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 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? 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: Pseudo-gynecomastia 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 Initial: Late (after >12 month): 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 Common at birth Second peak in puberty 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

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 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 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 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 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 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 Marijuana 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

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 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 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 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 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 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 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 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.

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 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 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 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 pseudo-gynecomastia

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