Gynecomastia: Clinical Practice

clinical practice
The new engl and j ournal 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 authors 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. Braunstein
at the Department of Medicine, Rm. 2119
Plaza Level, CedarsSinai 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 of
men and at autopsy in 40 to 55% of men.
1-7
The condition has usually been present
for 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
In
contrast, patients who present with symptoms of pain and tenderness generally
have 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 between
free 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, relatively
more estrogen may be produced by the testes and peripheral tissues before testos-
terone secretion reaches adult levels, resulting in the gynecomastia that commonly
occurs during this period. The testes may directly secrete too much estradiol from a
Leydig-cell or Sertoli-cell tumor. They may also secrete estradiol indirectly through
the stimulatory effects of a human chorionic gonadotropin (hCG)secreting tumor
of 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 of
the 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 with
advanced age, and one study indicated that 50% of men in their 70s have a low
free testosterone concentration.
11
An adrenal neoplasm may overproduce the weak androgen androstenedione and
other androgen precursors such as dehydroepiandrosterone, which are converted
into estrogens in peripheral tissues. An increase in aromatase activity has been re-
ported in a number of patients with gynecomastia associated with a variety of
disease processes, including thyrotoxicosis, Klinefelters syndrome, and adrenal and
testicular tumors.
12
Aromatase activity increases both with age and with an increase
The New England Journal of Medicine
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Copyright 2007 Massachusetts Medical Society. All rights reserved.
1230
in body fat. Since body fat also increases with
age, it is likely that a physiologic increase in the
activity of the aromatase enzyme complex with
normal aging is responsible for many cases of
asymptomatic gynecomastia in older men. Indeed,
there is a progressive increase in the prevalence
of 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 tissue.
4,5
Since estradiol and estrone bind less avidly to
sex hormonebinding globulin than does testos-
terone, drugs such as spironolactone may displace
relatively more estrogen than testosterone from
this protein, increasing the bioavailable fraction
of estrogen to a greater extent than bioavailable
androgen. Similarly, an increase in the sex hor-
monebinding globulin concentration, which oc-
curs with hyperthyroidism and some forms of
liver disease, may be associated with greater
binding of testosterone relative to estrogen, lead-
ing to a decrease in free testosterone relative to
free estrogen. Androgen-receptor abnormalities,
either due to a genetic defect or blockade by an
antagonist such as bicalutamide or due to stimu-
lation of the estrogen receptor by medications or
environmental estrogens, may also result in gy-
necomastia.
1
Solomon
Hogan
08/16/07
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Author
Fig #
Title
ME
DE
Artist
Issue date
COLOR FIGURE
Draft 9
Braunstein
KMK
Pathways of Estrogen and Androgen
production
09/20/07
Steroid-
producing organ
Blood Blood Extragonadal tissues Target cell
Testes
Adrenals
Increased with Leydig- or Sertoli-cell tumor
Increased with hCG-producing tumor
Decreased with primary or
secondary hypogonadism
Estrone
Estrone Estrone Estrone
Estradiol Estradiol Estradiol Estradiol
Testosterone
Testosterone
Testosterone Testosterone
Estrogen
receptor
Estrogen
receptor
Estrogen
receptor
Androgen
receptor
Androgen
receptor
Androstenedione
Andro-
stenedione
Androstenedione
Increased with
adrenal neoplasm
Increased because of
increased aromatase activity:

Physiologic (increased
adipose tissue and
advancing age)
Estradiol and
estrone
displaced by
some drugs,
increasing
free estrogens
Environmental
estrogens
Dihydro-
testosterone
Sex hormone
binding globulin
Defective receptors
with decreased
androgen action
Drug inhibition
+
+
+
+
+
Pathologic (congenital
or 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 hormonebinding globulin
and, 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 17-hydroxysteroid dehydrogenase. The bioavailable testosterone, estra-
diol, and estrone, derived from direct glandular secretion and extraglandular production, enter target tissues, where they bind to their
respective 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 5-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
clinical practice
1231
Strategies 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 subareolar
fat without enlargement of the breast glandular
component. The differentiation between gyneco-
mastia and pseudogynecomastia is made on phys-
ical examination, as shown in Figure 2. The other
important differentiation is between gynecomas-
tia and breast carcinoma. The tissue in gyneco-
mastia is soft, elastic, or firm but generally not
hard, the affected area is concentric to the nipple
areolar complex, and it is clinically bilateral in
approximately half of patients. Breast carcinoma
is usually hard or firm, is located outside the
nippleareolar complex, and is most often uni-
lateral. In addition, skin dimpling and nipple re-
traction are not present with gynecomastia, but
they 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 or
discharge is present in approximately 10% of men
with breast cancer, but it is not expected with
gynecomastia.
13
If the differentiation between
gynecomastia and breast carcinoma cannot be
made on the basis of clinical findings alone, the
Gynecomastia Other disorders (cancer)
Thumb and forefinger are drawn
together toward the areola
Areola
Hard or firm
mass
Concentric
mass
Mass outside
the areola
Rubbery or
firm mass
2
Solomon
Hogan
08/16/07
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Author
Fig #
Title
ME
DE
Artist
Issue date
COLOR FIGURE
Draft 5
Braunstein
KMK
Gynecomastia, physical exam
09/20/07
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 nippleareolar complex is felt, whereas in patients
with pseudogynecomastia, no such disk of tissue is found.
1232
patient should undergo diagnostic mammogra-
phy, which has 90% sensitivity and specificity for
distinguishing 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 the
treatment of prostate cancer, spironolactone,
cimetidine, environmental estrogens or antian-
drogens, and one or more components of highly
active 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, can
damage the testes and result in primary hypogo-
nadism. Other drugs, including phenytoin and
metoclopramide, have also been associated with
gynecomastia, but a cause-and-effect relationship
has not been proved.
15
An adolescent presenting with gynecomastia
usually 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 persistent
gynecomastia, but this is the apparent cause in
a large proportion of young men in their late
teens or 20s presenting for evaluation. Other con-
ditions to consider in adolescents and young
adults with gynecomastia are Klinefelters syn-
drome, familial or sporadic excessive aromatase
activity, 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 or
tender, and if the patients history and physical
examination do not reveal the cause (Table 1),
hCG, luteinizing hormone, testosterone, and es-
tradiol should be measured (Fig. 3).
30
Many of the
available measurements of testosterone have poor
accuracy and precision, especially in men with
testosterone levels at the low end of the normal
range.
31
Measurement of these levels in the morn-
ing is recommended, since testosterone and
luteinizing hormone secretion have a circadian
rhythm (with the highest levels in the morning)
as well as secretory bursts throughout the day. If
the 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 of
patients.
Laboratory tests to determine the cause of
asymptomatic gynecomastia in an adult without
a history suggestive of an underlying pathologic
cause, 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 without
other evidence of disease is reassuring; thus,
many clinicians take a minimalist approach to
evaluation. Nevertheless, measurement of the
morning 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 of
a low free or bioavailable testosterone level and
an elevated luteinizing hormone level indicates
primary testicular failure, whereas a low free or
bioavailable testosterone level and a normal or
low luteinizing hormone level may indicate sec-
ondary hypogonadism.
Treatment
If a specific cause of gynecomastia can be identi-
fied and treated during the painful proliferative
phase, there may be regression of the breast en-
largement. This regression most often occurs with
discontinuation 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 month
after discontinuation of the drug. However, if
the gynecomastia has been present for more than
1 year, it is unlikely to regress substantially, either
spontaneously or with medical therapy, because of
the presence of fibrosis. In such circumstances,
surgical subcutaneous mastectomy, ultrasound-
clinical practice
1233
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 to
interpret 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 of
gynecomastia, the selective estrogen-receptor mod-
ulator tamoxifen, administered orally at a dose of
20 mg daily for up to 3 months, has been shown
to be effective in randomized and nonrandom-
ized trials, resulting in partial regression of gyne-
comastia in approximately 80% of patients and
complete regression in about 60%.
36-45
Patients in
whom tamoxifen is effective usually experience a
decrease in pain and tenderness within 1 month.
In a retrospective analysis of a series of patients
with idiopathic gynecomastia, 78% of patients
treated with tamoxifen had complete resolution
of gynecomastia, as compared with only 40% of
patients receiving danazol.
42
In case series describ-
ing the use of tamoxifen for this condition in
more 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; decreased
libido
Testicular mass or enlargement, contralateral testis with
some atrophy, signs of feminization
Germ-cell Testicular pain, enlargement, or both; symptoms
of metastases (e.g., back pain, hemoptysis)
Testicular mass
Adrenocortical Weight loss, decreased libido, possible symp-
toms of coexisting Cushings syndrome or
mineralocorticoid excess
Abdominal mass, signs of Cushings syndrome or mineralo-
corticoid excess (hypertension)
Ectopic hCG-secreting Weight loss; respiratory symptoms with lung
carcinoma; abdominal symptoms with hepa-
tocellular, gastric, or renal-cell carcinoma
Dependent on location of primary tumor and presence or
absence of metastases
Hypogonadism
Primary Decreased libido, erectile dysfunction, vasomotor
symptoms
Decreased testicular size, hard texture with Klinefelters
syndrome, 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 a
pituitary 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 weight
gain with ascites), edema, jaundice, pruritus
Jaundice, enlarged or shrunken liver, ascites, edema
Renal disease Anorexia, fatigue, nausea, vomiting, oliguria or
polyuria, pruritus, yellowish skin
Lethargy, asterixis, uremic hue, hypertension
Androgen insensitivity Decreased libido, infertility Possible hypospadias or ambiguity of genitalia, possible
neurologic findings (e.g., proximal muscle weakness
with fasciculations and tremor in X-linked spinal and
bulbar muscular atrophy)
Familial or sporadic aroma-
tase excess syndrome
None Prepubertal onset of gynecomastia; accelerated increase
in height in childhood, reduced final height; incom-
plete virilization
1234
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clinical practice
1235
tients
38
and a post-traumatic deep-vein thrombo-
sis in 1 patient.
43
The aromatase inhibitor anastrozole was not
shown to be more effective than placebo in a ran-
domized, double-blind, placebo-controlled trial in
boys with pubertal gynecomastia.
46
Although in
an uncontrolled study of 10 patients with puber-
tal gynecomastia, the selective estrogen-receptor
modulator raloxifene was shown to result in more
than 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 time.
44
It has also been suggested that therapy with
tamoxifen may prevent the development of gyne-
comastia in men receiving monotherapy with
high doses of bicalutamide (Casodex) for prostate
cancer. In a randomized, double-blind, controlled
trial involving men receiving high-dose bicaluta-
mide (150 mg per day),
47
gynecomastia occurred
in 10% of patients who received tamoxifen at a
dose of 20 mg daily, but it occurred in 51% of
those who received anastrozole at a dose of 1 mg
daily and in 73% of those who received placebo,
over a period of 48 weeks; mastalgia occurred in
6%, 27%, and 39% of these patients, respectively.
In another trial
48
involving 3 months of therapy,
gynecomastia, mastalgia, or both occurred in
69.4% of patients receiving placebo, 11.8% receiv-
ing tamoxifen (P<0.001 for the comparison with
placebo), and 63.9% receiving anastrozole (not
significantly different from the rate in the placebo
group). Another randomized trial showed efficacy
of a 10-mg dose of tamoxifen as prophylaxis
against gynecomastia. Among patients treated
with bicalutamide alone, gynecomastia occurred
in 68.6% and mastalgia occurred in 56.8%. These
rates were significantly lower among patients re-
ceiving one 12-Gy fraction of radiation therapy to
the breast on the first day of treatment with bi-
calutamide (34% and 30%, respectively), and they
were further reduced among patients receiving
bicalutamide and tamoxifen (8% and 6%, respec-
tively).
49
Although it has been used in men treated
for prostate cancer, tamoxifen is not approved by
the Food and Drug Administration for this indi-
cation.
Areas of Uncertainty
The high prevalence of asymptomatic gyneco-
mastia among older men raises the question of
whether it should be considered to be pathologic
or a part of the normal process of aging. It is
likely, but unproved, that many cases of asymp-
tomatic gynecomastia are due to the enhanced
aromatization of androgens in subareolar fat tis-
sue, resulting in high local concentrations of es-
trogens, as well as to the age-related decline in
testosterone production.
11,12,50
Another possible
cause is unrecognized exposure over time to un-
identified environmental estrogens or antian-
drogens.
18,19,21
There is no uniformity of opinion regarding
what biochemical evaluation, if any, should be
performed in a patient with asymptomatic gyne-
comastia. The diagnostic tests for patients with
symptomatic gynecomastia of recent onset for
which no cause is discerned on the basis of the
history or physical examination (Fig. 3) have a
low yield; however, a prospective costbenefit
analysis in this population has not been per-
formed. In a retrospective study of 87 men with
symptomatic gynecomastia, 16% had apparent
liver or renal disease, 21% had drug-induced gy-
necomastia, and 2% had hyperthyroidism, where-
as 61% were considered to have idiopathic gyne-
comastia. Forty-five of the 53 patients in the
group with idiopathic gynecomastia underwent
endocrine testing, of whom only 1 patient (2%)
was found to have an endocrine abnormality
an occult Leydig-cell testicular tumor.
51
Finally, since the excessive aromatization of
androgens to estrogens has been shown to be
present in many patients with gynecomastia, it is
unclear why aromatase inhibitors have not been
more successful in the treatment of these pa-
tients or in the prevention of the development of
gynecomastia in patients with prostate cancer
treated with antiandrogens.
Guidelines
No professional guidelines are available for the
management of gynecomastia.
Conclusions and
Recommendations
Asymptomatic gynecomastia is a relatively com-
mon finding on physical examination, and a care-
ful history taking and physical examination are
usually sufficient to identify pubertal gynecomas-
tia, drug-induced causes, or an underlying patho-
logic process, with the possible exception of mild
1236
hypogonadism. Pubertal gynecomastia resolves
with time in the majority of adolescent boys, and
reassurance and follow-up physical examination
usually suffice. In adults who present with the
acute onset of painful gynecomastia without an
obvious cause, hormonal evaluation, including
measurements of serum hCG, testosterone, lutein-
izing hormone, and estradiol levels, should be
performed in order to rule out serious and treat-
able causes, although serious disease is unlikely
in this setting. During the acute florid stage of
gynecomastia, a trial of tamoxifen, at a dose of
20 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-standing
gynecomastia who are troubled by their appear-
ance, surgical removal of the breast glandular
tissue and subareolar fat is an option that has a
good 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 and
luteinizing hormone levels, although even the use
of these tests might be debated
52
) is recommend-
ed, and treatment other than weight reduction is
not warranted for the gynecomastia.
Dr. Braunstein reports receiving consulting fees from Abbott
Diagnostics, Esoterix, M&P Pharma, and Novartis and research
funding from Procter & Gamble and BioSante. No other poten-
tial conflict of interest relevant to this article was reported.
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The Journals Web site (www.nejm.org) sorts published articles into
more 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.

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