The new engl and journal of medicine

clinical practice
Gynecomastia
Glenn D. Braunstein, M.D.
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.
During an evaluation for low back pain, a 67-year-old man is found to have
gynecomastia on the right side that is nontender on palpation. Other than
a body-mass index the weight in kilograms divided by the s!uare of the
height in meters" of #$, the physical examination is normal. %is medical
history is notable only for hyperlipidemia& his only medication is a statin.
%ow should his gynecomastia be evaluated and managed'
The Clinical Problem
!"#symptomatic gynecomastia, or enlargement o$ the glandular tissue o$ the
breast, is common in older men% it is $ound on e&amination in one third to two
thirds o$ men and at autopsy in '( to ))* o$ men.+!, The condition has usually
been present $or months or years when it is $irst disco-ered during a physical
e&amination. .istologic e&amination o$ the breast tissue in this setting usually
shows dilated ducts with periductal $ibrosis, stromal hyalini/ation, and increased
subareolar $at.+!, 0n contrast, patients who present with symptoms o$ pain and
tenderness generally ha-e gynecomastia o$ more recent onset, and pathological
$indings include hyperplasia o$ the ductal epithelium, in$iltration o$ the periductal
tissue with in$lammatory cells, and increased subareolar $at.
(The pathophysiological process o$ gynecomastia in-ol-es an imbalance
between $ree estrogen and $ree androgen actions in the breast tissue% this
imbalance can occur through multiple mechanisms 12ig. 3. During mid!to!late
puberty, relati-ely more estrogen may be produced by the testes and peripheral
tissues be$ore testosterone secretion reaches adult le-els, resulting in the
gynecomastia that commonly occurs during this period. The testes may directly
secrete too much estradiol $rom a 4eydig!cell or 5ertoli!cell tumor. They may
also secrete estradiol indirectly through the stimulatory e$$ects o$ a human
chorionic gonadotropin 1hCG36secreting tumor o$ gonadal or e&tragonadal germ!
cell origin 1also called eutopic hCG production3 or a tumor deri-ed $rom a
nontrophoblastic tissue, such as a large!cell carcinoma o$ the lung or some
gastric or renal!cell carcinomas 1also called ectopic hCG production3. 0n addition,
the testes may secrete too little testosterone% this occurs in primary or secondary
hypogonadism. The pre-alence o$ these conditions increases with ad-anced
age, and one study indicated that )(* o$ men in their "(s ha-e a low $ree
testosterone concentration.
7#n adrenal neoplasm may o-erproduce the wea8 androgen androstenedione
and other androgen precursors such as dehydroepiandrosterone, which are
con-erted into estrogens in peripheral tissues. #n increase in aromatase acti-ity
has been reported in a number o$ patients with gynecomastia associated with a
-ariety o$ disease processes, including thyroto&icosis, 9line$elter:s syndrome,
and adrenal and testicular tumors. #romatase acti-ity increases both with age
and with an increase
n engl j med
;)"%7
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september 7(,
7(("
The New England Journal of Medicine 2rom the
Department o$ Medicine, Cedars6 5inai Medical
Center, 4os #ngeles. #ddress reprint re<uests to Dr.
Braunstein at the Department o$ Medicine, =m. 7,
Pla/a 4e-el, Cedars65inai Medical Center, >"((
Be-erly Bl-d., 4os #ngeles, C# ,(('>, or at
braunstein?cshs.org.
@ Angl J Med 7(("%;)"B77,!;".
Copyright 2! "assachusetts "edical #ociety.
77
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( Both bind to se& hormone6binding globulin and, to a lesser e&tent, albumin, and a small amount o$ each
hormone circulates in the $ree state. The $ree and albumin!bound steroids 1the Gbioa-ailableH $raction3 enter
e&tragonadal tissues, many o$ which contain the aromatase en/yme comple&, which con-erts some o$ the
testosterone to estradiol. This en/yme comple& also con-erts androstenedione o$ adrenal origin to estrone,
which may be $urther con-erted to the more potent estrogen estradiol through the action o$ "I!
hydro&ysteroid dehydrogenase. The bioa-ailable testosterone, estradiol, and estrone, deri-ed $rom direct
glandular secretion and e&traglandular production, enter target tissues, where they bind to their respecti-e
receptors and initiate gene acti-ation and transcription. 0n addition, some o$ the testosterone is con-erted to
the more potent metabolite dihydrotestosterone through the action o$ )a!reductase. Dihydrotestosterone
binds to the same androgen receptors as testosterone. Multiple processes can alter the pathways o$
estrogen and androgen production and action, resulting in gynecomastia $rom an enhanced estrogen e$$ect
or a diminished androgen e$$ect at the target!tissue le-el. 2igure was modi$ied $rom Mathur and Braunstein.
',)in body $at. 5ince body $at also increases
with age, it is li8ely that a physiologic
increase in the acti-ity o$ the aromatase
en/yme comple& with normal aging is
responsible $or many cases o$ asymptomatic
gynecomastia in older men. 0ndeed, there is
a progressi-e increase in the pre-alence o$
gynecomastia with an increase o$ the
bodymass inde&, probably re$lecting the local
paracrine e$$ects o$ estradiol production in
the subareolar $at on the breast glandular
tissue.
5ince estradiol and estrone bind less
a-idly to se& hormone6binding globulin
than does testosterone, drugs such as
spironolactone may displace relati-ely
more estrogen than testosterone $rom this
protein, increasing the bioa-ailable $raction
o$ estrogen to a greater e&tent than
bioa-ailable androgen. 5imilarly, an
increase in the se& hormone6binding
globulin concentration, which occurs with
hyperthyroidism and some $orms o$ li-er
disease, may be associated with greater
binding o$ testosterone relati-e to
estrogen, leading to a decrease in $ree
testosterone relati-e to $ree estrogen.
#ndrogen!receptor abnormalities, either
due to a genetic de$ect or bloc8ade by an
antagonist such as bicalutamide or due to
stimulation o$ the estrogen receptor by
medications or en-ironmental estrogens,
may also result in gynecomastia
.
7
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3ynecomastia Other disorders cancer
"=ubbery or $irm mass
Concentric mass
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Mass outside the areola
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The new engl and journal of medicine

'patient should undergo diagnostic
mammography, which has ,(* sensiti-ity
and speci$icity $or distinguishing malignant
$rom benign breast diseases.
* v a l u at i o n
)!7)Cnce the diagnosis o$ gynecomastia is
established, it is important to re-iew all
medications, including o-er!the!counter
drugs such as herbal products, that may be
associated with gynecomastia. 0ngestion o$
se& steroid hormones or their precursors
may cause gynecomastia through
biocon-ersion to estrogens. #ntiandrogens
used $or the treatment o$ prostate cancer,
spironolactone, cimetidine, en-ironmental
estrogens or antiandrogens, and one or
more components o$ highly acti-e anti-iral
therapy used $or human immunode$iciency
-irus in$ection 1especially protease inhibitors3
ha-e been clearly shown to be associated
with gynecomastia.) 5e-eral cancer
chemotherapeutic drugs, particularly
al8ylating agents, can damage the testes
and result in primary hypogonadism. Cther
drugs, including phenytoin and
metoclopramide, ha-e also been associated
with gynecomastia, but a cause!and!e$$ect
relationship has not been pro-ed.
7+!7>#n adolescent presenting with
gynecomastia usually has physiologic
pubertal gynecomastia, which generally
appears at ; or ' years o$ age, lasts $or +
months or less, and then regresses. 4ess
than )* o$ a$$ected boys ha-e persistent
gynecomastia, but this is the apparent cause
in a large proportion o$ young men in their
late teens or 7(s presenting $or e-aluation.
Cther conditions to consider in adolescents
and young adults with gynecomastia are
9line$elter:s syndrome, $amilial or sporadic
e&cessi-e aromatase acti-ity, incomplete
androgen insensiti-ity, $emini/ing testicular or
adrenal tumors, and hyperthyroidism.7, Drug
abuse, especially with anabolic steroids, but
also with alcohol, marijuana, or opioids, also
should be considered.ing is recommended,
since testosterone and luteini/ing hormone
secretion ha-e a circadian rhythm 1with the
highest le-els in the morning3 as well as
secretory bursts throughout the day. 0$ the
total testosterone le-el is borderline or low,
$ree or bioa-ailable testosterone should be
measured or calculated to con$irm
hypogonadism. #lthough such laboratory
e-aluation is prudent, no abnormalities are
detected in the majority o$ patients.
4aboratory tests to determine the cause o$
asymptomatic gynecomastia in an adult
without a history suggesti-e o$ an underlying
pathologic cause, with an otherwise normal
physical e&amination, are unli8ely to be
re-ealing, and the e&tent o$ hormonal
e-aluation that should be per$ormed in such
patients remains contro-ersial. The li8elihood
o$ disco-ering a pathologic abnormality is
low in patients with long!standing
asymptomatic gynecomastia in the $ibrotic
stage, and the long duration o$ the condition
without other e-idence o$ disease is
reassuring% thus, many clinicians ta8e a
minimalist approach to e-aluation.
@e-ertheless, measurement o$ the morning
testosterone le-el and $ree or bioa-ailable
testosterone and luteini/ing hormone le-els,
i$ the morning testosterone le-el is low, is
reasonable to detect hypogonadism, which is
increasingly common with ad-anced age. #
$inding o$ a low $ree or bioa-ailable
testosterone le-el and an ele-ated luteini/ing
hormone le-el indicates primary testicular
$ailure, whereas a low $ree or bioa-ailable
testosterone le-el and a normal or low
luteini/ing hormone le-el may indicate
secondary hypogonadism.
+ r e at m e n
t;(0$ an adolescent or adult presents with
unilateral or bilateral gynecomastia that is
pain$ul or tender, and i$ the patient:s history
and physical e&amination do not re-eal the
cause 1Table 3, hCG, luteini/ing hormone,
testosterone, and estradiol should be
measured 12ig. ;3.; Many o$ the a-ailable
measurements o$ testosterone ha-e poor
accuracy and precision, especially in men
with testosterone le-els at the low end o$
the normal range. Measurement o$ these
le-els in the morn!0$ a speci$ic cause o$
gynecomastia can be identi$ied and
treated during the pain$ul proli$erati-e
phase, there may be regression o$ the
breast enlargement. This regression most
o$ten occurs with discontinuation o$ an
o$$ending drug or a$ter initiation o$
testosterone treatment $or primary
hypogonadism. 0$ the gynecomastia is
drug!induced, decreased tenderness and
so$tening o$ the glandular tissue will
usually be apparent within month a$ter
discontinuation o$ the drug. .owe-er, i$ the
gynecomastia has been present $or more
than year, it is unli8ely to regress
substantially, either spontaneously or with
medical therapy, because o$ the presence
o$ $ibrosis. 0n such circumstances, surgical
subcutaneous mastectomy, ultrasound!
7;7
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jm.org
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+a b l e 0 . (igns and (ymptoms of 4athologic 4rocesses +hat 5ause 3ynecomastia.
5ondition (ymptoms (igns +umor
Testicular 4eydig!cell or 5ertoli!cell Testicular pain, enlargement, or both% decreased libido Testicular mass or
enlargement, contralateral testis with some atrophy, signs o$ $emini/ation Germ!cell Testicular pain,
enlargement, or both% symptoms o$ metastases 1e.g., bac8 pain, hemoptysis3 Testicular mas
s#drenocortical Jeight loss, decreased libido, possible
symptoms o$ coe&isting Cushing:s syndrome or
mineralocorticoid e&cess
Actopic hCG!secreting Jeight loss% respiratory
symptoms with lung carcinoma% abdominal
symptoms with hepatocellular, gastric, or renal!
cell carcinoma#bdominal mass, signs o$
Cushing:s syndrome or mineralocorticoid
e&cess 1hypertension3
Dependent on location o$ primary tumor and
presence or absence o$ metastases
-ndrogen insensitivity Decreased libido, in$ertility Possible hypospadias or ambiguity o$ genitalia, possible
neurologic $indings 1e.g., pro&imal muscle wea8ness with $asciculations and tremor in K!lin8ed spinal and bulbar
muscular atrophy3
/amilial or sporadic
aroma- tase excess
syndrome@one Prepubertal onset o$ gynecomastia% accelerated increase in height in
childhood, reduced $inal height% incomplete -irili/ation
5econdary Decreased libido, erectile dys$unction, symptoms
o$ other pituitary hormone de$iciency, headache, -isual
symptoms
%yperthyroidism Jeight loss, palpitations, increased
sweating, increased $re<uency o$ de$ecation, ner-ousness,
insomnia, heat intolerance
6iver disease #nore&ia, nausea, -omiting, weight loss 1or
weight gain with ascites3, edema, jaundice, pruritus
1enal disease #nore&ia, $atigue, nausea,
-omiting, oliguria or polyuria, pruritus,
yellowish s8inDecreased testicular si/e%
possible -isual!$ield cuts $rom a pituitary or
parasellar tumor% signs o$ hypothyroidism,
e&cess or de$iciency o$ growth hormone%
galactorrhea 1rare3
Goiter, tremor, tachycardia, upper!eyelid
retraction
Jaundice, enlarged or shrun8en li-er, ascites,
edema
4ethargy, asteri&is, uremic hue, hypertensio

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clinical practice
;>tients'; and a post!traumatic deep!-ein
thrombosis in patient.
'+The aromatase inhibitor anastro/ole was
not shown to be more e$$ecti-e than placebo
in a randomi/ed, double!blind, placebo!
controlled trial in boys with pubertal
gynecomastia.'' #lthough in an uncontrolled
study o$ ( patients with pubertal
gynecomastia, the selecti-e estrogen!
receptor modulator ralo&i$ene was shown to
result in more than a )(* decrease in the
si/e o$ the gynecomastia in the majority o$
the boys, there are insu$$icient data to
recommend its use at this time.
'"0t has also been suggested that therapy
with tamo&i$en may pre-ent the de-elopment
o$ gynecomastia in men recei-ing
monotherapy with high doses o$ bicalutamide
1Casode&3 $or prostate cancer. 0n a
randomi/ed, double!blind, controlled trial
in-ol-ing men recei-ing high!dose
bicalutamide 1)( mg per day3,'>
gynecomastia occurred in (* o$ patients
who recei-ed tamo&i$en at a dose o$ 7( mg
daily, but it occurred in )* o$ those who
recei-ed anastro/ole at a dose o$ mg daily
and in ";* o$ those who recei-ed placebo,
o-er a period o$ '> wee8s% mastalgia
occurred in +*, 7"*, and ;,* o$ these
patients, respecti-ely. 0n another trial',
in-ol-ing ; months o$ therapy, gynecomastia,
mastalgia, or both occurred in +,.'* o$
patients recei-ing placebo, .>* recei-ing
tamo&i$en 1PL(.(( $or the comparison with
placebo3, and +;.,* recei-ing anastro/ole
1not signi$icantly di$$erent $rom the rate in the
placebo group3. #nother randomi/ed trial
showed e$$icacy o$ a (!mg dose o$
tamo&i$en as prophyla&is against
gynecomastia. #mong patients treated with
bicalutamide alone, gynecomastia occurred
in +>.+* and mastalgia occurred in )+.>*.
These rates were signi$icantly lower among
patients recei-ing one 7!Gy $raction o$
radiation therapy to the breast on the $irst
day o$ treatment with bicalutamide 1;'* and
;(*, respecti-ely3, and they were $urther
reduced among patients recei-ing
bicalutamide and tamo&i$en 1>* and +*,
respecti-ely3. #lthough it has been used in
men treated $or prostate cancer, tamo&i$en is
not appro-ed by the 2ood and Drug
#dministration $or this indication.
#reas o$ Dncertainty
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The high pre-alence o$ asymptomatic
gynecomastia among older men raises the
<uestion o$ whether it should be considered
to be pathologic ,7,)(or a part o$ the normal
process o$ aging. 0t is li8ely, but unpro-ed,
that many cases o$ asymptomatic
gynecomastia are due to the enhanced
aromati/ation o$ androgens in subareolar $at
tissue, resulting in high local concentrations
o$ estrogens, as well as to the age!related
decline in testosterone production.>,,,7
#nother possible cause is unrecogni/ed
e&posure o-er time to unidenti$ied
en-ironmental estrogens or antiandrogens.
)There is no uni$ormity o$ opinion regarding
what biochemical e-aluation, i$ any, should
be per$ormed in a patient with asymptomatic
gynecomastia. The diagnostic tests $or
patients with symptomatic gynecomastia o$
recent onset $or which no cause is discerned
on the basis o$ the history or physical
e&amination 12ig. ;3 ha-e a low yield%
howe-er, a prospecti-e cost6bene$it analysis
in this population has not been per$ormed. 0n
a retrospecti-e study o$ >" men with
symptomatic gynecomastia, +* had
apparent li-er or renal disease, 7* had
drug!induced gynecomastia, and 7* had
hyperthyroidism, whereas +* were
considered to ha-e idiopathic gynecomastia.
2orty!$i-e o$ the ); patients in the group with
idiopathic gynecomastia underwent
endocrine testing, o$ whom only patient
17*3 was $ound to ha-e an endocrine
abnormality M an occult 4eydig!cell
testicular tumor.
2inally, since the e&cessi-e aromati/ation
o$ androgens to estrogens has been shown
to be present in many patients with
gynecomastia, it is unclear why aromatase
inhibitors ha-e not been more success$ul in
the treatment o$ these patients or in the
pre-ention o$ the de-elopment o$
gynecomastia in patients with prostate
cancer treated with antiandrogens.
Guidelines
@o pro$essional guidelines are a-ailable $or
the management o$ gynecomastia.
Conclusions and
=ecommendations
#symptomatic gynecomastia is a relati-ely
common $inding on physical e&amination,
and a care$ul history ta8ing and physical
e&amination are usually su$$icient to
identi$y pubertal gynecomastia, drug!
induced causes, or an underlying
pathologic process, with the possible
e&ception o$ mild
n engl j med ;)"%7 www.nejm.org september 7(, 7(("
The New England Journal of Medicine
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The new engl and journal of medicine
hypogonadism. Pubertal gynecomastia
resol-es with time in the majority o$
adolescent boys, and reassurance and
$ollow!up physical e&amination usually
su$$ice. 0n adults who present with the acute
onset o$ pain$ul gynecomastia without an
ob-ious cause, hormonal e-aluation,
including measurements o$ serum hCG,
testosterone, luteini/ing hormone, and
estradiol le-els, should be per$ormed in order
to rule out serious and treatable causes,
although serious disease is unli8ely in this
setting. During the acute $lorid stage o$
gynecomastia, a trial o$ tamo&i$en, at a dose
o$ 7( mg per day $or up to ; months, may be
attempted. 0$ the gynecomastia has not
regressed by year, or in patients who
present with long!standing gynecomastia
who are troubled by their appear!)7ance,
surgical remo-al o$ the breast glandular
tissue and subareolar $at is an option that
has a good cosmetic result in the majority o$
patients. 2or a patient such as the man in the
-ignette, who is asymptomatic, is not
bothered by his gynecomastia, and does not
ha-e a suggesti-e history or physical
e&amination, a more minimalist e-aluation
1i.e., measurements o$ testosterone and
luteini/ing hormone le-els, although e-en the
use o$ these tests might be debated3 is
recommended, and treatment other than
weight reduction is not warranted $or the
gynecomastia.
Dr. Braunstein reports recei-ing consulting $ees $rom
#bbott Diagnostics, Asoteri&, MNP Pharma, and
@o-artis and research $unding $rom Procter N
Gamble and Bio5ante. @o other potential con$lict o$
interest rele-ant to this article was reported
.0.1 e f e r e n c e s @uttall 2O.
Gynecomastia as a physi!
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med ;)"%7 www.nejm.org september 7(, 7(("
The New England Journal of Medicine
Downloaded from nejm.org on July 2, 2014. For er!onal u!e only. No o"her u!e! wi"hou"
ermi!!ion.
#oyrigh" $ 200% Ma!!achu!e""! Medical &ocie"y. 'll righ"! re!er(ed.

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Copyright 2! "assachusetts "edical
#ociety
.collections of articles on the j o u r n a l @s web site
The $ournal:s Jeb site 1www.neAm.org3 sorts published
articles into more than )( distinct clinical collections, which
can be used as con-enient
entry points to clinical content. 0n each collection, articles are
cited in re-erse chronologic order, with the most recent $irst.
n engl j
med ;)"%7
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org
september
7(, 7(("
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