Endocrinology & Medical Biology & Gynecology & Family Medicine
Macroprolactine | Clinique Omicron Québec
Macroprolactin is a molecular form of serum prolactin characterized by the formation of a high-molecular-weight complex (150-170 kDa) resulting from the binding of monomeric prolactin (23 kDa - the biologically active form) to endogenous IgG autoantibodies. This immunoglobulin-prolactin complex is detected by routine immunoassays as elevated total prolactin (biochemical hyperprolactinemia) - but its bioactivity is greatly reduced, if not eliminated, as the binding to the autoantibody prevents prolactin from interacting with its tissue receptor. Macroprolactinemia - the term for hyperprolactinemia in which macroprolactin is the dominant component - is the most frequent cause of asymptomatic moderate hyperprolactinemia in patients who benefit from routine prolactin testing. Its prevalence among patients with hyperprolactinemia is estimated at 10-46 %, depending on the studies and methods used. The distinction between benign macroprolactinemia and true hyperprolactinemia (due to prolactinoma + drugs + hypothyroidism + pregnancy + pathophysiological causes) is crucial, as their clinical and therapeutic implications are radically different: macroprolactinemia generally requires no treatment + no systematic pituitary MRI + no dopaminergic agonist. The reference technique for identifying macroprolactin is polyethylene glycol (PEG) precipitation - if the residual prolactin after PEG is <40-60 % of the initial prolactin, macroprolactin is the dominant component.
Biochemistry, mechanisms and differential diagnosis
- Prolactin biochemistry and molecular forms : molecular forms of serum prolactin: monomeric prolactin (little prolactin - 23 kDa): main biologically active form → binds to prolactin receptors in target tissues (breast + gonads + liver) → responsible for physiological effects (lactation + reproductive effects) → accounts for 80-90 % of normal serum prolactin + big prolactin (50-60 kDa) : dimer or glycosylated forms → less biologically active + macroprolactin (big-big prolactin - 150-170 kDa) : monomeric prolactin + IgG complex → poorly elaborated form → reduced renal clearance (too large to be filtered) → prolonged half-life → serum accumulation → detected as high total prolactin by immunoassays → very reduced bioactivity → mechanisms of macroprolactin formation : anti-prolactin IgG autoantibodies → bind to monomeric prolactin → form high-molecular-weight complexes → these autoantibodies are present in 15-40 % of the general population at variable titers → when these antibodies are in sufficient quantity to bind the majority of circulating prolactin → macroprolactinemia → why do autoantibodies appear? Exact mechanism unknown - perhaps related to immunizations or benign physiological autoimmune response + analytical detection of macroprolactin: routine immunoassays (ECLIA + CLIA + ELISA) measure total prolactin (monomeric + macroprolactin) → high result → misleading interpretation + steric exclusion chromatography (gel filtration): gold standard for separating forms → laborious + expensive + reserved for research + polyethylene glycol precipitation (PEG 6000): practical laboratory method → PEG selectively precipitates immunoglobulins and high molecular weight complexes → centrifugation → determination of supernatant (residual prolactin) → if recovered <40-60 % of initial prolactin → dominant macroprolactin → recommended by the European Society of Endocrinology + the Endocrine Society
- Causes of true hyperprolactinemia and differential diagnosis with macroprolactinemia : causes of true hyperprolactinemia (elevated biologically active monomeric prolactin) - to be distinguished from macroprolactinemia: drug causes (the most common biologically active hyperprolactinemia): antipsychotics (haloperidol + risperidone + amisulpride + chlorpromazine): block D2 dopamine receptors → removal of dopamine inhibitory tone on pituitary lactotropes → massive prolactin release → often prolactin >50-100 µg/L + antidepressants (SSRIs + tricyclics) + antiemetics (metoclopramide + domperidone) + opioids + calcium channel blockers (verapamil) + methyldopa + reserpine + hypothalamic and pituitary stem causes: tumor + granuloma + craniopharyngioma + stem section → lift pituitary dopaminergic inhibition + prolactinoma (prolactin-secreting pituitary adenoma): microprolactinoma (<1 cm) + macroprolactinome (>1 cm) → most frequent cause of tumoral hyperprolactinemia + pregnancy: physiologically elevated prolactin (up to 300-500 µg/L at term) + breastfeeding + primary hypothyroidism: TRH ↑ (stimulates lactotropes) → hypothyroidism → always assay TSH if prolactin elevated → CKD + cirrhosis (reduced clearance) → physical stress + blood sampling after meals + coitus + breast stimulation → false positives from sampling conditions → differential diagnosis macroprolactinemia vs. true hyperprolactinemia: macroprolactinemia: often asymptomatic + no hormonal symptoms (normal cycles + no galactorrhea + preserved libido) + incidental finding + positive PEG + residual prolactin <40–60 % → hyperprolactinémie vraie : galactorrhée + aménorrhée + infertilité + hypogonadisme + baisse de la libido + céphalées + troubles visuels si macroprolactinome + PEG négatif (prolactine résiduelle >60 %)
Diagnosis and management
| Aspect / situation | Procedure, interpretation and course of action | References and recommendations |
|---|---|---|
| Diagnostic approach to high prolactin levels Prolactin normal values - sampling conditions - PEG test - recovery interpretation - TSH hypothyroidism - drug assessment - prolactin 2nd assay - pituitary MRI - visual field - FSH LH estradiol - prolactinoma criteria |
Diagnostic approach to hyperprolactinemia discovered: normal prolactin values: non-pregnant woman: 2-20 µg/L (values vary according to laboratory and method) → man: 2-15 µg/L → full-term pregnancy: up to 300-500 µg/L → important pre-analytical conditions: sample taken in the morning on an empty stomach + 2h after waking up + avoid stress + breast stimulation + coitus in the previous 24h (transiently elevated prolactin) → first step - confirm hyperprolactinemia: repeat prolactin under optimal conditions → exclude false positives → second step - TSH (primary hypothyroidism → prolactin elevated by TRH) + drug assessment (antipsychotics + metoclopramide + SSRIs + opioids + verapamil) → third step - PEG (polyethylene glycol) test: indication: moderately elevated prolactin (20-150 µg/L) + asymptomatic patient + or discordant symptoms → PEG precipitation + supernatant assay → recovery >60 % → macroprolactin excluded → monomeric prolactin dominant → search for cause of true hyperprolactinemia → recovery <40-60 % → macroprolactinemia confirmed → generally benign → no treatment → no systematic MRI + fourth step (if true hyperprolactinemia confirmed): pituitary MRI with gadolinium: 1st intention to diagnose a prolactinoma → if microprolactinoma (1 cm) → prolactin often >250 µg/L → + complete pituitary hormone workup (TSH + cortisol + IGF-1 + LH + FSH + estradiol or testosterone) → visual field if macroprolactinoma (compression of optic chiasma) | Melmed 2011 - Journal of Clinical Endocrinology and Metabolism (Endocrine Society guidelines): hyperprolactinemia + diagnosis + treatment → reference + Vilar 2019 - Neuroendocrinology: macroprolactin + PEG + diagnosis → review + Kasum 2012 - Gynecological Endocrinology: macroprolactinemia + clinic + workup + Cavaco 2010 - Clinical Endocrinology: PEG + macroprolactin + sensitivity + specificity → Fahie-Wilson 2018 - Clinical Biochemistry Reviews: macroprolactin + diagnosis + PEG + CSEM (Canadian Society of Endocrinology and Metabolism) + INESSS Québec + RAMQ: prolactin + TSH + PEG + MRI → reimbursed according to indication |
| Macroprolactinemia - management and follow-up benign macroprolactinemia - no treatment - no systematic MRI - reassurance - annual follow-up - symptoms - rare galactorrhea - normal menstrual cycles - infertility excluded - treatment if symptoms - dopaminergic agonists if necessary |
Management of PEG-confirmed macroprolactinemia: pure macroprolactinemia (PEG recovery <40 %) + asymptomatic patient (normal cycles + no galactorrhea + no hypogonadism + no infertility) : rassurance + no drug treatment → no dopaminergic agonist (cabergoline + bromocriptine) → no systematic pituitary MRI → annual follow-up with total prolactin assay → no change in treatment as long as patient remains asymptomatic → patient information: macroprolactinemia is a benign entity → biologically active prolactin is normal → complications of true hyperprolactinemia (osteoporosis + infertility + hypogonadism) are not expected in macroprolactinemia → macroprolactinemia with symptoms (rare cases): galactorrhea in some patients with macroprolactinemia → discussed → but rare and not very disabling → treatment of symptoms if necessary + macroprolactinemia and desire for pregnancy: in a woman with macroprolactinemia + infertility → evaluate other causes of infertility as macroprolactinemia is rarely responsible → menstrual cycles often normal in macroprolactinemia → if amenorrhea + infertility coexist → look for residual true hyperprolactinemia or another cause of anovulation + macroprolactinemia and osteoporosis: the risk of osteoporosis is not increased in macroprolactinaemia (because biologically active prolactin is normal) → DXA not necessary in isolated asymptomatic macroprolactinaemia + if MRI mistakenly requested in a patient with macroprolactinaemia: pituitary incidentaloma possible (prevalence 10-15 % in general population) → do not overtreat → contextual interpretation + long-term stability: macroprolactinemia is a stable entity → total prolactin may fluctuate but macroprolactin generally persists for life | Melmed 2011 - JCEM (Endocrine Society guidelines): hyperprolactinemia → macroprolactin → no treatment if asymptomatic + Kasum 2012 - Gynecological Endocrinology: macroprolactinemia + clinical + benign + Vilar 2019 - Neuroendocrinology: macroprolactinemia + review + management + Gibney 2005 - Clinical Endocrinology: macroprolactinemia + follow-up + evolution → Hattori 2003 - European Journal of Endocrinology: macroprolactinemia + long-term results + CSEM (Canadian Society of Endocrinology and Metabolism) + INESSS Québec + RAMQ: cabergoline + bromocriptine → reimbursed if confirmed true hyperprolactinemia + prolactinoma |
| True hyperprolactinemia - prolactinoma and treatment with dopaminergic agonists Prolactinoma microprolactinoma macroprolactinoma - cabergoline bromocriptine - size reduction - galactorrhea amenorrhea treatment - vision optic chiasm - transsphenoidal surgery - radiotherapy - pregnant woman prolactin - annual MRI monitoring |
True hyperprolactinemia - treatment of prolactinoma (after exclusion of macroprolactin): dopaminergic agonists - 1st-line treatment of prolactinoma: cabergoline (Dostinex): reference treatment → long half-life D2 agonist → 0.25-1 mg × 2/week → efficacy: normalization of prolactin in 80-90 % of microprolactinomas + reduction of tumor volume in 70-80 % of macroprolactinomas → adverse effects: nausea + dizziness + orthostatic hypotension (less frequent than with bromocriptine) → at high doses (>3 mg/week): risk of cardiac valvulopathy (Parkinson's disease data - very high doses) → no significant risk at doses used for prolactinomas + bromocriptine (Parlodel) 2.5-15 mg/d : alternative + less well tolerated → used during pregnancy (safety data over 30+ years) → microprolactinoma: treatment with cabergoline if : galactorrhea + or amenorrhea + or infertility + or hypogonadism + or osteoporosis + macroprolactinoma: compulsory treatment (prolactinoma >1 cm) + ophthalmological monitoring (visual field if compression of chiasma) → follow-up MRI at 3-6 months → transsphenoidal surgery: if failure of dopaminergic agonists (non-responders) + or intolerance + or ophthalmological emergency (progressive vision loss) → surgical cure rate: 70-90 % for microprolactinomas + less good for macroprolactinomas + pregnancy and prolactinoma : if desire for pregnancy on cabergoline → stop cabergoline as soon as pregnancy is confirmed + monitor visual symptoms monthly + MRI if symptoms (no systematic MRI) + if microprolactinoma → very low risk of tumor growth during pregnancy (<5 %) + if macroprolactinoma → higher risk of growth (15-25 %) → bromocriptine sometimes maintained | Melmed 2011 - JCEM (Endocrine Society guidelines): prolactinoma + cabergoline + treatment → reference + Molitch 2014 - JCEM: prolactinoma + dopaminergic agonists + results → Colao 2012 - NEJM: prolactinoma + review + treatment → Dekkers 2010 - European Journal of Endocrinology: cabergoline + macroprolactinoma + results + Auriemma 2013 - Journal of Clinical Endocrinology: prolactinoma + pregnancy + follow-up + CSEM (Canadian Society of Endocrinology and Metabolism) + INESSS Québec + RAMQ: cabergoline + bromocriptine → reimbursed if prolactinoma confirmed + pituitary MRI with gadolinium → reimbursed |
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Macroprolactinemia is the most frequent cause of asymptomatic moderate hyperprolactinemia - it accounts for 10 to 46 % of hyperprolactinemias and requires neither treatment nor systematic pituitary MRI if the patient is asymptomatic: the PEG precipitation test is essential before starting treatment with a dopamine agonist or ordering pituitary MRI in a patient with moderate hyperprolactinaemia with no obvious symptoms. A PEG recovery of less than 40-60 % confirms macroprolactinaemia. TSH should always be measured to exclude primary hypothyroidism as a cause of hyperprolactinaemia.
Situations requiring urgent endocrinological evaluation
Severe hyperprolactinemia (>250 µg/L) + or macroprolactinoma (>1 cm on MRI) + visual disturbances (reduced visual field + diplopia) + or headache + or pituitary insufficiency (fatigue + hypogonadism + polyuria) → compressive macroprolactinoma → urgent endocrinology consultation → cabergoline 0.25-0.5 mg × 2/week immediately + visual field → if rapid loss of vision → emergency transphenoidal neurosurgery.
Pregnant woman with history of macroprolactinoma + new headache + worsening headache + or visual disorders → tumor growth durante graviditate → pituitary MRI (without gadolinium if pregnant) → bromocriptine to be resumed if compression + endocrinology + ophthalmology consultation.
Hyperprolactinemia discovered + very high TSH + symptoms of hypothyroidism (coldness + constipation + bradycardia + weight gain) → primary hypothyroidism as cause of hyperprolactinemia → levothyroxine treatment → expected normalization of prolactin under hypothyroidism treatment → NO cabergoline needed → NO pituitary MRI needed if prolactin normalizes with LT4.
Consult at Clinique Omicron
Clinique Omicron's doctors assess any new-onset hyperprolactinemia by checking sampling conditions, measuring TSH, performing the PEG test to distinguish macroprolactinemia from true hyperprolactinemia, referring to an endocrinologist and pituitary MRI if indicated, and prescribing dopaminergic agonists (cabergoline) if the diagnosis of prolactinoma is confirmed. 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. Macroprolactinemia is a benign entity - do not treat asymptomatic macroprolactinemia with dopaminergic agonists without prior confirmation of the nature of the hyperprolactinemia by the PEG test.
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