The macroprolactinemia problem and its solution.

Symptoms of the hyperprolactinemic syndrome (menstrual disturbance, infertility and galactorrhea in women, impotence and loss of libido in men) are common and nonspecific and in the investigation of patients with these symptoms much depends on the measurement of serum prolactin (PRL) concentration. This is especially true of the diagnosis of prolactinoma because confirmatory imaging techniques are insensitive and nonspecific. Unfortunately immunoassays for serum prolactin are also nonspecific; in addition to detecting the free, monomeric form of circulating PRL, immunoassays also react with a high molecular mass complex of PRL, macro-prolactin or big-big PRL, which has minimal bioactivity in vivo. In some individuals, as in the case reported in this issue by Khandwala et al, macroprolactin is the predominant form of circulating immunoreactive PRL (macroprolactinemia) and, if the cause is not recognized, the coincidence of apparent hyperprolactinemia and symptoms of the hyperprolactinemic syndrome can lead to misdiagnosis and mistreatment, unnecessary concern for patient and physician and waste of healthcare resources. (1)

The first case of macroprolactinemia was reported in 1981, in an asymptomatic volunteer, and macroprolactin was shown to be a common cause of hyperprolactinemia nearly 25 years ago. (3) It has taken a remarkably long time for this problem to be recognized in clinical and laboratory circles, but two recent, comprehensive reviews indicate a mature body of knowledge on the subject and agree about the solution to the problem. (4,5) Macroprolactin is most frequently a complex of PRL with immunoglobulin G, but the composition is variable and this is reflected in variable reactivity in immunoassays. Nevertheless, whatever the composition macroprolactin has, no recognized clinical significance other than the diagnostic confusion which it can cause and hyperprolactinemia has been described with all immunoassays tested to date. Overall, macroprolactin is a common cause of hyperprolactinemia, and it has been calculated that it may be responsible for up to 10% of all elevated results in the USA and UK. (6) Since macroprolactinemia is a common problem, it has been suggested (1,4) that laboratories should take the initiative and test for macroprolactin in all cases with elevated total serum PRL. A simple and inexpensive test is available; polyethylene glycol (PEG) precipitates high molecular mass forms of PRL and the residual PRL is a measure of the free, monomeric PRL which is known to be bioactive in vivo. The PEG precipitation test is not perfect, but there is no doubt that modifications of it are applicable to the majority of the most widely used immunoassays for PRL, and introduction of this approach in all laboratories would largely solve the problem of macroprolactinemia. It has also been suggested that manufacturers should design assays for PRL which do not react or have minimal reactivity with macroprolactin. Since macroprolactin has a variable composition, it may not be possible to avoid some cross reactivity, but it is encouraging to note that Roche has recently introduced a modified version of their Elecsys PRL assay which has much reduced reactivity with macroprolactin.

Khandwala et al urge physicians to familiarize themselves with macroprolactinemia and consider testing for it in patients with hyperprolactinemia, but as their case report demonstrates, and as others have pointed out, (1) clinical awareness rarely leads to detection of macroprolactinemia before misdiagnosis and mistreatment have occurred. Macroprolactinemia may be an issue which physicians should be aware of, but laboratories should and could do much more to solve the problem. Physicians should encourage the laboratories they use to screen for macroprolactinemia in all cases where an elevated total serum PRL is found and to report a measure of the free, monomeric PRL which is bioactive in vivo.

References

1. Suliman AM, Smith TP. Gibney J, et al. Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: application of a new strict laboratory definition of macroprolactinemia. Clin Chem 2003;49:1504-1509.

2. Whittaker PG, Wilcox T, Lind T. Maintained fertility in a patient with hyperprolactinemia due to big, big prolactin. J Clin Endocrinol Metab 1981;53:863-866.

3. Soong YK, Ferguson KM, MeGarrick G, Jeffcoate SL. Size heterogeneity of immunoreactive prolactin in hyperprolactinaemic serum. Clin Endocrinol (Oxf) 1982;16:259-265.

4. Fahie-Wilson M, John R, Ellis AR. Macroprolactin; high molecular mass forms of circulating prolactin. Ann Clin Biochem 2005;42:175-192.

5. Gibney J, Smith TP, McKenna TJ. Clinical relevance of macroprolactin. Clin Endocrinol (Oxf) 2005;62:633-643.

6. Smith TP, Suliman AM, Fahie-Wilson MN, McKenna TJ. Gross variability in the detection of prolactin in sera containing big big prolactin (macroprolactin) by commercial immunoassays. J Clin Endocrinol Metab 2002;87:5410-5415.

Michael Fahie-Wilson MPhil, MRSc

From the Southend Hospital, Westcliff-on-Sea, Essex, United Kingdom.

Reprint requests to Michael Fahie-Wilson, Consultant Clinical Biochemist, Southend Hospital, Westcliff-on-Sea, Essex SSO ORY, United King-dome. Email: [e-mail]

Accepted June 27, 2006.