Adolescent Health Care: A Practical Guide

Chapter 11

Gynecomastia

Alain Joffe

Definition

Gynecomastia refers to an increase in the glandular and stromal tissue of the male breast. When identified during puberty, it is usually a benign and transient condition. Even at this stage of development, however, gynecomastia can be due to a serious underlying disorder or can persist long enough that the adolescent seeks treatment. With the increase in obesity that has occurred over the last few decades, true gynecomastia must be distinguished from fatty tissue overlying the pectoral muscles.

Epidemiology

  1. Gynecomastia occurs in 19.6% of 10.5-year-old males, reaches a peak prevalence of 64.6% at age 14 years, and becomes less common thereafter. In one study, 17% of males 19 years and younger and 33% of 20- to 24-year-olds had palpable breast tissue at least 2 cm in diameter. Approximately 4% of adolescents will have severe gynecomastia (sometimes know as “type III” gynecomastia; >4.0 cm in diameter or approximately equal to the midpubertal female breast) that persists into adulthood. Mean age at onset is 13 years 2 months (SD 0.8 years).
  2. Onset of gynecomastia correlates best with pubertal development; typically, its onset occurs 1.2 years (SD 0.6) after a boy reaches stage 2 genital development and 0.4 (SD 0.7) years after reaching stage 2 pubic hair. Genital stage at onset of gynecomastia is as follows:

o    Genital stage 1: 20%

o    Genital stage 2: 50%

o    Genital stage 3: 20%

o    Genital stage 4: 10%

Etiology

Breast tissue of males and females is similar at birth and responds similar to estrogens during childhood. At puberty, the breast tissue of boys demonstrates both ductal and periductal mesenchymal tissue proliferation. This tissue involutes and atrophies as testicular androgens increase to adult levels. In pubertal females, under the influence of increasing levels of both estrogen and progesterone, breast tissue continues to undergo ductal enlargement, branching, and acini development. The balance between estrogen and testosterone levels determines the extent of breast tissue development in males. As estrogens stimulate and androgens antagonize breast tissue development, an increase in estrogen relative to testosterone can lead to gynecomastia. Because estradiol levels increase by three- to five-fold during puberty whereas testosterone levels increase 30- to 40-fold, peak estradiol levels may be reached before adult testosterone levels. Aromatase (estrogen synthetase) plays a key role in estrogen production among men. The adult male's testes produce only 15% of the estradiol and <5% of the estrone circulating in the blood. The remainder is produced in extraglandular sites through aromatization. Hence, significant increases in extraglandular tissue (such as in obesity) result in significant elevations of circulating estrogens.

Alterations in the ratio of estrogens to androgens have been demonstrated in individuals with gynecomastia related to Klinefelter syndrome, thyrotoxicosis, cirrhosis, adrenal and testicular neoplasms, primary hypogonadism, and malnutrition. Use of various medications or drugs can also alter the hormonal milieu. In many patients with gynecomastia, serum hormone levels are within the reference range; however, there is experimental evidence to suggest that in some of these patients, altered sensitivity of the breast tissue to hormones may be responsible for the breast enlargement.

Mechanisms to account for an increase in estrogen or a decrease in androgen activity include the following:

  1. Increase in serum estrogen concentrations
  2. Increase in estradiol secretion from testes (e.g., Leydig cell tumors) or from adrenal tumors
  3. Excessive extraglandular conversion of androgens to estrogens by aromatase
  • Overproduction of adrenal precursors (mainly androstenedione) that are then converted by aromatase into estrone
  • Overproduction of testicular precursors (mainly testosterone) that are then converted to estradiol
  • Enhancement of extraglandular aromatase activity
  • –Disease states (hyperthyroidism, liver disease)
  • –Increased body fat (obesity)
  • –Medication (e.g., spironolactone) or drug use

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  • –Idiopathic (caused by persistence of a fetal form of aromatase)
  1. Increase in bioavailability of estrogens: a decrease in the amount of estrogen bound to sex hormone-binding globulin (SHBG) (e.g., use of spironolactone or ketoconazole)
  2. Exogenous intake of estrogens, either through oral intake or from use of topical estrogens
  3. Decrease in serum androgen concentrations
  4. Impairment of testicular production in Leydig cells
  • Primary hypogonadism (e.g., anorchia, Klinefelter syndrome)
  • Secondary hypogonadism through disorders of hypothalamus or pituitary
  • Congenital enzyme defects
  • Drug-induced inhibition of enzymes needed in testosterone synthesis (e.g., spironolactone or ketoconazole)
  • Chronic stimulation of Leydig cells by high levels of human chorionic gonadotropin (hCG) (e.g., hCG-secreting tumors) can lead to a reduction in testosterone biosynthesis
  • Hyperestrogenic states leading to suppression of luteinizing hormone (LH) and testosterone secretion
  1. Increased hepatic clearance of androgens
  2. Increase in SHBG, leading to a decrease in free testosterone (e.g., liver disease and hyperestrogenic states)
  3. Alterations of estrogen and androgen receptors
  4. Androgen-receptor deficiency states (e.g., androgen insensitivity syndromes)
  5. Drug interference with androgen receptors (e.g., spironolactone, flutamide, or cimetidine)
  6. Drugs that mimic estrogens and stimulate estrogen-receptor sites (e.g., digoxin and phytoestrogens in some marijuana preparations)

Sher et al. (1998) reviewed the etiology of gynecomastia in 60 male subjects aged 9 and older referred to a pediatric endocrine clinic for evaluation of significant gynecomastia (more than 4 cm in diameter). Seven patients were determined to have an endocrine disorder (including Klinefelter syndrome, 46,XX maleness, primary testicular failure, partial androgen insensitivity, fibrolamellar hepatocarcinoma, and increased aromatase activity). An additional eight patients had other medical problems, including five with neurological disorders, but it is not clear that these conditions were causally related to the gynecomastia. The 45 remaining subjects were considered to have significant idiopathic gynecomastia (normal follicle-stimulating hormone (FSH), LH, testosterone, and estradiol levels); interestingly, they were noted to be both taller and heavier than average.

Clinical Manifestations

  1. Forms
  2. Type I: One or more subareolar nodules, freely movable
  3. Type II: Breast nodules beneath areola but also extending beyond the areolar perimeter
  4. Type III: Resembles breast development of sexual maturity rating 3 (SMR 3) in girls
  5. Occurs bilaterally in 77% to 95% of cases, with concurrent or sequential involvement of both breasts
  6. Physical examination
  7. Types I and II are associated with a firm, rubbery consistency of the breasts whereas type III has a consistency similar to that of the female breast
  8. Types I and II gynecomastia are usually associated with tenderness on palpation or when clothing touches the breast

Differential Diagnosis

Differential diagnosis includes (Braunstein, 1993):

  1. Physiological—pubertal gynecomastia
  2. Medication or drug use. There is some controversy as to which medications truly cause gynecomastia. More than 300 drugs have been reported as causing gynecomastia to the Committee on Safety of Medicines in the United Kingdom since 1963. Thompson and Carter (1993) believe that sufficient evidence exists to implicate calcium-channel blockers, cancer chemotherapeutic agents, histamine2-receptor blockers, ketoconazole, and spironolactone. Braunstein (1993) considers that a strong relationship exists for those marked with an asterisk (*) in the list that follows:
  3. Hormones: Estrogens*, testosterone*, anabolic steroids*, chorionic gonadotropin*
  4. Psychoactive agents: Phenothiazines, atypical antipsychotic agents, diazepam, haloperidol, tricyclic antidepressants
  5. Cardiovascular drugs: Digoxin*, verapamil, captopril, methyldopa, nifedipine, enalapril, reserpine, minoxidil
  6. Antiandrogens or inhibitors of androgen synthesis: Cyproterone*, spironolactone*, flutamide*
  7. Antibiotics: Isoniazid, metronidazole, ketoconazole*
  8. Antiulcer medications: Cimetidine*, ranitidine, omeprazole
  9. Cancer chemotherapeutics, particularly alkylating agents*
  10. Drugs of abuse: Marijuana, alcohol, amphetamines, heroin, methadone
  11. Other: Phenytoin, penicillamine, theophylline, metoclopramide, saquinavir, indinavir (and other antiretroviral drugs)
  12. Underlying medical disorders
  13. Renal failure and dialysis
  14. Recovery from malnutrition
  15. Primary gonadal failure: Including Klinefelter syndrome and Reifenstein syndrome
  16. Secondary hypogonadism
  17. Hyperthyroidism
  18. Liver disease, including cirrhosis and hepatoma
  19. Neoplasms
  • Testicular: Germ cell, Leydig cell, or Sertoli cell
  • Adrenal adenomas and carcinoma
  • Ectopic hCG production (particularly lung, liver, and kidney cancer)
  1. Enzyme defects in testosterone biosynthesis
  2. Androgen insensitivity syndromes
  3. Excessive extraglandular aromatase activity
  4. Pseudogynecomastia: Caused by adipose tissue in some obese males or prominent musculature in some physically fit adolescent boys
  5. Breast mass because of cancer, dermoid cyst, lipoma, hematoma, or neurofibroma

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Diagnosis

  1. History: Screen for medication and drug use and clues suggesting systemic illness
  2. Physical examination
  3. Differentiation of gynecomastia from pseudogynecomastia caused by prominent musculature or excessive adipose tissue
  • The teen is placed in the supine position, with his hands behind his head; the examiner then places the thumb and forefinger at opposing margins of the breast
  • In gynecomastia, as the fingers are brought together, rubbery or firm breast tissue can be felt as a freely movable, and occasionally tender, disk of tissue concentric to the areola; in pseudogynecomastia, no discrete mass is felt
  • In other conditions, such as a lipoma or dermoid cyst, the mass is usually eccentric to the areola
  1. Findings suggestive of hypogonadism, hyperthyroidism, or hypothyroidism
  2. Testicular mass or atrophy
  3. Findings suggestive of liver disease

Pubertal gynecomastia can be presumed as the etiology of the breast enlargement in adolescents who (a) present with a unilateral or bilateral, subareolar, rubbery or firm mass; (b) are not using any medications or drugs possibly associated with gynecomastia; (c) have a normal testicular examination; and (d) lack any evidence of renal, hepatic, thyroid, or other endocrine disease. No further tests are necessary but the patient should be reevaluated in 6 months. If medication or drug use is suspected, it should be discontinued and the adolescent reexamined in 1 month. At that time, breast tenderness, if present, should decrease and breast size may decrease.

If an endocrine disorder is suspected, the practitioner should order measurements of hCG, LH, serum testosterone, and estradiol (or, as some authors recommend, estrone sulphate). These tests will help in differentiating the cause of nonpubertal gynecomastia.

Findings and Implications of Serum HCG, LH, Testosterone, and Estradiol

Evaluate laboratory studies as follows (Braunstein, 1993):

  1. Elevated hCG concentration: Perform testicular ultrasonography
  2. Mass found: Testicular germ cell tumor
  3. Normal sonogram: Extragonadal germ cell tumor or hCG-secreting neoplasm likely; chest film and abdominal computed tomography (CT) indicated
  4. Decreased testosterone concentration with:
  5. Elevated LH concentration: Primary hypogonadism, including Klinefelter syndrome, and testicular atrophy caused by mumps orchitis
  6. Normal or low LH concentration: Measure serum prolactin
  • Elevated prolactin level: Probably prolactin-secreting pituitary tumor; obtain magnetic resonance imaging (MRI) of hypothalamic pituitary area
  • Normal prolactin level: Secondary hypogonadism
  1. Elevated testosterone and LH concentrations: Measure thyroxine (T4) and thyroid-stimulating hormone (TSH) concentrations
  2. Elevated T4and low TSH concentrations: Hyperthyroidism (elevated testosterone is secondary to the increase in SHBG, leading to an increase in total testosterone; the etiology of increased LH levels in association with hyperthyroidism is uncertain)
  3. Normal T4and TSH concentrations: Androgen resistance
  4. Elevated estradiol with low or normal LH concentrations: Perform testicular ultrasonography
  5. Mass on sonogram: Leydig or Sertoli cell tumor
  6. Normal: Perform adrenal CT or MRI
  • Mass found: Adrenal neoplasm
  • No mass: Increased extraglandular aromatase activity
  1. Normal concentrations of hCG, LH, testosterone, and estradiol: Idiopathic gynecomastia

Therapy

  1. Underlying causes should be treated as appropriate. If a medication or drug is suspected, it should be discontinued, if possible.
  2. Pubertal gynecomastia: In most individuals with pubertal gynecomastia, particularly with mild to moderate degrees, only reassurance is needed. In most cases, the condition will improve or resolve within 6 to 12 months.
  3. Medical intervention
  4. Several drugs have been tried to reduce gynecomastia, including androgens (testosterone, dihydrotestosterone and the androgenic progesterone, danazol), antiestrogens (clomiphene, tamoxifen, and raloxifene), and aromatase inhibitors (testolactone, anastrozole, letrozole, and formestane). None of these is approved by the U.S. Food and Drug Administration for the treatment of adolescent gynecomastia, and studies using these medications in adolescents are limited. Dihydrotestosterone can lead to a reduction in breast volume in 75% of individuals, with 25% having a complete response (Kuhn et al., 1983). However, this medication is not readily available. Danazol has some limited effectiveness but is associated with significant side effects and would not be recommended in the treatment of adolescents. Tamoxifen has been evaluated in a number of studies. At a dose of 10 mg twice a day, tamoxifen resulted in a statistically significant reduction in breast size and pain without side effects. Ting et al. (2000) compared the efficacy of tamoxifen (23 patients) with that of danazol (20 patients) in the treatment of 23 males of a wide age range with idiopathic gynecomastia (mean age, 39.5; range 13 to 82). In this study, either tamoxifen (20 mg/day) or danazol (400 mg/day) was offered and continued until a constant response was obtained. Complete resolution of the gynecomastia occurred in 18 patients (78.2%) treated with tamoxifen but only in 8 patients (40%) in the danazol group. Five patients, all from the tamoxifen group, developed recurrence of breast mass. The wide age range of the patients treated precludes a clear determination as to whether tamoxifen

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is completely safe or effective in teens. Lawrence et al. (2004) reviewed their experience in managing 38 patients with persistent pubertal gynecomastia using either tamoxifen (10–20 mg twice daily) or raloxifene (60 mg daily) for 3 to 9 months. Mean reduction in breast diameter was 2.1 cm with tamoxifen versus 2.5 cm with raloxifene. Overall improvement was comparable (tamoxifen, 86%; raloxifene, 91%) but more raloxifene-treated patients (86%) than tamoxifen-treated patients (41%) had at least a 50% reduction in breast size. However, the study was neither randomized nor blinded and there was no true control group. Testolactone, an aromatase inhibitor, has also been found in an uncontrolled study to decrease pubertal gynecomastia without side effects.

  1. Medical therapy should be reserved for those individuals who have more than mild to moderate gynecomastia and who are significantly concerned about the condition. Tamoxifen could be used at an oral dosage of 10 to 20 mg twice daily for 3 months. This should lead to a decrease in tenderness and pain, followed by a reduction in the size of breast tissue.
  2. Surgical intervention: In older adolescents with moderate to severe gynecomastia associated with psychological sequelae, or in older patients in whom gynecomastia is unlikely to resolve spontaneously, surgical treatment is preferable. Recent surgical advances include the use of ultrasonic liposuction.

Prognosis

Pubertal gynecomastia usually resolves in 12 to 18 months. In 27% of affected adolescents, the condition lasts for >1 year, and in 7.7% >2 years. A small percentage of cases may persist into adulthood. There has been no proven relationship between gynecomastia and the development of breast cancer in male subjects.

Web Sites

For Teenagers and Parents

http://www.mayoclinic.com/health/gynecomastia/DS00850.htm. Mayo clinic article on gynecomastia.

http://www.keepkidshealthy.com/adolescent/adolescentproblems/gynecomastia.html. Teen-oriented site with information about gynecomastia and other health issues.

http://kidshealth.org/teen/question/just_guys/boybrst. html. Teen site with information about gynecomastia and other health issues.

http://www.choc.org/pediatricadvisor/pa/pa_gynecoma_hhg.htm Pediatric Advisor information on gynecomastia.

For Health Professionals

http://155.37.5.42/eAtlas/Breast/1694.htm. Site with pathology slide on gynecomastia.

http://www.emedicine.com/med/topic934.htm. E-medicine site on gynecomastia.

References and Additional Readings

Ardick KR. Holiday gynecomastia related to marijuana? Ann Intern Med 1993;119:253.

Bembo SA, Carlson HE. Gynecomastia: its features and when and how to treat it. Cleve Clin J Med 2004;71:511.

Biro FM, Lucky AW, Fluster GA, et al. Hormonal studies and physical maturation in adolescent gynecomastia. J Pediatr 1990;116:450.

Bowers SP, Pearlman NW, McIntyre RC Jr, et al. Cost-effective management of gynecomastia. Am J Surg 1998;176:638.

Braunstein GD. Gynecomastia. N Engl J Med 1993;328:490.

Braunstein GD. Aromatase and gynecomastia. Endocr Relat Cancer 1999;6:315.

Braunstein GD, Glassman HA. Gynecomastia. Curr Ther Endocrinol Metab 1997;6:401.

Brenner P, Berger A, Schneider W, et al. Male reduction mammoplasty in serious gynecomastias. Aesthetic Plast Surg 1992;16:325.

Buchanan CR. Abnormalities of growth and development in puberty. J R Coll Physicians Lond 2000;34:141.

Derman O, Kannbur NO, Kutluk T. Tamoxifen treatment for pubertal gynecomastia. Int J Adolesc Med Health 2003;15:359.

Derman O, Kanbur NO, Tokur TE. The effect of tamoxifen on sex hormone binding globulin in adolescents with pubertal gynecomastia. J Pediatr Endocrinol Metab 2004;18:1115.

Eberle AL, Sparrow JT, Keenan BS. Treatment of persistent pubertal gynecomastia with dihydrotestosterone heptanoate. J Pediatr 1986;109:144.

Hodgson ELB, Fruhstorfer BH, Malata CM. Ultrasonic liposuction in the treatment of gynecomastia. Plast Reconstr Surg 2005;116:646.

Ismail AAA, Barth JH. Endocrinology of gynaecomastia. Ann Clin Biochem 2001;38:596.

Kuhn JM, Roca R, Laudat MH, et al. Studies on the treatment of idiopathic gynaecomastia with percutaneous dihydrotestosterone. Clin Endocrinol 1983;19:513.

Large DM, Anderson DC. Twenty-four-hour profiles of circulating androgens and oestrogens in male puberty with and without gynecomastia. Clin Endocrinol 1979;11:505.

Lawrence SE, Faught KA, Vethamuthu J, et al. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr 2004;145:71.

Madani S, Tolia V. Gynecomastia with metoclopramide use in pediatric patients. J Clin Gastroenterol 1997;24:79.

Mahoney CP. Adolescent gynecomastia: differential diagnosis and management. Pediatr Clin North Am 1990;37:1389.

Marynick SP, Nisula BC, Pita JC Jr, et al. Persistent pubertal macromastia. J Clin Endocrinol Metab 1980;50:128.

Moore DC, Schlaepfer LV, Paunier L, et al. Hormonal changes during puberty. V. transient pubertal gynecomastia: abnormal androgen-estrogen ratio. J Clin Endocrinol Metab1984;58:492.

Neuman JF. Evaluation and treatment of gynecomastia. Am Fam Physician 1997;55:1835.

Nuttall FQ. Gynecomastia as a physical finding in normal men. J Clin Endocrinol Metab 1979;48:338.

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Nydick M, Bustos J, Dale JH, et al. Gynecomastia in adolescent boys. JAMA 1961;178:449.

Parker LN, Gray DR, Lai MK, et al. Treatment of gynecomastia with tamoxifen: a double-blind crossover study. Metabolism 1986;35:705.

Peters MH, Vastine V, Knox L, et al. Treatment of adolescent gynecomastia using a bipedicle technique. Ann Plast Surg 1998;40:241.

Sher ES, Migeon CJ, Berkovitz GD. Evaluation of boys with marked breast development at puberty. Clin Pediatr 1998;37:367.

Thompson DE, Carter JR. Drug-induced gynecomastia. Pharmacotherapy 1993;13:37.

Ting AC, Chow LW, Leung YF. Comparison of tamoxifen with danazol in the management of idiopathic gynecomastia. Am Surg 2000;66:38.