Gynecomastia

Definition

Enlargement of the male breast glandular tissue resulting from excess estrogen action, usually due to an increased estrogen/androgen ratio. True gynecomastia involves glandular tissue >4 cm in diameter, often tender, and should be distinguished from pseudogynecomastia (excess adipose tissue/lipomastia).

Glandular tissue = firmer, contains fibrous-like cords
Adipose tissue = softer, diffuse

Physiologic Phases (Normal Occurrence)

Phase	Mechanism
Neonatal	Transplacental transfer of maternal/placental estrogens
Pubertal (ages 12–15)	High estrogen-to-androgen ratio in early puberty; often unilateral
Senescent (men 50–70)	Age-related testosterone decline + increased aromatase activity in adipose tissue; usually bilateral

Prevalence increases with age and BMI (adipose tissue aromatase activity).

Pathophysiology

Core mechanism: ↑ estrogen / ↓ androgen ratio

Estrogen Excess

Gonadal tumors: Leydig cell tumors, Sertoli cell tumors (isolated or in Peutz-Jeghers / Carney complex), granulosa-theca cell tumors
hCG-secreting tumors: Testicular germ cell tumors (choriocarcinoma, seminoma, embryonal carcinoma) — stimulate Leydig cell estrogen synthesis
Non-testicular tumors: Adrenal cortical neoplasms, lung carcinoma, hepatocellular carcinoma
Liver disease: Cirrhosis impairs estrogen catabolism → androstenedione shunted to aromatase at peripheral sites
Hyperthyroidism: Elevated SHBG → increased free estradiol/free testosterone ratio
Obesity: Increased aromatization of androgen precursors to estrogens
Inherited aromatase excess (CYP19 mutation/chromosomal rearrangement): Pre-pubertal/peripubertal gynecomastia, advanced bone age, short stature, hypogonadotropic hypogonadism

Androgen Deficiency

Primary testicular failure: Klinefelter syndrome (47,XXY) — classic association; also Reifenstein syndrome, Rosewater-Gwinup-Hamwi syndrome, Kallmann syndrome
Secondary testicular failure: Trauma, orchitis, cryptorchidism
Androgen insensitivity disorders
Androgen deprivation therapy (GnRH analogues ± AR blockers for prostate cancer): causes painful breast enlargement
Renal failure (any cause)
Refeeding gynecomastia: Resumption of pituitary gonadotropin secretion after pituitary shutdown following starvation/malnourishment

Drug-Induced Causes

Mechanism	Drugs
Direct estrogenic activity	Oral contraceptives, phytoestrogens, digitalis, anabolic steroids
Inhibit androgen synthesis	GnRH agonists, ketoconazole
Inhibit androgen action (AR blocker)	Spironolactone, enzalutamide, bicalutamide, cimetidine
Enhance estrogen synthesis	hCG
Uncertain mechanism	Imatinib, antiretroviral drugs (HIV), phenytoin, alcohol, marijuana, heroin

Histopathology (Robbins)

Subareolar button-like enlargement, unilateral or bilateral
Microscopically: dense collagenous connective tissue + epithelial hyperplasia of duct lining
Lobule formation almost never seen (distinguishes from female breast hypertrophy)

Grading (Schwartz's Surgery)

Grade	Features
I	Mild enlargement, no skin redundancy
IIa	Moderate enlargement, no skin redundancy
IIb	Moderate enlargement with skin redundancy
III	Marked enlargement with skin redundancy and ptosis

Clinical Features

Subareolar, disc-like, rubbery or firm mass — often tender
May be unilateral or bilateral
Nipple retraction, skin dimpling, or hard/fixed tissue → red flags for malignancy
In Klinefelter syndrome: small testes, azoospermia, hypergonadotropic hypogonadism — increased risk of male breast cancer

Evaluation

Harrison's Principles of Internal Medicine 22E — Fig. 403-7: Evaluation of gynecomastia

Workup for glandular tissue >4 cm with unclear cause:

Total/free testosterone, SHBG, LH, FSH, E2 (17β-estradiol), TSH, β-hCG
Markedly elevated E2 + suppressed LH → search for estrogen-secreting testicular/adrenal tumor
Elevated hCG → testicular USS + CT chest/abdomen for hCG-producing tumor
Very small testes → karyotype to exclude Klinefelter syndrome
Liver function tests

Treatment

Scenario	Management
Cause identified and corrected early	Breast tissue usually regresses over months
Long-standing gynecomastia	Surgery most effective
Painful gynecomastia (medical)	Tamoxifen 20 mg/day — reduces pain and size in >50%; raloxifene also used
Early proliferative phase	Aromatase inhibitors (anastrozole) — effective early; not better than placebo for established gynecomastia
Prostate cancer + ADT	Tamoxifen for prevention and treatment of breast enlargement/pain
Indications for surgery	Severe psychological distress, continued growth, failure of medical therapy, suspected malignancy

Cancer Risk

The relative risk of breast cancer is increased in men with gynecomastia, but the absolute risk remains small.
Klinefelter syndrome carries a meaningfully higher breast cancer risk than gynecomastia from other causes.

Sources: Harrison's Principles of Internal Medicine 22E, p. 3159–3160; Robbins, Cotran & Kumar Pathologic Basis of Disease; Schwartz's Principles of Surgery 11E

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