ProlactinomasProlactinomas

Yona Greenman MDYona Greenman MDInstitute of Endocrinology and Institute of Endocrinology and

MetabolismMetabolismTel Aviv-Sourasky Medical CenterTel Aviv-Sourasky Medical Center

IssuesIssues

DiagnosisDiagnosis MacroprolactinMacroprolactin Hook effectHook effect

TreatmentTreatment Long term follow Long term follow

upup Discontinuation of Discontinuation of

treatmenttreatment Pregnancy Pregnancy

ProlactinProlactin

Human PRL is synthesized as a prehormone of 26 Human PRL is synthesized as a prehormone of 26 kDa. Preprolactin is cleaved into a 199 a.a. peptide kDa. Preprolactin is cleaved into a 199 a.a. peptide with a molecular weight of 23 kDa with a molecular weight of 23 kDa

This monomeric form accounts for 85% of This monomeric form accounts for 85% of circulating PRL in both normal and circulating PRL in both normal and hyperprolactinemic serahyperprolactinemic sera

Big PRL (50 kDa), a covalently bound dimer of PRL Big PRL (50 kDa), a covalently bound dimer of PRL accounts for 10-15% of total PRLaccounts for 10-15% of total PRL

Big Big PRL (>150 kDa) or macroprolactinBig Big PRL (>150 kDa) or macroprolactin Post-translational modifications of PRL (glycosylated Post-translational modifications of PRL (glycosylated

an phosphorylated variants), and 14, 16 and 22 kDa an phosphorylated variants), and 14, 16 and 22 kDa proteolysed forms proteolysed forms

MacroprolactinMacroprolactin

Macroprolactin is a macromolecular complex Macroprolactin is a macromolecular complex of monomeric PRL and an immunoglobulin, of monomeric PRL and an immunoglobulin, generally an IgG antibodygenerally an IgG antibody

Reduced clearance of this complex accounts Reduced clearance of this complex accounts for persistent hyperprolactinemia for persistent hyperprolactinemia

The macroprolactin complex is confined to The macroprolactin complex is confined to the intravascular space, has limited the intravascular space, has limited bioavailability, hence its reduced bioactivitybioavailability, hence its reduced bioactivity

Clinical FeaturesClinical Features

It is present in significant amounts in up to 24 % of It is present in significant amounts in up to 24 % of hyperprolactinemic sera hyperprolactinemic sera

Often the condition is identified serendipitously, in Often the condition is identified serendipitously, in the absence of classic symptoms of the absence of classic symptoms of hyperprolactinemiahyperprolactinemia

Symptoms leading to the measurement of Symptoms leading to the measurement of prolactin, such as menstrual disorders, galactorhea prolactin, such as menstrual disorders, galactorhea or various degree of infertility, are not specific, and or various degree of infertility, are not specific, and may occur coincidentally in macroprolactinemic may occur coincidentally in macroprolactinemic patients patients

High prevalence of pituitary lesions identified High prevalence of pituitary lesions identified incidentally by imaging procedures may coexist incidentally by imaging procedures may coexist with macroprolactinemiawith macroprolactinemia

Clinical DiagnosisClinical Diagnosis Differentiation of Differentiation of

macroprolactinemic macroprolactinemic patients from those patients from those with true with true hyperprolactinemia on hyperprolactinemia on clinical grounds is clinical grounds is unreliableunreliable

The percentage of The percentage of clinically significant clinically significant hyperprolactinemic hyperprolactinemic samples explained by samples explained by hyperprolactinemia is hyperprolactinemia is similar across all levels similar across all levels of total prolactinof total prolactin

Gibney et al (2005) J Clin Endocrinol Metab 90:3927-3932 .

The Macroprolactin ProblemThe Macroprolactin Problem

Misdiagnosis of hyperprolactinemia Misdiagnosis of hyperprolactinemia may result in unnecessary diagnostic may result in unnecessary diagnostic procedures and inappropriate procedures and inappropriate treatmenttreatment

Recognition of macroprolactin and Recognition of macroprolactin and the “pseudohyperprolactinemia” the “pseudohyperprolactinemia” affords the opportunity to make a affords the opportunity to make a correct diagnosis of the patient’s correct diagnosis of the patient’s clinical condition clinical condition

Clinical QuestionClinical Question

Should every hyperprolactinemic Should every hyperprolactinemic serum be screened for serum be screened for macroprolactin?macroprolactin?

Identification of Macroprolactin Identification of Macroprolactin by Gel Chromatographyby Gel Chromatography

A- First peak (69%)- big-big PRL (fractions 15–23; molecular A- First peak (69%)- big-big PRL (fractions 15–23; molecular mass >100 kDa); Second peak (15%)- big PRL (fractions mass >100 kDa); Second peak (15%)- big PRL (fractions 27–31; 50 kDa); Third peak (16%) -monomeric PRL 27–31; 50 kDa); Third peak (16%) -monomeric PRL (fractions 33–39; 23–25 kDa) (fractions 33–39; 23–25 kDa)

B- Monomeric PRL secreted by the tumor in vitroB- Monomeric PRL secreted by the tumor in vitro

Vallette-Kasic et al JCEM (2002) 87: 581-588

PEG PrecipitationPEG Precipitation

Prolactin recovery < 40% after PEG Prolactin recovery < 40% after PEG consistent with macroprolactinemiaconsistent with macroprolactinemia

Prolactin levels fall within the normal Prolactin levels fall within the normal range following removal of range following removal of macroprolactin by PEG (because macroprolactin by PEG (because there is coprecipitation of monomeric there is coprecipitation of monomeric PRL by PEG, values obtained by PRL by PEG, values obtained by treating normal serum are used as treating normal serum are used as reference)reference)

Gibney et al (2005) Clin Endocrinol 62 (6), 633-643.

Detection of Prolactin in Serum Detection of Prolactin in Serum Containing Macroprolactin Containing Macroprolactin

Smith et al (2002) J Clin Endocrinol Metab 87: 5410-5415

Is macroprolactin just a laboratory Is macroprolactin just a laboratory artifact that should be dismissed?artifact that should be dismissed?

1) 1) Possibility that macroprolactin has some Possibility that macroprolactin has some biological activity, or maybe if functions biological activity, or maybe if functions as a pool of monomeric prolactin that as a pool of monomeric prolactin that intermittently dissociates from the low intermittently dissociates from the low affinity high capacity IgG complex, thus affinity high capacity IgG complex, thus causing symptoms of prolactin excess.causing symptoms of prolactin excess.

-Calls for assays able to detect -Calls for assays able to detect macroprolactinmacroprolactin

2) Macroprolactin is asymptomatic and 2) Macroprolactin is asymptomatic and causes diagnostic confusioncauses diagnostic confusion

- Calls for assays that do not recognize - Calls for assays that do not recognize macroprolactinmacroprolactin

ConclusionsConclusions

Each center must know the specific Each center must know the specific characteristics of the prolactin characteristics of the prolactin immunoassay they use. immunoassay they use.

For confirmation of For confirmation of macroprolactinemia, polyethylene macroprolactinemia, polyethylene glycol precipitation is the most glycol precipitation is the most practical method.practical method.

ConclusionConclusion

There is no consensus as to whether There is no consensus as to whether macroprolactin should be looked for macroprolactin should be looked for in sera of all hyperprolactinemic in sera of all hyperprolactinemic patients. patients.

Hook EffectHook Effect

High amount of circulating PRL causes High amount of circulating PRL causes antibody saturation in the antibody saturation in the immunoradiometric assay, leading to immunoradiometric assay, leading to artifactually low results artifactually low results

Giant macroprolactinomasGiant macroprolactinomas Patients undergo surgery because of an Patients undergo surgery because of an

initial diagnosis of non-functioning initial diagnosis of non-functioning tumorstumors

Hint for diagnosis- elevation of prolactin Hint for diagnosis- elevation of prolactin levels after surgery, pathology ICHlevels after surgery, pathology ICH

MacroPRLMacroPRLNFANFAHook Hook effecteffect

N N 1111545444

Age (y)Age (y)29 (20-70)29 (20-70)51 (21-79)51 (21-79)38 (32-52)38 (32-52)

Prolactin Prolactin (mU/l)(mU/l)

9140 9140 (1530-(1530-83850)83850)

1530 1530 (162-(162-3210)3210)

2120 2120 (1470-(1470-4500)*4500)*

Tumor Tumor size size (mm)(mm)

29 (10-35)29 (10-35)25 (10-77)25 (10-77)54 (33-60)54 (33-60)

Giant Giant tumortumor

3/113/1116/5416/544/44/4

St-Jean et al, Clin Endocrinol (1996) 44:305-309

*Prolactin levels after dilution: 317520-950000 mU/l

ImmunoassaysImmunoassays

Immulite 2000 immunometric assay Immulite 2000 immunometric assay performance data:performance data:

High dose hook effect: none up to High dose hook effect: none up to 20,500 ng/ml (434,600 mU/l)20,500 ng/ml (434,600 mU/l)

Other assays?Other assays?

ConclusionsConclusions

To overcome the hook effect, an To overcome the hook effect, an immunoradiometric PRL assay should immunoradiometric PRL assay should be performed with serum dilution at be performed with serum dilution at 1:1001:100

The hook effect should be excluded The hook effect should be excluded in new patients with giant pituitary in new patients with giant pituitary macroadenomas who have mildly macroadenomas who have mildly elevated PRL levelselevated PRL levels

SurgerySurgery

MicroprolactinomaMicroprolactinoma Normoprolactinemia in 71 % of casesNormoprolactinemia in 71 % of cases Recurrence rate of 17 %Recurrence rate of 17 % Long term cure rate of 59 % Long term cure rate of 59 %

MacroprolactinomaMacroprolactinoma Initial normoprolactinemia in 32 % of Initial normoprolactinemia in 32 % of

casescases Long-term cure inn 26 %Long-term cure inn 26 %

SurgerySurgery

About 10 percent of patients may require About 10 percent of patients may require surgery: surgery:

Resistance to dopamine agonist therapyResistance to dopamine agonist therapy Visual field deficits do not improve with Visual field deficits do not improve with

medical therapymedical therapy Apoplexy with neurological signsApoplexy with neurological signs Cystic macroprolactinomas that in general Cystic macroprolactinomas that in general

do not respond well to dopamine agonist do not respond well to dopamine agonist treatmenttreatment

Intolerance to dopamine agonistsIntolerance to dopamine agonists

Medical TreatmentMedical Treatment

Drug of choiceDrug of choice For how long?For how long? Discontinuation of Discontinuation of

treatmenttreatment Long term follow Long term follow

upup

Medical therapyMedical therapy Large comparative studies of cabergoline and Large comparative studies of cabergoline and

bromocriptine have convincingly demonstrated bromocriptine have convincingly demonstrated the superiority of cabergoline in terms of the superiority of cabergoline in terms of tolerability, patient convenience, decreasing tolerability, patient convenience, decreasing prolactin secretion, restoration of gonadal prolactin secretion, restoration of gonadal function, and reduction of tumor volume. function, and reduction of tumor volume.

Although cabergoline is more effective, Although cabergoline is more effective,

bromocriptine has been used satisfactorily for bromocriptine has been used satisfactorily for years, and, being less expensive, should be years, and, being less expensive, should be considered in medical systems with strong considered in medical systems with strong budget constraints.budget constraints.

Does the Initial Choice Affect Does the Initial Choice Affect Outcome? Outcome?

The prevalence and The prevalence and extent of extent of macroprolactinoma macroprolactinoma shrinkage after shrinkage after cabergoline treatment cabergoline treatment is higher in naive is higher in naive patientspatients

These results suggest These results suggest the use of cabergoline the use of cabergoline as first line in as first line in macroprolactinomamacroprolactinoma

Colao et al, J Clin Endocrinol Metab (2000) 85:2247-2252

Natural History of ProlactinomasNatural History of Prolactinomas

Less than 5% of microprolactinomas Less than 5% of microprolactinomas progress in the long term to progress in the long term to macroprolactinomasmacroprolactinomas

Hyperprolactinemia resolves Hyperprolactinemia resolves spontaneously in about 30% of spontaneously in about 30% of microadenomas (mainly with microadenomas (mainly with menopause or post-pregnancy)menopause or post-pregnancy)

Schlechte et al, JCEM (1989) 68:412Karunakaran et al, Clin Endocrinol (2001) 54:295

Treatment WithdrawalTreatment Withdrawal

In this study withdrawal was In this study withdrawal was considered if prolactin levels were considered if prolactin levels were normal, if MRI showed no tumor or a normal, if MRI showed no tumor or a 50% size reduction, with a minimum 50% size reduction, with a minimum distance of 5 mm from optic chiasmdistance of 5 mm from optic chiasm

Minimal treatment period of 24 months Minimal treatment period of 24 months 25 non-tumoral 25 non-tumoral

hyperprolactinemia ,105 hyperprolactinemia ,105 microprolactinomas, 70 microprolactinomas, 70 macroprolactinomas macroprolactinomas Colao, A. et al. NEJM (2003) 349:2023

Recurrence (Elevation of PRL)Recurrence (Elevation of PRL)

78% 78% of macroprolactinomas with residual of macroprolactinomas with residual tumor on MRI at the time of treatment tumor on MRI at the time of treatment withdrawalwithdrawal

33% of macroprolactinomas with normal 33% of macroprolactinomas with normal MRI at the time of treatment withdrawalMRI at the time of treatment withdrawal

42% of microprolactinomas with positive 42% of microprolactinomas with positive MRIMRI

26% of microprolactinomas with negative 26% of microprolactinomas with negative MRIMRI

Passos et al, JCEM(2002) 87: 3578

14-yr-old girl harboring a MAC.A, Before treatment, B, 2 months on BRC;C, 8 months on BRC; D, 16 months after BRC withdrawal

Colao et al. NEJM (2003) 349:2023

ConclusionsConclusions

If a patient has normal PRL levels after If a patient has normal PRL levels after therapy with dopamine agonists for at therapy with dopamine agonists for at least 3 years and the tumor volume is least 3 years and the tumor volume is markedly reduced, a trial of tapering markedly reduced, a trial of tapering and stopping these drugs may be and stopping these drugs may be initiatedinitiated

    Such patients need to be followed Such patients need to be followed carefully to detect recurrence of carefully to detect recurrence of hyperprolactinemia and tumor hyperprolactinemia and tumor enlargement so that treatment can be enlargement so that treatment can be resumedresumed

PregnancyPregnancy

Microadenomas- risk for adenoma Microadenomas- risk for adenoma growth during pregnancy appears to growth during pregnancy appears to be 1-2 % after drug discontinuationbe 1-2 % after drug discontinuation

Macroadenomas- 23% risk of tumor Macroadenomas- 23% risk of tumor enlargementenlargement

Pre-pregnancy debulking of Pre-pregnancy debulking of macroprolactinoma- 2.8% risk of macroprolactinoma- 2.8% risk of tumor enlargementtumor enlargement

Molitch M. J Reprod Med (1999) 44:1121

Pregnancy- microprolactinomaPregnancy- microprolactinoma

Dopamine-agonists can be safely Dopamine-agonists can be safely stopped in patients with stopped in patients with microprolactinomas as soon as microprolactinomas as soon as pregnancy has been confirmed.pregnancy has been confirmed.

Patients should be advised to Patients should be advised to report for urgent assessment in in report for urgent assessment in in the event of severe headaches or the event of severe headaches or visual disturbances.visual disturbances.

Serial PRL determinations are not Serial PRL determinations are not necessary necessary

Pregnancy- MacroprolactinomaPregnancy- Macroprolactinoma

Options for such women Options for such women include stopping the include stopping the dopamine agonist when dopamine agonist when pregnancy is confirmed pregnancy is confirmed with close surveillance with close surveillance or continuing the or continuing the dopamine agonist dopamine agonist through the pregnancy through the pregnancy

Debulking surgery before pregnancy in women Debulking surgery before pregnancy in women

with macroprolactinomas to reduce the with macroprolactinomas to reduce the likelihood of major tumor expansion, is a less likelihood of major tumor expansion, is a less preferable option, as medical therapy during preferable option, as medical therapy during pregnancy is probably less harmful than pregnancy is probably less harmful than surgerysurgery

If the enlarged tumor does not respond to If the enlarged tumor does not respond to reinstitution of dopamine agonist therapy, reinstitution of dopamine agonist therapy, alternatives include delivery if the pregnancy alternatives include delivery if the pregnancy is far enough advanced, or transsphenoidal is far enough advanced, or transsphenoidal surgerysurgery

Pregnancy- MacroprolactinomaPregnancy- Macroprolactinoma

LactationLactation     Women wishing to Women wishing to

breast-feed their breast-feed their infants should not be infants should not be given dopamine given dopamine agonists as this will agonists as this will lower PRL levels and lower PRL levels and impair lactation. There impair lactation. There are no data to suggest are no data to suggest that breast-feeding that breast-feeding may cause an increase may cause an increase in tumor sizein tumor size