Galactorrhea and Nipple Discharge

• Galactorrhoea is milky discharge unrelated to breastfeeding, usually bilateral and from multiple ducts, and reflects hyperprolactinaemia rather than breast pathology.
• Causes include prolactinoma, stalk compression from any sellar mass (loss of dopaminergic inhibition), primary hypothyroidism (raised TRH stimulates prolactin), chronic kidney disease, pregnancy and lactation, chest wall stimulation, and drugs — antipsychotics, metoclopramide, methyldopa, verapamil, opioids and oestrogens.
• Workup begins with a prolactin level, TSH and pregnancy test before imaging.
• Physiological discharge is bilateral, multiductal, non-bloody and provoked by expression.
• Pathological discharge is unilateral, spontaneous, uniductal, and bloody or serosanguineous. The most common cause is an intraductal papilloma, but ductal carcinoma in situ and invasive carcinoma must be excluded with imaging and tissue diagnosis.

Loss of dopaminergic inhibition (drug-induced — the most common cause of non-tumoural hyperprolactinaemia)

• D2 receptor antagonists: antipsychotics, especially risperidone and paliperidone (high D2 occupancy, poor blood-brain barrier exclusion at the tuberoinfundibular tract, which lies outside the barrier); typical agents such as haloperidol behave similarly.
• Antiemetics/prokinetics: metoclopramide, promethazine, domperidone.
• Others: methyldopa and reserpine (catecholamine depletion), verapamil, opioids, oestrogens, and — inconsistently — SSRIs and H2 blockers.

• Prolactin is unique among pituitary hormones in being under tonic inhibition: hypothalamic dopamine reaches lactotrophs through the hypophyseal portal system and suppresses secretion via D2 receptors. Anything that removes dopamine — a D2 blocker, stalk compression, or dopamine depletion — releases lactotrophs from the brake and raises prolactin. This is why any sellar mass, functioning or not, can cause galactorrhoea.
• Prolactin drives milk protein synthesis in alveolar epithelium that has already been primed by oestrogen, progesterone, and growth factors. Because both breasts are equally exposed to a circulating hormone, galactorrhoea is bilateral and multiductal — the pattern that distinguishes it from ductal pathology.
• Hyperprolactinaemia suppresses GnRH pulsatility, lowering LH and FSH. The resulting hypogonadism explains oligomenorrhoea/amenorrhoea and infertility in women and low testosterone, decreased libido, and erectile dysfunction in men. Chronic oestrogen or testosterone deficiency causes low bone mineral density, a commonly tested downstream consequence.
• In primary hypothyroidism, loss of negative feedback raises TRH, which stimulates both thyrotrophs and lactotrophs; thyrotroph hyperplasia can even enlarge the pituitary and mimic an adenoma, reversing with levothyroxine.
• Macroadenomas cause symptoms by mass effect: upward extension compresses the optic chiasm at the decussating nasal fibres, producing bitemporal hemianopsia; lateral extension into the cavernous sinus causes cranial nerve III, IV, VI palsies.
• Pathological (non-milky) discharge is a plumbing problem, not a hormonal one. A papilloma is a friable, fibrovascular frond within a single lactiferous duct; minor torsion or infarction bleeds into that duct, giving unilateral, spontaneous, uniductal bloody or serosanguineous discharge. DCIS produces discharge by the same intraductal mechanism, which is why the clinical picture cannot distinguish the two.
• Duct ectasia involves periductal inflammation and fibrosis of dilated subareolar ducts, yielding thick green-brown discharge and sometimes nipple retraction.

Galactorrhoea (hyperprolactinaemia)

• Bilateral, multiductal milky discharge, often expressible rather than staining clothing — reflects a circulating hormone acting on both breasts.
• Oligomenorrhoea, amenorrhoea, infertility, vaginal dryness and dyspareunia in women from GnRH suppression; the stem is classically a reproductive-age woman on an antipsychotic or a woman with amenorrhoea and a negative pregnancy test.
• Men present late, with decreased libido, erectile dysfunction, gynaecomastia and infertility; galactorrhoea is uncommon because male breast tissue is not oestrogen-primed. Consequently men more often present with mass-effect symptoms and a macroadenoma.
• Headache and bitemporal hemianopsia (chiasmal compression) suggest a macroadenoma; ask about peripheral vision and bumping into door frames.
• Hypothyroid features — fatigue, cold intolerance, constipation, delayed relaxation of reflexes — point to TRH-driven prolactin elevation.
• Chest wall scar, zoster rash, or nipple piercing/stimulation planted in the history is a neurogenic cause.

Pathological nipple discharge

• Unilateral, spontaneous, single-duct, bloody or serosanguineous discharge in a woman typically in her 40s–50s: intraductal papilloma is the most common cause, and a small, soft subareolar nodule may be palpable, with discharge reproduced by pressing one radial point at the areolar margin (trigger point).
• Red flags for malignancy: associated palpable mass, skin dimpling, nipple retraction, axillary lymphadenopathy, older age, or male sex (male nipple discharge is malignant until proven otherwise).
• Paget disease: unilateral eczematous, scaling, ulcerated nipple-areolar complex with discharge that fails to respond to topical steroids.
• Duct ectasia/periductal mastitis: thick, sticky green-brown or multicoloured discharge, often bilateral and multiductal, in a smoker, sometimes with subareolar tenderness or a fistula.
• Physiological discharge: bilateral, multiductal, non-bloody, only on expression, frequently provoked by breast stimulation or a new medication.

Milky/bilateral discharge — endocrine pathway

• Serum prolactin, TSH with free T4, and creatinine are the initial tests. Draw prolactin in a non-stressed state; venepuncture stress, exercise, nipple examination, sleep and meals all cause transient rises, so repeat a borderline value before acting.
• Interpretation (Endocrine Society guidance): mild elevations are typical of drugs, stalk effect, hypothyroidism or renal failure; markedly elevated levels, conventionally above roughly 200 ng/mL, are essentially diagnostic of a prolactinoma, and prolactin concentration correlates loosely with tumour size.
• Hook effect: an enormous prolactinoma can saturate immunoassay antibodies and yield a falsely normal or mildly raised value — request serial dilution when a large sellar mass is present.
• Macroprolactin: biologically inactive IgG-bound prolactin causing asymptomatic elevation; identified by polyethylene glycol precipitation.
• MRI of the pituitary with gadolinium is the imaging study of choice once pregnancy, hypothyroidism, renal failure and drugs are excluded. Formal visual field testing is indicated for any macroadenoma abutting the chiasm.

Non-milky/pathological discharge — breast pathway

• Diagnostic mammography plus targeted subareolar ultrasound is the standard initial imaging in older women per the ACR Appropriateness Criteria; ultrasound is the preferred first test in young women and in pregnancy, with mammography added by age.
• Contrast-enhanced breast MRI is used when standard imaging is negative but discharge remains pathological; ductography is now largely historical.
• Tissue diagnosis — image-guided core biopsy of any lesion; discharge cytology is insensitive and a negative result never excludes carcinoma.
• Central or single-duct excision (microdochectomy) is both the definitive diagnostic manoeuvre and the treatment when imaging is non-diagnostic.

Treat the cause first.

• Primary hypothyroidism: levothyroxine normalises TRH drive and resolves both hyperprolactinaemia and any pituitary hyperplasia — no dopamine agonist needed.
• Drug-induced: stop or substitute the offending agent when clinically safe. For antipsychotic-associated hyperprolactinaemia the Endocrine Society advises consulting the prescribing psychiatrist before withdrawal; switching to a prolactin-sparing agent (the D2 partial agonist aripiprazole) is a standard strategy. Do not stop an antipsychotic unilaterally.

Prolactinoma — first-line therapy is medical, not surgical

• Dopamine agonists: cabergoline is preferred by the Endocrine Society over bromocriptine for greater efficacy in normalising prolactin, shrinking tumour and better tolerability; it is dosed once or twice weekly. Bromocriptine is the alternative and the agent with the longest pregnancy safety record.
• Indications to treat include symptomatic hypogonadism, bothersome galactorrhoea, infertility, and any macroadenoma. An asymptomatic microadenoma with preserved gonadal function may simply be monitored.
• Titrate to prolactin normalisation and tumour shrinkage; after sustained response and no visible tumour, tapering or withdrawal may be attempted.
• Common adverse effects — nausea, orthostatic hypotension, nasal congestion; take at bedtime with food.

Escalation and definitive management

• Transsphenoidal resection for dopamine agonist resistance or intolerance, progressive visual loss, CSF rhinorrhoea, or pituitary apoplexy. Radiotherapy is reserved for aggressive or resistant tumours; temozolomide for malignant prolactinoma.
• Pregnancy: dopamine agonists are typically stopped once pregnancy is confirmed in microadenoma; macroadenomas require close visual-field surveillance and, in some cases, continued bromocriptine.

Pathological nipple discharge

• Duct excision (microdochectomy, or central duct excision if the duct cannot be localised) is the definitive management for spontaneous unilateral bloody or serous discharge, guided by NCCN and surgical society practice — it excises papillomas and excludes occult DCIS.
• Malignancy is managed per NCCN breast cancer pathways.
• Contraindicated/avoid: dopamine antagonists in a patient with hyperprolactinaemia; oestrogens in an untreated prolactinoma; reassurance alone for unilateral bloody discharge with "negative" cytology.

Of untreated hyperprolactinaemia

• Infertility and hypogonadism from suppressed GnRH pulsatility — anovulation in women, low testosterone in men.
• Osteopenia and osteoporosis from chronic sex-steroid deficiency; consider DXA in prolonged hyperprolactinaemia. The finding that signals it is a fragility fracture or low bone density in a young amenorrhoeic patient.
• Progressive visual field loss from chiasmal compression by a macroadenoma — bitemporal hemianopsia that becomes permanent if compression is prolonged.
• Hypopituitarism from compression of remaining pituitary tissue: secondary hypothyroidism, secondary adrenal insufficiency (potentially life-threatening), growth hormone deficiency.
• Pituitary apoplexy — an emergency: haemorrhage or infarction into the adenoma presenting with sudden severe headache, ophthalmoplegia, visual loss and hypotension from acute cortisol deficiency. Give stress-dose glucocorticoids immediately and obtain urgent neurosurgical and endocrine input.

Of therapy

• Dopamine agonist cardiac valvulopathy: ergot-derived agonists stimulate 5-HT2B receptors on valve fibroblasts, causing fibrotic regurgitant lesions. The risk is established at the high doses used in Parkinson disease and is far less clear at hyperprolactinaemia doses; echocardiography is used selectively.
• Impulse control disorders — pathological gambling, hypersexuality, compulsive shopping — from mesolimbic D3 stimulation; ask about them directly at follow-up.
• Psychosis exacerbation when a dopamine agonist is added to a patient with schizophrenia.
• CSF rhinorrhoea when a large invasive macroadenoma shrinks rapidly and unplugs a skull-base defect — an emergency because of meningitis risk.
• Post-transsphenoidal surgery: transient diabetes insipidus, SIADH, hypopituitarism, CSF leak.

Of nipple discharge and its management

• Missed carcinoma when negative cytology falsely reassures — the reason tissue diagnosis or duct excision is pursued.
• Duct excision may cause nipple numbness, nipple inversion, and inability to breastfeed after central duct excision.
• Duct ectasia/periductal mastitis can progress to subareolar abscess and a chronic mammary duct fistula, particularly in smokers.

• Milky, bilateral, multiductal = endocrine; bloody, unilateral, uniductal, spontaneous = ductal. This single split drives nearly every question on this topic.
• The single best next step in a woman with galactorrhoea and amenorrhoea is a pregnancy test, then prolactin and TSH. Imaging the pituitary before excluding pregnancy, hypothyroidism, renal failure and drugs is the classic wrong answer.
• Primary hypothyroidism causes galactorrhoea because elevated TRH stimulates lactotrophs — the answer is levothyroxine, not cabergoline. Examiners love pairing fatigue, constipation, weight gain and milky discharge.
• Cabergoline is first-line for prolactinoma, even for macroadenomas with chiasmal compression — this is the one pituitary tumour where medicine beats surgery. Surgery is for resistance, intolerance, apoplexy or CSF leak.
• **The most common cause of pathological bloody nipple discharge is an *intraductal papilloma*, which is benign — but the distractor is assuming benignity clinically. DCIS and invasive carcinoma cannot be excluded without imaging and tissue**; negative discharge cytology never rules out cancer.
• **A falsely normal prolactin with a huge sellar mass is the *hook effect* — ask for serial dilution. Conversely, an asymptomatic patient with elevated prolactin may have macroprolactin**, detected by PEG precipitation.
• Risperidone is the antipsychotic most associated with hyperprolactinaemia; aripiprazole (D2 partial agonist) is the prolactin-sparing switch. Never stop an antipsychotic without psychiatry input.
• **Unilateral eczematous, ulcerated nipple that fails topical steroids is *Paget disease*** — biopsy the nipple and look for an underlying carcinoma; do not treat as dermatitis.
• Sudden headache, ophthalmoplegia and hypotension in a known adenoma is pituitary apoplexy — stress-dose glucocorticoids and urgent neurosurgery.