Endocrinology & Gynecology & Family Medicine
Prolactin
Prolactin (PRL) is a 199 amino acid polypeptide hormone synthesized and secreted by lactotropic (mammotropic) cells of the anterior pituitary gland, which account for 10 to 25 % of the pituitary cell population. Its main physiological function is the initiation and maintenance of lactation after delivery - it stimulates milk synthesis in mammary glands differentiated by estrogen and progesterone during pregnancy, and simultaneously inhibits gonadotropic function by reducing the pulsatility of hypothalamic GnRH, explaining the physiological amenorrhea and relative infertility of the lactation period. Its regulation is unique among pituitary hormones in that it is under permanent inhibitory control of the hypothalamus via dopamine (also known as prolactin inhibitory factor or PIF) secreted by tubero-infundibular neurons - unlike most other pituitary hormones, which are stimulated by their corresponding hypothalamic releasing hormone. This dominant dopaminergic regulation explains why any drug blocking dopaminergic D2 receptors - typical and atypical antipsychotics, antiemetics (metoclopramide, domperidone) - causes hyperprolactinemia, which is sometimes very marked, and why dopaminergic agonists (cabergoline, bromocriptine) are the first-line treatment for prolactinomas. Hyperprolactinemia is the most common pituitary endocrine anomaly, accounting for up to 40 % of secondary amenorrhea in young women, and causing hypogonadotropic hypogonadism with galactorrhea, menstrual cycle disorders, infertility and erectile dysfunction in men. Prolactinoma - a prolactin-secreting pituitary adenoma - is the most common functional pituitary adenoma (40-50 % of all pituitary adenomas), with an estimated prevalence of 10 cases per 100,000 population.
Reference and pre-analytical values
| Population | Normal prolactin (µg/L = ng/mL) | Normal prolactin (mUI/L) |
|---|---|---|
| Non-pregnant + non-breast-feeding women (follicular phase) | 3 to 25 µg/L | 62 to 520 mUI/L |
| Women in the luteal phase | Slightly higher - up to 30 µg/L | Up to 620 mUI/L |
| Pregnant women (3rd trimester) | 50 to 400 µg/L | 1,000 to 8,000 mIU/L (physiological elevation) |
| Nursing mothers | Variable - can reach 100-300 µg/L | 2,000 to 6,000 mUI/L |
| Adult male | 3 to 15 µg/L | 62 to 310 mUI/L |
| Unit conversion | 1 µg/L = 1 ng/mL = 20.6 mUI/L (according to WHO) + 1 mUI/L = 0.047 µg/L + check laboratory convention (some use 21.2 mUI/µg) | |
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Prolactin is subject to significant physiological and pre-analytical variations, which can generate false positives: elevation by stress (anxiety linked to venipuncture - the «needle effect»), sleep (nocturnal peak at the onset of sleep), physical effort, sexual intercourse, nipple stimulation, a protein-rich meal, and medication. For a reliable result, the sample should be taken in the morning (1 to 3 hours after rising), in a sitting or lying position for at least 20 to 30 minutes, preferably fasting, without breast stimulation or recent physical activity. If moderate hyperprolactinemia is found, repeat the test under ideal conditions before drawing any conclusions.
Causes of hyperprolactinemia
| Cause | Mechanism and agents | Elevation level and characteristics |
|---|---|---|
| Physiological | Pregnancy + breastfeeding + sampling stress + sleep + nipple stimulation + physical exercise + meals (protein) | Moderate (generally < 100 µg/L except in advanced pregnancy) + transient + obvious context |
| Medication - most frequent cause of pathological hyperprolactinemia | Typical antipsychotics (haloperidol ++ + chlorpromazine) + atypical antipsychotics (risperidone +++ + olanzapine + quetiapine - lesser) + antiemetics (metoclopramide + domperidone ++) + antidepressants (SSRIs - slight increase) + antihypertensives (methyldopa + verapamil) + opiates + high-dose estrogens + mechanism: D2 dopamine receptor blockade | Varies according to drug: metoclopramide + haloperidol + risperidone → elevations often significant (50-200 µg/L) + confirmation: discontinue drug for 72 h if possible → normalization confirms etiology |
| Prolactinoma (microadenoma < 10 mm) | Prolactin-secreting pituitary adenoma + size 200 µg/L | PRL 25-200 µg/L + pituitary MRI with thin coronal sections + gadolinium + treatment: cabergoline |
| Macroprolactinoma (≥ 10 mm) | Prolactinoma ≥ 10 mm + possible chiasmatic compression + invasion of the cavernous sinus + very high PRL + sometimes PRL paradoxically decreases if the tumor is very large (hook effect). | PRL often > 200-500 µg/L (sometimes several thousand) + headache + visual field deficit + hypopituitarism + hook effect may falsely normalize PRL at very high concentrations → dilute serum if macroprolactinoma suspected |
| Other organic causes | Primary hypothyroidism (high TRH → direct stimulation of lactotropes) + chronic renal failure (reduced PRL clearance) + hepatic cirrhosis + hypothalamic or pituitary stem causes (tumors + sarcoidosis + trauma - reduced dopaminergic tone) | Hypothyroidism: normalization under L-thyroxine + CKD: PRL rarely > 100 µg/L + hypothalamic causes: PRL often moderately elevated (30-150 µg/L) + stem compression = «stem effect».» |
| Macroprolactinemia (false hyperprolactinemia) | Presence of biologically inactive immunoglobulin-prolactin complexes (big-big prolactin) + assayed by immunoassays as prolactin + diagnosis: polyethylene glycol (PEG) precipitation → if monomeric prolactin recovery < 40 % after PEG = macroprolactinemia | PRL 25-200 µg/L + ASYMPTOMATIC (no galactorrhea + regular cycles + no infertility) + normal MRI + no treatment + macroprolactinemia is a frequent cause of incidental finding of moderate hyperprolactinemia. |
Clinical presentation of hyperprolactinemia
- For women: galactorrhea (milky discharge from the nipples outside pregnancy and breastfeeding - present in 50-70 % of hyperprolactinemias) + menstrual cycle disorders (oligomenorrhea + secondary amenorrhea) + anovulatory infertility + decreased libido + vaginal dryness + osteoporosis (chronic hypoestrogenism) + in macroprolactinomas : headache + visual deficit (bitemporal hemianopia due to compression of the optic chiasma)
- In humans : hypogonadotropic hypogonadism (decreased libido + erectile dysfunction + reduced spermatogenesis → infertility + reduced testicular volume) + galactorrhea (less frequent than in women - 20-30 %) + gynecomastia + headaches + visual deficit if macroprolactinoma + osteoporosis
- Warning signs of macroprolactinoma : chronic headaches + progressive visual field deficit (bitemporal hemianopsia) + diplopia (invasion of cavernous sinus) + hypopituitarism (asthenia + hypothyroidism + severe hypogonadism + adrenal insufficiency) → urgent pituitary MRI
Treatment - prolactinoma
- Cabergoline (Dostinex®) - reference treatment : long-acting D2 dopaminergic agonist + 0.25 to 3 mg po 2×/week (dose varies according to response) + normalizes prolactin in 80-90 % of microprolactinomas + reduces tumor volume by 50-75 % in macroprolactinomas + treatment for at least 2 years then attempt to stop if PRL normalized and MRI stable for ≥ 2 years → remission maintained in 30-40 % after stopping + adverse effects: nausea + headache + orthostatic hypotension (reduce by taking at bedtime with food) + cardiac valvulopathy at high doses (very low risk at usual prolactinoma doses)
- Bromocriptine (Parlodel®) - alternative : less selective dopaminergic agonist + 2.5 to 15 mg/day po + less effective and less well tolerated than cabergoline (nausea ++) + but preferred in early pregnancy (more extensive safety data) + cabergoline is also considered safe during pregnancy at usual doses
- Transphenoidal pituitary surgery : indicated if intolerance to dopaminergic agonists + resistance (PRL does not normalize despite maximum doses) + macroprolactinoma with pituitary apoplexy (intratumoral hemorrhage + neurosurgical emergency) + refusal of medical treatment + large macroadenoma compressing surrounding structures resistant to DAs
- Radiotherapy : reserved for aggressive or malignant prolactinomas resistant to surgery and dopaminergic agonists + stereotactic (Gamma Knife) or fractionated + slow effect (normalization over years) + risk of long-term hypopituitarism
- Pregnancy on dopamine agonists : discontinuation of cabergoline or bromocriptine as soon as pregnancy is confirmed (except macroprolactinoma with risk of chiasmatic compression) + monthly clinical monitoring (visual fields + headaches) + gadolinium-free MRI if signs of tumour growth + resumption of treatment after delivery if hyperprolactinaemia recurs
Situations requiring urgent medical attention
Consult a physician or endocrinologist promptly if hyperprolactinemia is accompanied by severe headache + visual deficit (reduced peripheral vision or double vision) + or pituitary apoplexy (sudden headache + vomiting + confusion + diplopia + acute loss of vision) - these signs indicate a compressive macroprolactinoma requiring urgent pituitary MRI and possibly immediate neurosurgical management.
For prolactin measurement and interpretation, pituitary MRI if indicated, and initiation of cabergoline for the treatment of a diagnosed microprolactinoma, Clinique Omicron offers medical consultations at its points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's specialized physicians and nurse practitioners (SPNs) prescribe and interpret prolactin assays, identify common drug causes (antipsychotics + metoclopramide + domperidone), prescribe pituitary MRI if indicated, initiate cabergoline treatment for diagnosed microprolactinomas, and refer to endocrinology for macroprolactinomas, resistant forms and specialized monitoring. Consultations are available at several points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The contents of this page are provided for information purposes only and do not replace the advice of a physician or endocrinologist. Interpretation of an elevated prolactin assay requires a thorough drug history, standardized sampling conditions and pituitary MRI imaging - asymptomatic macroprolactinemia must be excluded before treatment.
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