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Gynecomastia. Question. 24 year-old male presents to PCP for painless enlargement of breasts for past six months Gradual onset without discharge or pain No past medical history, medications, or supplements Social ETOH use – less than 5 drinks per week Exam: BMI: 31

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question
Question
  • 24 year-old male presents to PCP for painless enlargement of breasts for past six months
    • Gradual onset without discharge or pain
  • No past medical history, medications, or supplements
    • Social ETOH use – less than 5 drinks per week
  • Exam:
    • BMI: 31
    • Breast – bilateral retro-areolar rubbery mass
    • Testicular – No masses, tenderness; normal size
  • Evaluation:
    • LH – 4.8 mIU/ml (NML 1.5-9.3 mIU/ml)
    • Testosterone – 482 ng/dl (NML 241/827 ng/dl)
    • TSH - 0.52 mIU/ml (NML 0.4-5.5 mIU/ml)
what is the next step
What is the next step?
  • 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
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
Definition
  • Clinical:
    • Rubbery or firm mass extending concentrically from the nipple
  • Pathologic:
    • Benign proliferation of the glandular tissue of the male breast
  • Pseudo-gynecomastia
    • Fat deposition without glandular proliferation
histology
Histology
  • Initial:

1) Ductal epithelial hyperplasia

2) Proliferation of periductal inflammatory cells

3) Periductal fibroblastic proliferation.

  • Late (after >12 month):

1) Increased number of ducts with dilatation

2) No epithelial cell proliferation

3) Increased fibrosis

Normal male breast

Early gynecomastia

www.uptodate.com

epidemiology
Epidemiology
  • Common at birth
    • Found in up to 60 - 90% of male infants
  • Second peak in puberty
    • 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

slide12

Prevalence of gynecomastia from multiple population studies

Braunstein. Gynecomastia. In: Diseases of the Breast. Harris, Lippincott-Raven, Philadelphia 1996. p. 54.

pathophysiology
Pathophysiology

Braunstein G. N Engl J Med 1993;328:490-495

etiologies
Etiologies
  • Persistent pubertal gynecomastia 25%
  • Medications 10 - 25%
  • Idiopathic 25%
  • Cirrhosis or malnutrition 8%
  • Hypogonadism:
    • Hypergonadotropic 8 %
    • Hypogonadotropic 2 %
  • Testicular tumors 3%
  • Hyperthyroidism 1.5%
  • Chronic renal insufficiency 1%

Braunstein, Glenn.“Gynecomastia”. NEJM 1993;328:490-95

persistent pubertal gynecomastia
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

etiologies1
Etiologies
  • Persistent pubertal gynecomastia 25%
  • Medications 10 - 25%
  • Idiopathic 25%
  • Cirrhosis or malnutrition 8%
  • Hypogonadism:
    • Hypergonadotropic 8 %
    • Hypogonadotropic 2 %
  • Testicular tumors 3%
  • Hyperthyroidism 1.5%
  • Chronic renal insufficiency 1%

Braunstein, Glenn.“Gynecomastia”. NEJM 1993;328:490-95

medications
Medications

Braunstein G. N Engl J Med 1993;328:490-495

spironolactone
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

spironolactone1
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
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
      • 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
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
Drugs
  • Other well described association:
    • ETOH
      • Inhibition of H-P-T axis as well as direct testicular toxicity
    • Marijuana
      • Androgen receptor antagonist
    • Tree oils and lotions
    • Any estrogen containing creams
    • HAART
      • More commonly pseudo-gynecomastia
      • Lipodystrophy also possible

Warren, S. “Lipodystrophy” NEJM 2005;352:62

etiologies2
Etiologies
  • Persistent pubertal gynecomastia 25%
  • Medications 10 - 25%
  • Idiopathic 25%
  • Cirrhosis or malnutrition 8%
  • Hypogonadism:
    • Hypergonadotropic 8 %
    • Hypogonadotropic 2 %
  • Testicular tumors 3%
  • Hyperthyroidism 1.5%
  • Chronic renal insufficiency 1%

Braunstein, Glenn.“Gynecomastia”. NEJM 1993;328:490-95

idiopathic obesity normal aging
Idiopathic/Obesity/Normal Aging
  • Androgen Insensitivity
  • Aromatase excess
    • Due to excess adipose tissue
    • Hereditary aromatase excess
idiopathic obesity normal aging1
Idiopathic/Obesity/Normal Aging

Braunstein, Glenn.“Aromatase and Gynecomastia”. Endocrine-Related Cancer 1999;6:315-24

etiologies3
Etiologies
  • Persistent pubertal gynecomastia 25%
  • Medications 10 - 25%
  • Idiopathic 25%
  • Cirrhosis or malnutrition 8%
  • Hypogonadism:
    • Hypergonadotropic 8 %
    • Hypogonadotropic 2 %
  • Testicular tumors 3%
  • Hyperthyroidism 1.5%
  • Chronic renal insufficiency 1%

Braunstein, Glenn.“Gynecomastia”. NEJM 1993;328:490-95

cirrhosis starvation
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
etiologies4
Etiologies
  • Persistent pubertal gynecomastia 25%
  • Medications 10 - 25%
  • Idiopathic 25%
  • Cirrhosis or malnutrition 8%
  • Hypogonadism:
    • Hypergonadotropic 8 %
    • Hypogonadotropic 2 %
  • Testicular tumors 3%
  • Hyperthyroidism 1.5%
  • Chronic renal insufficiency 1%

Braunstein, Glenn.“Gynecomastia”. NEJM 1993;328:490-95

hypergonadotropic hypogonadism
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
Hypogonadotropic Hypogonadism
  • Predominance of adrenal androgens
  • Testicular estradiol production may persist
etiologies5
Etiologies
  • Persistent pubertal gynecomastia 25%
  • Medications 10 - 25%
  • Idiopathic 25%
  • Cirrhosis or malnutrition 8%
  • Hypogonadism:
    • Hypergonadotropic 8 %
    • Hypogonadotropic 2 %
  • Testicular tumors 3%
  • Hyperthyroidism 1.5%
  • Chronic renal insufficiency 1%

Braunstein, Glenn.“Gynecomastia”. NEJM 1993;328:490-95

testicular neoplasm
Testicular Neoplasm
  • Germ cell cancers (95% of testicular cancer) are associated with gynecomastia in 2.5-6%
    • Most common with elevated hCG from choriocarcinoma
      • hCG stimulates aromatase in Leydig cells
      • Poor prognostic indicator – 50% mortality rate in small case series of cases
  • Incidence of gynecomastia is 20-30% with Leydig cell cancers (2% of all testicular cancers)
    • 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.

etiologies6
Etiologies
  • Persistent pubertal gynecomastia 25%
  • Medications 10 - 25%
  • Idiopathic 25%
  • Cirrhosis or malnutrition 8%
  • Hypogonadism:
    • Hypergonadotropic 8 %
    • Hypogonadotropic 2 %
  • Testicular tumors 3%
  • Hyperthyroidism 1.5%
  • Chronic renal insufficiency 1%

Braunstein, Glenn.“Gynecomastia”. NEJM 1993;328:490-95

thyrotoxicosis
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

etiologies7
Etiologies
  • Persistent pubertal gynecomastia 25%
  • Medications 10 - 25%
  • Idiopathic 25%
  • Cirrhosis or malnutrition 8%
  • Hypogonadism:
    • Hypergonadotropic 8 %
    • Hypogonadotropic 2 %
  • Testicular tumors 3%
  • Hyperthyroidism 1.5%
  • Chronic renal insufficiency 1%

Braunstein, Glenn.“Gynecomastia”. NEJM 1993;328:490-95

renal failure
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
Review:Etiologies of Gynecomastia

www.cbsnews.com

Braunstein G. N Engl J Med 1993;328:490-495

differential diagnosis
Differential Diagnosis
  • Pseudo-gynecomastia
  • Breast cancer
  • Lipoma or cyst

Hannekin, S. Ann Int Med 2004;140:497-98

evaluation
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
evaluation1
Evaluation
  • Red flags:
    • New onset
    • No risk factors or common medications
    • Young, post-puberty
    • Painful
    • Hard nodule
    • Nipple discharge
hormonal evaluation
Hormonal Evaluation
  • Indicated if no obvious cause for symptoms on history and physical
  • Laboratory evaluation:
    • LH
    • hCG
    • Testosterone (including free fraction)
    • Estradiol
    • TSH
slide44

Elevated hCG = cancer

Low testosterone = hypogonadism

High estradiol = cancer or aromatase

Braunstein G. N Engl J Med 1993;328:490-495

radiographic evaluation
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 pseudo-gynecomastia
mammography
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

treatment1
Treatment
  • Cause specific:
    • Stop offending medications
    • Weight loss
    • Alcohol cessation
    • Treatment of underlying disorder
    • Most idiopathic cases will resolve or regress within six months
treatment2
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
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
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
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 cancer1
Gynecomastia in Prostate Cancer

Tamoxifen group

Boccardo, F. J Clin Onc 2005;23:808-15

recommendations
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
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 points1
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
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
references1
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