Hyperprolactinemia case Presentation By Usama Ragab Youssif Based on one of ESAP cases Presented on non-commercial Endo-ISMA 2020 conference

1. Prolactine Case Presentation
The Road is NOT Always Straight
Usama Ragab Youssif, MD
Consultant Internal Medicine
Lecturer of Medicine
Zagazig University
Email: usamaragab@medicine.zu.edu.eg
Slideshare: https://www.slideshare.net/dr4spring/
Mobile: 00201000035863
2nd ENDO-ISMA 2020 – Hybrid Conference

2. Case 1
• A 51-year-old man presents with decreased libido and
erectile dysfunction and is found to have the following
laboratory values:
Testosterone = 197 ng/mL (300-900 ng/dL)
Prolactin = 39 ng/mL (4-23 ng/mL)
• A 14-mm pituitary adenoma is identified on MRI.

3. Case 1 (cont.)
• While taking cabergoline, 0.5 mg twice weekly, his PRL
and testosterone levels normalize and his libido and
erectile function improve.
• Two years later, he develops headaches and erectile
dysfunction again despite maintaining a normal PRL
level on cabergoline therapy.

4. Which of the following should be the next
management step?
A. Discontinue cabergoline
B. Switch cabergoline to bromocriptine
C. Increase the cabergoline dosage to 1.0 mg twice
weekly
D. Perform another pituitary-directed MRI

5. The correct Answer…
• Diagnosis is determined by basal PRL
levels, which generally correlate with
prolactinoma size
• Discrepancy between his PRL level of
only 39 ng/mL and the size of the
adenoma—14 mm.
• Although this discrepancy could be
due to inefficient production of
prolactin by a prolactinoma, it is more
likely due to stalk dysfunction.
• Microprolactinoma:
 50 – 150 ng/mL
• Macroadenoma 1 – 2 cm:
 200 – 1000 ng/mL
• If size > 2 cm:
 1000 – 50000 ng/mL
BestPractResClinEndocrinolMetab.2019Apr;33(2):101290.

6. Stalk effect
• Suprasellar or sellar lesions extending
dorsally to involve the pituitary stalk can
lead to hyperPRL and galactorrhea
• Such lesion cause ↓ ↓ of dopamine
secretion from hypothalamus or its
transport to pituitary
• These lesion include large non-
functioning pituitary adenoma, germ cell
tumor, craniopharyngioma, Rathek’s cleft
cyst, meningioma etc…
• Generally PRL levels are rarely higher
than 100 mcg/L.
Americanfamilyphysician,85(11),1073-1080.

7. Cont.
• A dopamine agonist could indeed normalize PRL
levels and, if the hypogonadism were the result of
hyperprolactinemia, correct decreased libido and
erectile dysfunction but have no effect on the growth of
a mass lesion that is not a prolactinoma.
• He now has symptoms suggestive of hypogonadism
with a normal PRL, raising concerns about increased
mass effect = pituitary failure…

8. PrinciplesofNeurologicalSurgery(2012)

9. Which of the following should be the next
management step?
A. Discontinue cabergoline
It leads to normalization of PRL levels, it will be of benefit till more definitve treatment approaches used
B. Switch cabergoline to bromocriptine
The patient’s prolactin level has normalized with cabergoline at the current dosage, so there is no reason to
switch to bromocriptine
C. Increase the cabergoline dosage to 1.0 mg twice weekly
Increasing the cabergoline dosage would not help distinguish a prolactinoma from a nonsecreting tumor.
D. Perform another pituitary-directed MRI
Therefore, performing a pituitary directed MRI to assess for an increase in tumor size should be the next
management step, not stopping treatment (Answer A).

10. Stalk effect bottom line
• PRL levels generally correlate with tumor size
• Therefore, when a macroadenoma is present with PRL
level below 100 ng/mL, pituitary stalk compression
from a non-functioning tumor should be suspected for
the cause of the hyperprolactinemia, rather than
prolactinoma.

11. PRL levels vs symptoms vs tumor
1- If PRL is high but patient is asymptomatic = False Positive
= Macroprolactin
= Heterophil antibodies
2- If PRL is mildly elevated in presence of large tumor
= Stalk effect
= Hook effect = False Negative
3- If PRL is high, patient is symptomatic but non tumor is detected
= Other causes rather than adenoma e.g. another
endocrinopathy
Gibney et ai., JCEM 2005. Petakov et al., J endocrinol Invest 1998

13. History of PRL assay
• Following the discovery that pituitary
extracts induce milk production, a
relatively crude bioassay for PRL was
devised, based on the stimulation of
production of a milk-like substance by
the crop sacs of pigeons.
• However, because even very highly
purified preparations of human GH
have high lactogenic activity, it was
not possible to differentiate human
PRL from GH using this assay.
AmJPhysiol.1933;105:191–216

14. To Date PRL assay
• Now automated and employ
nonradioactive, enzymatic, or
chemiluminescent labels.
• These assays are based on the
sandwich principle in which the PRL
molecule reacts with both a capture
antibody, immobilized on a solid
phase, and a labeled detection
antibody, used to detect the PRL.
• After a wash step to remove unused
labeled antibody, the signal generated
is proportional to the concentration of
PRL in the sample.
NatureClinicalPracticeEndocrinology&Metabolism3,no.3(2007):279-289.
Capture Ab
Detection Ab

15. Case 2
• A 45-year-old man presents for evaluation off an elevated
PRL level.
• He is previously healthy and takes no medications or
supplements, but has recently been feeling depressed and
fatigued.
• As part of the evaluation, his PCP sent a set of blood tests.
• The comprehensive metabolic panel, thyroid function, and
CBC were normal.

16. Case 2 (cont.)
• In addition, the following results were obtained:
Total testosterone= 764 (240-950 ng /dL)
Free testosterone= 13.1 (4.26-16.4 ng /dL)
Prolactin= 39 (4-15.2 ng/mL)
• The patient denies any erectile dysfunction although he
does endorse some reduced libido since experiencing
low mood.

17. What is the next step in caring for this patient?
A. Request PRL level on serial dilutions of serum
B. Initiate bromocriptine therapy
C. Obtain a pituitary MRI
D. Order a macroprolactin level
E. Refer for neurosurgical evaluation

18. The Clinical Biochemist Reviews 39, no. 1 (2018): 3.

19. Macroprolactinemia
• Macroprolactin is an aggregate of
monomeric PRL molecule with
IgG which probably interferes with
reactivity between PRL and
antibodies (capture and detection)
involved in the sandwich reaction
of PRL immunoassays.
• PRL in this form has reduced
biologically activity but produces a
laboratory finding of
hyperprolactinemia.

20. Macroprolactinemia (cont.)
• False hyperprolactinemia =
misdiagnosis = mismanagement
• When hyperprolactinemia is detected,
is to sub-fractionate the serum, using
polyethylene glycol (PEG) 12.5%
• This procedure removes the higher
molecular weight forms of PRL by
precipitation, leaving the monomeric
forms in the supernatant.
EndocrPract.2015;21:1427-1435BestPractice&ResearchClinicalEndocrinology&Metabolism27(2013)725–742

21. What is the next step in caring for this patient?
A. Request PRL level on serial dilutions of serum
It is the evaluation of “hook effect”
B. Initiate bromocriptine therapy
Premature as true hyperprolactinemia is not confirmed
C. Obtain a pituitary MRI
Premature
D. Order a macroprolactin level
Most appropriate as the elevated levels of PRL is not correlated with symptoms or other lab
E. Refer for neurosurgical evaluation
Premature

22. Macroprolactin bottm line
• Don’t measure PRL unless symptomatic
• If symptoms equivocal & PRL levels are elevated,
consider assessing for macroprolactin (PEG
precipitation)

23. Heterophilic antibody
• Heterophilic Ab are human Ig capable
of recognizing animal Igs which
bridge the capture antibody and the
labeled antibody and, by mimicking
the role of the PRL, induce a false
signal
• Anti-animal antibodies (such as
human anti-mouse antibodies –
HAMA). More common in animal
handlers.
• May aggregate PRL (macro- one)

24. Innocent question?
Q: What is the problem in doing MRI for every one?
A: The big issue of pituitary incidentaloma…

25. Hook effect
• The “hook effect” is an artefact due
to saturation of the antibodies at
excessively high PRL
concentrations preventing
antibody-PRL-antibody sandwich
formation.
• Sandwich failure; PRL antigen
binds to separate antibodies
PrinciplesofNeurologicalSurgery(2012)
Sandwich failure…

26. Hook effect; the recommendation
• Therefore for large adenomas (> 3 cm) with a normal
PRL level, have the lab perform several dilutions
(1:100) of the serum sample and re-run the PRL,
especially in patients with clinical hyperprolcatinemia
(unless you know that your assay is not affected by
this).

29. As a rule of thumb
PRL levels correlates with the size of prolactinoma
But Remember
Stalk compression
Hook effect

30. NatureClinicalPracticeEndocrinology&Metabolism3,no.3(2007):279-289.
PEG treatment of the sample
Serial dilution of the sample
Blocking agent that neutralize antibodies