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*GYNECOMASTIA          See gynecomastia2007.pdf                               Causes  |  Diff-Dx  |  Lab  |  Rx  

A benign glandular enlargement of the male breast that is generally bilateral (may be asymmetric, or rarely, unilateral)
Gynecomastia is affected by increased estrogen/androgen ratio.

Types of Gynecomastia:

• Type I: Benign adolescent hypertrophy
  • Physiologic discoid subacute mass
  • Resolves spontaneously
• Type II: Physiologic gynecomastia  -  Generalized enlargement to greater degree
• Type III: Obesity simulates gynecomastia
• Type IV: Pectoral muscle hypertrophy

Marshall & Tanner Stages of breast enlargement/ development
[Adapted from Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969: 44:2291-303.]
Stage 1:  Preadolescent; only papillae are elevated.
Stage 2:  Breast bud and papilla are elevated and a small mount is present; areola diameter is enlarged.
Stage 3:  Further enlargement of breast mound; increased palpable glandular tissue.
Stage 4: Areola and papilla are elevated to form a second mound above the level of the rest of the breast.
Stage 5: Adult mature breast; recession of areola to the mound of breast tissue, rounding of the breast mound,
             and projection of only the papilla are evident.

CAUSES          

Physiologic cause - transient in neonatal boys, at puberty, aging; and idiopathic cause. 

Pathological causes:
1. Decreased production or action of testosterone

• Congenital anorchia
• Klinefelter syndrome: XXY chromosomes. Common features are small testes, minimal spermatogenesis, low testosterone, infertility. If the buccal smear is chromatin positive, the testosterone level is reduced, & FSH level is high, a definitive diagnosis can be made.
• Androgen resistance (testicular feminization & Reifenstein syndrome), Androgen production deficiency,
• Defects in testosterone synthesis; Testicular failure
• Secondary testicular failure: trauma castration, viral hepatitis, renal failure, neurological & granulomatous disease.

2. Increased estrogen production

• Estrogen secretion
  (1) True hermaphroditism
  (2) Testicular tumors: germinal cell testicular tumors.
  (3) Ca of lung: gonadotropin producing bronchogenic Ca
  (4) Tumors - estrogen secreting, gonadotropin secreting and prolactin secreting pituitary adenomas
• Increased substrate for peripheral aromatase
  (1) Adrenal tumors
  (2) Liver cirrhosis
  (3) Starvation
  (4) Hyperthyroidism

3. Drug-induced gynecomastia :

1. Inhibitors of testosterone synthesis +/or actions:
   ketoconazole, metrodazole, alkylating agents, cisplatin, spironolactone(Aldactone), cimetidine(Tagament), metoclopramide, flutamide, etomidate
2. Estrogens, DES, Birth control pill, digoxin, phytoestrogens
3. Drugs that enhance endogenous estrogen secretion as: Gonadotropins, clomiphene
4. Unknown mechanism:  heroin, marijuana, sedatives as diazepam, amphetamine, busulphan, cytotoxic drugs,  INH, BP meds as: methyldopa, ACE inhibitors, Ca-blockers; tricyclic antidepressant, ethionamide, ?Flexeril, etc. primary hyperparathyroidism; Amphotericin B toxicity

4. Idiopathic pathologic gynecomastia
In all published series half or more of subjects evaluated for gynecomastia do not have an underlying endocrinopathy that is diagnosable at autopsy or by careful endocrine work-up. If one adds those instances in all large series in which the designated cause is tenuous, the idiopathic category accounts for approximately three fourths of cases.

DIFFERENTIAL DIAGNOSIS       

• Physiological: newborn, adolescence, aging
• Obesity with increase in adipose tissue, lipomas
• Breast Carcinoma of the male;  adrenal, testicular, or other tumors (lung Ca, hepatoblastoma, etc.) especially with recent progressive, painful gynecomastia.
• Neurofibromas
• Cirrhosis, Thyrotoxicosis, Renal failure, etc.

LABORATORY

• Plasma testosterone, LH & FSH measurements - help diagnose hypogonadism
• Serum estradiol E2, serum prolactin, Liver function , Thyroid function test, BUN, Creat, 24-hour urine 17 KS (Ketosteroids) level.
• Human chorionic gonadotropin HCG levels - high levels may lead to finding a choriocarcinoma or other hCG-secreting malignant tumor
• Others if clinically indicated e.g., thyroid function, chromosomal analysis
• Full endocrine investigations may be indicated
• CT, ultrasonography (rarely indicated)
• Biopsy, if suspicious for cancer

An elevated estrogen level indicates the need for testicular ultrasonography and adrenal CT or MRI.
Estradiol, however, is so potent that significant gynecomastia can develop without elevation of the plasma estradiol level. Progressive gynecomastia without a known explanation (e.g., puberty, cirrhosis, hyperthyroidism) should therefore be evaluated by imaging of the adrenals and testes.

The combination of recent gynecomastia with elevated estrogen and hCG titers should prompt a search for a primary tumor. Although the finding of hCG in the plasma of normal people has thickened the plot, high hCG titers and dynamic studies can be used to identify a tumor as the probable cause.

TREATMENT

• Correct underlying disorder
• Withdrawal of causative drug if feasible
• Observation with reassurance that problem is transient
• Subcutaneous mastectomy for severe, persistent cases or those with psychological concerns
• Tamoxifen (Norvadex), estrogen antagonist , has been used and anastrozole  (Arimidex), a potent and selective fourth-generation aromatase inhibitor, is also known to be effective in Tanner stage III or less gynecomastia.  (Suggested by YC 10-18-1999)
  Various drug regimens have been tried for gynecomastia with varying degrees of success, including the antiestrogens tamoxifen and clomiphene, the aromatase inhibitor testolactone, and danazol, a weak androgen that acts by inhibiting gonadotropin secretion and causing a fall in plasma testosterone. Treatment with dihydrotestosterone (which cannot be aromatized to estrogen) is also reported to cause significant symptomatic improvement in gynecomastia. However, no prospective controlled studies have been performed with any of these regimens, and their clinical usefulness is not established.
  [Serels S; Melman A: J Urol 1998 Apr;159(4):1309 Tamoxifen use in gynecomastia
  Staiman VR; Lowe FC: Urology 1997 Dec;50(6):929-33 - tamoxifen 10-30 mg/day for 1 month
  McDermott MT, et al Tamoxifen therapy for painful idiopathic gynecomastia. South Med J 83: 1283, 1990
  Anastrozole, an aromatase inhibitor Tx for gynecomastia reported by groups from Southwestern Med Ctr in Dallas and also from Harbor-UCLA in Torrence at Endo Society mtg at San Diego Jun. of 1999.
  Plourde PV, et al.:Breast Cancer Res Treat. 1994;30(1):103-11 - Arimedex (anastrozole)
  Lonning PE, et al.: "anastrozole" -Breast Cancer Res Treat. 1998;49 Suppl 1:S53-7; discussion S73-7. Review..]

Ref:
Dambro: Griffith's 5-Minute Clinical Consult, 1999 ed.- Timothy L. Black
Scientific American Medicine 10-1999

2007