2. Gynecomastia
Table 1. Causes of Gynecomastia
Table 2. Mechanism of Effect of Agents
Commonly Associated with Gynecomastia
Cause
Frequency (%)
Physiologic gynecomastia
Idiopathic or unknown cause
Medication or substance use (Table 2)
Cirrhosis
Primary hypogonadism
5α-reductase deficiency
Androgen insensitivity syndrome
Congenital anorchia
Hemochromatosis
Klinefelter syndrome
Testicular torsion
Testicular trauma
Viral orchitis
Tumors
Adrenal tumors
Gastric carcinoma producing hCG
Large cell lung cancer producing hCG
Pituitary tumors
Renal cell carcinoma producing hCG
Testicular tumors, particularly Leydig or
Sertoli cell tumors
Secondary hypogonadism
Kallmann syndrome
Hyperthyroidism
Chronic renal insufficiency
Other
Familial gynecomastia
Human immunodeficiency virus
Malnutrition and disorders of impaired
absorption (e.g., ulcerative colitis,
cystic fibrosis)
25
25
10 to 25
8
8
3
2
2
1
6
hCG = human chorionic gonadotropin.
Adapted with permission from Derkacz M, Chmiel-Perzynska I, Nowakowski A. Gynecomastia—a difficult diagnostic problem. Endokrynol
Pol. 2011;62(2):191, with additional information from reference 1.
Antiandrogenic
properties
Alkylating agents
Bicalutamide (Casodex)
Cimetidine (Tagamet)
Cisplatin
Flutamide
Isoniazid
Ketoconazole
Marijuana
Methotrexate
Metronidazole (Flagyl)
Omeprazole (Prilosec)
Penicillamine (Cuprimine)
Ranitidine (Zantac)
Spironolactone (Aldactone)
Vinca alkaloids
Estrogenic properties
Anabolic steroids
Diazepam (Valium)
Digoxin
Estrogen agonists
Estrogens
Gonadotropin-releasing
hormone agonists
Human chorionic
gonadotropins
Phenytoin (Dilantin)
Phytoestrogens
Increases metabolism
of androgens
Alcohol
Increases sex hormone–
binding globulin
concentration
Diazepam
Phenytoin
Induces hyperprolactinemia
Haloperidol
Metoclopramide (Reglan)
Phenothiazines
Unknown mechanism
Amiodarone
Amlodipine (Norvasc)
Amphetamines
Angiotensin-converting
enzyme inhibitors
Antiretroviral agents
Atorvastatin (Lipitor)
Didanosine (Videx)
Diltiazem
Etomidate (Amidate)
Fenofibrate (Tricor)
Finasteride
Fluoxetine (Prozac)
Heroin
Methadone
Methyldopa
Minocycline (Minocin)
Minoxidil
Mirtazapine (Remeron)
Nifedipine (Procardia)
Nilutamide (Nilandron)
Paroxetine (Paxil)
Reserpine
Risperidone (Risperdal)
Rosuvastatin (Crestor)
Sulindac (Clinoril)
Theophylline
Tricyclic antidepressants
Venlafaxine (Effexor)
Verapamil
Information from references 7, and 9 through 11.
MEDICATIONS AND SUBSTANCES
After persistent pubertal gynecomastia, medication use
and substance use are the most common causes of nonphysiologic gynecomastia. Agents associated with gynecomastia are listed in Table 2.7,9-11 Common contributors
include antipsychotics, antiretrovirals, and prostate cancer
therapies with long-term use.12 Spironolactone (Aldactone)
also has high propensity to cause gynecomastia, although
other mineralocorticoid receptor antagonists, such as
eplerenone (Inspra), have not produced similar effects.13,14
Discontinuing use of the contributing agent often results
in regression of breast tissue within three months.
Additionally, lavender, tea tree oil, dong quai, and Tribulus terrestris (an ingredient in performance-enhancing
April 1, 2012
◆
Volume 85, Number 7
supplements) have been linked to gynecomastia.15-17
Although soy consumption is thought to be safe, consuming more than 300 mg per day has been reported
to cause gynecomastia.18 All supplement use in patients
with gynecomastia should be scrutinized given the variability in marketed preparations.19
Anabolic steroid use often causes irreversible gynecomastia. The injection of exogenous testosterone
inhibits natural production of testosterone, which cannot recover rapidly enough between steroid-injecting
cycles to prevent estrogen predominance. Attempts
to prevent gynecomastia with the use of concomitant
www.aafp.org/afp
American Family Physician 717
3. Gynecomastia
tamoxifen or other aromatase inhibitors may result in
irreversible adverse effects.20 Use of marijuana, heroin,
or amphetamines also may contribute to irreversible
gynecomastia.10,11
CIRRHOSIS
Liver injury may impair hepatic degradation of estrogens
and increase levels of sex hormone–binding globulin that
contribute to increased peripheral estrogens. Patients
with alcohol-related liver disease are at particular risk of
gynecomastia because phytoestrogens in alcohol and the
direct inhibition of testosterone production by ethanol
further disrupt the estrogen-to-testosterone ratio.
PRIMARY HYPOGONADISM
Gynecomastia may be the only presenting symptom
in men with primary hypogonadism. For example,
one-half of men with Klinefelter syndrome have gynecomastia.21 Suspicion for primary hypogonadism is
warranted in any adolescent with persistent pubertal
gynecomastia.
TUMORS
Although testicular tumors are rare, approximately
10 percent of persons with testicular tumors present
with gynecomastia alone.22,23 In a study of 175 men
who were referred to a breast surgeon for evaluation
of gynecomastia, a testicular tumor was diagnosed in
3 percent.23 Leydig cell tumors, although often benign,
are prone to cause gynecomastia because they secrete
estradiol.
Adrenal tumors may secrete estrogen and estrogen
precursors, causing a similar disruption in the estrogento-testosterone ratio. These tumors can be detected by
elevated serum dehydroepiandrosterone sulfate levels
or increased urinary 17-ketosteroid levels. Similarly,
the presence of human
chorionic gonadotroNo cause is found
pin (hCG) in serum can
in 25 percent of
be used to detect hCGpatients who develop
secreting tumors that
gynecomastia.
may include testicular
germ cell, liver, gastric,
or bronchogenic carcinomas. All of these tumors require
surgical excision.
HYPERTHYROIDISM
Gynecomastia occurs in 10 to 40 percent of men with
hyperthyroidism, although it is rarely the only symptom
at presentation.24,25 Restoration of euthyroid state will
resolve gynecomastia in one to two months.
718 American Family Physician
CHRONIC RENAL INSUFFICIENCY
Hormonal dysfunction is common in men with renal
failure because of overall suppression of testosterone
production and direct testicular damage secondary to
uremia.26 Malnutrition occurs in up to 40 percent of
patients with renal failure; this may contribute to gynecomastia in men.27 Dialysis improves malnutritionassociated gynecomastia, but only renal transplant effectively resolves nutritional and hormonal causes of gynecomastia in those with renal failure.
OTHER
Conditions that impair absorption, such as ulcerative
colitis and cystic fibrosis, may result in gynecomastia.
Refeeding after prolonged malnutrition can also trigger
breast tissue proliferation. Although malnutrition suppresses hormone production, refeeding helps resume
production. However, the liver lags in recovery and cannot fully degrade estrogens.9 As the liver recovers, gynecomastia usually resolves within one to two years after
resumption of a balanced diet.
Although obesity causes pseudogynecomastia (a proliferation of adipose rather than glandular tissue), elevated weight is also associated with true gynecomastia.
New research suggests that leptin and aromatase activity
associated with obesity contribute to increased circulating estrogens, causing gynecomastia.28
Other rare causes of gynecomastia include exposure
to phthalates and lead, emotional stress, and repetitive
mechanical stress causing unilateral symptoms.29-31 Testicular injury from illnesses (e.g., mumps orchitis), infiltrative processes (e.g., tuberculosis, hemochromatosis),
or trauma may decrease testosterone production and
lead to gynecomastia. Additionally, patients with human
immunodeficiency virus infection may develop gynecomastia from the disease process or use of antiretroviral
medications. No cause is found in 25 percent of patients
who develop gynecomastia.7,30,31
Diagnosis
Some patients with gynecomastia may present with
breast pain, embarrassment, or fear of breast cancer. In
other patients, gynecomastia is discovered on routine
physical examination and causes no emotional or physical distress. Understanding the patient’s concerns can
help direct treatment.
HISTORY AND PHYSICAL EXAMINATION
The history should rule out other causes of breast
enlargement, such as those listed in Table 3.31-33 Physicians
should review patients’ use of medications, supplements,
www.aafp.org/afp
Volume 85, Number 7
◆
April 1, 2012
4. Table 3. Diagnoses in Men Referred for Imaging or Biopsy
Because of Breast Enlargement
Diagnosis
and illicit drugs. Symptoms that last longer
than one to two years suggest nonphysiologic
causes that require intervention for resolution. Nipple discharge; skin changes; rapidly
enlarging, firm breast masses; coincident testicular masses; or systemic symptoms such as
weight loss should raise concern.
The physical examination should include
evaluation of height and weight, and examination of the breasts, genitals, liver, lymph
nodes, and thyroid. Assessment of symmetry
and consistency of breast tissue is critical on
breast examination. Most commonly, gynecomastia is bilateral, although unilateral symptoms can occur and are usually left-sided.
Palpable, firm glandular tissue in a concentric
mass around the nipple areolar complex is
most consistent with gynecomastia. Increases
in subareolar fat are more likely pseudogynecomastia, whereas hard, immobile masses
should be considered breast carcinoma until
proven otherwise. Similarly, masses associated with skin changes, nipple retraction,
nipple discharge, or enlarged lymph nodes
should raise concern for malignancy.
Frequency (%)
Findings
Gynecomastia
63 to 93
Pseudogynecomastia
5.4
Breast cancer
1.4 to 2.9
Lipoma
Sebaceous cyst
0.9 to 2.9
1.4 to 2
Mastitis
Fat necrosis
0.8 to 1.1
0.3 to 0.9
Dermoid cyst
0.9
Hematoma
0.9
Discrete, round, mobile mass
under areola; usually bilateral
Increased adipose rather than
glandular tissue on examination
Patient falls outside of age range
for physiologic gynecomastia
Bloody nipple discharge
Axillary lymphadenopathy
Nonpainful mass (pain more
common in gynecomastia)
Often unilateral
Personal history of malignancy
Asymmetric breast enlargement
Drainage of material from site
Swelling feels closer to skin than
a part of deeper tissue
Asymmetric breast enlargement
Systemic signs of infection
History of injury to the area may
be present
May be a local swelling, not over
nipple areolar complex
Asymmetric breast enlargement
Painless lump that may enlarge;
may be anywhere in the breast
History of injury to the area may
be present
Asymmetric breast enlargement
History of cancer
Nonspecific breast tenderness
Solid mass; diagnosis made with
pathologic examination
Diagnosis made on pathology
specimen after removal of mass
History of surgery
DIAGNOSTIC TESTING
The history and physical examination
Metastatic disease
0.8
should direct the laboratory and imaging
Ductal ectasia
0.5
workup (Figure 1). Laboratory studies to
Hamartoma
0.5
investigate the underlying cause of gyneLymphoplasmacytic
0.5
comastia should include measurement of
inflammation
hepatic transaminase, serum creatinine, and
Postsurgical
0.5
thyroid-stimulating hormone levels for all
changes
patients. Levels of serum beta hCG, serum
dehydroepiandrosterone sulfate, or urinary
Information from references 31 through 33.
17-ketosteroid should be obtained to rule out
testicular, adrenal, or other tumors when
clinically suspected. Likewise, total and free
testosterone, estradiol, luteinizing hormone, and follicle- testicular tumors that were missed on clinical examinastimulating hormone levels define hormonal imbalances tion.34 However, a more widely advocated, conservative
resulting from primary or secondary hypogonadism. approach is to perform testicular ultrasonography only
Hyperprolactinemia is not common in patients with gyne- in those with palpable testicular masses, gynecomastia
comastia. Laboratory studies may be ordered using a step- larger than 5 cm, or otherwise unexplained gynecomaswise approach guided by history and physical examination, tia. Breast imaging should be guided by examination.
but a diagnosis of physiologic gynecomastia should not be Just as in women, mammography and breast ultrasonogmade until underlying etiologies have been excluded.
raphy may be useful in men if the physical examination
Recommendations for imaging studies are based raises suspicion for breast malignancy.35
mainly on case reports and expert opinion. Some studFine-needle aspiration of masses for cytology should
ies have suggested routine testicular ultrasonogra- be pursued only if malignancy is suspected. Men with
phy in men with gynecomastia to detect nonpalpable Klinefelter syndrome have a risk of breast cancer 16 to
April 1, 2012
◆
Volume 85, Number 7
www.aafp.org/afp
American Family Physician 719
5. Gynecomastia
Diagnosis of Gynecomastia
Patient presents with breast enlargement
Yes
Is the patient a newborn?
Likely transplacental; should
resolve within four weeks
No
Yes
Is the patient taking a medication
or substance listed in Table 2?
Discontinue agent and
monitor for resolution
No
Perform physical examination
Testicular mass
Perform testicular
ultrasonography
Gynecomastia
Breast mass that raises
suspicion for malignancy
Unremarkable
examination
Perform mammography
and breast ultrasonography
with biopsy
Provide reassurance
Pseudogynecomastia
Test hepatic function and
measure creatinine and thyroidstimulating hormone levels
Evidence of chronic disease?
Recommend
weight loss
Yes
Treat underlying disease
No
Measure serum human chorionic gonadotropin,
dehydroepiandrosterone, luteinizing hormone, follicle-stimulating
hormone, estradiol, testosterone, and prolactin levels
High level of estradiol and low
level of luteinizing hormone
Perform testicular
ultrasonography
High level of prolactin
Perform magnetic
resonance imaging
for pituitary adenoma
High level of
human chorionic
gonadotropin
Low levels of
luteinizing hormone
and testosterone
Perform testicular
ultrasonography
for germ cell tumor
Secondary
hypogonadism
High level of luteinizing
hormone and low level
of testosterone
Primary
hypogonadism
All hormone
levels normal
Idiopathic
gynecomastia
Ultrasonography results normal
Consider exogenous estrogen use, stress, or
underlying chronic disease as possible cause
Figure 1. Algorithm for the diagnosis of gynecomastia.
30 times higher than other men. Even with a reassuring
examination, men with gynecomastia and Klinefelter
syndrome may require imaging.7,36
Treatment
Few patients with gynecomastia need treatment for cosmesis or analgesia.37 In a study on treatment for gynecomastia, about one-half of men were not significantly
bothered by symptoms.38 Pain is more common in
patients with gynecomastia that is rapidly progressive or
of recent onset. For patients with nonphysiologic gynecomastia, treatment is directed toward improving the
720 American Family Physician
underlying illness or discontinuing use of the contributing. Watchful waiting with biannual follow-up is appropriate for those with physiologic gynecomastia who are
untroubled by symptoms and who have no features that
suggest underlying disease or malignancy. Early treatment will maximize benefit in men with significant
physical symptoms or emotional distress. Medications
are more effective if used as early as possible after symptoms are first noted, whereas surgery can be performed
at any time with similar results.
A number of medications have been used to treat gynecomastia. A retrospective chart review of men presenting
www.aafp.org/afp
Volume 85, Number 7
◆
April 1, 2012
6. Gynecomastia
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Clinical recommendation
Evidence
rating
References
More studies are needed to assess the
effectiveness of aromatase inhibitors, such
as anastrozole (Arimidex; 1 mg per day).
C
34
One trial of 42 pubertal boys demonstrated
a 57 percent reduction in breast volume
with anastrozole treatment.43 However,
a randomized controlled trial of 80 parC
35
ticipants demonstrated no statistically
significant difference between anastrozole
B
4, 37, 42
and placebo in the percentage of patients
with greater than 50 percent breast volume
reduction at three months.44
Surgery can be performed at any time
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limitedto reduce breast tissue, and a number of
quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual
practice, expert opinion, or case series. For information about the SORT evidence
techniques have been used.32,33,45 Longer
rating system, go to http://www.aafp.org/afpsort.xml.
duration of symptoms, higher-grade disease, or inability to tolerate medications
may prompt surgery as a first-line option.
to a breast clinic for gynecomastia found that only 13 of However, unilateral symptoms, high-grade disease, and
220 patients required medication for treatment. Patients long duration of symptoms are also associated with more
were treated with 10 mg of tamoxifen per day for three surgical complications.46
months, and 10 of the 13 had resolution of pain and
If pseudogynecomastia is suspected, no workup is
breast enlargement.37 Although tamoxifen is thought to needed, and the patient can be reassured that weight loss
be an effective and safe treatment for physiologic, per- will lead to resolution of pseudogynecomastia and also
sistent pubertal, or idiopathic gynecomastia, two small be most beneficial for overall health.46 If necessary, lipodouble-blind, crossover trials found only modest benefit suction procedures can reduce breast enlargement secwhen compared with placebo.39,40
ondary to subareolar fat accumulation.
Gynecomastia is a common adverse effect of bicalu- The author thanks Anne Walling, MD, and Scott Moser, MD, for their
tamide (Casodex) therapy that may prompt some men assistance with this manuscript.
to discontinue prostate cancer treatment. Tamoxifen Data Sources: Essential Evidence Plus and PubMed were searched for
has been recommended as a preventive agent for gyne- relevant articles using the following search terms: gynecomastia, physicomastia in these patients. A double-blind study of ologic gynecomastia, and breast enlargement. Each term was searched
282 men randomized to receive 20 mg of tamoxifen once individually and in conjunction with the following terms: males, men,
diagnosis, treatment, and management. A search using the same words
per day with bicalutamide or bicalutamide alone found was also completed within http://www.guidelines.gov and the Cochrane
that after six months, gynecomastia and breast pain were collection. Search dates: December 10 to 25, 2010.
significantly reduced in men who received tamoxifen
(8.8 versus 96.7 percent in the control group).41 An Italian The Author
randomized controlled trial of 80 participants also found
that 20 mg of tamoxifen once per week is as effective as GRETCHEN DICKSON, MD, MBA, is director of the Family Medicine Clerkship, and assistant professor of family medicine at the University of Kansas
20 mg once per day.42
School of Medicine in Wichita.
In a retrospective chart review of 38 patients in a pediAddress correspondence to Gretchen Dickson, MD, MBA, University of
atric endocrinology clinic, raloxifene (Evista; 60 mg Kansas School of Medicine, 1010 N. Kansas, Wichita, KS 67214 (e-mail:
once per day for three to nine months) reduced pubertal gdickson@kumc.edu). Reprints are not available from the author.
gynecomastia in 91 percent of patients, whereas tamoxi- Author disclosure: No relevant financial affiliations to disclose.
fen (10 to 20 mg twice per day for three to nine months)
was effective in 86 percent of patients.4 However, there
was no control group, and given the natural history REFERENCES
of pubertal gynecomastia (i.e., self-limited), placebo- 1. Braunstein GD. Clinical practice. Gynecomastia. N Engl J Med. 2007;
357(12):1229-1237.
controlled trials are still needed. Dihydrotestosterone, 2. McKiernan JF, Hull D. Breast development in the newborn. Arch Dis
danazol, and clomiphene (Clomid) have also been used
Child. 1981;56(7):525-529.
to treat gynecomastia with varying success.
3. Georgiadis E, Papandreou L, Evangelopoulou C, et al. Incidence of
Discontinuing use of spironolactone
(Aldactone) often results in regression of
breast tissue within three months.
Routine testicular ultrasonography should be
considered in men with gynecomastia to
detect nonpalpable testicular tumors that
were missed on clinical examination.
Mammography and breast ultrasonography
should be performed in men if the physical
examination raises suspicion for breast cancer.
Tamoxifen and raloxifene (Evista) are effective
for preventing and treating gynecomastia in
men being treated for prostate cancer.
April 1, 2012
◆
Volume 85, Number 7
B
13, 14
www.aafp.org/afp
American Family Physician 721
7. Gynecomastia
gynaecomastia in 954 young males and its relationship to somatometric
parameters. Ann Hum Biol. 1994;21(6):579-587.
2
7. Mehrotra R, Kopple JD. Nutritional management of maintenance dialysis
patients: why aren’t we doing better? Annu Rev Nutr. 2001;21:343-379.
4. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Beneficial effects
of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.
J Pediatr. 2004;145(1):71-76.
2
8. Dundar B, Dundar N, Erci T, Bober E, Büyükgebiz A. Leptin levels in boys
with pubertal gynecomastia. J Pediatr Endocrinol Metab. 2005;18(10):
929-934.
5. Biro FM, Lucky AW, Huster GA, Morrison JA. Hormonal studies and
physical maturation in adolescent gynecomastia. J Pediatr. 1990;116(3):
450-455.
2
9. Spyropoulou G, Karamatsoukis S, Foroglou P. Unilateral pseudogynecomastia: an occupational hazard in manual metal-pressing factories?
Aesthetic Plast Surg. 2011;35(2):270-273.
6. LaFranchi SH, Parlow AF, Lippe BM, Coyotupa J, Kaplan SA. Pubertal
gynecomastia and transient elevation of serum estradiol level. Am J Dis
Child. 1975;129(8):927-931.
3
0. Durmaz E, Ozmert EN, Erkekoglu P, et al. Plasma phthalate levels in
pubertal gynecomastia. Pediatrics. 2010;125(1):e122-e129.
7. Braunstein GD. Gynecomastia. N Engl J Med. 1993;328(7):490-495.
8. Niewoehner CB, Nuttal FQ. Gynecomastia in a hospitalized male population. Am J Med. 1984;77(4):633-638.
9. Derkacz M, Chmiel-Perzynska I, Nowakowski A. Gynecomastia—a difficult diagnostic problem. Endokrynol Pol. 2011;62(2):190-202.
1
0. Thompson DF, Carter JR. Drug-induced gynecomastia. Pharmacotherapy. 1993;13(1):37-45.
1. Eckman A, Dobs A. Drug-induced gynecomastia. Expert Opin Drug Saf.
1
2008;7(6):691-702.
1
2. Roke Y, van Harten PN, Boot AM, Buitelaar JK. Antipsychotic medication in children and adolescents: a descriptive review of the effects on
prolactin level and associated side effects. J Child Adolesc Psychopharmacol. 2009;19(4):403-414.
3
1. Den Hond E, Dhooge W, Bruckers L, et al. Internal exposures to pollutants and sexual maturation in Flemish adolescents. J Expo Sci Environ
Epidemiol. 2011;21(3):224-233.
3
2. Laituri CA, Garey CL, Ostlie DJ, St Peter SD, Gittes GK, Snyder CL. Treatment of adolescent gynecomastia. J Pediatr Surg. 2010;45(3):650-654.
3
3. Rho YK, Kim BJ, Kim MN, Kang KS, Han HJ. Laser lipolysis with pulsed
1064 nm Nd:YAG laser for the treatment of gynecomastia. Int J Dermatol. 2009;48(12):1353-1359.
3
4. Kolitsas N, Tsambalas S, Dimitriadis F, et al. Gynecomastia as a first
clinical sign of nonseminomatous germ cell tumor. Urol Int. 2011;87(2):
248-250.
3
5. Muñoz Carrasco R, Alvarez Benito M, Muñoz Gomariz E, Raya Povedano
JL, Martínez Paredes M. Mammography and ultrasound in the evaluation of male breast disease. Eur Radiol. 2010;20(12):2797-2805.
1
3. Engbaek M, Hjerrild M, Hallas J, Jacobsen IA. The effect of low-dose
spironolactone on resistant hypertension. J Am Soc Hypertens. 2010;
4(6):290-294.
3
6. Brinton LA, Carreon JD, Gierach GL, McGlynn KA, Gridley G. Etiologic
factors for male breast cancer in the U.S. Veterans Affairs medical care
system database. Breast Cancer Res Treat. 2010;119(1):185-192.
1
4. McKenna C, Burch J, Suekarran S, et al. A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness
of aldosterone antagonists for postmyocardial infarction heart failure.
Health Technol Assess. 2010;14(24):1-162.
3
7. Hanavadi S, Banerjee D, Monypenny IJ, Mansel RE. The role of tamoxifen in the management of gynaecomastia. Breast. 2006;15(2):276-280.
1
5. Henley DV, Lipson N, Korach KS, Bloch CA. Prepubertal gynecomastia
linked to lavender and tea tree oils. N Engl J Med. 2007;356(5):479-485.
3
8. Ozen H, Akyol F, Toktas G, et al. Is prophylactic breast radiotherapy
necessary in all patients with prostate cancer and gynecomastia and/or
breast pain? J Urol. 2010;184(2):519-524.
1
6. Goh SY, Loh KC. Gynaecomastia and the herbal tonic “Dong Quai”.
Singapore Med J. 2001;42(3):115-116.
3
9. Parker LN, Gray DR, Lai MK, Levin ER. Treatment of gynecomastia with
tamoxifen: a double-blind crossover study. Metabolism. 1986;35(8):
705-708.
7. Jameel JK, Kneeshaw PJ, Rao VS, Drew PJ. Gynaecomastia and the plant
1
product “Tribulis terrestris.” Breast. 2004;13(5):428-430.
4
0. McDermott MT, Hofeldt FD, Kidd GS. Tamoxifen therapy for painful
idiopathic gynecomastia. South Med J. 1990;83(11):1283-1285.
1
8. Messina M. Soybean isoflavone exposure does not have feminizing
effects on men: a critical examination of the clinical evidence. Fertil
Steril. 2010;93(7):2095-2104.
4
1. Fradet Y, Egerdie B, Andersen M, et al. Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide
150 mg monotherapy in patients with prostate cancer: a randomised,
placebo-controlled, dose-response study. Eur Urol. 2007;52(1):106-114.
1
9. Toorians AW, Boyee TF, De Rooy J, Stolker LA, Hoogenboom RL. Gynaecomastia linked to the intake of a herbal supplement fortified with
diethylstillbestrol. Food Addit Contam Part A Chem Anal Control Expo
Risk Assess. 2010;27(7):917-925.
2
0. Basaria S. Androgen abuse in athletes: detection and consequences.
J Clin Endocrinol Metab. 2010;95(4):1533-1543.
2
1. Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006;1:42.
2
2. Harris M, Rizvi S, Hindmarsh J, Bryan R. Testicular tumour presenting as
gynaecomastia. BMJ. 2006;332(7545):837.
2
3. Daniels IR, Layer GT. Testicular tumours presenting as gynaecomastia.
Eur J Surg Oncol. 2003;29(5):437-439.
2
4. Muthusamy E. Hyperthyroidism with gynaecomastia, galactorrhoea and
periodic paralysis. Singapore Med J. 1991;32(5):371-372.
2
5. Becker KL, Winnacker JL, Matthews MJ, Higgins GA Jr. Gynecomastia
and hyperthyroidism. An endocrine and histological investigation. J Clin
Endocrinol Metab. 1968;28(2):277-285.
2
6. Iglesias P, Carrero JJ, Díez JJ. Gonadal dysfunction in men with chronic
kidney disease: clinical features, prognostic implications and therapeutic options. J Nephrol. 2012;25(1):31-42.
722 American Family Physician
4
2. Bedognetti D, Rubagotti A, Conti G, et al. An open, randomised, multicentre, phase 3 trial comparing the efficacy of two tamoxifen schedules
in preventing gynaecomastia induced by bicalutamide monotherapy in
prostate cancer patients. Eur Urol. 2010;57(2):238-245.
4
3. Mauras N, Bishop K, Merinbaum D, Emeribe U, Agbo F, Lowe E. Pharmacokinetics and pharmacodynamics of anastrozole in pubertal boys
with recent-onset gynecomastia. J Clin Endocrinol Metab. 2009;94(8):
2975-2978.
4
4. Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy of anastrozole
for the treatment of pubertal gynecomastia: a randomized, doubleblind, placebo-controlled trial. J Clin Endocrinol Metab. 2004;89(9):
4428-4433.
4
5. Cigna E, Tarallo M, Fino P, De Santo L, Scuderi N. Surgical correction of
gynecomastia in thin patients. Aesthetic Plast Surg. 2011;35(4):439-445.
4
6. Colombo-Benkmann M, Buse B, Stern J, Herfarth C. Indications for and
results of surgical therapy for male gynecomastia. Am J Surg. 1999;178
(1):60-63.
www.aafp.org/afp
Volume 85, Number 7
◆
April 1, 2012
9. Gynecomastia: Pathophysiology, Evaluation, and Management
TABLE 1. Elements of Patient History and Physical Examination
Relevant for Evaluation of Gynecomastia
History
Duration of symptoms
Localized symptoms, such as a palpable mass, breast tenderness or
enlargement, and nipple discharge
History of an undescended testis, mumps, or liver or kidney disease
Detailed history of medications, supplements, illicit drugs, anabolic
steroids
History of coping with potential distress caused by breast condition
Physical examination
Height, weight
Signs of feminization, current Tanner stage
Stigmata of liver disease
Breast and overlying skin
Regional lymph nodes
Thyroid
Scrotum
sulfate and a normal estrogen-testosterone ratio. However,
free testosterone levels in these patients are lower than
those of controls without gynecomastia.8
Eventually, the exposure to the hormonal imbalance leads
to proliferation of glandular tissues, ie, ductal hyperplasia.
CLINICAL MANIFESTATIONS AND DIAGNOSIS
Careful history taking and physical examination (the relevant elements of which are presented in Table 1) often
reveal that patients actually are presenting with pseu
dogynecomastia, which means accumulation of subareolar fat without real proliferation of glandular tissue.
Examination of these patients reveals diffuse breast enlargement without a subareolar palpable nodule. These
patients do not need additional work-up and only require
reassurance. Gynecomastia is usually bilateral,3,9 but patients may present with asymmetrical or unilateral findings. Palpation usually demonstrates a palpable, tender,
firm, mobile, disclike mound of tissues1,4 that is not as
hard as breast cancer and is located centrally under the
nipple-areolar complex. When palpable masses are unilateral, hard, fixed, peripheral to the nipple, and associated
with nipple discharge, skin changes, or lymphadenopathy,
breast cancer should be suspected and thorough evaluation is recommended. Anthropometric measurements (eg,
body mass index) may also be helpful because obesity
can be associated with increased peripheral conversion of
androgens to estrogens and is associated with a higher
prevalence of gynecomastia.3,10 The presence of varicoceles has also been strongly associated with gynecomastia.9 A family history of gynecomastia has been elicited
in 58% of patients with persistent pubertal gynecomastia.
History may also reveal a clear and temporal association
Mayo Clin Proc.
•
with a causative drug and obviate the need for extensive
and costly evaluation. If the association with a drug is
unclear, then evaluation is recommended. Table 2 depicts
the numerous medications that have been associated with
gynecomastia. It has also been associated with the use
of alcohol and illicit drugs, such as marijuana, heroin,
methadone, and amphetamines.4 Several herbal supplements, particularly those containing phyto strogen, may
e
also cause gynecomastia.12
In one case series, history and physical examination detected a predisposing medical condition or causative medication in 83% of cases of gynecomastia.13 All breast cancer
cases in that series presented with a dominant mass on clinical examination or other signs suggestive of malignancy.
Diagnostic Approach
After initial history and examination exclude pseudogynecomastia and other obvious explanatory conditions,
mammography can differentiate true gynecomastia from
a mass that requires tissue sampling to exclude malignancy. Mammography was found to be fairly accurate
in distinguishing between malignant and benign male
breast diseases and can substantially reduce the need for
biopsies. The sensitivity and specificity of mammography for benign and malignant breast conditions exceed
90%; however, the positive predictive value for malignant
conditions is low (55%) because of the low prevalence
of malignancy in patients presenting with gynecomastia.14
TABLE 2. Drugs Associated With Gynecomastiaa
Hormonesb
Androgens, anabolic steroids,
estrogens, estrogen agonists, and hCG
Antiandrogens/
Bicalutamide, flutamide, nilutamide,
inhibitors of cyproterone, and GRH agonists (leuprolide
androgen synthesis and goserelin)
Antibiotics
Metronidazole, ketoconazole,b minocycline,
isoniazid
Antiulcer medications Cimetidine,b ranitidine, and omeprazole
Chemotherapeutic
Methotrexate, alkylating agents, and vinca
agents alkaloids
Cardiovascular drugs Digoxin,b ACEIs (eg, captopril and enalapril),
calcium channel blockers (diltiazem,
nifedipine, verapamil), amiodarone,
methyldopa, spironolactone, reserpine,
and minoxidil
Psychoactive agents
Anxiolytic agents (eg, diazepam), tricyclic
antidepressants, phenothiazines, haloperidol,
and atypical antipsychotic agents
Miscellaneous
Antiretroviral therapy for HIV, metoclopramide,
penicillamine, phenytoin, sulindac, and
theophylline
a
ACEI = angiotensin-converting enzyme inhibitor; GRH = gonadotropinreleasing hormone; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus.
b
Denotes stronger association.
Adapted from N Engl J Med.1
November 2009;84(11):1010-1015
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
a
1011
10. Gynecomastia: Pathophysiology, Evaluation, and Management
Imaging of the scrotum is only recommended if palpable
masses are present.
Laboratory investigations are pursued in cases of true
gynecomastia without clear explanation. Liver, kidney,
and thyroid function tests exclude the respective medical
conditions. Hormonal testing measures levels of total and
bioavailable testosterone, estradiol, prolactin, luteinizing
hormone, and hCG, and its findings can direct toward pituitary, gonadal, and extragonadal endocrinopathies and
neoplasms as seen in the stepwise algorithm depicted in
the Figure. If all testing is unrevealing, idiopathic gynecomastia is diagnosed.
Differential Diagnosis
The differential diagnosis of a palpable breast mass in a
male patient includes pseudogynecomastia, gynecomastia,
breast cancer, and numerous other benign conditions. A review of all mammographic findings for men for a period of
5 years at Mayo Clinic in Jacksonville, FL, revealed a 1%
rate of malignancy. Most cases were due to benign causes;
of these, gynecomastia represented 62%, with other causes
including lipomas, dermoid cysts, sebaceous cysts, lymphoplasmacytic inflammation, ductal ectasia, hematomas,
and fat necrosis.13 In contrast, the differential diagnosis of
gynecomastia per se, as demonstrated in a series of young
adult patients with gynecomastia aged 19 through 29 years,
includes idiopathic gynecomastia (58%), hypogonadism
(25%), hyperprolactinemia (9%), chronic liver disease
(4%), and drug-induced gynecomastia (4%).10 The frequency distribution of these etiologies is imprecise because of
the small number of cases reported in the literature and may
vary widely across publications and practice settings.
MANAGEMENT AND PROGNOSIS
Overall, gynecomastia is a benign condition and is usually
self-limited. Over time, fibrotic tissue replaces symptomatic proliferation of glandular tissue and tenderness resolves.
If the appropriate work-up does not reveal considerable underlying pathology, reassurance and periodic follow-up are
recommended. Although evidence is lacking to support a
recommendation for follow-up intervals, 6 months seems
reasonable. Causative medications should be withdrawn
or the underlying causative medical conditions (eg, hyperthyroidism) should be addressed. Most cases of pubertal
gynecomastia usually resolve in less than a year.8 If gynecomastia persists and is associated with pain or psychological distress and if the patient wishes to pursue treatment, pharmacological and surgical options are available.
Pharmacotherapy is likely beneficial if implemented early
before fibrous tissue replaces glandular tissue, whereas
surgery can be performed at any time.
1012
Mayo Clin Proc.
•
Pharmacotherapy
Several pharmacological agents have been used to manipulate the hormonal imbalances thought to cause gynecomastia. However, the studies that evaluated their efficacy
were in general small and uncontrolled, making inference
challenging.
Estrogen receptor modifiers appear to be fairly safe and
beneficial. Alagaratnam15 treated 61 Chinese men with tamoxifen for a median of 2 months with 36 months of follow-up, demonstrating an 84% rate of complete regression
of breast swelling. Lawrence et al16 used a 3- to 9-month
course of estrogen receptor modifiers (tamoxifen or raloxifene) to treat 38 consecutive patients with persistent pubertal gynecomastia and demonstrated a mean reduction in
breast nodule diameter of 2.1 cm with no serious adverse
effects. Similar results were reported in another case series
of 37 patients who used tamoxifen; reductions in pain and
nodule size were seen in all patients without long-term adverse effects.17
Dihydrotestosterone, danazol, clomiphene, and aromatase inhibitors such as testolactone and anastrozole may
also have benefit but are less commonly studied and used.4
Overall, the use of all these drugs is supported by a very
low quality of evidence, and the uncertainty about the balance of their benefits and harms should be highlighted to
candidate patients.
Surgical Correction
Surgery is the criterion standard treatment for gynecomastia. The most commonly used technique is subcutaneous
mastectomy that involves the direct resection of the glandular tissue using a periareolar or transareolar approach with
or without associated liposuction. Liposuction alone may
be sufficient if breast enlargement is purely due to excess
fatty tissue without substantial glandular hypertrophy.18
Skin resection is needed for more advanced cases.
In general, surgical treatment produces good cosmesis
and is well tolerated. Newer, less invasive techniques that
require minimal surgical incision have recently emerged
and may offer faster recovery and lower rates of local complications.18-20 Histologic analysis is recommended in true
gynecomastia corrections because unexpected histologic
findings such as spindle-cell hemangioendothelioma and
papilloma may occur in 3% of cases.21
Patients with gynecomastia have a favorable prognosis.
These patients present with 2 main concerns: ruling out
breast cancer and cosmetic correction. The first concern
is adequately addressed by following the appropriate diagnostic evaluation. Breast cancer is rare in males, representing less than 1% of all cases of breast cancer; only 1%
of mammograms in men reveal breast cancer.13 Therefore,
the decision to treat and the choice of treatment should be
November 2009;84(11):1010-1015
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
a
11. Gynecomastia: Pathophysiology, Evaluation, and Management
Pseudogynecomastia or
obvious causative drug
or condition
History and physical
examination
Gynecomastia
LFTs and calcium,
creatine, and TSH assays
Palpable
scrotal mass
Provide assurance,
remove/treat cause,
provide periodic follow-up
Testicular US
Suspect breast mass
(hard, eccentric)
Renal, hepatic, or
thyroid disease
Image-guided or
surgical biopsy as
needed
Mammography
Treat underlying
disease
Hormone testing (total and
bioavailable T, E2, prolactin,
LH, hCG assays)
↓T + ↑LH
↓T + ↓LH
↑hCG
↑Prl with or
without ↓T and
normal or low LH
↑E2 and normal
to low LH
Negative work-up
Primary
hypogonadism
Secondary
hypogonadism
Testicular US
MRI of the head
Testicular US
Idiopathic
gynecomastia
Testicular
germ
cell tumor
Normal
findings
Pituitary adenoma,
empty sella, or mass
panhypopituitarism
Mass (Leydig
or Sertoli
cell tumor)
Normal
findings
CT of the abdomen
Evaluate for:
Extragonadal germ cell tumors
(bronchogenic, hepatic, renal)
Nontrophoblastic hCG-secreting
tumors
Adrenal
neoplasm
Normal
findings
Increased aromatase activity
(obesity, adrenal or liver
disease, thyrotoxicosis)
Exogenous estrogens (eg, sex
reassignment, phytoestrogens)
FIGURE. Diagnostic algorithm for gynecomastia. CT = computed tomography; E2 = estradiol; hCG = human chorionic gonadotropin; LFT = liver
function test; LH = luteinizing hormone; Prl = prolactin; T = testosterone; TSH = thyroid-stimulating hormone; US = ultrasonography.
Adapted from N Engl J Med.11
Mayo Clin Proc.
•
November 2009;84(11):1010-1015
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
a
1013
12. Gynecomastia: Pathophysiology, Evaluation, and Management
based on the degree to which this condition has affected
the quality of life and mental health of patients and on their
desire for cosmetic correction. The body of research supporting the diagnostic approach and treatment strategies for
gynecomastia consists of expert opinion, case series, and
observational studies; hence, the evidence is considered to
be of low to very low quality. By acknowledging this low
quality of evidence when discussing testing and treatment
options with patients, physicians allow room in the process
of decision making for consideration of other factors, such
as resources, availability of services, and patients’ values
and preferences.22
18. Courtiss EH. Gynecomastia: analysis of 159 patients and current recommendations for treatment. Plast Reconstr Surg. 1987;79(5):740-753.
19. Prado AC, Castillo PF. Minimal surgical access to treat gynecomastia
with the use of a power-assisted arthroscopic-endoscopic cartilage shaver.
Plast Reconstr Surg. 2005;115(3):939-942.
20. Zhu J, Huang J. Surgical management of gynecomastia under endoscope. J Laparoendosc Adv Surg Techniq A. 2008;18(3):433-437.
21. Handschin AE, Bietry D, Hüsler R, Banic A, Constantinescu M. Surgical management of gynecomastia—a 10-year analysis. World J Surg. 2008;
32(1):38-44.
22. Swiglo BA, Murad MH, Schünemann HJ, et al. A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and
evaluation system. J Clin Endocrinol Metab. 2008 Mar;93(3):666-673. Epub
2008 Jan 2.
CME Questions About Gynecomastia
CONCLUSION
The evaluation of gynecomastias can be complex. A stepwise approach that starts with careful history taking and
physical examination may obviate the need for extensive
work-up. Subsequent selective imaging and laboratory
testing help exclude possible neoplasms and endocrinopathies. The etiology is usually benign.
1. Which one of the following statements best describes a
typical presentation of gynecomastia?
References
1. Braunstein GD. Gynecomastia. N Engl J Med. 2007;357(12):1229-1237.
2. Georgiadis E, Papandreou L, Evangelopoulou C, et al. Incidence of gynaecomastia in 954 young males and its relationship to somatometric parameters. Ann Hum Biol. 1994;21(6):579-587.
3. Niewoehner CB, Nuttal FQ. Gynecomastia in a hospitalized male population. Am J Med. 1984;77(4):633-638.
4. Nordt CA, DiVasta AD. Gynecomastia in adolescents. Curr Opin Pediatr. 2008;20(4):375-382.
5. McKiernan JF, Hull D. Breast development in the newborn. Arch Dis
Child. 1981;56(7):525-529.
6. Braunstein GD. Aromatase and gynecomastia. Endocr Relat Cancer. 1999;
6(2):315-324.
7. Mathur R, Braunstein GD. Gynecomastia: pathomechanisms and treatment strategies. Horm Res. 1997;48(3):95-102.
8. Biro FM, Lucky AW, Huster GA, Morrison JA. Hormonal studies and physical maturation in adolescent gynecomastia. J Pediatr. 1990;116(3):450-455.
9. Kumanov P, Deepinder F, Robeva R, Tomova A, Li J, Agarwal A. Relationship of adolescent gynecomastia with varicocele and somatometric
parameters: a cross-sectional study in 6200 healthy boys. J Adolesc Health.
2007;41(2):126-131.
10. Ersöz H, Onde ME, Terekeci H, Kurtoglu S, Tor H. Causes of gynaecomastia in young adult males and factors associated with idiopathic gynaecomastia. Int J Androl. 2002;25(5):312-316.
11. Braunstein GD. Gynecomastia. N Engl J Med. 1993;328(7):490-495.
12. Braunstein GD. Environmental gynecomastia [editorial]. Endocr Pract.
2008;14(4):409-410.
13. Hines SL, Tan WW, Yasrebi M, DePeri ER, Perez EA. The role of mammography in male patients with breast symptoms. Mayo Clin Proc. 2007;82(3):
297-300.
14. Evans GF, Anthony T, Turnage RH, et al. The diagnostic accuracy of
mammography in the evaluation of male breast disease [published correction
appears in Am J Surg. 2001;181(6):579]. Am J Surg. 2001;181:96-100.
15. Alagaratnam TT. Idiopathic gynecomastia treated with tamoxifen: a preliminary report. Clin Ther. 1987;9(5):483-487.
16. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J
Pediatr. 2004;145(1):71-76.
17. Derman O, Kanbur NO, Kutluk T. Tamoxifen treatment for pubertal gynecomastia. Int J Adolesc Med Health. 2003;15(4):359-363.
2. Which one of the following statements best describes
the recommendations for gynecomastia evaluation?
1014
Mayo Clin Proc.
•
a. Unilateral peripheral mass
b. Painless bilateral hard and fixed masses
c. A mass associated with nipple discharge
d. Bilateral painful masses in an anxious adolescent
e. Bilateral masses with minimal axillary
lymphadenopathy
a. Diagnostic work-up for gynecomastia is
recommended if initial history and findings on
examination do not reveal an obvious cause
b. Any case of gynecomastia requires laboratory tests
and imaging to rule out endocrinopathies and
malignancies
c. A disclike mound of tissue just beneath the
nipple-areolar complex is a feature of malignancy
d. Breast pain is a sign of malignancy
e. Mammography is recommended to rule out
pseudogynecomastia
3. Which one of the following statements best describes
the interpretation of laboratory results in patients with
gynecomastia?
a. Elevated luteinizing hormone and low testosterone
levels suggest secondary hypogonadism
b. Elevated levels of prolactin are common in
gynecomastia and do not require additional
evaluation
c. Elevated levels of human chorionic gonadotropin
(hCG) and normal findings on testicular
ultrasonography indicate the need for evaluation
for extragonadal hCG-secreting tumors
d. Elevated estradiol levels with normal findings on
testicular ultrasonography do not require additional
work-up
e. If results on all laboratory testing are normal,
pseudogynecomastia is diagnosed
November 2009;84(11):1010-1015
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
a
13. Gynecomastia: Pathophysiology, Evaluation, and Management
4. Which one of the following statements best
describes the available pharmacological agents for
gynecomastia?
a. Randomized trials have shown estrogen receptor
modifiers to be safe and effective
b. Tamoxifen is effective but produces serious adverse
effects
c. Tamoxifen treatment reduces the future risk of
developing breast cancer
d. Pharmacotherapy is most effective when instituted
early
e. Tamoxifen reduces breast size but is unlikely to
resolve breast pain
5. Which one of the following statements best describes
the surgical options available to treat gynecomastia?
a. Surgical therapy for gynecomastia is the criterion
standard for treatment of patients interested in
cosmesis
b. Liposuction is very effective for most cases of
gynecomastia
c. Mastectomy with axillary dissection is the treatment
of choice for gynecomastia
d. The newer endoscopic approach is only appropriate
when the breast is enlarged primarily as a result of
fat accumulation
e. Resection of glandular tissue is always
recommended because of the increased risk of
neoplastic transformation of benign gynecomastia
This activity was designated for 1 AMA PRA Category 1 Credit(s).™
Because the Concise Review for Clinicians contributions are now a CME activity, the answers to
the questions will no longer be published in the print journal. For CME credit and the answers, see
the link on our Web site at mayoclinicproceedings.com.
Mayo Clin Proc.
•
November 2009;84(11):1010-1015
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
a
1015