Gynecomastia - evaluation and current treatment options.

CLINICAL QUESTION: What is the best management approach for gynecomastia?
RESULTS: In most patients, surgical correction usually leads to immediate cosmetic and symptomatic improvement and is considered the best approach. In men who are being treated with antiandrogen therapies, pharmacological intervention with tamoxifen is the most effective approach, followed by radiotherapy. IMPLEMENTATION: Pitfalls to avoid when treating gynecomastia Failure to detect the very rare male breast cancerOverly aggressive early intervention or evaluationAppropriate medical interventionWhen to refer to specialist treatment.

Gynecomastia

Definition:

Gynecomastia is the benign proliferation of the glandular tissue in the male breast beneath the nipple (subareolar region). True gynecomastia is typically a rubbery or firm mound of tissue that is concentric with the nipple-areolar complex. This is to be distinguished from pseudogynecomastia, which lacks such a disk of tissue, as it is an increase in subareolar fat without enlargement of the breast glandular component. In about half of the cases, the process is clinically bilateral. Most cases are benign. Diagnostic evaluation is needed only when the palpable mass is unilateral, hard, fixed, peripheral to the nipple, or associated with nipple discharge, skin changes, or lymphadenopathy.1,2

Etiology:

Gynecomastia is likely caused by an imbalance between increased estrogen activity and decreased androgen activity at the breast tissue level. Several medical conditions are associated with gynecomastia such as primary or secondary gonadal failure, androgen resistance syndromes, hyperthyroidism, chronic liver disease, use of some medications such as spironolactone, digoxin, bicalutamide, cimetidine and drugs of abuse such as alcohol and marijuana.1,2

Incidence:

Prevalence of asymptomatic gynecomastia is 60%–90% in neonates, 50%–60% in adolescents, and up to 70% in men age 50–69 years.3–6 Trimodal distribution for asymptomatic gynecomastia is noted (neonatal, pubertal, and in elderly males). Prevalence of symptomatic gynecomastia is markedly lower.

Economics:

No previous study has evaluated the economic burden of gynecomastia, but aggressive unnecessary work up in low risk cases, which are the most common, can be costly.

Level of evidence used in this summary:

RCTs, systemic reviews, and observational studies.

Search sources:

MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, the Cochrane Register of Controlled Trials, ISI Web of Science and Scopus.

Identification of underlying medical conditions or associated medications

Resolution of breast pain

Cosmesis (decreased breast size)

Identification of the rare cases of male breast cancer

Resolution of psychological impact of gynecomastia

Avoidance of excessive laboratory and radiologic evaluation

Consumer summary:

Gynecomastia is the development of glandular and ductal tissue in the male breast. It is typically caused by an imbalance of the action of estrogens (female hormones) and androgens (male hormones) on the breast tissue. A variety of medications, medical conditions and age-related factors can cause or contribute to this condition. The condition is generally benign and if it does not resolve spontaneously, can be effectively treated.

The evidence

What is the best treatment for gynecomastia in men taking antiandrogen therapies for prostate cancer?

The systematic review7 concluded that serum estrogen receptor modulators (SERMS, e.g. tamoxifen), aromatase inhibitors (AIs, e.g. anastrazole), radiotherapy (RT) or both, prevent or reduce gynecomastia and breast pain associated with antiandrogen (AA) use. Of the three options, tamoxifen is most effective.

Conclusions

Serum estrogen receptor modulators, particularly tamoxifen, or radiotherapy may help prevent or reduce gynecomastia in men taking antiandrogen therapies.

What is the best treatment for gynecomastia in all other males (not taking antiandrogen therapies)?

No high quality evidence exists to support a role for pharmacological agents or radiotherapy in this setting. Case series showed reduction in glanular tissue size after using SERMS (e.g. tamoxifen or raloxifene).

Surgical correction is considered the gold standard treatment. Although similar to pharmacological interventions, surgical correction has been tested only in case series and not in randomized trials. Published case series demonstrates clinical success with cosmetic, symptomatic, and psychological improvements with minimal adverse effects.

more invasive (ie, subcutaneous mastectomy that involves the direct resection of the glandular tissue using a peri-areolar or transareolar approach, with or without associated liposuction).

less invasive techniques that require minimal surgical incision utilizing an axillary approach and endoscopic visualization and resection.

Surgery can be either

No high quality evidence exists to support one surgical approach over the other.

Conclusion

Surgery is the gold standard therapy for symptomatic gynecomastia in most patients.

Decision about pursuing therapy

Asymptomatic gynecomastia is a common and physiologic finding at three stages of the life of men and does not require intervention. Symptomatic gynecomastia in adult males can be efficiently diagnosed and reassurance and/or interventions can readily be initiated.

In general, the decision to treat gynecomastia depends on the values and preferences of the patient and on the impact of gynecomastia on their quality of life. If no improvement is noted after the withdrawal of causative medications or treatment of the associated underlying medical conditions, surgical correction, pharmacological therapies, or radiotherapy can be considered.

All masses that are not located in the subareolar (under the nipple) area should be evaluated further for the possibility of male breast cancer.

Pseudogynecomastia (the presence of fatty tissue only in the breasts) associated with obesity, does not require evaluation or treatment.

The practice

Management

Gynecomastia can generally be managed by non-specialists. Indications for specialist referral are given below.

Assessment

A thorough history and physical examination should exclude pseudogynecomastia. History should include all medications, supplements, hormones, and drugs of abuse including alcohol and marijuana. Diagnostic evaluation is needed only when the palpable mass is unilateral, hard, fixed, peripheral to the nipple, or associated with nipple discharge, skin changes, or lymphadenopathy.

If a mass is palpated in an eccentric area (non-subareolar), mammography is quite accurate in distinguishing malignant from benign male breast disease and substantially reduces the need for biopsy. Sensitivity and specificity of mammography for benign and malignant breast conditions exceeds 90%.

If palpable scrotal mass is present, scrotal ultrasound imaging is recommended.

Basic laboratory evaluation includes blood profile for liver, kidney, and thyroid function to exclude respective medical conditions. Hormonal blood levels for total and bioavailable testosterone, estradiol, prolactin, leuteinizing hormone, and human chorionic gonadotropin can direct evaluation toward pituitary, gonadal, or extra gonadal endocrinopathies and neoplasms.

If all testing is unrevealing, idiopathic gynecomastia is diagnosed.

Treatment

Gynecomastia is a benign condition and usually self-limited.

Over time fibrotic tissue replaces symptomatic proliferation of glandular tissue and tenderness resolves.

If history, physical, and lab studies do not reveal an underlying pathology, reassurance and periodic follow-up are recommended.

Causative medications or supplements should be withdrawn and underlying causative medical conditions, e.g. hyperthyroidism, should be addressed as a first step.

If gynecomastia persists and is associated with pain and/or psychological distress and the patient wishes to pursue treatment, pharmacologic and surgical options are available.

Pharmacologic therapy is likely beneficial if implemented in the first several months before fibrous tissue replaces glandular tissue, a process that is irreversible.

The efficacy of pharmacotherapy is supported by low quality evidence SERMs, e.g. tamoxifen or raloxifene, and more recently aromataste inhibitors, e.g. anastrozole.

Surgical correction in benign gynecomastia is done primarily for cosmetic indications (see indications for specialist referral).

Patient has significant persistent bilateral or asymmetric unilateral breast development of cosmetic concern.

Further enlargement of the male breast despite appropriate medical intervention.

Psychological distress for patient due to breast appearance.

Systematic reviews	1
RCTs	8

RCT	1
Case series: multiple

Summary of RCTs

Author	Number randomized	Population	Interventions	Results
Ozen8	125	Men on AA	RT vs no RT	RT best; P < 0.001
Fradet9	282	Men on AA	tamoxifen (different dosing schedules)	20 mg/day better than smaller doses
Saltzstein10	107	Men on AA	tamoxifen vs anastrozole	tamoxifen better
Perdonà11	51	Men on AA	tamoxifen vs RT	tamoxifen better than RT
Di Lorenzo12	102	Men on AA	tamoxifen vs RT	tamoxifen better than RT
Boccardo13	114	Men on AA	tamoxifen vs anastrozole	tamoxifen better than anastrozole
Tyrrell14	106	Men on AA	RT vs sham RT	RT better; P < 0.001

Abbreviations: AA, anti-androgen drugs; RT, radiotherapy

Summary of RCTs

Author	Number randomized	Population	Interventions	Results
Plourde15	80	Boys 11–18 years	anastrozole	Null results

Summary of selected case series

Author	Sample size	Interventions	Results
Prado16	25	minimally invasive surgery	All had good results with no complications or need for revision
Handschin17	100 (160 procedures)	subcutaneous mastectomy	All had good results, revision rate 7% and early surgical complication rate 31%
Alagaratnam18	61	40 mg of tamoxifen daily for 1–4 months	80% complete regression. No long-term side effects over a follow-up of 36 months
Lawrence19	38	3- to 9-month course of tamoxifen or raloxifene	Both groups had significant reduction in breast size. No side effects in any patients
Derman20	37	tamoxifen	Pain and size reduction was seen in all patients