Transcript שקופית 1

Prolactinomas
Yona Greenman MD
Institute of Endocrinology and
Metabolism
Tel Aviv-Sourasky Medical Center
Issues
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Diagnosis
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Treatment
Long term follow
up
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Macroprolactin
Hook effect
Discontinuation of
treatment
Pregnancy
Prolactin
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Human PRL is synthesized as a prehormone of 26 kDa.
Preprolactin is cleaved into a 199 a.a. peptide with a
molecular weight of 23 kDa
This monomeric form accounts for 85% of circulating PRL
in both normal and hyperprolactinemic sera
Big PRL (50 kDa), a covalently bound dimer of PRL
accounts for 10-15% of total PRL
Big Big PRL (>150 kDa) or macroprolactin
Post-translational modifications of PRL (glycosylated an
phosphorylated variants), and 14, 16 and 22 kDa
proteolysed forms
Macroprolactin
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Macroprolactin is a macromolecular complex of
monomeric PRL and an immunoglobulin,
generally an IgG antibody
Reduced clearance of this complex accounts for
persistent hyperprolactinemia
The macroprolactin complex is confined to the
intravascular space, has limited bioavailability,
hence its reduced bioactivity
Clinical Features
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It is present in significant amounts in up to 24 % of
hyperprolactinemic sera
Often the condition is identified serendipitously, in the
absence of classic symptoms of hyperprolactinemia
Symptoms leading to the measurement of prolactin, such
as menstrual disorders, galactorhea or various degree of
infertility, are not specific, and may occur coincidentally
in macroprolactinemic patients
High prevalence of pituitary lesions identified
incidentally by imaging procedures may coexist with
macroprolactinemia
Clinical Diagnosis
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Differentiation of
macroprolactinemic
patients from those with
true hyperprolactinemia
on clinical grounds is
unreliable
The percentage of
clinically significant
hyperprolactinemic
samples explained by
hyperprolactinemia is
similar across all levels of
total prolactin
Gibney et al (2005) J Clin Endocrinol Metab 90:3927-3932 .
The Macroprolactin Problem
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Misdiagnosis of hyperprolactinemia may
result in unnecessary diagnostic
procedures and inappropriate treatment
Recognition of macroprolactin and the
“pseudohyperprolactinemia” affords the
opportunity to make a correct diagnosis of
the patient’s clinical condition
Clinical Question
Should every hyperprolactinemic serum be
screened for macroprolactin?
Identification of Macroprolactin
by Gel Chromatography
A- First peak (69%)- big-big PRL (fractions 15–23; molecular mass
>100 kDa); Second peak (15%)- big PRL (fractions 27–31; 50
kDa); Third peak (16%) -monomeric PRL (fractions 33–39; 23–25
kDa)
B- Monomeric PRL secreted by the tumor in vitro
Vallette-Kasic et al JCEM (2002) 87: 581-588
PEG Precipitation
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Prolactin recovery < 40% after PEG
consistent with macroprolactinemia
Prolactin levels fall within the normal
range following removal of macroprolactin
by PEG (because there is coprecipitation
of monomeric PRL by PEG, values
obtained by treating normal serum are
used as reference)
Gibney et al (2005) Clin Endocrinol 62 (6), 633-643.
Detection of Prolactin in Serum
Containing Macroprolactin
Smith et al (2002) J Clin Endocrinol Metab 87: 5410-5415
Is macroprolactin just a laboratory
artifact that should be dismissed?
1) Possibility that macroprolactin has some
biological activity, or maybe if functions as a
pool of monomeric prolactin that intermittently
dissociates from the low affinity high capacity
IgG complex, thus causing symptoms of
prolactin excess.
-Calls for assays able to detect macroprolactin
2) Macroprolactin is asymptomatic and causes
diagnostic confusion
- Calls for assays that do not recognize
macroprolactin
Conclusions
Each center must know the specific
characteristics of the prolactin
immunoassay they use.
For confirmation of macroprolactinemia,
polyethylene glycol precipitation is the
most practical method.
Conclusion
There is no consensus as to whether
macroprolactin should be looked for in
sera of all hyperprolactinemic patients.
Hook Effect
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High amount of circulating PRL causes
antibody saturation in the
immunoradiometric assay, leading to
artifactually low results
Giant macroprolactinomas
Patients undergo surgery because of an
initial diagnosis of non-functioning tumors
Hint for diagnosis- elevation of prolactin
levels after surgery, pathology ICH
MacroPRL
NFA
N
11
54
Hook
effect
4
Age (y)
29 (20-70)
51 (21-79)
38 (32-52)
Prolactin
(mU/l)
Tumor
size (mm)
Giant
tumor
9140 (1530- 1530 (162- 2120 (147083850)
3210)
4500)*
29 (10-35)
25 (10-77) 54 (33-60)
3/11
16/54
4/4
*Prolactin levels after dilution: 317520-950000 mU/l
St-Jean et al, Clin Endocrinol (1996) 44:305-309
Immunoassays
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Immulite 2000 immunometric assay
performance data:
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High dose hook effect: none up to 20,500
ng/ml (434,600 mU/l)
Other assays?
Conclusions
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To overcome the hook effect, an
immunoradiometric PRL assay should be
performed with serum dilution at 1:100
The hook effect should be excluded in
new patients with giant pituitary
macroadenomas who have mildly elevated
PRL levels
Surgery
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Microprolactinoma
 Normoprolactinemia in 71 % of cases
 Recurrence rate of 17 %
 Long term cure rate of 59 %
Macroprolactinoma
 Initial normoprolactinemia in 32 % of cases
 Long-term cure inn 26 %
Surgery
About 10 percent of patients may require
surgery:
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Resistance to dopamine agonist therapy
Visual field deficits do not improve with medical
therapy
Apoplexy with neurological signs
Cystic macroprolactinomas that in general do not
respond well to dopamine agonist treatment
Intolerance to dopamine agonists
Medical Treatment
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Drug of choice
For how long?
Discontinuation of
treatment
Long term follow up
Medical therapy
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Large comparative studies of cabergoline and
bromocriptine have convincingly demonstrated
the superiority of cabergoline in terms of
tolerability, patient convenience, decreasing
prolactin secretion, restoration of gonadal
function, and reduction of tumor volume.
Although cabergoline is more effective,
bromocriptine has been used satisfactorily for
years, and, being less expensive, should be
considered in medical systems with strong budget
constraints.
Does the Initial Choice Affect
Outcome?
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The prevalence and
extent of
macroprolactinoma
shrinkage after
cabergoline treatment
is higher in naive
patients
These results suggest
the use of cabergoline
as first line in
macroprolactinoma
Colao et al, J Clin Endocrinol Metab (2000) 85:2247-2252
Natural History of Prolactinomas
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Less than 5% of microprolactinomas
progress in the long term to
macroprolactinomas
Hyperprolactinemia resolves
spontaneously in about 30% of
microadenomas (mainly with menopause
or post-pregnancy)
Schlechte et al, JCEM (1989) 68:412
Karunakaran et al, Clin Endocrinol (2001) 54:295
Treatment Withdrawal
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In this study withdrawal was considered if
prolactin levels were normal, if MRI
showed no tumor or a 50% size reduction,
with a minimum distance of 5 mm from
optic chiasm
Minimal treatment period of 24 months
25 non-tumoral hyperprolactinemia ,105
microprolactinomas, 70
macroprolactinomas
Colao, A. et al. NEJM (2003) 349:2023
Recurrence (Elevation of PRL)
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78% of macroprolactinomas with residual tumor
on MRI at the time of treatment withdrawal
33% of macroprolactinomas with normal MRI at
the time of treatment withdrawal
42% of microprolactinomas with positive MRI
26% of microprolactinomas with negative MRI
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
Passos et al, JCEM(2002) 87: 3578
Conclusions
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If a patient has normal PRL levels after
therapy with dopamine agonists for at
least 3 years and the tumor volume is
markedly reduced, a trial of tapering and
stopping these drugs may be initiated
Such patients need to be followed
carefully to detect recurrence of
hyperprolactinemia and tumor
enlargement so that treatment can be
resumed
Pregnancy
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Microadenomas- risk for adenoma growth
during pregnancy appears to be 1-2 %
after drug discontinuation
Macroadenomas- 23% risk of tumor
enlargement
Pre-pregnancy debulking of
macroprolactinoma- 2.8% risk of tumor
enlargement
Molitch M. J Reprod Med (1999) 44:1121
Pregnancy- microprolactinoma
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Dopamine-agonists can be safely
stopped in patients with
microprolactinomas as soon as
pregnancy has been confirmed.
Patients should be advised to report
for urgent assessment in in the event
of severe headaches or visual
disturbances.
Serial PRL determinations are not
necessary
Pregnancy- Macroprolactinoma
Options for such women
include stopping the
dopamine agonist when
pregnancy is confirmed with
close surveillance or
continuing the dopamine
agonist through the
pregnancy
Pregnancy- Macroprolactinoma
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Debulking surgery before pregnancy in women
with macroprolactinomas to reduce the
likelihood of major tumor expansion, is a less
preferable option, as medical therapy during
pregnancy is probably less harmful than surgery
If the enlarged tumor does not respond to
reinstitution of dopamine agonist therapy,
alternatives include delivery if the pregnancy is
far enough advanced, or transsphenoidal
surgery
Lactation
Women wishing to
breast-feed their
infants should not be
given dopamine
agonists as this will
lower PRL levels and
impair lactation.
There are no data to
suggest that breastfeeding may cause an
increase in tumor size