Review Article
Gynecomastia: Etiologies, Clinical Presentations, Diagnosis, and Management Barry Ladizinski, MD, Kachiu Cecilia Lee, MD, MPH, F.N.U. Nutan, H. William Higgins, II, MD, and Daniel G. Federman, MD Abstract: Gynecomastia is a common finding that is present in up to 57% of men. It is caused by proliferation of the mammary glands, which leads to the development of dense subareolar tissue. The condition results from both physiologic (eg, hypogonadism, altered estrogen-to-androgen ratio) and nonphysiologic (eg, drugs, herbal products) causes. Most cases are benign and resolve spontaneously. Treatment is usually unnecessary, although there are specific signs and symptoms that warrant further workup. Psychosocial effects also are of concern, particularly among adolescents. Knowledge of the possible causes of gynecomastia and a thoughtful approach to the patient presenting with this condition can lead to improved outcomes and patient satisfaction. This concise review of the common presentation, etiologies, diagnosis, and treatment of gynecomastia should aid healthcare professionals who may encounter these patients in their practices. Key Words: andrology, breast enlargement, gynecomastia, hypogonadism, men, pseudogynecomastia
G
ynecomastia is the abnormal development of dense subareolar tissue in men, secondary to benign proliferation of mammary glands. It is a common condition that causes concern among many patients and healthcare practitioners. Typically, the male breast contains minimal amounts of glandular and adipose tissue. In gynecomastia, the estrogen:androgen ratio (estrogen stimulates breast growth; androgen inhibits breast growth) is disrupted, leading to enlargement of the male breast through glandular tissue proliferation.1,2 Gynecomastia can result from both physiological and nonphysiological causes and has distinct clinical, histological, and radiologic features.
MD,
Epidemiology Gynecomastia, from the Greek gynaik, meaning woman, is the most common benign condition of the male breast, accounting for up to 80% of referrals to specialized breast care centers.3,4 A minority of these patients may seek medical attention for this condition. On routine physical examination, gynecomastia is found in 36% to 57% of men.5Y7 Physiologically, there are three age peaks for gynecomastia: infancy, puberty, and past 50 years.5 These peaks represent periods of hormonal transition within the body, causing an imbalance in the free-estrogen:free-androgen ratio. An estimated 60% to 90% of neonates have transient gynecomastia, which regresses within the first year. During adolescence, 48% to 64% of boys experience gynecomastia caused by hormonal and growth changes, with peak onset at 13 to 14 years old (Tanner stage 3 or 4); this typically resolves by age 18.5,8 In adults, gynecomastia is most commonly found in the 50- to 60-year-old age group and is present in up to 57% of healthy older men and up to 55% of men at autopsy.9 Higher body mass index (BMI) also is associated with this condition, because excess adipose tissue leads to increased conversion of androgen precursors to estrogen. The prevalence of gynecomastia rises above 80% in men with BMIs 925 kg/m2.2,6
Clinical Features Gynecomastia is present typically for months to years before it is discovered on physical examination and presents clinically as a unilateral or bilateral (Table 1) enlargement of
Key Points From the Department of Dermatology, Brown University, Providence, Rhode Island, the Department of Internal Medicine, Medstar Good Samaritan Hospital, Baltimore, Maryland, and the Department of Internal Medicine, Veterans Administration Hospital, West Haven, Connecticut. Reprint requests to Dr Barry Ladizinski, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD. E-mail: [email protected] The authors have no financial relationships to disclose and no conflicts of interest to report. Accepted June 4, 2013. Copyright * 2014 by The Southern Medical Association 0038-4348/0Y2000/107-44 DOI: 10.1097/SMJ.0000000000000033
44
& Gynecomastia is a common condition, affecting up to 57% of men. & Gynecomastia is caused by benign proliferation of mammary glands, which leads to the development of dense subareolar tissue. & Most cases of gynecomastia are benign and resolve spontaneously. & Treatment is typically not necessary, although certain signs and symptoms warrant further workup. Psychosocial issues often need to be addressed.
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Review Article
Table 1. Differential diagnosis of a palpable breast mass in male patients
have a higher BMI, higher body fat percentage, and lower levels of serum testosterone and luteinizing hormone.8,16
Nonphysiologic Causes
Pseudogynecomastia Gynecomastia Breast cancer Benign conditions: lipoma, dermoid cyst, sebaceous cyst, lymphoplasmacytic inflammation, ductal ectasia, hematoma, fat necrosis
concentric breast tissue around the areola, with the tissue usually soft and uniform to palpation.10Y12 Gynecomastia usually is asymptomatic, although localized pain and tenderness occasionally can be present, particularly during the early months of rapid glandular proliferation. Unilateral proliferations of glandular tissue are more common on the left side, with the prevalence of unilateral presentation ranging from 14% to 50% of all cases of gynecomastia.10,13,14 Unilateral presentation can be psychologically concerning to patients.15 In a case study of 10 subjects with unilateral gynecomastia, one-third of subjects feared they had breast cancer. In contrast, pseudogynecomastia (fatty breasts) results from the enlargement of adipose breast tissue instead of the proliferation of glandular tissue seen in true gynecomastia. Pseudogynecomastia tissue feels softer to palpation, with some describing it having a less rubbery feel. True gynecomastia also has been described as having a spongy or concentric disc-shape feel, centered around the areola. Comparison of subareolar tissue with other areas of fatty subcutaneous tissue can help differentiate this condition from true gynecomastia.5 Besides gynecomastia and pseudogynecomastia, other conditions can cause enlargement of breast tissue in men. Asymmetric enlargement of the breast with the presence of a firm mass is most consistent with other causes such as breast cancer, which accounts for approximately 0.2% of all malignancies in men.5 Malignant tumors typically present in an eccentric location, rather than centrally around the areola, as seen in gynecomastia. Other findings, such as skin dimpling, peau d’orange, nipple retraction, and lymphadenopathy should also raise concern for malignancy.11
A thorough medication history always should be obtained, because drugs are a frequently cited cause of benign gynecomastia (Table 3), accounting for up to 25% of all cases.11,17,18 In addition, over-the-counter herbal products, such as panax ginseng, tea tree oil, and topical lavender (used in some shampoos, soaps, and lotions), have been associated with gynecomastia.19Y22 Consumption of 9300 mg of soy per day also has been reported to cause the condition, although other studies have failed to find a similar association.23,24 Of note, breasts with medication-induced gynecomastia can be extremely tender, but the cessation of medications, with the exception of anabolic steroid use, usually leads to reversal of the condition within a few weeks.25 Medical conditions that can cause gynecomastia include hypogonadism (eg, primary hypogonadism, pituitary insufficiency, Klinefelter syndrome), cirrhosis/liver disease, hyperthyroidism, end-stage renal disease/dialysis, malnutrition, and malignancies of the testes, adrenal glands, or pituitary gland.5 Although rare, gynecomastia is the presenting sign in up to 10% of patients with testicular cancer. This symptom may
Table 2. Nonmedication causes of gynecomastia Idiopathic gynecomastia Physiological gynecomastia Newborn gynecomastia Adolescent gynecomastia Elderly gynecomastia Chronic diseases Cirrhosis Diabetes mellitus Heart failure Renal insufficiency Tuberculosis Increases in estrogens or androgens Puberty Obesity Testicular tumor (eg, Leydig cell tumor, choriocarcinoma)
Physiologic Causes Physiologic occurrence of gynecomastia is commonly seen in neonates (secondary to transfer of maternal hormones across the placenta), adolescent boys (secondary to increased conversion of testosterone to estradiol via aromatase), and men older than 50 years (secondary to decreased free testosterone) (Table 2). Physiologic gynecomastia is usually self-limiting and resolves spontaneously in most patients. Adolescent gynecomastia typically resolves within 1 to 2 years, but rarely persists (G5% of cases). Compared with healthy controls, patients with persistent pubertal gynecomastia are more likely to Southern Medical Journal
Hyperthyroidism Abuse of anabolic steroids Hypergonadotropic hypogonadism Klinefelter syndrome Antiandrogen therapy Testicular feminization syndrome Reifenstein syndrome (familial pseudohermaphroditism) Bilateral testicular disease or bilateral loss of testes (eg, mumps orchitis) Hyperprolactinemia Pituitary adenoma
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& Gynecomastia
Table 3. Drug-induced causes of gynecomastia1 Anabolic steroids, androgens Antiandrogens (eg, flutamide, finasteride, spironolactone) Antibiotics (eg, minocycline) Antifungals (eg, ketoconazole) Cardiovascular medications (eg, amlodipine, angiotensin-converting enzyme inhibitors, calcium channel blockers, digoxin, diltiazem, furosemide, verapamil) Estrogens (eg, estrogen agonists, phytoestrogens) Ethanol Histamine blockers (eg, cimetidine) HIV/AIDS medications (eg, efavirenz) Illicit drugs (eg, amphetamines, heroin, methadone, marijuana) Over-the-counter supplements/products (eg, panax ginseng, tea tree oil) Psychiatric medications (eg, risperidone, phenytoin, haloperidol, paroxetine, benzodiazepines, tricyclic antidepressants)
precede a palpable testicular mass or detectable hormonal abnormalities,9 and ultrasound of the scrotum may be necessary to detect these tumors.26Y28 Specifically, Leydig cell tumors are likely to cause gynecomastia because of the secretion of estradiol.29,30 Ultrasound is recommended in young patients with a palpable testicular mass or in those who show other signs of hormonal changes. The incidence and prevalence of testicular cancer in those presenting with gynecomastia is unknown.
Diagnostic Considerations Gynecomastia typically is discovered upon routine physical examination and is usually asymptomatic; however, some patients may present with complaints of pain, tenderness, psychosocial distress caused by cosmetic concerns, or fear of malignancy. Given the broad differential, a comprehensive clinical examination with a diagnostic workup is occasionally required (Fig.). History and physical examination should form the basis of any investigation into gynecomastia. If the patient is symptomatic, then physicians should inquire about the duration of symptoms and presence of nipple discharge, overlying skin changes, or firm masses. Symptoms such as weight loss or presence of a testicular mass should prompt concern and further diagnostic testing.9 Patients with macromastia (breast tissue 95 cm), rapidly progressive gynecomastia, persistent mastodynia, or other evidence of malignancy (eg, palpable, fixed, peripheral lymph nodes 91.5 cm) should undergo further evaluation with breast imaging. Gynecomastia itself is not a risk factor for malignancy, with the exception of patients with Klinefelter syndrome.5 Breast cancer should be considered in patients with asymmetric enlargement of the breast or in those with other risk factors. A review of patients’ prescription and over-the-counter medications/vitamin and herbal supplements is necessary.31 Specific questions should be asked regarding topical preparations,
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growth hormones, anabolic steroids, and use of alcohol and/or illicit recreational drugs (eg, marijuana, heroin, amphetamines). Although some studies have associated marijuana use with gynecomastia, others have not found a similar link.31Y34 Patients may not volunteer information regarding these medications unless asked about them directly, and when speaking with an adolescent, it is prudent to conduct parts of the interview without parent(s) in the room. When alone, the adolescent may be more apt to admit to over-the-counter medication use or use of illicit drugs, such as marijuana or anabolic steroids. Physical examination requires palpation of the breast tissue, with assessment of symmetry and consistency. Eccentric, immobile, and firm masses are suggestive of malignancy or other causes and require diagnostic workup. Skin examination for nipple discharge, retraction, or peau d’orange is reason for concern. A testicular examination is also necessary to determine the presence of any masses.4
Diagnostic Testing Most patients presenting with gynecomastia do not need a complete workup, which should be reserved for those in whom clinical suspicion for malignancy or other comorbidities is high. In these patients, laboratory tests to consider include a comprehensive metabolic panel, and tests to determine levels of thyroid-stimulating hormone, free thyroxine, free and total testosterone, estradiol, dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and prolactin levels. Testicular ultrasound should be considered if bloodwork reveals hormonal dysregulation or if testicular cancer is a concern.2,5 Ultrasound, rather than mammography, is the radiologic modality of choice for diagnosing gynecomastia, which will typically reveal hyperechoic fibroglandular tissue.4 Mammography and possible fine-needle aspiration or breast biopsy can be considered if breast cancer is a concern. Mammography for the detection of male breast cancer has a reported sensitivity of 92% and specificity of 91%.23 No established guidelines exist regarding regular mammographic screening for men with gynecomastia; however, if the patient is BRCA (the breast cancer gene) positive, an annual screening mammogram is generally recommended.2 BRCA screening should be performed only in patients with a strong family history of BRCA-associated cancers (eg, breast, ovarian, prostate, pancreatic cancers, malignant melanoma). Tissue sampling should be obtained only in patients with high suspicion for malignancy. Histology of breast tissue can be obtained by fine-needle biopsy, with gynecomastia usually demonstrating increased subareolar fat, stromal hyalinization, and fibrosis.10 Factors that increase the risk of male breast cancer include high circulating estrogen levels, Klinefelter syndrome, family history of breast cancer, presence of BRCA gene mutations, hyperprolactinemia, and history of prior radiation therapy.16,35Y40 In a Department of Veterans Affairs study of African American patients, cholelithiasis was a significant predictor of breast cancer * 2014 Southern Medical Association
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Review Article
Fig. Diagnostic algorithm for gynecomastia. in men.36 Still, no increased risk of breast cancer associated with gynecomastia in men has been demonstrated.
Treatment Options Gynecomastia is typically benign in nature, but breasts sometimes can be tender, especially during adolescence. Most men seek reassurance that their condition is benign and that no intervention is required. Enlargement of breast tissue G4 cm is most likely to resolve spontaneously, whereas pubertal gynecomastia will resolve within months to years in nearly 90% of patients. Some individuals experience significant psychosocial distress; therefore, it is important to offer psychological support as part of any treatment regimen.3 Southern Medical Journal
For patients who are symptomatic and require treatment, medications should be started early, because patients with gynecomastia for 912 months may have poor responses compared with those with disease lasting G12 months.3 This is the result of irreversible deposition of fibrous tissue in the breasts. There are no therapies for gynecomastia that have been approved by the Food and Drug Administration, but proposed treatments include anti-estrogens (eg, clomiphene41), selective estrogen receptor blockers (eg, tamoxifen42Y48), synthetic testosterone derivatives (eg, danazol49), aromatase inhibitors (eg, anastrazole50,51), and parenteral or transdermal testosterone (Table 4). Of note, testosterone used for treating hypogonadism can sometimes lead to gynecomastia secondary to peripheral conversion to estrogen. Radiation also has been
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& Gynecomastia
Table 4. Evidence-based treatment strategies for gynecomastia Men receiving antiandrogen therapy with gynecomastia Tamoxifen: most effectiveVlevel I evidence42Y44 RadiotherapyVlevel I evidence45,46 Anastrazole: less effective than tamoxifenVlevel I evidence47 Gynecomastia in all other cases Anastrazole: not effectiveVlevel I evidence48 Tamoxifen/raloxifenVlevel IV evidence49Y51 DanazolVlevel IV evidence39 Surgical excisionVlevel IV evidence52 Levels of evidence: Level I: evidence obtained from at least one properly designed randomized controlled trial; level II: evidence obtained from welldesigned controlled trials without randomization; level III: evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group; level IV: evidence obtained from multiple time series with or without intervention, such as case studies (dramatic results in uncontrolled trials also may be regarded as this type of evidence); level V: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
used as gynecomastia prophylaxis in patients with prostate cancer who are receiving estrogen therapy. Gynecomastia caused by an underlying medical condition (eg, testicular cancer, hyperthyroidism) often can be reversed by treatment of the underlying cause, and discontinuation of the offending agent usually results in resolution of medicationinduced gynecomastia. Obese patients should be counseled on weight loss strategies and low-fat diets or offered consultation with a nutritionist. Liposuction, endoscopic subcutaneous mastectomy, or reduction mammoplasty is indicated in cases of macromastia, long-standing cases of or refractory gynecomastia, or for cosmetic reasons.52 Gynecomastia also can have psychosocial effects on patients. Young men with gynecomastia often are reticent to participate in athletic activities that may result in exposing the chest, they may avoid showers and swimming pools, and they may camouflage their bodies by wearing loose-fitting clothes. Posture also can be affected because patients tend to minimize the deformation by rolling their shoulders toward the midline and slouching forward; thus, these psychosocial issues may need to be addressed foremost in those patients.53 Although most patients do not require psychotherapy, they should be provided with reassurance about the self-limited nature of the condition, encouragement to participate in social and physical activities, and counseling on lifestyle modifications.
Conclusions Gynecomastia is a common problem that is vexing to both patients and healthcare professionals. Knowledge of potential causes and a thoughtful approach to the patient presenting with gynecomastia have the potential to lead to improved outcomes and patient satisfaction.
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References 1. Krause W. Drug-inducing gynaecomastiaVa critical review. Andrologia 2012;44:621Y626. 2. Narula HS, Carlson HE. Gynecomastia. Endocrinol Metab Clin North Am 2007;36:497Y519. 3. Al-Allak A, Govindarajulu S, Shere M, et al. Gynaecomastia: a decade of experience. Surgeon 2011;9:255Y258. 4. Daniels IR, Layer GT. Gynaecomastia. Eur J Surg 2001;167:885Y892. 5. Bembo SA, Carlson HE. Gynecomastia: its features, and when and how to treat it. Cleve Clin J Med 2004;71:511Y517. 6. Niewoehner CB, Nuttal FQ. Gynecomastia in a hospitalized male population. Am J Med 1984;77:633Y638. 7. Nuttall FQ. Gynecomastia as a physical finding in normal men. J Clin Endocrinol Metab 1979;48:338Y340. 8. 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;21:579Y587. 9. Hassan HC, Cullen IM, Casey RG, et al. Gynaecomastia: an endocrine manifestation of testicular cancer. Andrologia 2008;40:152Y157. 10. Bannayan GA, Hajdu SI. Gynecomastia: clinicopathologic study of 351 cases. Am J Clin Pathol 1972;57:431Y437. 11. Braunstein GD. Clinical practice. Gynecomastia. N Engl J Med 2007; 357:1229Y1237. 12. Hines SL, Tan WW, Yasrebi M, et al. The role of mammography in male patients with breast symptoms. Mayo Clin Proc 2007;82:297Y300. 13. Wiesman IM, Lehman JA Jr, Parker MG, et al. Gynecomastia: an outcome analysis. Ann Plast Surg 2004;53:97Y101. 14. Colombo-Benkmann M, Buse B, Stern J, et al. Indications for and results of surgical therapy for male gynecomastia. Am J Surg 1999;178:60Y63. 15. Al-Qattan M, Hassanain J, Mahmoud S, et al. On the neglected entity of unilateral gynecomastia. Ann Plast Surg 2005;55:255Y257. 16. Ersoz H, Onde ME, Terekeci H, et al. Causes of gynaecomastia in young adult males and factors associated with idiopathic gynaecomastia. Int J Androl 2002;25:312Y316. 17. Deepinder F, Braunstein GD. Drug-induced gynecomastia: an evidencebased review. Expert Opin Drug Saf 2012;11:779Y795. 18. Eckman A, Dobs A. Drug-induced gynecomastia. Expert Opin Drug Saf 2008;7:691Y702. 19. Block SL. The possible link between gynecomastia, topical lavender, and tea tree oil. Pediatr Ann 2012;41:56Y58. 20. Henley DV, Lipson N, Korach KS, et al. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med 2007;356:479Y485. 21. Kakisaka Y, Ohara T, Tozawa H, et al. Panax ginseng: a newly identified cause of gynecomastia. Tohoku J Exp Med 2012;228:143Y145. 22. Korde LA, Zujewski JA, Kamin L, et al. Multidisciplinary meeting on male breast cancer: summary and research recommendations. J Clin Oncol 2010; 28:2114Y2122. 23. Martinez J, Lewi JE. An unusual case of gynecomastia associated with soy product consumption. Endocr Pract 2008;14:415Y418. 24. Messina M. Soybean isoflavone exposure does not have feminizing effects on men: a critical examination of the clinical evidence. Fertil Steril 2010; 93:2095Y2104. 25. Hartgens F, Kuipers H. Effects of androgenic-anabolic steroids in athletes. Sports Med 2004;34:513Y554. 26. Emory TH, Charboneau JW, Randall RV, et al. Occult testicular interstitialcell tumor in a patient with gynecomastia: ultrasonic detection. Radiology 1984;151:474. 27. Hendry WS, Garvie WH, Ah-See AK, et al. Ultrasonic detection of occult testicular neoplasms in patients with gynaecomastia. Br J Radiol 1984; 57:571Y572. 28. Mudde AH, Haak A, Kruyt RH. Ultrasonic detection of occult Leydig cell tumours in two patients with gynaecomastia. Neth J Med 1987;31:72Y76.
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Review Article
29. Haas GP, Pittaluga S, Gomella L, et al. Clinically occult Leydig cell tumor presenting with gynecomastia. J Urol 1989;142:1325Y1327. 30. Mellor SG, McCutchan JD. Gynaecomastia and occult Leydig cell tumour of the testis. Br J Urol 1989;63:420Y422. 31. Goldman RD. Drug-induced gynecomastia in children and adolescents. Can Fam Physician 2010;56:344Y345. 32. Dardick KR. Holiday gynecomastia related to marijuana? Ann Intern Med 1993;119:253. 33. Thompson DF, Carter JR. Drug-induced gynecomastia. Pharmacotherapy 1993;13:37Y45. 34. Cates W Jr, Pope JN. Gynecomastia and cannabis smoking. A nonassociation among US Army soldiers. Am J Surg 1977;134:613Y615. 35. Brinton LA. Breast cancer risk among patients with Klinefelter syndrome. Acta Paediatr 2011;100:814Y818. 36. Brinton LA, Carreon JD, Gierach GL, et al. Etiologic factors for male breast cancer in the U.S. Veterans Affairs medical care system database. Breast Cancer Res Treat 2010;119:185Y192. 37. Johansen Taber KA, Morisy LR, Osbahr AJ 3rd, et al. Male breast cancer: risk factors, diagnosis, and management. Oncol Rep 2010;24:1115Y1120. 38. Krause W. Male breast cancerVan andrological disease: risk factors and diagnosis. Andrologia 2004;36:346Y354. 39. Maksimovic S. Bilateral breast carcinoma in patients with Klinefeleter syndrome: report of case. Med Arch 2010;64:250Y252. 40. Zygogianni AG, Kyrgias G, Gennatas C, et al. Male breast carcinoma: epidemiology, risk factors and current therapeutic approaches. Asian Pac J Cancer Prev 2012;13:15Y19. 41. Plourde PV, Kulin HE, Santner SJ. Clomiphene in the treatment of adolescent gynecomastia. Clinical and endocrine studies. Am J Dis Child 1983;137:1080Y1082. 42. 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;57:238Y245.
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43. 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;52:106Y114. 44. Di Lorenzo G, Perdona S, De Placido S, et al. Gynecomastia and breast pain induced by adjuvant therapy with bicalutamide after radical prostatectomy in patients with prostate cancer: the role of tamoxifen and radiotherapy. J Urol 2005;174:2197Y2203. 45. Perdona S, Autorino R, De Placido S, et al. Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial. Lancet Oncol 2005;6:295Y300. 46. Lawrence SE, Faught KA, Vethamuthu J, et al. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr 2004;145:71Y76. 47. Derman O, Kanbur NO, Kutluk T. Tamoxifen treatment for pubertal gynecomastia. Int J Adolesc Med Health 2003;15:359Y363. 48. Alagaratnam TT. Idiopathic gynecomastia treated with tamoxifen: a preliminary report. Clin Ther 1987;9:483Y487. 49. Jones DJ, Holt SD, Surtees P, et al. A comparison of danazol and placebo in the treatment of adult idiopathic gynaecomastia: results of a prospective study in 55 patients. Ann R Coll Surg Engl 1990;72:296Y298. 50. Saltzstein D, Sieber P, Morris T, et al. Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole. Prostate Cancer Prostatic Dis 2005;8:75Y83. 51. Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:4428Y4433. 52. Hanavadi S, Banerjee D, Monypenny IJ, et al. The role of tamoxifen in the management of gynaecomastia. Breast 2006;15:276Y280. 53. Wassersug RJ, Oliffe JL. The social context for psychological distress from iatrogenic gynecomastia with suggestions for its management. J Sex Med 2009;6:989Y1000.
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Gynecomastia: Etiologies, Clinical Presentations, Diagnosis, and Management Barry Ladizinski, MD, Kachiu Cecilia Lee, MD, MPH, F.N.U. Nutan, H. William Higgins, II, MD, and Daniel G. Federman, MD Abstract: Gynecomastia is a common finding that is present in up to 57% of men. It is caused by proliferation of the mammary glands, which leads to the development of dense subareolar tissue. The condition results from both physiologic (eg, hypogonadism, altered estrogen-to-androgen ratio) and nonphysiologic (eg, drugs, herbal products) causes. Most cases are benign and resolve spontaneously. Treatment is usually unnecessary, although there are specific signs and symptoms that warrant further workup. Psychosocial effects also are of concern, particularly among adolescents. Knowledge of the possible causes of gynecomastia and a thoughtful approach to the patient presenting with this condition can lead to improved outcomes and patient satisfaction. This concise review of the common presentation, etiologies, diagnosis, and treatment of gynecomastia should aid healthcare professionals who may encounter these patients in their practices. Key Words: andrology, breast enlargement, gynecomastia, hypogonadism, men, pseudogynecomastia
G
ynecomastia is the abnormal development of dense subareolar tissue in men, secondary to benign proliferation of mammary glands. It is a common condition that causes concern among many patients and healthcare practitioners. Typically, the male breast contains minimal amounts of glandular and adipose tissue. In gynecomastia, the estrogen:androgen ratio (estrogen stimulates breast growth; androgen inhibits breast growth) is disrupted, leading to enlargement of the male breast through glandular tissue proliferation.1,2 Gynecomastia can result from both physiological and nonphysiological causes and has distinct clinical, histological, and radiologic features.
MD,
Epidemiology Gynecomastia, from the Greek gynaik, meaning woman, is the most common benign condition of the male breast, accounting for up to 80% of referrals to specialized breast care centers.3,4 A minority of these patients may seek medical attention for this condition. On routine physical examination, gynecomastia is found in 36% to 57% of men.5Y7 Physiologically, there are three age peaks for gynecomastia: infancy, puberty, and past 50 years.5 These peaks represent periods of hormonal transition within the body, causing an imbalance in the free-estrogen:free-androgen ratio. An estimated 60% to 90% of neonates have transient gynecomastia, which regresses within the first year. During adolescence, 48% to 64% of boys experience gynecomastia caused by hormonal and growth changes, with peak onset at 13 to 14 years old (Tanner stage 3 or 4); this typically resolves by age 18.5,8 In adults, gynecomastia is most commonly found in the 50- to 60-year-old age group and is present in up to 57% of healthy older men and up to 55% of men at autopsy.9 Higher body mass index (BMI) also is associated with this condition, because excess adipose tissue leads to increased conversion of androgen precursors to estrogen. The prevalence of gynecomastia rises above 80% in men with BMIs 925 kg/m2.2,6
Clinical Features Gynecomastia is present typically for months to years before it is discovered on physical examination and presents clinically as a unilateral or bilateral (Table 1) enlargement of
Key Points From the Department of Dermatology, Brown University, Providence, Rhode Island, the Department of Internal Medicine, Medstar Good Samaritan Hospital, Baltimore, Maryland, and the Department of Internal Medicine, Veterans Administration Hospital, West Haven, Connecticut. Reprint requests to Dr Barry Ladizinski, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD. E-mail: [email protected] The authors have no financial relationships to disclose and no conflicts of interest to report. Accepted June 4, 2013. Copyright * 2014 by The Southern Medical Association 0038-4348/0Y2000/107-44 DOI: 10.1097/SMJ.0000000000000033
44
& Gynecomastia is a common condition, affecting up to 57% of men. & Gynecomastia is caused by benign proliferation of mammary glands, which leads to the development of dense subareolar tissue. & Most cases of gynecomastia are benign and resolve spontaneously. & Treatment is typically not necessary, although certain signs and symptoms warrant further workup. Psychosocial issues often need to be addressed.
* 2014 Southern Medical Association
Copyright © 2013 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Review Article
Table 1. Differential diagnosis of a palpable breast mass in male patients
have a higher BMI, higher body fat percentage, and lower levels of serum testosterone and luteinizing hormone.8,16
Nonphysiologic Causes
Pseudogynecomastia Gynecomastia Breast cancer Benign conditions: lipoma, dermoid cyst, sebaceous cyst, lymphoplasmacytic inflammation, ductal ectasia, hematoma, fat necrosis
concentric breast tissue around the areola, with the tissue usually soft and uniform to palpation.10Y12 Gynecomastia usually is asymptomatic, although localized pain and tenderness occasionally can be present, particularly during the early months of rapid glandular proliferation. Unilateral proliferations of glandular tissue are more common on the left side, with the prevalence of unilateral presentation ranging from 14% to 50% of all cases of gynecomastia.10,13,14 Unilateral presentation can be psychologically concerning to patients.15 In a case study of 10 subjects with unilateral gynecomastia, one-third of subjects feared they had breast cancer. In contrast, pseudogynecomastia (fatty breasts) results from the enlargement of adipose breast tissue instead of the proliferation of glandular tissue seen in true gynecomastia. Pseudogynecomastia tissue feels softer to palpation, with some describing it having a less rubbery feel. True gynecomastia also has been described as having a spongy or concentric disc-shape feel, centered around the areola. Comparison of subareolar tissue with other areas of fatty subcutaneous tissue can help differentiate this condition from true gynecomastia.5 Besides gynecomastia and pseudogynecomastia, other conditions can cause enlargement of breast tissue in men. Asymmetric enlargement of the breast with the presence of a firm mass is most consistent with other causes such as breast cancer, which accounts for approximately 0.2% of all malignancies in men.5 Malignant tumors typically present in an eccentric location, rather than centrally around the areola, as seen in gynecomastia. Other findings, such as skin dimpling, peau d’orange, nipple retraction, and lymphadenopathy should also raise concern for malignancy.11
A thorough medication history always should be obtained, because drugs are a frequently cited cause of benign gynecomastia (Table 3), accounting for up to 25% of all cases.11,17,18 In addition, over-the-counter herbal products, such as panax ginseng, tea tree oil, and topical lavender (used in some shampoos, soaps, and lotions), have been associated with gynecomastia.19Y22 Consumption of 9300 mg of soy per day also has been reported to cause the condition, although other studies have failed to find a similar association.23,24 Of note, breasts with medication-induced gynecomastia can be extremely tender, but the cessation of medications, with the exception of anabolic steroid use, usually leads to reversal of the condition within a few weeks.25 Medical conditions that can cause gynecomastia include hypogonadism (eg, primary hypogonadism, pituitary insufficiency, Klinefelter syndrome), cirrhosis/liver disease, hyperthyroidism, end-stage renal disease/dialysis, malnutrition, and malignancies of the testes, adrenal glands, or pituitary gland.5 Although rare, gynecomastia is the presenting sign in up to 10% of patients with testicular cancer. This symptom may
Table 2. Nonmedication causes of gynecomastia Idiopathic gynecomastia Physiological gynecomastia Newborn gynecomastia Adolescent gynecomastia Elderly gynecomastia Chronic diseases Cirrhosis Diabetes mellitus Heart failure Renal insufficiency Tuberculosis Increases in estrogens or androgens Puberty Obesity Testicular tumor (eg, Leydig cell tumor, choriocarcinoma)
Physiologic Causes Physiologic occurrence of gynecomastia is commonly seen in neonates (secondary to transfer of maternal hormones across the placenta), adolescent boys (secondary to increased conversion of testosterone to estradiol via aromatase), and men older than 50 years (secondary to decreased free testosterone) (Table 2). Physiologic gynecomastia is usually self-limiting and resolves spontaneously in most patients. Adolescent gynecomastia typically resolves within 1 to 2 years, but rarely persists (G5% of cases). Compared with healthy controls, patients with persistent pubertal gynecomastia are more likely to Southern Medical Journal
Hyperthyroidism Abuse of anabolic steroids Hypergonadotropic hypogonadism Klinefelter syndrome Antiandrogen therapy Testicular feminization syndrome Reifenstein syndrome (familial pseudohermaphroditism) Bilateral testicular disease or bilateral loss of testes (eg, mumps orchitis) Hyperprolactinemia Pituitary adenoma
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Table 3. Drug-induced causes of gynecomastia1 Anabolic steroids, androgens Antiandrogens (eg, flutamide, finasteride, spironolactone) Antibiotics (eg, minocycline) Antifungals (eg, ketoconazole) Cardiovascular medications (eg, amlodipine, angiotensin-converting enzyme inhibitors, calcium channel blockers, digoxin, diltiazem, furosemide, verapamil) Estrogens (eg, estrogen agonists, phytoestrogens) Ethanol Histamine blockers (eg, cimetidine) HIV/AIDS medications (eg, efavirenz) Illicit drugs (eg, amphetamines, heroin, methadone, marijuana) Over-the-counter supplements/products (eg, panax ginseng, tea tree oil) Psychiatric medications (eg, risperidone, phenytoin, haloperidol, paroxetine, benzodiazepines, tricyclic antidepressants)
precede a palpable testicular mass or detectable hormonal abnormalities,9 and ultrasound of the scrotum may be necessary to detect these tumors.26Y28 Specifically, Leydig cell tumors are likely to cause gynecomastia because of the secretion of estradiol.29,30 Ultrasound is recommended in young patients with a palpable testicular mass or in those who show other signs of hormonal changes. The incidence and prevalence of testicular cancer in those presenting with gynecomastia is unknown.
Diagnostic Considerations Gynecomastia typically is discovered upon routine physical examination and is usually asymptomatic; however, some patients may present with complaints of pain, tenderness, psychosocial distress caused by cosmetic concerns, or fear of malignancy. Given the broad differential, a comprehensive clinical examination with a diagnostic workup is occasionally required (Fig.). History and physical examination should form the basis of any investigation into gynecomastia. If the patient is symptomatic, then physicians should inquire about the duration of symptoms and presence of nipple discharge, overlying skin changes, or firm masses. Symptoms such as weight loss or presence of a testicular mass should prompt concern and further diagnostic testing.9 Patients with macromastia (breast tissue 95 cm), rapidly progressive gynecomastia, persistent mastodynia, or other evidence of malignancy (eg, palpable, fixed, peripheral lymph nodes 91.5 cm) should undergo further evaluation with breast imaging. Gynecomastia itself is not a risk factor for malignancy, with the exception of patients with Klinefelter syndrome.5 Breast cancer should be considered in patients with asymmetric enlargement of the breast or in those with other risk factors. A review of patients’ prescription and over-the-counter medications/vitamin and herbal supplements is necessary.31 Specific questions should be asked regarding topical preparations,
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growth hormones, anabolic steroids, and use of alcohol and/or illicit recreational drugs (eg, marijuana, heroin, amphetamines). Although some studies have associated marijuana use with gynecomastia, others have not found a similar link.31Y34 Patients may not volunteer information regarding these medications unless asked about them directly, and when speaking with an adolescent, it is prudent to conduct parts of the interview without parent(s) in the room. When alone, the adolescent may be more apt to admit to over-the-counter medication use or use of illicit drugs, such as marijuana or anabolic steroids. Physical examination requires palpation of the breast tissue, with assessment of symmetry and consistency. Eccentric, immobile, and firm masses are suggestive of malignancy or other causes and require diagnostic workup. Skin examination for nipple discharge, retraction, or peau d’orange is reason for concern. A testicular examination is also necessary to determine the presence of any masses.4
Diagnostic Testing Most patients presenting with gynecomastia do not need a complete workup, which should be reserved for those in whom clinical suspicion for malignancy or other comorbidities is high. In these patients, laboratory tests to consider include a comprehensive metabolic panel, and tests to determine levels of thyroid-stimulating hormone, free thyroxine, free and total testosterone, estradiol, dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and prolactin levels. Testicular ultrasound should be considered if bloodwork reveals hormonal dysregulation or if testicular cancer is a concern.2,5 Ultrasound, rather than mammography, is the radiologic modality of choice for diagnosing gynecomastia, which will typically reveal hyperechoic fibroglandular tissue.4 Mammography and possible fine-needle aspiration or breast biopsy can be considered if breast cancer is a concern. Mammography for the detection of male breast cancer has a reported sensitivity of 92% and specificity of 91%.23 No established guidelines exist regarding regular mammographic screening for men with gynecomastia; however, if the patient is BRCA (the breast cancer gene) positive, an annual screening mammogram is generally recommended.2 BRCA screening should be performed only in patients with a strong family history of BRCA-associated cancers (eg, breast, ovarian, prostate, pancreatic cancers, malignant melanoma). Tissue sampling should be obtained only in patients with high suspicion for malignancy. Histology of breast tissue can be obtained by fine-needle biopsy, with gynecomastia usually demonstrating increased subareolar fat, stromal hyalinization, and fibrosis.10 Factors that increase the risk of male breast cancer include high circulating estrogen levels, Klinefelter syndrome, family history of breast cancer, presence of BRCA gene mutations, hyperprolactinemia, and history of prior radiation therapy.16,35Y40 In a Department of Veterans Affairs study of African American patients, cholelithiasis was a significant predictor of breast cancer * 2014 Southern Medical Association
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Review Article
Fig. Diagnostic algorithm for gynecomastia. in men.36 Still, no increased risk of breast cancer associated with gynecomastia in men has been demonstrated.
Treatment Options Gynecomastia is typically benign in nature, but breasts sometimes can be tender, especially during adolescence. Most men seek reassurance that their condition is benign and that no intervention is required. Enlargement of breast tissue G4 cm is most likely to resolve spontaneously, whereas pubertal gynecomastia will resolve within months to years in nearly 90% of patients. Some individuals experience significant psychosocial distress; therefore, it is important to offer psychological support as part of any treatment regimen.3 Southern Medical Journal
For patients who are symptomatic and require treatment, medications should be started early, because patients with gynecomastia for 912 months may have poor responses compared with those with disease lasting G12 months.3 This is the result of irreversible deposition of fibrous tissue in the breasts. There are no therapies for gynecomastia that have been approved by the Food and Drug Administration, but proposed treatments include anti-estrogens (eg, clomiphene41), selective estrogen receptor blockers (eg, tamoxifen42Y48), synthetic testosterone derivatives (eg, danazol49), aromatase inhibitors (eg, anastrazole50,51), and parenteral or transdermal testosterone (Table 4). Of note, testosterone used for treating hypogonadism can sometimes lead to gynecomastia secondary to peripheral conversion to estrogen. Radiation also has been
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Table 4. Evidence-based treatment strategies for gynecomastia Men receiving antiandrogen therapy with gynecomastia Tamoxifen: most effectiveVlevel I evidence42Y44 RadiotherapyVlevel I evidence45,46 Anastrazole: less effective than tamoxifenVlevel I evidence47 Gynecomastia in all other cases Anastrazole: not effectiveVlevel I evidence48 Tamoxifen/raloxifenVlevel IV evidence49Y51 DanazolVlevel IV evidence39 Surgical excisionVlevel IV evidence52 Levels of evidence: Level I: evidence obtained from at least one properly designed randomized controlled trial; level II: evidence obtained from welldesigned controlled trials without randomization; level III: evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group; level IV: evidence obtained from multiple time series with or without intervention, such as case studies (dramatic results in uncontrolled trials also may be regarded as this type of evidence); level V: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
used as gynecomastia prophylaxis in patients with prostate cancer who are receiving estrogen therapy. Gynecomastia caused by an underlying medical condition (eg, testicular cancer, hyperthyroidism) often can be reversed by treatment of the underlying cause, and discontinuation of the offending agent usually results in resolution of medicationinduced gynecomastia. Obese patients should be counseled on weight loss strategies and low-fat diets or offered consultation with a nutritionist. Liposuction, endoscopic subcutaneous mastectomy, or reduction mammoplasty is indicated in cases of macromastia, long-standing cases of or refractory gynecomastia, or for cosmetic reasons.52 Gynecomastia also can have psychosocial effects on patients. Young men with gynecomastia often are reticent to participate in athletic activities that may result in exposing the chest, they may avoid showers and swimming pools, and they may camouflage their bodies by wearing loose-fitting clothes. Posture also can be affected because patients tend to minimize the deformation by rolling their shoulders toward the midline and slouching forward; thus, these psychosocial issues may need to be addressed foremost in those patients.53 Although most patients do not require psychotherapy, they should be provided with reassurance about the self-limited nature of the condition, encouragement to participate in social and physical activities, and counseling on lifestyle modifications.
Conclusions Gynecomastia is a common problem that is vexing to both patients and healthcare professionals. Knowledge of potential causes and a thoughtful approach to the patient presenting with gynecomastia have the potential to lead to improved outcomes and patient satisfaction.
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References 1. Krause W. Drug-inducing gynaecomastiaVa critical review. Andrologia 2012;44:621Y626. 2. Narula HS, Carlson HE. Gynecomastia. Endocrinol Metab Clin North Am 2007;36:497Y519. 3. Al-Allak A, Govindarajulu S, Shere M, et al. Gynaecomastia: a decade of experience. Surgeon 2011;9:255Y258. 4. Daniels IR, Layer GT. Gynaecomastia. Eur J Surg 2001;167:885Y892. 5. Bembo SA, Carlson HE. Gynecomastia: its features, and when and how to treat it. Cleve Clin J Med 2004;71:511Y517. 6. Niewoehner CB, Nuttal FQ. Gynecomastia in a hospitalized male population. Am J Med 1984;77:633Y638. 7. Nuttall FQ. Gynecomastia as a physical finding in normal men. J Clin Endocrinol Metab 1979;48:338Y340. 8. 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;21:579Y587. 9. Hassan HC, Cullen IM, Casey RG, et al. Gynaecomastia: an endocrine manifestation of testicular cancer. Andrologia 2008;40:152Y157. 10. Bannayan GA, Hajdu SI. Gynecomastia: clinicopathologic study of 351 cases. Am J Clin Pathol 1972;57:431Y437. 11. Braunstein GD. Clinical practice. Gynecomastia. N Engl J Med 2007; 357:1229Y1237. 12. Hines SL, Tan WW, Yasrebi M, et al. The role of mammography in male patients with breast symptoms. Mayo Clin Proc 2007;82:297Y300. 13. Wiesman IM, Lehman JA Jr, Parker MG, et al. Gynecomastia: an outcome analysis. Ann Plast Surg 2004;53:97Y101. 14. Colombo-Benkmann M, Buse B, Stern J, et al. Indications for and results of surgical therapy for male gynecomastia. Am J Surg 1999;178:60Y63. 15. Al-Qattan M, Hassanain J, Mahmoud S, et al. On the neglected entity of unilateral gynecomastia. Ann Plast Surg 2005;55:255Y257. 16. Ersoz H, Onde ME, Terekeci H, et al. Causes of gynaecomastia in young adult males and factors associated with idiopathic gynaecomastia. Int J Androl 2002;25:312Y316. 17. Deepinder F, Braunstein GD. Drug-induced gynecomastia: an evidencebased review. Expert Opin Drug Saf 2012;11:779Y795. 18. Eckman A, Dobs A. Drug-induced gynecomastia. Expert Opin Drug Saf 2008;7:691Y702. 19. Block SL. The possible link between gynecomastia, topical lavender, and tea tree oil. Pediatr Ann 2012;41:56Y58. 20. Henley DV, Lipson N, Korach KS, et al. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med 2007;356:479Y485. 21. Kakisaka Y, Ohara T, Tozawa H, et al. Panax ginseng: a newly identified cause of gynecomastia. Tohoku J Exp Med 2012;228:143Y145. 22. Korde LA, Zujewski JA, Kamin L, et al. Multidisciplinary meeting on male breast cancer: summary and research recommendations. J Clin Oncol 2010; 28:2114Y2122. 23. Martinez J, Lewi JE. An unusual case of gynecomastia associated with soy product consumption. Endocr Pract 2008;14:415Y418. 24. Messina M. Soybean isoflavone exposure does not have feminizing effects on men: a critical examination of the clinical evidence. Fertil Steril 2010; 93:2095Y2104. 25. Hartgens F, Kuipers H. Effects of androgenic-anabolic steroids in athletes. Sports Med 2004;34:513Y554. 26. Emory TH, Charboneau JW, Randall RV, et al. Occult testicular interstitialcell tumor in a patient with gynecomastia: ultrasonic detection. Radiology 1984;151:474. 27. Hendry WS, Garvie WH, Ah-See AK, et al. Ultrasonic detection of occult testicular neoplasms in patients with gynaecomastia. Br J Radiol 1984; 57:571Y572. 28. Mudde AH, Haak A, Kruyt RH. Ultrasonic detection of occult Leydig cell tumours in two patients with gynaecomastia. Neth J Med 1987;31:72Y76.
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Copyright © 2013 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
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29. Haas GP, Pittaluga S, Gomella L, et al. Clinically occult Leydig cell tumor presenting with gynecomastia. J Urol 1989;142:1325Y1327. 30. Mellor SG, McCutchan JD. Gynaecomastia and occult Leydig cell tumour of the testis. Br J Urol 1989;63:420Y422. 31. Goldman RD. Drug-induced gynecomastia in children and adolescents. Can Fam Physician 2010;56:344Y345. 32. Dardick KR. Holiday gynecomastia related to marijuana? Ann Intern Med 1993;119:253. 33. Thompson DF, Carter JR. Drug-induced gynecomastia. Pharmacotherapy 1993;13:37Y45. 34. Cates W Jr, Pope JN. Gynecomastia and cannabis smoking. A nonassociation among US Army soldiers. Am J Surg 1977;134:613Y615. 35. Brinton LA. Breast cancer risk among patients with Klinefelter syndrome. Acta Paediatr 2011;100:814Y818. 36. Brinton LA, Carreon JD, Gierach GL, et al. Etiologic factors for male breast cancer in the U.S. Veterans Affairs medical care system database. Breast Cancer Res Treat 2010;119:185Y192. 37. Johansen Taber KA, Morisy LR, Osbahr AJ 3rd, et al. Male breast cancer: risk factors, diagnosis, and management. Oncol Rep 2010;24:1115Y1120. 38. Krause W. Male breast cancerVan andrological disease: risk factors and diagnosis. Andrologia 2004;36:346Y354. 39. Maksimovic S. Bilateral breast carcinoma in patients with Klinefeleter syndrome: report of case. Med Arch 2010;64:250Y252. 40. Zygogianni AG, Kyrgias G, Gennatas C, et al. Male breast carcinoma: epidemiology, risk factors and current therapeutic approaches. Asian Pac J Cancer Prev 2012;13:15Y19. 41. Plourde PV, Kulin HE, Santner SJ. Clomiphene in the treatment of adolescent gynecomastia. Clinical and endocrine studies. Am J Dis Child 1983;137:1080Y1082. 42. 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;57:238Y245.
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43. 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;52:106Y114. 44. Di Lorenzo G, Perdona S, De Placido S, et al. Gynecomastia and breast pain induced by adjuvant therapy with bicalutamide after radical prostatectomy in patients with prostate cancer: the role of tamoxifen and radiotherapy. J Urol 2005;174:2197Y2203. 45. Perdona S, Autorino R, De Placido S, et al. Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial. Lancet Oncol 2005;6:295Y300. 46. Lawrence SE, Faught KA, Vethamuthu J, et al. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr 2004;145:71Y76. 47. Derman O, Kanbur NO, Kutluk T. Tamoxifen treatment for pubertal gynecomastia. Int J Adolesc Med Health 2003;15:359Y363. 48. Alagaratnam TT. Idiopathic gynecomastia treated with tamoxifen: a preliminary report. Clin Ther 1987;9:483Y487. 49. Jones DJ, Holt SD, Surtees P, et al. A comparison of danazol and placebo in the treatment of adult idiopathic gynaecomastia: results of a prospective study in 55 patients. Ann R Coll Surg Engl 1990;72:296Y298. 50. Saltzstein D, Sieber P, Morris T, et al. Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole. Prostate Cancer Prostatic Dis 2005;8:75Y83. 51. Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:4428Y4433. 52. Hanavadi S, Banerjee D, Monypenny IJ, et al. The role of tamoxifen in the management of gynaecomastia. Breast 2006;15:276Y280. 53. Wassersug RJ, Oliffe JL. The social context for psychological distress from iatrogenic gynecomastia with suggestions for its management. J Sex Med 2009;6:989Y1000.
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