Download Gynecomastia

Gynecomastia
Question

24 year-old male presents to PCP for painless
enlargement of breasts for past six months


No past medical history, medications, or supplements


Social ETOH use – less than 5 drinks per week
Exam:




Gradual onset without discharge or pain
BMI: 31
Breast – bilateral retro-areolar rubbery mass
Testicular – No masses, tenderness; normal size
Evaluation:



LH –
Testosterone –
TSH -
4.8 mIU/ml
482 ng/dl
0.52 mIU/ml
(NML 1.5-9.3 mIU/ml)
(NML 241/827 ng/dl)
(NML 0.4-5.5 mIU/ml)
What is the next step?
A)
B)
C)
D)
E)
Observation – this will likely regress
Referral for elective surgery – patient
has cosmetic concerns regarding breasts
Trial of tamoxifen for six months
Encourage weight loss and ETOH
avoidance with follow-up
Work-up is not complete – continue
evaluation
Take Home Points



Gynecomastia may be a transient complaint, or
the only manifestation of a fatal disease
Gynecomastia requires a thorough
investigation for cause; including
hormonal evaluation if indicated
Treatment of gynecomastia is cause specific
Definition

Clinical:


Pathologic:


Rubbery or firm mass extending concentrically
from the nipple
Benign proliferation of the glandular tissue of
the male breast
Pseudo-gynecomastia

Fat deposition without glandular proliferation
Histology

Initial:
1) Ductal epithelial
hyperplasia
2) Proliferation of periductal
inflammatory cells
3) Periductal fibroblastic
proliferation.

Normal male breast
Late (after >12 month):
1) Increased number of ducts
with dilatation
2) No epithelial cell
proliferation
3) Increased fibrosis
Early gynecomastia
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Epidemiology

Common at birth


Second peak in puberty




Found in up to 60 - 90% of male infants
Estimated at 4-69% of males
Most common ages 11-12 (Tanner 3)
Uncommon after age 17
Highest peak ages > 50

Estimated 24-65% of men affected
Braunstein G. N Engl J Med 1993;328:490-495
Braunstein G. N Engl J Med 1993;328:490-495
Prevalence of gynecomastia from multiple population studies
Braunstein. Gynecomastia. In: Diseases of the Breast. Harris,
Lippincott-Raven, Philadelphia 1996. p. 54.
Steroid Pathways
Pathophysiology
Braunstein G. N Engl J Med 1993;328:490-495
Etiologies





Persistent pubertal gynecomastia
Medications
Idiopathic
Cirrhosis or malnutrition
Hypogonadism:





Hypergonadotropic
Hypogonadotropic
Testicular tumors
Hyperthyroidism
Chronic renal insufficiency
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
25%
10 - 25%
25%
8%
8%
2%
3%
1.5%
1%
Persistent Pubertal Gynecomastia

Usually occurs age
11-12 (Tanner 3)



Initial estradiol surge
at puberty
Followed by
testosterone surge
Persists up to two
years in 25%
Hands, L. Gynaecomastia. Br. J. Surg. 1991, 78:907-911
Etiologies





Persistent pubertal gynecomastia
Medications
Idiopathic
Cirrhosis or malnutrition
Hypogonadism:





Hypergonadotropic
Hypogonadotropic
Testicular tumors
Hyperthyroidism
Chronic renal insufficiency
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
25%
10 - 25%
25%
8%
8%
2%
3%
1.5%
1%
Medications
Braunstein G. N Engl J Med
1993;328:490-495
Spironolactone


Symptoms in almost every male at doses of 100
mg/day
Small study of six patients on spironolactone
with gynecomastia compared to control patients

Spironolactone patients had significantly lower
testosterone and higher estradiol (p<0.01)



Androgen receptor antagonist
Increased peripheral aromatization to estradiol
Decreased testosterone production
Rose, L. Ann Intern Med 1977;87:398-403
Spironolactone

Randomized Aldactone Evaluation Study (RALES)

Evaluate spironolactone in heart failure




Double-blind, placebo controlled with 1663 patients included in
study
Spironolactone or placebo at 25 – 50 mg daily
Trial stopped early due to significant reduction in cardiovascular
mortality
Gynecomastia



Treatment group - 9% (p<0.001)
Placebo group - 1%
In a second study, epleronone, a selective aldosterone
antagonist, had equal incidence of gynecomastia as
placebo in over 6500 patients
Pitt, B et. Al. NEJM 1999;341:709-17; NEJM 2003;348:1309-21
Anti-Ulcer Medications


Many case reports of gynecomastia related to
anti-histamine and proton pump inhibitor
medications
Open cohort study from UK – 1989-92

Evaluated 81,535 men aged 25-84 given prescription
for cimetidine, omeprazole, or ranitidine


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Omeprazole and ranitidine had no increased risk of
gynecomastia
Cimetidine had significant increased risk for gynecomastia
(RR 7.2)
Noted verapamil RR 9.7 and spironolactone RR 9.3
Rodriquez, LA. “Risk of gynaecomastia associated with cimetidine, opeprazole, and other antiulcer drugs”. BMJ 1994;308:503-6
Anti-Androgen Medications

Flutamide, bicalutamide, nilutamide


Used commonly in prostate cancer to
suppress androgen stimulation of cancer
Bind to androgen receptors to block
testosterone and DHT response


Excess testosterone aromatized to estradiol
Finasteride

5-alpha reductase inhibitor

Blocks conversion of testosterone to DHT
Drugs

Other well described
association:

ETOH

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Marijuana



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Inhibition of H-P-T axis as well as
direct testicular toxicity
Androgen receptor antagonist
Tree oils and lotions
Any estrogen containing creams
HAART


More commonly pseudogynecomastia
Lipodystrophy also possible
Warren, S. “Lipodystrophy” NEJM 2005;352:62
Etiologies





Persistent pubertal gynecomastia
Medications
Idiopathic
Cirrhosis or malnutrition
Hypogonadism:





Hypergonadotropic
Hypogonadotropic
Testicular tumors
Hyperthyroidism
Chronic renal insufficiency
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
25%
10 - 25%
25%
8%
8%
2%
3%
1.5%
1%
Idiopathic/Obesity/Normal Aging


Androgen Insensitivity
Aromatase excess


Due to excess adipose
tissue
Hereditary aromatase
excess
Idiopathic/Obesity/Normal Aging
Braunstein, Glenn. “Aromatase and Gynecomastia”. Endocrine-Related Cancer 1999;6:315-24
Etiologies





Persistent pubertal gynecomastia
Medications
Idiopathic
Cirrhosis or malnutrition
Hypogonadism:





Hypergonadotropic
Hypogonadotropic
Testicular tumors
Hyperthyroidism
Chronic renal insufficiency
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
25%
10 - 25%
25%
8%
8%
2%
3%
1.5%
1%
Cirrhosis/Starvation

Several mechanisms:



Decreased clearance of androgens leading to
increased conversion to estrogen
Increased sex hormone binding globulin
(SHBG) decreasing free testosterone
Decreased testosterone production
Etiologies





Persistent pubertal gynecomastia
Medications
Idiopathic
Cirrhosis or malnutrition
Hypogonadism:





Hypergonadotropic
Hypogonadotropic
Testicular tumors
Hyperthyroidism
Chronic renal insufficiency
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
25%
10 - 25%
25%
8%
8%
2%
3%
1.5%
1%
Hypergonadotropic Hypogonadism

Predominance of adrenal
androgens with peripheral
conversion to estradiol

Congenital:




Klinefelter’s Syndrome
Cryptorchidism
Myotonic dystrophy and other rare
androgen receptor disorders
Acquired:


Drugs
Viral or traumatic injury



HIV and mumps
Radiation injury
Chronic illness


Hemochromatosis
Autoimmune disease
Bagatell, C. Androgens in Men – Uses and Abuses.
NEJM 1996;334:707-14
Hypogonadotropic Hypogonadism


Predominance of
adrenal
androgens
Testicular
estradiol
production may
persist
Etiologies





Persistent pubertal gynecomastia
Medications
Idiopathic
Cirrhosis or malnutrition
Hypogonadism:





Hypergonadotropic
Hypogonadotropic
Testicular tumors
Hyperthyroidism
Chronic renal insufficiency
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
25%
10 - 25%
25%
8%
8%
2%
3%
1.5%
1%
Testicular Neoplasm

Germ cell cancers (95% of testicular cancer) are
associated with gynecomastia in 2.5-6%

Most common with elevated hCG from choriocarcinoma



Incidence of gynecomastia is 20-30% with Leydig cell
cancers (2% of all testicular cancers)


hCG stimulates aromatase in Leydig cells
Poor prognostic indicator – 50% mortality rate in small case series
of cases
Leydig cells produce high levels of estradiol
Commonly occurs after treatment of testicular cancer
due to hypergonadotropic hypogonadism

Does not change prognosis if symptoms occur after treatment
Tseng, A. “Gynecomastia in testicular cancer patients. Prognostic and therapeutic
implications.” Cancer 1985; 56:2534.
Etiologies





Persistent pubertal gynecomastia
Medications
Idiopathic
Cirrhosis or malnutrition
Hypogonadism:





Hypergonadotropic
Hypogonadotropic
Testicular tumors
Hyperthyroidism
Chronic renal insufficiency
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
25%
10 - 25%
25%
8%
8%
2%
3%
1.5%
1%
Thyrotoxicosis

Multiple pathways:



Increased Sex
Hormone Binding
Globulin (SHBG)
Increased
androstenedione
production rates
Increased peripheral
aromatization of
testosterone to
estradiol
Pearlman, G. The Endocrinologist 2006;16:109-15
Etiologies





Persistent pubertal gynecomastia
Medications
Idiopathic
Cirrhosis or malnutrition
Hypogonadism:





Hypergonadotropic
Hypogonadotropic
Testicular tumors
Hyperthyroidism
Chronic renal insufficiency
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
25%
10 - 25%
25%
8%
8%
2%
3%
1.5%
1%
Renal Failure

Similar mechanism to starvation


Decreased testicular function preceding
dialysis
Increased hormone production after initiating
dialysis with increased estrogens first
Review:
Etiologies of Gynecomastia
Braunstein G. N Engl J Med 1993;328:490-495
www.cbsnews.com
Differential Diagnosis



Pseudo-gynecomastia
Breast cancer
Lipoma or cyst
Hannekin, S. Ann Int Med 2004;140:497-98
Evaluation

History and Physical Exam Including:




Onset and duration of symptoms
Detailed medication history
Evaluation for evidence of other systemic disease
Physical exam focus:





Body habitus, body mass index
Bilateral breast exam
Testicular exam: Size, masses
Hair distribution
Thyroid exam
Braunstein, Glenn. Gynecomastia. NEJM 2007;357:1229-35
Evaluation

Red flags:






New onset
No risk factors or common medications
Young, post-puberty
Painful
Hard nodule
Nipple discharge
Hormonal Evaluation


Indicated if no obvious cause for
symptoms on history and physical
Laboratory evaluation:





LH
hCG
Testosterone (including free fraction)
Estradiol
TSH
Elevated hCG = cancer
Low testosterone = hypogonadism
High estradiol = cancer or aromatase
Braunstein G. N Engl J Med 1993;328:490-495
Radiographic Evaluation


Consider testicular ultrasound
Mammogram to evaluate for cancer:
Klinefelter’s Syndrome
 Family history of male breast cancer
 Suspicious mass


Ultrasound effective to diagnose pseudogynecomastia
Appelbaum, AH. Scientific Exhibit 1999;19:599-68
Mammography

In experienced
centers:



Gynecomastia can be
diagnosed
Suspicious nodular
findings must be
evaluated with biopsy
Overlap between
malignant and benign
limit utility
Appelbaum, AH. Scientific Exhibit 1999;19:599-68
Treatment
Treatment

Cause specific:





Stop offending medications
Weight loss
Alcohol cessation
Treatment of underlying disorder
Most idiopathic cases will resolve or regress
within six months
Treatment

Medical therapy

No FDA approved treatment currently
Testosterone therapy if indicated for
hypogonadism
 Increased conversion to estradiol may worsen
symptoms



Anti-estrogen therapy: Tamoxifen or
clomiphene
Aromatase inhibitor therapy: anastrozole
Anti-estrogen Therapy

Tamoxifen in adolescents



No double-blind placebo controlled studies
Retrospective review of 14 patients found reduction in
breast size, but 40% still went to surgery
Tamoxifen in prostate cancer



Somewhat effective in treating the gynecomastia
induced by anti-androgen treatment
Decreased breast tenderness and slight reduction in
size
No adverse events or increase cancer risk on therapy
Staiman VR. ”Tamoxifen for flutamide/finasteride-induced gynecomastia.” Urology 1997;50:929-933
Lawrence, SE. “Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal
gynecomastia.” J Pediatr 2004; 145:71.
Aromatase Inhibitor

Double-blind, placebo controlled study of
87 male patients aged 11-18 years-old

Treated with anastrozole (Arimidex) 1mg daily


Primary endpoint >50% reduction in breast
volume
No significant difference between groups after
6 months of treatment

Primary endpoint met in 38% of treatment arm
and 31% of placebo arm (p=0.47)
Plourde, P. J Clin Endocrinol Metab 2004;89:4428-33
Gynecomastia in Prostate Cancer

Double-blind, placebo controlled study of
114 patient treated with bicalutamide
(Casodex) for advanced prostate cancer


Prophylactic treatment with placebo,
tamoxifen, or anastrozole
Assessed with clinical exam, ultrasound, and
calipers
Boccardo, F. J Clin Onc 2005;23:808-15
Gynecomastia in Prostate Cancer
Tamoxifen group
Boccardo, F. J Clin Onc 2005;23:808-15
Recommendations

Adolescents


If negative work-up and persistent severe symptoms,
a brief three month trial of tamoxifen 10 mg daily can
be considered (3C)
Adults (including prostate cancer patients)



If negative work-up and persistent severe symptoms,
a three to six month trial of tamoxifen may be
considered (3C)
Aromatase inhibitors are not recommended (2B)
If persistently troublesome for >1 year, surgical
intervention may be considered (2B)
Braunstein, Glenn. Uptodate.com
Surgery

Consider surgical options:




After 12 months of symptoms
For pain or emotional distress
When unable to correct underlying condition
Low complication risk when performed at
experienced center
Take Home Points



Gynecomastia may be a transient complaint, or
the only manifestation of a fatal disease
Gynecomastia requires a thorough
investigation for cause; including
hormonal evaluation if indicated
Treatment must address the cause
References












Appelbaum, AH. “Mammographic Appearances of Male Breast Disease.” Scientific
Exhibit 1999;19:599-68
Bagatell, C. “Androgens in Men – Uses and Abuses”. NEJM 1996;334:707-14
Braunstein, Glenn. “Gynecomastia”. NEJM 2007;357:1229-35
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95
Braunstein, Glenn. “Aromatase and Gynecomastia”. Endocrine-Related Cancer
1999;6:315-24
Carlson, H. “Gynecomastia”. NEJM 1980;303:795-99
Boccardo, F. “Evaluation of Tamoxifen and Anastrozole in the Prevention of
Gynecomastia and Breast Pain Induced byBicalutamide Monotherapy of Prostate
Cancer.” J Clin Onc 2005;23:808-15
Hands, L. “Gynaecomastia”. Br. J. Surg. 1991; 78:907-11
Harlan, WR “Secondard sex characteristics of boys 12-17 years of age; the U.S. Health
Examination Survey.” J Pediatrics 1979;95:293-97
Hannekin, S. “Unilateral Pseudogynecomastia: A Novel Work-Related Disease.” Ann
Int Med 2004;140:497-98
Hirshberg, B. “Ectopic LH Secretion and Anovulation”. NEJM 2003;348:312-17
Larsen: Williams Textbook of Endocrinology, 10th ed
References













Lawrence, SE. “Beneficial effects of raloxifene and tamoxifen in the treatment of
pubertal gynecomastia.” J Pediatr 2004; 145:71.
Mignon, M. “Gynaecomastia and H2 antagonists.” Lancet 1982;ii:499
Nydick M. “Gynecomastia in adolescent boys.” JAMA 1961; 178:449–454
Pearlman, G. “Gynecomastia, An Update.” The Endocrinologist 2006;16:109-15
Pitt, B et. Al. “The effect of spironolactone on morbidity and mortality in patients with
severe heart failure.” NEJM 1999;341:709-17
Pitt, B et. Al. “Eplerenone, a selective aldosterone blocker, in patients with left
ventricular dysfunction after myocardial infarction .” NEJM 2003;348:1309-21
Plourde, P. “Saftery and Efficacy of Anastrozole for the Treatment of Pubertal
Gynecomastia.” J Clin Endocrinol Metab 2004;89:4428-33
Rodriquez, LA. “Risk of gynaecomastia associated with cimetidine, opeprazole, and
other antiulcer drugs”. BMJ 1994;308:503-6
Rose, L. “Pathophysiology of spironolactone-induced gynecomastia.” Ann Intern Med
1977;87:398-403
Scully, R. “Case Records”. NEJM 2000; 342:1196-1204
Staiman VR. ”Tamoxifen for flutamide/finasteride-induced
gynecomastia.” Urology 1997;50:929-933
Tseng, A. “Gynecomastia in testicular cancer patients. Prognostic and therapeutic
implications.” Cancer 1985; 56:2534.
UpToDate.com