Prolactinomas

1
Prolactinomas

• Yona Greenman MD
• Institute of Endocrinology and Metabolism
• Tel Aviv-Sourasky Medical Center

2
Issues

• Diagnosis
• Macroprolactin
• Hook effect
• Treatment
• Long term follow up
• Discontinuation of treatment
• Pregnancy

3
Prolactin

• 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 (gt150 kDa) or macroprolactin
• Post-translational modifications of PRL
  (glycosylated an phosphorylated variants), and
  14, 16 and 22 kDa proteolysed forms

4
Macroprolactin

• 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

5
Clinical Features

• 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

6
Clinical Diagnosis

• 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
903927-3932 .
7
The Macroprolactin Problem

• 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
  patients clinical condition

8
Clinical Question

• Should every hyperprolactinemic serum be
  screened for macroprolactin?

9
Identification of Macroprolactin by Gel
Chromatography

• A- First peak (69)- big-big PRL (fractions
  1523 molecular mass gt100 kDa) Second peak
  (15)- big PRL (fractions 2731 50 kDa) Third
  peak (16) -monomeric PRL (fractions 3339 2325
  kDa)
• B- Monomeric PRL secreted by the tumor in vitro

Vallette-Kasic et al JCEM (2002) 87 581-588
10
PEG Precipitation

• Prolactin recovery lt 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), 633-64
3.
11
Detection of Prolactin in Serum Containing
Macroprolactin
Smith et al (2002) J Clin Endocrinol Metab 87
5410-5415
12
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

13
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.

14
Conclusion

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

15
Hook Effect

• 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

16
Hook effect NFA MacroPRL
4 54 11 N
38 (32-52) 51 (21-79) 29 (20-70) Age (y)
2120 (1470-4500) 1530 (162-3210) 9140 (1530-83850) Prolactin (mU/l)
54 (33-60) 25 (10-77) 29 (10-35) Tumor size (mm)
4/4 16/54 3/11 Giant tumor
Prolactin levels after dilution 317520-950000
mU/l
St-Jean et al, Clin Endocrinol (1996) 44305-309
17
Immunoassays

• Immulite 2000 immunometric assay performance
  data
• High dose hook effect none up to 20,500 ng/ml
  (434,600 mU/l)
• Other assays?

18
Conclusions

• To overcome the hook effect, an
  immunoradiometric PRL assay should be performed
  with serum dilution at 1100
• The hook effect should be excluded in new
  patients with giant pituitary macroadenomas who
  have mildly elevated PRL levels

19
Surgery

• 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

20
Surgery

• About 10 percent of patients may require
  surgery
• 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

21
Medical Treatment

• Drug of choice
• For how long?
• Discontinuation of treatment
• Long term follow up

22
Medical therapy

• 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.

23
Does the Initial Choice Affect Outcome?

• 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)
852247-2252
24
Natural History of Prolactinomas

• 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) 68412 Karunakaran
et al, Clin Endocrinol (2001) 54295
25
Treatment Withdrawal

• 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) 3492023
26
Recurrence (Elevation of PRL)

• 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

27
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
Passos et al, JCEM(2002) 87 3578
Colao et al. NEJM (2003) 3492023
28
Conclusions

• 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

29
Pregnancy

• 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) 441121
30
Pregnancy- microprolactinoma

• 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

31
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

32

Pregnancy- Macroprolactinoma

• 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

33
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 breast-feeding may
  cause an increase in tumor size

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