of gynecomastia?Which histologic findings are characteristic of gynecomastia?What is the significance of vascular findings in the evaluation of gynecomastia?What are the focus of treatment for gynecomastia?What algorithm can be used for the management of gynecomastia?Why do men with gynecomastia undergo surgery?What is the role of medications in the treatment of gynecomastia?When is reduction mammoplasty indicated for the treatment of gynecomastia?When is extensive plastic surgery indicated in the treatment of gynecomastia?What is the prevalence of surgical complications in gynecomastia?What is the role of endoscopic subcutaneous mastectomy in the treatment of gynecomastia?What are possible complications of breast surgery for gynecomastia?Which medications are used in the treatment of gynecomastia?Which medications in the drug class Selective Estrogen Receptor Modulators are used in the treatment of Gynecomastia?Which medications in the drug class Androgens are used in the treatment of Gynecomastia?

Author

George Ansstas, MD, Assistant Professor of Medicine, Division of Medical Oncology, Washington University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Michael Ansstas, MD, Fellow in Allergy and Immunology, Department of Internal Medicine, St Louis University Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Mark R Allee, MD Associate Professor, Department of Medicine, University of Oklahoma College of Medicine

Mark R Allee, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Mary Zoe Baker, MD Professor, Department of Medicine, Section of Endocrinology, Metabolism and Hypertension, University of Oklahoma College of Medicine; Medical Director, Medicine Specialty Clinic, General Medicine Clinic and Medicine Residents' Clinic, University of Oklahoma Physicians

Mary Zoe Baker, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Chemical Society, and American College of Physicians-American Society of Internal Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

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Adolescent gynecomastia.

Adolescent gynecomastia.

Prominent areolae with dense subareolar ductal tissue.

Suggested algorithm for the management of gynecomastia.

Adolescent gynecomastia.

Prominent areolae with dense subareolar ductal tissue.

Suggested algorithm for the management of gynecomastia.