1. Gynecomastia

2. 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 – mIU/ml (NML mIU/ml)
Testosterone – 482 ng/dl (NML 241/827 ng/dl)
TSH mIU/ml (NML mIU/ml)

3. 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

4. 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

8. 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

9. 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

10. Epidemiology Common at birth Second peak in puberty
Found in up to % of male infants
Second peak in puberty
Estimated at 4-69% of males
Most common ages (Tanner 3)
Uncommon after age 17
Highest peak ages > 50
Estimated 24-65% of men affected
Braunstein G. N Engl J Med 1993;328:

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

12. Prevalence of gynecomastia from multiple population studies
Braunstein. Gynecomastia. In: Diseases of the Breast. Harris, Lippincott-Raven, Philadelphia p. 54.

13. Steroid Pathways

14. Pathophysiology
Braunstein G. N Engl J Med 1993;328:

15. Etiologies Persistent pubertal gynecomastia 25% Medications 10 - 25%
Idiopathic %
Cirrhosis or malnutrition 8%
Hypogonadism:
Hypergonadotropic 8 %
Hypogonadotropic 2 %
Testicular tumors 3%
Hyperthyroidism %
Chronic renal insufficiency 1%
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95

16. Persistent Pubertal Gynecomastia
Usually occurs age (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:

17. Etiologies Persistent pubertal gynecomastia 25% Medications 10 - 25%
Idiopathic %
Cirrhosis or malnutrition 8%
Hypogonadism:
Hypergonadotropic 8 %
Hypogonadotropic 2 %
Testicular tumors 3%
Hyperthyroidism %
Chronic renal insufficiency 1%
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95

18. Medications
Braunstein G. N Engl J Med 1993;328:

19. 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:

20. 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:

21. Anti-Ulcer Medications
Many case reports of gynecomastia related to anti-histamine and proton pump inhibitor medications
Open cohort study from UK –
Evaluated 81,535 men aged 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

22. 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

23. 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

24. Etiologies Persistent pubertal gynecomastia 25% Medications 10 - 25%
Idiopathic %
Cirrhosis or malnutrition 8%
Hypogonadism:
Hypergonadotropic 8 %
Hypogonadotropic 2 %
Testicular tumors 3%
Hyperthyroidism %
Chronic renal insufficiency 1%
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95

25. Idiopathic/Obesity/Normal Aging
Androgen Insensitivity
Aromatase excess
Due to excess adipose tissue
Hereditary aromatase excess

26. Idiopathic/Obesity/Normal Aging
Braunstein, Glenn. “Aromatase and Gynecomastia”. Endocrine-Related Cancer 1999;6:315-24

27. Etiologies Persistent pubertal gynecomastia 25% Medications 10 - 25%
Idiopathic %
Cirrhosis or malnutrition 8%
Hypogonadism:
Hypergonadotropic 8 %
Hypogonadotropic 2 %
Testicular tumors 3%
Hyperthyroidism %
Chronic renal insufficiency 1%
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95

28. 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

29. Etiologies Persistent pubertal gynecomastia 25% Medications 10 - 25%
Idiopathic %
Cirrhosis or malnutrition 8%
Hypogonadism:
Hypergonadotropic 8 %
Hypogonadotropic 2 %
Testicular tumors 3%
Hyperthyroidism %
Chronic renal insufficiency 1%
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95

30. 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

31. Hypogonadotropic Hypogonadism
Predominance of adrenal androgens
Testicular estradiol production may persist

32. Etiologies Persistent pubertal gynecomastia 25% Medications 10 - 25%
Idiopathic %
Cirrhosis or malnutrition 8%
Hypogonadism:
Hypergonadotropic 8 %
Hypogonadotropic 2 %
Testicular tumors 3%
Hyperthyroidism %
Chronic renal insufficiency 1%
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95

33. 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.

34. Etiologies Persistent pubertal gynecomastia 25% Medications 10 - 25%
Idiopathic %
Cirrhosis or malnutrition 8%
Hypogonadism:
Hypergonadotropic 8 %
Hypogonadotropic 2 %
Testicular tumors 3%
Hyperthyroidism %
Chronic renal insufficiency 1%
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95

35. 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

36. Etiologies Persistent pubertal gynecomastia 25% Medications 10 - 25%
Idiopathic %
Cirrhosis or malnutrition 8%
Hypogonadism:
Hypergonadotropic 8 %
Hypogonadotropic 2 %
Testicular tumors 3%
Hyperthyroidism %
Chronic renal insufficiency 1%
Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95

37. Renal Failure Similar mechanism to starvation
Decreased testicular function preceding dialysis
Increased hormone production after initiating dialysis with increased estrogens first

38. Review: Etiologies of Gynecomastia
Braunstein G. N Engl J Med 1993;328:

39. Differential Diagnosis
Pseudo-gynecomastia
Breast cancer
Lipoma or cyst
Hannekin, S. Ann Int Med 2004;140:497-98

40. 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

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

42. Evaluation Red flags: New onset No risk factors or common medications
Young, post-puberty
Painful
Hard nodule
Nipple discharge

43. Hormonal Evaluation
Indicated if no obvious cause for symptoms on history and physical
Laboratory evaluation: LH
hCG
Testosterone (including free fraction)
Estradiol
TSH

44. Elevated hCG = cancer Low testosterone = hypogonadism
High estradiol = cancer or aromatase
Braunstein G. N Engl J Med 1993;328:

45. 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

46. Appelbaum, AH. Scientific Exhibit 1999;19:599-68

47. 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

48. Treatment

49. Treatment Cause specific: Stop offending medications Weight loss
Alcohol cessation
Treatment of underlying disorder
Most idiopathic cases will resolve or regress within six months

50. 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

51. 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:
Lawrence, SE. “Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.” J Pediatr 2004; 145:71.

52. Aromatase Inhibitor
Double-blind, placebo controlled study of 87 male patients aged 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:

53. 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

54. Gynecomastia in Prostate Cancer
Tamoxifen group
Boccardo, F. J Clin Onc 2005;23:808-15

55. 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

56. 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

57. 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

58. 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:
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 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

59. 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:
Plourde, P. “Saftery and Efficacy of Anastrozole for the Treatment of Pubertal Gynecomastia.” J Clin Endocrinol Metab 2004;89:
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:
Scully, R. “Case Records”. NEJM 2000; 342:
Staiman VR. ”Tamoxifen for flutamide/finasteride-induced gynecomastia.” Urology  1997;50:
Tseng, A. “Gynecomastia in testicular cancer patients. Prognostic and therapeutic implications.” Cancer 1985; 56:2534.
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