Gynecomastia

• Physiological gynaecomastia occurs in three normal windows: the neonate (transplacental maternal oestrogen), puberty (transient oestrogen–androgen imbalance, usually resolving within 1–2 years) and older age (rising aromatase activity in adipose tissue with falling testosterone).
• Pathological causes include cirrhosis, chronic kidney disease, hyperthyroidism, hypogonadism of any cause, and tumours that secrete hCG (testicular germ cell, lung) or oestrogen (adrenal, Sertoli–Leydig).
• Drugs are a leading cause and the highest-yield exam angle: spironolactone, cimetidine, ketoconazole, antiandrogens, 5-alpha reductase inhibitors, oestrogens, anabolic steroids, some antipsychotics and antiretrovirals.

Increased oestrogen production or availability

• hCG-secreting tumours: testicular germ cell tumours (choriocarcinoma, embryonal), and ectopic hCG from large-cell lung carcinoma or hepatoblastoma; hCG acts on the LH receptor and drives Leydig-cell aromatase.
• Oestrogen-secreting tumours: adrenocortical carcinoma, Sertoli-cell and Leydig-cell tumours (classic in Peutz–Jeghers and Carney complex).
• Increased peripheral aromatisation: obesity, ageing, hyperthyroidism (thyroid hormone upregulates aromatase and SHBG), and exogenous androgen/anabolic steroid use, where excess substrate is aromatised to oestradiol.

Decreased androgen production or action

• Primary hypogonadism: Klinefelter syndrome (47,XXY) — the single most tested congenital association — plus orchitis (mumps), trauma, chemotherapy, radiation.
• Secondary hypogonadism: pituitary tumour, hyperprolactinaemia (prolactin suppresses GnRH), opioids, chronic illness.
• **Partial androgen insensitivity (Reifenstein syndrome) and defects of testosterone biosynthesis**: androgen receptor signalling fails or androgen substrate is inadequate while oestrogen signalling remains intact.
• Contrast pearl: partial androgen insensitivity → gynaecomastia is prominent at puberty; 5-alpha reductase deficiency → virilisation at puberty WITHOUT gynaecomastia (testosterone and LH are normal-to-high and androgen receptor signalling is intact). Complete androgen insensitivity presents as a phenotypic female and is not evaluated as male gynaecomastia.

Altered clearance and binding

• Cirrhosis: reduced hepatic clearance of androstenedione with increased peripheral aromatisation, plus elevated SHBG that preferentially binds testosterone.
• Chronic kidney disease/dialysis: Leydig-cell dysfunction with hyperprolactinaemia.
• Refeeding after starvation, illness or imprisonment: a "second puberty" as the gonadal axis reawakens.

• The final common pathway is a rise in the effective oestradiol-to-testosterone ratio at the breast bud, not an absolute oestrogen excess. Either arm can shift: more oestrogen (aromatisation, tumour secretion, impaired clearance) or less androgen effect (reduced synthesis, receptor blockade, SHBG sequestration).
• Breast tissue is bipotential: oestrogen is the growth signal for ductal epithelium and periductal stroma, while androgen acting through the androgen receptor is the brake. Removing the brake (spironolactone, cimetidine, bicalutamide) produces the same histology as adding oestrogen.
• SHBG amplifies small changes: SHBG binds testosterone with far greater affinity than oestradiol, so any SHBG rise (hyperthyroidism, cirrhosis) disproportionately lowers free testosterone and unmasks free oestradiol.
• hCG mechanism: hCG shares an alpha subunit with LH and stimulates the Leydig-cell LH receptor, which preferentially upregulates testicular aromatase — hence a germ-cell tumour can cause breast growth before any testicular mass is palpable.
• 5-alpha reductase inhibitors block conversion of testosterone to the more potent dihydrotestosterone, shunting substrate toward aromatisation and weakening androgen receptor signalling.

Why the exam findings look the way they do

• Florid (early) phase, roughly the first several months: ductal epithelial hyperplasia, periductal oedema, inflammatory infiltrate and stromal vascularity — this is why early gynaecomastia is tender and painful and why it can regress fully once the trigger is removed.
• Fibrotic (late) phase, after about a year: hyalinised stroma with dense fibrosis and little epithelium — now a firm, non-tender, painless disc that no longer responds to medical therapy, explaining why timing dictates treatment choice.
• Concentric subareolar growth reflects tissue arising from the ducts radiating out from the nipple, in contrast to the eccentric, off-centre mass of carcinoma.

Classic findings

• Rubbery or firm, mobile, concentric subareolar disc of tissue palpable directly beneath and radiating symmetrically from the nipple-areolar complex — the pathognomonic examination finding. Best elicited with the patient supine, thumb and forefinger pinched together toward the nipple.
• Breast tenderness or a burning discomfort, often the presenting complaint in the florid phase, reflecting periductal oedema and inflammation. Long-standing fibrotic disease is painless.
• Bilateral but often asymmetric involvement; one side may appear or hurt first, which does not imply malignancy.

Findings pointing to the underlying cause

• Small, firm testes with tall stature, long limbs and infertility: Klinefelter syndrome in an adolescent or young man.
• A palpable testicular mass or unilateral testicular enlargement: hCG- or oestrogen-secreting germ-cell or Leydig-cell tumour.
• Spider angiomata, palmar erythema, testicular atrophy, ascites: cirrhosis, the classic hyperoestrogenic stigmata cluster.
• Weight loss, tremor, heat intolerance, tachycardia: hyperthyroidism.
• Galactorrhoea with headache or bitemporal hemianopsia: prolactinoma (prolactin causes galactorrhoea; the gynaecomastia is driven by secondary hypogonadism).
• Acne, striae, mood change, testicular atrophy in a weightlifter: anabolic androgenic steroid use.

Step 1 — History and physical examination

• Medication and supplement review first, including anabolic steroids, herbals (lavender, tea tree oil) and antiretrovirals; drugs and physiological causes account for most cases and often end the workup.
• Palpation distinguishes true gynaecomastia from pseudogynaecomastia: true disease has a discrete firm subareolar disc, generally accepted as at least a half-centimetre of glandular tissue, whereas pseudogynaecomastia is soft fat with no palpable disc. Testicular examination is mandatory in every case.

• hCG, LH, total testosterone and oestradiol, plus TSH, prolactin, LFTs and creatinine. Add free testosterone or SHBG when binding is altered — cirrhosis, hyperthyroidism, obesity — since total testosterone can look normal while free testosterone is low.
• Elevated hCG → testicular tumour or ectopic source; obtain testicular ultrasound, and if negative, chest and abdominal imaging.
• Low testosterone with high LH → primary hypogonadism; obtain a karyotype if Klinefelter is suspected.
• Low testosterone with low or inappropriately normal LH → secondary hypogonadism; check prolactin and consider pituitary MRI.
• High oestradiol with suppressed LH and normal hCG → oestrogen-secreting adrenal or testicular tumour; image the adrenals and testes.
• High testosterone with high LH → androgen resistance or, in a hyperthyroid pattern, elevated SHBG.

Step 1 — Treat the cause, not the breast

• Withdraw or substitute the offending drug: switch spironolactone to eplerenone (a selective mineralocorticoid antagonist with negligible androgen receptor affinity), cimetidine to famotidine, and reconsider 5-alpha reductase inhibitors. Regression, if it occurs, is usually seen within the first few months.
• Correct the underlying disorder: thyroidectomy/antithyroid therapy for hyperthyroidism, dopamine agonist (cabergoline) for prolactinoma, orchiectomy and chemotherapy for germ-cell tumour, adrenalectomy for an oestrogen-secreting adrenal tumour.
• Testosterone replacement is indicated only in documented hypogonadism, per the Endocrine Society testosterone guideline; giving testosterone to a eugonadal man can worsen gynaecomastia through aromatisation and is a favourite distractor.

Step 2 — Observation

• Pubertal and neonatal gynaecomastia: reassurance and interval re-examination, since most resolve spontaneously. Weight loss and exercise address pseudogynaecomastia.

Step 3 — Medical therapy (florid phase only, generally within the first year)

• Selective oestrogen receptor modulators: tamoxifen blocks oestrogen receptors in breast epithelium and is the best-supported agent for painful, recent-onset gynaecomastia. Use is off-label in the United States.
• Aromatase inhibitors: anastrozole reduces peripheral oestradiol synthesis but has performed less well than tamoxifen and is second-line.
• Prophylaxis in prostate cancer: NCCN prostate cancer guidance supports prophylactic breast irradiation or tamoxifen before or shortly after starting bicalutamide monotherapy, because antiandrogen-induced breast pain is common and once fibrotic is irreversible.

Step 4 — Surgery (definitive)

• Subcutaneous mastectomy with periareolar excision of the glandular disc, with or without liposuction, is the definitive treatment for fibrotic, long-standing, or cosmetically distressing disease that has failed medical therapy.

Of the disease

• Psychosocial morbidity: body-image distress, social withdrawal and avoidance of sport are frequent in adolescents and are a legitimate indication for surgical referral.
• Chronic breast pain and irreversible fibrosis: unrelieved oestrogen stimulation beyond roughly a year produces hyalinised stroma that no longer responds to tamoxifen — the finding that signals this is a firm, painless, long-standing disc.
• Missed male breast carcinoma: the most consequential complication. Signalled by a hard, eccentric, fixed unilateral mass, skin dimpling, nipple retraction, bloody discharge, or axillary nodes. This warrants urgent diagnostic mammography and biopsy, not observation.
• Missed hCG-secreting germ-cell tumour: gynaecomastia can precede a palpable testicular mass. A markedly elevated hCG with a testicular lesion demands urgent oncologic referral — advanced choriocarcinoma can present with haemorrhagic pulmonary or cerebral metastases, a true emergency.
• Klinefelter syndrome carries a markedly increased lifetime risk of male breast cancer relative to other men, along with infertility, osteoporosis and metabolic syndrome.

Of treatment

• Tamoxifen: venous thromboembolism (oestrogen receptor effects on hepatic coagulation protein synthesis) — signalled by unilateral leg swelling or pleuritic chest pain and treated as an emergency; also hot flushes and, rarely, ocular toxicity.
• Aromatase inhibitors: accelerated bone loss and arthralgia from systemic oestrogen depletion; oestrogen is the dominant regulator of male bone density.
• Breast irradiation for antiandrogen prophylaxis: skin erythema, chronic breast tenderness and a small long-term second-malignancy risk.
• Subcutaneous mastectomy: haematoma, infection, nipple-areolar sensory loss, nipple necrosis from devascularisation, and over-resection producing a saucer deformity or tethered nipple.
• Withdrawal of spironolactone in heart failure: loss of mortality benefit — substitute eplerenone rather than simply stopping mineralocorticoid antagonism.

• Spironolactone is the single most tested drug cause — it blocks the androgen receptor, displaces testosterone from SHBG, and inhibits androgen synthesis. The best next step is switching to eplerenone, which preserves mineralocorticoid blockade without androgen receptor antagonism. Do not simply stop the drug in a heart failure patient.
• True gynaecomastia versus pseudogynaecomastia hinges on one physical finding: a firm, concentric, mobile subareolar disc radiating from the nipple. Soft fat with no disc in an obese man is pseudogynaecomastia — treat with weight loss, not tamoxifen or surgery.
• Unilateral, hard, eccentric, fixed mass with nipple retraction or bloody discharge is carcinoma until proven otherwise. Next step: diagnostic mammography with ultrasound (ACR Appropriateness Criteria), then core biopsy — never reassurance.
• Young man with gynaecomastia → examine the testes. A palpable testicular mass with elevated hCG points to a germ-cell tumour; hCG stimulates the Leydig LH receptor and drives aromatase. Testicular ultrasound is the next step.
• Klinefelter (47,XXY) is the classic congenital association: tall, small firm testes, infertility, high LH/FSH with low testosterone, and a markedly increased male breast cancer risk. Confirm with karyotype.
• Timing determines therapy: tender, recent-onset (florid) disease may respond to a SERM such as tamoxifen; a painless disc present for over a year is fibrotic and needs surgery.
• Do not give testosterone to a eugonadal man — it is aromatised to oestradiol and worsens the problem. The Endocrine Society restricts testosterone to documented hypogonadism.
• Cirrhosis and hyperthyroidism both raise SHBG, which binds testosterone far more avidly than oestradiol, so the free oestrogen-to-androgen ratio rises even when total testosterone looks normal.