Ginekomastia Jurnal

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T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 357;12 www.nejm.org september 20, 2007 1229

This Journal feature begins with a case vignette highlighting a common clinical problem.Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the author’s clinical recommendations.

Gynecomastia

Glenn D. Braunstein, M.D.

From the Department of Medicine, Cedars–Sinai Medical Center, Los Angeles. Ad-dress reprint requests to Dr. Braunsteinat the Department of Medicine, Rm. 2119Plaza Level, Cedars–Sinai Medical Center,8700 Beverly Blvd., Los Angeles, CA 90048,or at [email protected].

N Engl J Med 2007;357:1229-37.

Copyright © 2007 Massachusetts Medical Society.

During an evaluation for low back pain, a 67-year-old man is found to have gyneco-mastia on the right side that is nontender on palpation. Other than a body-mass index(the weight in kilograms divided by the square of the height in meters) of 32, the phys-ical examination is normal. His medical history is notable only for hyperlipidemia; his only medication is a statin. How should his gynecomastia be evaluated and managed?

The Clinical Problem

Asymptomatic gynecomastia, or enlargement of the glandular tissue of the breast,is common in older men; it is found on examination in one third to two thirds ofmen and at autopsy in 40 to 55% of men.1-7 The condition has usually been presentfor months or years when it is first discovered during a physical examination. His-tologic examination of the breast tissue in this setting usually shows dilated ducts with periductal fibrosis, stromal hyalinization, and increased subareolar fat.6-9 Incontrast, patients who present with symptoms of pain and tenderness generallyhave gynecomastia of more recent onset, and pathological findings include hyper-plasia of the ductal epithelium, infiltration of the periductal tissue with inflamma-tory cells, and increased subareolar fat.6-9

The pathophysiological process of gynecomastia involves an imbalance betweenfree estrogen and free androgen actions in the breast tissue; this imbalance can oc-cur through multiple mechanisms (Fig. 1).10 During mid-to-late puberty, relativelymore estrogen may be produced by the testes and peripheral tissues before testos-terone secretion reaches adult levels, resulting in the gynecomastia that commonlyoccurs during this period. The testes may directly secrete too much estradiol from aLeydig-cell or Sertoli-cell tumor. They may also secrete estradiol indirectly throughthe stimulatory effects of a human chorionic gonadotropin (hCG)–secreting tumorof gonadal or extragonadal germ-cell origin (also called eutopic hCG production)or a tumor derived from a nontrophoblastic tissue, such as a large-cell carcinoma ofthe lung or some gastric or renal-cell carcinomas (also called ectopic hCG produc-

tion). In addition, the testes may secrete too little testosterone; this occurs in pri-mary or secondary hypogonadism. The prevalence of these conditions increases withadvanced age, and one study indicated that 50% of men in their 70s have a lowfree testosterone concentration.11

An adrenal neoplasm may overproduce the weak androgen androstenedione andother androgen precursors such as dehydroepiandrosterone, which are convertedinto estrogens in peripheral tissues. An increase in aromatase activity has been re-ported in a number of patients with gynecomastia associated with a variety ofdisease processes, including thyrotoxicosis, Klinefelter’s syndrome, and adrenal andtesticular tumors.12 Aromatase activity increases both with age and with an increase

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n engl j med 357;12 www.nejm.org september 20, 20071230

in body fat. Since body fat also increases withage, it is likely that a physiologic increase in theactivity of the aromatase enzyme complex withnormal aging is responsible for many cases of

asymptomatic gynecomastia in older men. Indeed,there is a progressive increase in the prevalenceof gynecomastia with an increase of the body-mass index, probably reflecting the local para-crine effects of estradiol production in the sub-areolar fat on the breast glandular t issue.4,5

Since estradiol and estrone bind less avidly tosex hormone–binding globulin than does testos-terone, drugs such as spironolactone may displacerelatively more estrogen than testosterone from

this protein, increasing the bioavailable fractionof estrogen to a greater extent than bioavailableandrogen. Similarly, an increase in the sex hor-mone–binding globulin concentration, which oc-

curs with hyperthyroidism and some forms ofliver disease, may be associated with greaterbinding of testosterone relative to estrogen, lead-ing to a decrease in free testosterone relative tofree estrogen. Androgen-receptor abnormalities,either due to a genetic defect or blockade by anantagonist such as bicalutamide or due to stimu-lation of the estrogen receptor by medications orenvironmental estrogens, may also result in gy-necomastia.

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Steroid-producing organ

Blood BloodExtragonadal tissues Target cell

Testes

Adrenals

Increased with Leydig- or Sertoli-cell tumor

Increased with hCG-producing tumor

Decreased with primary orsecondary hypogonadism

Estrone

EstroneEstrone Estrone

Estradiol Estradiol Estradiol Estradiol

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Estrogenreceptor

Estrogenreceptor

Androgenreceptor

Androgenreceptor

Androstenedione

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Androstenedione

Increased withadrenal neoplasm

Increased because of increased aromatase activity:

Physiologic (increasedadipose tissue andadvancing age)

Estradiol andestronedisplaced bysome drugs,increasingfree estrogens

Environmentalestrogens

Dihydro-testosterone

Sex hormone–binding globulin

Defective receptorswith decreasedandrogen action

Drug inhibition

+

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Pathologic (congenitalor acquired)

Figure 1. Estradiol and Estrone, Displaced by Some Drugs, Resulting in an Increase in Free Estrogen.

Most testosterone and approximately 15% of estradiol are secreted directly by the testes. 10 Both bind to sex hormone–binding globulinand, to a lesser extent, albumin, and a small amount of each hormone circulates in the free state. The free and albumin-bound steroids

(the “bioavailable” fraction) enter extragonadal tissues, many of which contain the aromatase enzyme complex, which converts some of

the testosterone to estradiol. This enzyme complex also converts androstenedione of adrenal origin to estrone, which may be further convert-

ed to the more potent estrogen estradiol through the action of 17β-hydroxysteroid dehydrogenase. The bioavailable testosterone, estra-diol, and estrone, derived from direct glandular secretion and extraglandular production, enter target tissues, where they bind to theirrespective receptors and initiate gene activation and transcription. In addition, some of the testosterone is converted to the more potent

metabolite dihydrotestosterone through the action of 5α-reductase. Dihydrotestosterone binds to the same androgen receptors as testos-terone. Multiple processes can alter the pathways of estrogen and androgen production and action, resulting in gynecomastia from an

enhanced estrogen effect or a diminished androgen effect at the target-tissue level. Figure was modified from Mathur and Braunstein. 10





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Str ategies and Evidence

Diagnosis

The first step in the clinical evaluation of pa-tients is to determine whether the enlarged breast

tissue or mass is gynecomastia. Pseudogyneco-mastia is characterized by increased subareolarfat without enlargement of the breast glandularcomponent. The differentiation between gyneco-mastia and pseudogynecomastia is made on phys-ical examination, as shown in Figure 2. The otherimportant differentiation is between gynecomas-tia and breast carcinoma. The tissue in gyneco-mastia is soft, elastic, or firm but generally nothard, the affected area is concentric to the nipple–

areolar complex, and it is clinically bilateral inapproximately half of patients. Breast carcinomais usually hard or firm, is located outside thenipple–areolar complex, and is most often uni-lateral. In addition, skin dimpling and nipple re-

traction are not present with gynecomastia, butthey may be seen in patients with breast carci-noma. Tenderness may be present in gynecomas-tia of less than 6 months’ duration, but it is un-usual with breast carcinoma. Nipple bleeding ordischarge is present in approximately 10% of men with breast cancer, but it is not expected withgynecomastia.13 If the differentiation betweengynecomastia and breast carcinoma cannot bemade on the basis of clinical findings alone, the

Gynecomastia Other disorders (cancer)

Thumb and forefinger are drawntogether toward the areola

Areola

Hard or firmmass

Concentricmass

Mass outsidethe areola

Rubbery orfirm mass

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Figure 2. Differentiation of Gynecomastia from Pseudogynecomastia and Other Disorders by Physical Examination.

The patient lies flat on his back with his hands clasped beneath his head. Using the separated thumb and forefinger,

the examiner slowly brings the fingers together from either side of the breast. In patients with true gynecomastia,a rubbery or firm mound of tissue that is concentric with the nipple–areolar complex is felt, whereas in patients

with pseudogynecomastia, no such disk of tissue is found.





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patient should undergo diagnostic mammogra-phy, which has 90% sensitivity and specificity fordistinguishing malignant from benign breast dis-eases.14

Evaluation

Once the diagnosis of gynecomastia is established,

it is important to review all medications, includ-ing over-the-counter drugs such as herbal prod-ucts, that may be associated with gynecomastia.Ingestion of sex steroid hormones or their pre-cursors may cause gynecomastia through biocon- version to estrogens. Antiandrogens used for thetreatment of prostate cancer, spironolactone,cimetidine, environmental estrogens or antian-drogens, and one or more components of highlyactive antiviral therapy used for human immuno-deficiency virus infection (especially protease in-hibitors) have been clearly shown to be associated

with gynecomastia.15-25 Several cancer chemother-apeutic drugs, particularly alkylating agents, candamage the testes and result in primary hypogo-nadism. Other drugs, including phenytoin andmetoclopramide, have also been associated withgynecomastia, but a cause-and-effect relationshiphas not been proved.15

An adolescent presenting with gynecomastiausually has physiologic pubertal gynecomastia, which generally appears at 13 or 14 years of age,lasts for 6 months or less, and then regresses.Less than 5% of affected boys have persistentgynecomastia, but this is the apparent cause ina large proportion of young men in their lateteens or 20s presenting for evaluation. Other con-ditions to consider in adolescents and youngadults with gynecomastia are Klinefelter’s syn-drome, familial or sporadic excessive aromataseactivity, incomplete androgen insensitivity, femi-nizing testicular or adrenal tumors, and hyper-thyroidism.26-28 Drug abuse, especially with ana-bolic steroids, but also with alcohol, marijuana,or opioids, also should be considered.29

If an adolescent or adult presents with unilat-eral or bilateral gynecomastia that is painful ortender, and if the patient’s history and physicalexamination do not reveal the cause (Table 1),hCG, luteinizing hormone, testosterone, and es-tradiol should be measured (Fig. 3).30 Many of theavailable measurements of testosterone have pooraccuracy and precision, especially in men withtestosterone levels at the low end of the normalrange.31 Measurement of these levels in the morn-

ing is recommended, since testosterone andluteinizing hormone secretion have a circadianrhythm (with the highest levels in the morning)as well as secretory bursts throughout the day. Ifthe total testosterone level is borderline or low,free or bioavailable testosterone should be mea-sured or calculated to confirm hypogonadism.

Although such laboratory evaluation is prudent,no abnormalities are detected in the majority ofpatients.

Laboratory tests to determine the cause ofasymptomatic gynecomastia in an adult withouta history suggestive of an underlying pathologiccause, with an otherwise normal physical exami-nation, are unlikely to be revealing, and the ex-tent of hormonal evaluation that should be per-formed in such patients remains controversial.The likelihood of discovering a pathologic abnor-mality is low in patients with long-standing

asymptomatic gynecomastia in the fibrotic stage,and the long duration of the condition withoutother evidence of disease is reassuring; thus,many clinicians take a minimalist approach toevaluation. Nevertheless, measurement of themorning testosterone level and free or bioavail-able testosterone and luteinizing hormone levels,if the morning testosterone level is low, is reason-able to detect hypogonadism, which is increas-ingly common with advanced age.11 A finding ofa low free or bioavailable testosterone level andan elevated luteinizing hormone level indicatesprimary testicular failure, whereas a low free orbioavailable testosterone level and a normal orlow luteinizing hormone level may indicate sec-ondary hypogonadism.

Treatment

If a specific cause of gynecomastia can be identi-fied and treated during the painful proliferativephase, there may be regression of the breast en-largement. This regression most often occurs withdiscontinuation of an offending drug or after ini-

tiation of testosterone treatment for primary hypo-gonadism. If the gynecomastia is drug-induced,decreased tenderness and softening of the glan-dular tissue will usually be apparent within 1 monthafter discontinuation of the drug. However, ifthe gynecomastia has been present for more than1 year, it is unlikely to regress substantially, eitherspontaneously or with medical therapy, because ofthe presence of fibrosis. In such circumstances,surgical subcutaneous mastectomy, ultrasound-





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assisted liposuction, and suction-assisted lipec-tomy are the best options for cosmetic improve-ment, as described in several case series.32,33

During the rapid, proliferative phase, manifest-ed clinically as breast pain and tenderness, medi-cal therapy may be attempted. Most studies of

drugs — including testosterone (in patients with-out hypogonadism), dihydrotestosterone, danazol,clomiphene citrate, tamoxifen, and testolactone— have been uncontrolled and thus difficult tointerpret because gynecomastia may resolve spon-taneously.34,35 The few randomized, double-blind,placebo-controlled trials generally have been lim-ited by small samples.

Although not approved for the treatment ofgynecomastia, the selective estrogen-receptor mod-

ulator tamoxifen, administered orally at a dose of20 mg daily for up to 3 months, has been shownto be effective in randomized and nonrandom-ized trials, resulting in partial regression of gyne-comastia in approximately 80% of patients andcomplete regression in about 60%.36-45 Patients in

whom tamoxifen is effective usually experience adecrease in pain and tenderness within 1 month.In a retrospective analysis of a series of patients with idiopathic gynecomastia, 78% of patientstreated with tamoxifen had complete resolutionof gynecomastia, as compared with only 40% ofpatients receiving danazol.42 In case series describ-ing the use of tamoxifen for this condition inmore than 225 patients, adverse events were un-common; they included epigastric distress in 2 pa-

Table 1. Signs and Symptoms of Pathologic Processes That Cause Gynecomastia.

Condition Symptoms Signs

Tumor

Testicular

Leydig-cell or Sertoli-cell Testicular pain, enlargement, or both; decreasedlibido

Testicular mass or enlargement, contralateral testis withsome atrophy, signs of feminization

Germ-cell Testicular pain, enlargement, or both; symptomsof metastases (e.g., back pain, hemoptysis)

Testicular mass

Adrenocortical Weight loss, decreased libido, possible symp-toms of coexisting Cushing’s syndrome ormineralocorticoid excess

Abdominal mass, signs of Cushing’s syndrome or mineralo-corticoid excess (hypertension)

Ectopic hCG-secreting Weight loss; respiratory symptoms with lungcarcinoma; abdominal symptoms with hepa-tocellular, gastric, or renal-cell carcinoma

Dependent on location of primary tumor and presence orabsence of metastases

Hypogonadism

Primary Decreased libido, erectile dysfunction, vasomotorsymptoms

Decreased testicular size, hard texture with Klinefelter’ssyndrome, soft texture if acquired; incomplete devel-opment of secondary sexual characteristics with pre-pubertal onset; possible findings of a systemic disorder(e.g., hemochromatosis)

Secondary Decreased libido, erectile dysfunction, symp-toms of other pituitary hormone deficiency,headache, visual symptoms

Decreased testicular size; possible visual-field cuts from apituitary or parasellar tumor; signs of hypothyroidism, ex-cess or deficiency of growth hormone; galactorrhea (rare)

Hyperthyroidism Weight loss, palpitations, increased sweating,increased frequency of defecation, nervous-ness, insomnia, heat intolerance

Goiter, tremor, tachycardia, upper-eyelid retraction

Liver disease Anorexia, nausea, vomiting, weight loss (or weightgain with ascites), edema, jaundice, pruritus

Jaundice, enlarged or shrunken liver, ascites, edema

Renal disease Anorexia, fatigue, nausea, vomiting, oliguria orpolyuria, pruritus, yellowish skin

Lethargy, asterixis, uremic hue, hypertension

Androgen insensitivity Decreased libido, infertility Possible hypospadias or ambiguity of genitalia, possibleneurologic findings (e.g., proximal muscle weaknesswith fasciculations and tremor in X-linked spinal and

bulbar muscular atrophy)Familial or sporadic aroma-

tase excess syndromeNone Prepubertal onset of gynecomastia; accelerated increase

in height in childhood, reduced final height; incom-plete virilization





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tients38 and a post-traumatic deep-vein thrombo-sis in 1 patient.43

The aromatase inhibitor anastrozole was notshown to be more effective than placebo in a ran-domized, double-blind, placebo-controlled trial inboys with pubertal gynecomastia.46 Although inan uncontrolled study of 10 patients with puber-

tal gynecomastia, the selective estrogen-receptormodulator raloxifene was shown to result in morethan a 50% decrease in the size of the gynecomas-tia in the majority of the boys, there are insuffi-cient data to recommend its use at this t ime.44

It has also been suggested that therapy withtamoxifen may prevent the development of gyne-comastia in men receiving monotherapy withhigh doses of bicalutamide (Casodex) for prostatecancer. In a randomized, double-blind, controlledtrial involving men receiving high-dose bicaluta-mide (150 mg per day),47 gynecomastia occurred

in 10% of patients who received tamoxifen at adose of 20 mg daily, but it occurred in 51% ofthose who received anastrozole at a dose of 1 mgdaily and in 73% of those who received placebo,over a period of 48 weeks; mastalgia occurred in6%, 27%, and 39% of these patients, respectively.In another trial48 involving 3 months of therapy,gynecomastia, mastalgia, or both occurred in69.4% of patients receiving placebo, 11.8% receiv-ing tamoxifen (P


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hypogonadism. Pubertal gynecomastia resolves with time in the majority of adolescent boys, andreassurance and follow-up physical examinationusually suff ice. In adults who present with theacute onset of painful gynecomastia without anobvious cause, hormonal evaluation, includingmeasurements of serum hCG, testosterone, lutein-

izing hormone, and estradiol levels, should beperformed in order to rule out serious and treat-able causes, although serious disease is unlikelyin this sett ing. During the acute f lorid stage ofgynecomastia, a trial of tamoxifen, at a dose of20 mg per day for up to 3 months, may be attempt-ed. If the gynecomastia has not regressed by 1 year,or in patients who present with long-standinggynecomastia who are troubled by their appear-

ance, surgical removal of the breast glandulartissue and subareolar fat is an option that has agood cosmetic result in the majority of patients.For a patient such as the man in the vignette, who is asymptomatic, is not bothered by his gy-necomastia, and does not have a suggestive his-tory or physical examination, a more minimalist

evaluation (i.e., measurements of testosterone andluteinizing hormone levels, although even the useof these tests might be debated52) is recommend-ed, and treatment other than weight reduction isnot warranted for the gynecomastia.

Dr. Braunstein reports receiving consulting fees from AbbottDiagnostics, Esoterix, M&P Pharma, and Novartis and researchfunding from Procter & Gamble and BioSante. No other poten-tial conf lict of interest relevant to this article was reported.

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COLLECTIONS OF ARTICLES ON THE JOURNAL’S WEB SITE

The Journal’s Web site (www.nejm.org ) sorts published articles intomore than 50 distinct clinical collections, which can be used as convenient

entry points to clinical content. In each collection, articles are cited in reverse

chronologic order, with the most recent first.



Documents

Ginekomastia Jurnal