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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



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


Braunstein, Glenn. Gynecomastia. NEJM 2007;357:1229-35


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


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