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Summary Table

Category	Details
Risk Factors	Three physiologic peaks (neonates, puberty, men over 50); use of antiandrogens, H2 blockers, antifungals, antiretrovirals, anabolic steroids, marijuana, alcohol; chronic liver or kidney disease; hyperthyroidism; hypogonadism
Etiology	Imbalance between estrogen activity and androgen activity at the breast tissue level (relative or absolute estrogen excess)
Patient Presentation	Bilateral or asymmetric breast enlargement, often tender, with a rubbery disc of tissue palpable beneath the areola; recent onset is typically tender, longstanding lesions are firm and painless
Classic Physical Exam	Concentric, mobile, rubbery glandular tissue under the nipple-areolar complex; testicular exam is mandatory to look for mass, atrophy, or asymmetry
Key Diagnostic Results	History and exam alone in most physiologic and drug-induced cases; when pathologic cause is suspected: $\beta$-hCG, LH, FSH, total testosterone, estradiol, TSH, prolactin, liver and renal panel; testicular ultrasound when a testicular abnormality is found
Management	Reassurance for physiologic forms; remove the offending drug; treat underlying disease; selective estrogen receptor modulator (tamoxifen) for painful or persistent disease within 12 months; subcutaneous mastectomy for fibrotic, cosmetically distressing, or refractory cases
Keywords	"Tender subareolar disc," "rubbery breast tissue in a male," "spironolactone for heart failure," "cirrhotic male with breast enlargement," "elderly man on cimetidine," "adolescent with bilateral breast bud," "germ cell tumor with breast enlargement"

1. Pathophysiology

Gynecomastia is the benign proliferation of glandular breast tissue in a male, driven by a shift in the estrogen-to-androgen activity ratio within the breast. Either an absolute rise in estrogen, an absolute drop in androgen, increased peripheral aromatization, displacement of androgen from sex hormone-binding globulin (SHBG), or blockade of the androgen receptor will produce the same end result: estrogen-mediated ductal epithelial hyperplasia and periductal stromal proliferation.

The glandular response evolves through three histologic phases, and recognizing this timeline is high-yield. The early florid phase (under six months) shows ductal proliferation with edematous stroma and is tender, soft, and reversible with treatment. The intermediate phase is transitional. After roughly twelve months, the lesion enters the fibrotic phase, in which the stroma becomes hyalinized, the ductal proliferation regresses, and the tissue becomes firm, nontender, and irreversible by medical therapy. This timeline determines whether tamoxifen will work or whether surgery is needed.

Physiologic gynecomastia reflects predictable hormonal swings. Neonatal gynecomastia results from transplacental maternal estrogens and resolves within weeks. Pubertal gynecomastia (peaking at ages 13–14) reflects a transient lag between the early rise in estradiol and the later rise in testosterone; it resolves spontaneously in over 90% of boys within two years. Senile gynecomastia in older men reflects declining testosterone, rising SHBG (which lowers free testosterone further), and increasing peripheral aromatase activity in fat tissue.

Pathologic causes operate through identifiable mechanisms. Cirrhosis raises estrogen by impairing hepatic clearance and increasing aromatization, while alcohol independently suppresses testicular testosterone. Hyperthyroidism raises SHBG, lowering free testosterone and raising the estrogen ratio. Primary hypogonadism (notably Klinefelter syndrome, 47,XXY) produces low testosterone with high LH and FSH, and Klinefelter carries a real 20-fold increased risk of male breast cancer, which is testable. Testicular tumors are a high-yield cause: germ cell tumors secrete $\beta$-hCG (which stimulates Leydig cell estradiol production), while Leydig and Sertoli cell tumors directly secrete estrogens. Drug-induced gynecomastia operates through several mechanisms summarized below.

The tenderness of early disease reflects active ductal proliferation and stromal edema; the firm painless disc of late disease reflects fibrosis. Pseudogynecomastia, by contrast, is pure adipose tissue without glandular proliferation and lacks the palpable rubbery subareolar disc, a distinction that is the single most common testable trap.

2. Classification and Clinical Manifestation

Classification	Setting	Mechanism	Clinical Clues
Neonatal physiologic	First weeks of life	Transplacental maternal estrogen	Transient bilateral breast bud, sometimes with milky discharge ("witch's milk"); resolves in weeks
Pubertal physiologic	Boys aged 10–14	Transient estrogen-androgen imbalance	Bilateral, tender, often asymmetric; resolves in <2 years; reassurance is the answer
Senile physiologic	Men over 50–60	Falling testosterone, rising aromatization in adipose tissue	Slowly progressive; rule out drugs and pathology before labeling as physiologic
Drug-induced	Any age	Antiandrogen effect, estrogenic activity, increased prolactin, or aromatization	Temporal link to drug initiation (typical onset within months)
Hypogonadism (primary or secondary)	Variable	Low testosterone with relative estrogen excess	Small testes, low libido; in Klinefelter, tall stature and elevated LH/FSH
Tumor-related	Any age, but consider in young men	hCG-secreting germ cell tumor; estrogen-secreting Leydig or Sertoli tumor; adrenal cortical tumor	Testicular mass or asymmetry; rapid onset; elevated $\beta$-hCG or estradiol
Systemic disease	Adults	Cirrhosis (impaired estrogen clearance), hyperthyroidism (high SHBG), kidney failure (multifactorial)	Stigmata of chronic liver disease, thyrotoxicosis, or uremia
Refeeding	Post-starvation, post-illness	Resumption of gonadotropin axis after suppression	Onset weeks after nutritional recovery
Idiopathic	Adults	Diagnosis of exclusion	Normal workup

Drug categories worth memorizing (mechanism in parentheses): spironolactone and eplerenone (androgen receptor blockade), ketoconazole (steroidogenesis inhibition), cimetidine (androgen receptor blockade), finasteride and bicalutamide and flutamide (antiandrogens), GnRH agonists such as leuprolide (chemical castration), anabolic steroids (peripheral aromatization), exogenous estrogens, marijuana, alcohol, opioids, antiretrovirals (efavirenz), tricyclic antidepressants, antipsychotics and metoclopramide (prolactin elevation), and digoxin (estrogen-like effect).

3. Diagnostic Workup

Test	Role
Focused history	Best initial step; drug timeline, duration, tenderness, systemic symptoms
Breast and testicular exam	Best initial test; differentiates true gynecomastia from pseudogynecomastia and screens for testicular tumor and breast cancer
$\beta$-hCG, LH, FSH, total testosterone, estradiol, TSH, prolactin	First-line labs when no obvious physiologic or drug cause
Liver function tests, renal panel	Assess for cirrhosis or kidney disease
Testicular ultrasound	Indicated for any palpable testicular abnormality, elevated $\beta$-hCG, or elevated estradiol with normal exam
Mammography and breast ultrasound	Indicated for features concerning for malignancy (see below)
Core needle biopsy	Confirmatory for suspected breast cancer
Adrenal CT, brain MRI	Reserved for elevated estradiol with normal testes, or hyperprolactinemia

The workup begins with a careful history and physical exam, which alone resolves most cases. Ask about the time course, breast tenderness, libido and erectile function, sexual development, weight changes, and a complete medication and substance review including over-the-counter products, herbal supplements (lavender oil, tea tree oil), anabolic steroids, alcohol, and marijuana. On exam, pinch the tissue between thumb and forefinger and roll toward the nipple: a concentric, rubbery, mobile disc of tissue beneath the areola confirms true gynecomastia, whereas soft, diffuse fatty enlargement without a palpable disc is pseudogynecomastia. Always perform a testicular exam, because a missed testicular tumor is a classic exam trap.

Red flags pointing to male breast cancer rather than gynecomastia include a unilateral, hard, fixed, eccentric mass off the nipple line, skin dimpling or peau d'orange, nipple retraction or bloody discharge, and axillary lymphadenopathy. Any of these warrants diagnostic mammography and ultrasound, with core needle biopsy as the gold standard for confirmation.

If history and exam do not reveal a physiologic or drug cause, order the first-line hormonal panel: $\beta$-hCG, LH, FSH, total and free testosterone, estradiol, TSH, and prolactin, along with liver and kidney function. The pattern guides the next step:

Elevated $\beta$-hCG points to a germ cell testicular tumor or, less commonly, an extragonadal germ cell tumor or hepatocellular carcinoma. Order testicular ultrasound.
Elevated estradiol with low or normal LH suggests an estrogen-secreting tumor: testicular ultrasound first, then adrenal CT if testes are normal.
Low testosterone with high LH and FSH indicates primary hypogonadism; consider karyotype if Klinefelter syndrome is suspected.
Low testosterone with low or inappropriately normal LH and FSH indicates secondary hypogonadism; check prolactin and consider pituitary MRI.
Elevated prolactin prompts pituitary MRI.
Elevated free $T_4$ with suppressed TSH confirms hyperthyroidism.
Abnormal liver enzymes with low albumin and prolonged INR support cirrhosis.

When the entire workup is unrevealing, the diagnosis is idiopathic gynecomastia.

4. Management and Treatment

Scenario	Preferred Treatment	Notes
Neonatal	Reassurance	Resolves in weeks
Pubertal	Reassurance, reassess in 6 months	Over 90% resolve within 2 years
Drug-induced	Discontinue or substitute the offending drug	Improvement expected within 1 to 3 months
Underlying disease (cirrhosis, hyperthyroidism, hypogonadism, tumor)	Treat the cause	Testosterone replacement only in confirmed hypogonadism
Painful or persistent gynecomastia within 12 months	Tamoxifen 10–20 mg daily for 3 to 6 months	Most effective in florid phase; off-label use
Alternative medical therapy	Raloxifene 60 mg daily; aromatase inhibitors (anastrozole) are less effective	Reserved cases
Fibrotic, longstanding, or cosmetically distressing disease	Subcutaneous mastectomy (with or without liposuction)	Definitive
Prophylaxis in prostate cancer on antiandrogens	Prophylactic radiation to the breast or tamoxifen	Used when starting bicalutamide monotherapy

The first decision is whether the patient needs treatment at all. Physiologic gynecomastia in neonates and adolescents requires only reassurance and follow-up, and treating it is a common wrong-answer choice. For pubertal disease, reassess in three to six months. If the lesion is shrinking, continue observation; if it persists beyond two years or causes psychological distress, consider medical or surgical therapy.

For drug-induced gynecomastia, the next best step is to stop or substitute the offending agent. For example, switch spironolactone to eplerenone in heart failure if breast tenderness is intolerable, or switch cimetidine to a proton pump inhibitor. Symptoms typically improve within one to three months; if no improvement is seen and the lesion has been present under twelve months, add a selective estrogen receptor modulator.

When an underlying disease is identified, treatment of that disease is primary. Testosterone replacement is appropriate only when hypogonadism is confirmed; giving testosterone to a eugonadal man with gynecomastia can paradoxically worsen the condition through peripheral aromatization to estradiol, a high-yield trap.

Tamoxifen 10 to 20 mg orally once daily for 3 to 6 months is the medical therapy of choice for painful or persistent gynecomastia in the active florid phase. Response rates exceed 80% when used early and fall sharply once fibrosis has developed beyond twelve months. Raloxifene is an alternative. Aromatase inhibitors such as anastrozole have shown limited benefit in trials and are not first-line.

Surgical therapy by subcutaneous mastectomy, often combined with liposuction, is the definitive treatment for fibrotic disease, cosmetically significant disease unresponsive to medical therapy, or any case in which malignancy cannot be excluded.

A testable special case is the man starting bicalutamide monotherapy for prostate cancer, in whom prophylactic breast irradiation or prophylactic tamoxifen is given before therapy begins to prevent the high incidence of painful gynecomastia.

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Pseudogynecomastia	Bilateral male breast enlargement, especially in obese patients	No palpable concentric rubbery disc beneath the areola; soft fatty tissue only; weight loss resolves it
Male breast cancer	Unilateral breast mass in a man	Hard, fixed, eccentric (off the nipple line) mass, skin dimpling, nipple retraction, bloody discharge, axillary nodes; older age; mammography and biopsy required
Lipoma	Soft male chest mass	Well-circumscribed, mobile, not centered under the areola, no glandular disc
Sebaceous cyst or abscess	Localized swelling	Fluctuance, erythema, overlying punctum, fever; not glandular
Mastitis	Tender swollen breast tissue	Erythema, warmth, fever, leukocytosis; rare in adult men
Neurofibroma or other soft tissue tumor	Subcutaneous chest mass	Located outside the nipple-areolar complex; typical features of the underlying syndrome
Klinefelter syndrome (as a cause, not a mimic)	Bilateral gynecomastia in a young man	Tall stature, small firm testes, high LH and FSH, low testosterone, 47,XXY karyotype; 20-fold breast cancer risk
Refeeding gynecomastia	Bilateral breast enlargement	Recent recovery from prolonged starvation or severe illness; self-limited

6. Traps and High-Yield Pearls

The single most common error is failing to distinguish true gynecomastia from pseudogynecomastia. The exam will hand you an obese man with bilateral chest enlargement and tempt you toward hormonal workup; the correct answer is to feel for the concentric subareolar disc on exam first. If there is no palpable glandular tissue, the diagnosis is pseudogynecomastia and the answer is weight loss, not endocrine testing.

The second major trap is missing a testicular tumor. A young man with new-onset breast enlargement requires a testicular exam, and any abnormality demands testicular ultrasound. An elevated $\beta$-hCG or estradiol with a normal exam still warrants ultrasound to look for an occult Leydig or germ cell tumor.

The third trap is mishandling the drug history. Reviewers love to bury the answer in the medication list: an elderly man with heart failure on spironolactone, a patient with reflux on cimetidine, a man with prostatic hyperplasia on finasteride, a young athlete using anabolic steroids, or a transplant recipient on cyclosporine. The next best step is to stop or substitute the drug, not to start tamoxifen.

The fourth trap is giving testosterone to the wrong patient. Testosterone replacement is correct only in confirmed hypogonadism; in a eugonadal patient, exogenous testosterone aromatizes to estradiol and worsens the disease.

The fifth trap is timing of medical therapy. Tamoxifen works in the florid phase (under twelve months) when ductal proliferation predominates. After fibrosis sets in, the answer is surgery, not more medication. Recognize the timeline cue in the vignette ("for the past two years") as a signal that medical therapy will fail.

The sixth trap is reassurance versus workup in adolescents. A 13-year-old with bilateral tender breast buds, normal puberty, no drug exposure, and a normal exam needs reassurance and follow-up, not a hormonal panel. Conversely, a prepubertal boy or one with delayed puberty, a unilateral mass, or a testicular abnormality needs a full workup.

Finally, never forget the Klinefelter connection. Bilateral gynecomastia, tall stature, small firm testes, and infertility in a young adult man should trigger karyotyping, and these patients carry a markedly elevated lifetime risk of male breast cancer that justifies clinical breast surveillance.

The core competency tested across these vignettes is mechanistic reasoning: identify the source of the estrogen-androgen imbalance, distinguish reversible from irreversible disease by timeline, and match the intervention to the phase and the cause rather than reflexively starting medication.

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