Prolactin

Prolactin is a 199 amino acid hormone made by lactotroph cells of the anterior pituitary. Dopamine from the hypothalamus tonically inhibits its release, so dopamine antagonists, pituitary stalk compression and drugs raise it. Its main actions are breast development and lactation, with suppression of gonadotropin releasing hormone, which explains the amenorrhoea, infertility and hypogonadism of hyperprolactinaemia. It is measured by two site immunoassay in serum, in mIU/L or microg/L (1 microg/L is about 21 to 30 mIU/L, depending on the assay).

The test finds the cause of galactorrhoea, menstrual disturbance, infertility, sexual dysfunction and hypogonadism, supports the diagnosis of prolactinoma and hypopituitarism, and monitors treatment.

Hyperprolactinaemia is found in 0.4% of the general adult population and 9 to 17% of women with reproductive disorders. Prolactinomas are the commonest functioning pituitary adenoma, with a prevalence of about 50 per 100 000 and a female preponderance (micro-adenomas in women, macro-adenomas more often in men).

Indications. Galactorrhoea, oligomenorrhoea or amenorrhoea, infertility, reduced libido, erectile dysfunction, gynaecomastia, delayed puberty, osteoporosis in young people, pituitary mass or visual field defect, headache, suspected hypopituitarism, and monitoring of prolactinoma treatment.

Specimen. Serum or heparin plasma, taken at least 2 to 3 hours after waking, with the patient resting for 20 to 30 minutes, since stress, exercise, sleep, venepuncture, nipple stimulation and a recent meal raise levels. Avoid sampling soon after breast examination. Repeat once if the result is mildly raised.

Reference range. Women (non-pregnant): under 25 microg/L (under 530 mIU/L), men: under 15 to 20 microg/L (under 400 mIU/L). Assay specific.

Magnitude and likely cause.

• Mild (up to 100 microg/L, 2000 mIU/L): drugs, stress, hypothyroidism, polycystic ovary syndrome, kidney failure, stalk effect from a non-functioning macroadenoma or other sellar mass, microprolactinoma.
• Moderate (100 to 250 microg/L): microprolactinoma, drugs (especially antipsychotics, metoclopramide, domperidone).
• Marked (over 250 microg/L, 5000 mIU/L): macroprolactinoma. A level over 500 microg/L is almost always a prolactinoma. A macroadenoma with a level under 100 microg/L usually indicates stalk compression by a non-functioning mass.

Causes of raised prolactin.

• Physiological: pregnancy, breastfeeding, nipple stimulation, stress, exercise, sleep, coitus, and a protein meal.
• Pituitary: prolactinoma, stalk compression (non-functioning adenoma, craniopharyngioma, meningioma, germinoma, empty sella), acromegaly (co-secretion), and hypophysitis.
• Drugs: antipsychotics (risperidone, amisulpride, haloperidol, with olanzapine and aripiprazole less so), metoclopramide, domperidone, methyldopa, verapamil, opioids, antidepressants (tricyclics, serotonin reuptake inhibitors), oestrogens, protease inhibitors.
• Systemic: primary hypothyroidism (thyrotropin releasing hormone stimulates prolactin), chronic kidney disease, cirrhosis, polycystic ovary syndrome, chest wall injury or herpes zoster, and ectopic production.
• Macroprolactin: a high-molecular-weight complex of prolactin and IgG that is biologically inactive, found in 10 to 25% of hyperprolactinaemia and causes no symptoms.

Causes of low prolactin. Hypopituitarism (failure of lactation after delivery in Sheehan syndrome), pituitary apoplexy and dopamine agonist therapy. It indicates pituitary damage when combined with other deficits.

Prolactinoma assessment. Prolactin proportional to tumour size. Macroadenomas need visual field testing, MRI and the other pituitary hormones. Dopamine agonists (cabergoline, bromocriptine) normalise prolactin in over 85% and shrink the tumour. Prolactin is checked 1 month after starting and then at 3 to 6 months.

Hook effect. In a macroadenoma, extremely high prolactin can saturate the assay and give a falsely low result. Serial dilution of the sample (1 to 100) unmasks it. It should be considered when a large sellar mass is found with a surprisingly low or normal result.

Critical values and findings needing immediate action.

• Prolactin over 250 microg/L with visual field loss, ophthalmoplegia or severe headache (macroprolactinoma with chiasmal compression, or pituitary apoplexy).
• Large pituitary mass with panhypopituitarism, hypotension or hyponatraemia, which needs urgent cortisol replacement.
• Pregnancy with a known macroprolactinoma and new headache or visual symptoms.

Interferences and pitfalls.

• Stress and venepuncture itself can raise prolactin to 2 times the upper limit, so a mildly raised result is repeated on a separate day, resting and well hydrated.
• Macroprolactin gives a falsely high result. It is detected by polyethylene glycol precipitation, and the monomeric result is used.
• The hook effect gives a falsely low result in large tumours.
• Heterophile antibodies can cause false positives.
• Drug induced hyperprolactinaemia is confirmed by stopping the drug for 3 days if clinically safe, or by changing agent, with specialist advice.
• Hypothyroidism is excluded before pituitary imaging.
• Biotin and sample haemolysis can interfere.

Special groups.

• Neonates: prolactin is high at birth and falls over 2 to 3 months.
• Children and adolescents: delayed or arrested puberty and primary amenorrhoea are the presentations.
• Pregnancy: prolactin rises 10-fold and it is not measured. Prolactinoma may enlarge, particularly a macroadenoma, and visual symptoms need urgent assessment.
• Postmenopausal women: levels fall, and a macroadenoma is the usual finding when raised.
• Men: presenting late with symptoms of mass effect, hypogonadism and low libido.

Follow up tests. Repeat prolactin with macroprolactin screen, thyroid function tests, pregnancy test, urea and creatinine, liver function tests, luteinising hormone, follicle stimulating hormone, oestradiol or testosterone, cortisol, IGF-1, other anterior pituitary hormones, MRI of the pituitary, visual fields, and bone density.