In response to Dr. Collins questions regarding significance of
macroprolactin I have asked Mike Fahie-Wilson from Southend to comment
(they may have the brains at Southend but they dont have the
technology!). I think the length of his response is a testimony to his
enthusiasm and expertise on the subject!

Tony Everitt
Basildon Hospital

Mike writes:

IMMUNOREACTIVITY OF MACROPROLACTIN

All immunoassays for prolactin tested so far react with macroprolactin,
but to a variable extent. The Chiron assays (ACS and Centaur) react with
macroprolactin but rather less than most others. In the UK NEQAS
distribution 226, specimen 141 contained 93% macroprolactin and the
monomeric PRL was 260mU/l (calculated from gel filtration chromatography
and the Delfia assay) but the Centaur method mean was 521mU/l. I have
done some work with John Cameron (Colchester) which confirms that
hyperprolactinaemia due to macroprolactin occurs with some samples on
the ACS 180.

BIOACTIVITY OF MACROPROLACTIN

Whether you want to detect macroprolactin depends on whether you believe
it is biologically active and thereby, clinically significant. I think
the evidence is that macroprolactin certainly has reduced bioactivity in
vivo and probably minimal bioactivity. 
Clinical evidence over 20 years is provided by numerous case reports
(see list of references accompanying UK NEQAS report on P141) of
patients with hyperprolactinaemia due to macroprolactin but without
symptoms of hyper-prolactinaemic syndrome.
Most of our requests for PRL are in patients with symptoms which might
be related to hyperprolactinaemia but most do not have elevated serum
PRL. Macroprolactin is a common cause of apparent hyperprolactinaemia in
some assays and it is not surprising that we sometimes find this in
patients with symptoms which might be attributed to hyperprolactinaemia.
In 20 such macroprolactinaemic patients we have followed up, we found
other causes for the symptoms in 19 and the best explanation seems to be
that the presence of hyperprolactinaemia due to macroprolactin is
coincidental.

Two other pieces of evidence are:

1. Patients with hyperprolactinaemia due to macroprolactin have a normal
response to dopamine antagonists (Domperidone test). Patients with true
hyperprolactinaemia have a suppressed response.
2. The frequency distribution of monomeric PRL concentration in patients
with macroprolactinaemia is very similar to that of PRL in the
population without which suggests macroprolactin is not suppressing
normal monmeric PRL secretion.

These data indicate that macroprolactin is not affecting the short loop
feedback control mechanism i.e. it is not bioactive in vivo.


CONCLUSION
Macroprolactin causes apparent hyperprolactinaemia which can lead to
diagnostic confusion and inappropriate treatment.
It would be better to have an assay which does not detect macroprolactin
but, since all assays detect macroprolactin to some extent it is
essential to screen for macroprolactin in samples with apparent
hyperprolactinaemia. Use of an assay which reacts less with
macroprolactin (e.g. Chiron) will reduce the numbers of samples to be
screened.


-- 
Tony Everitt


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