Macroprolactinemia in a patient with infertility and hyperprolactinemia.

Abstract: A significant number of patients with hyperprolactinemia have macroprolactinemia, a condition characterized by the preponderance of big-big prolactin with normal levels of free prolactin. As macroprolactin does not have biologic activity, such patients do not require further investigations or treatment for hyperprolactinemia. The case of a patient with hyperprolactinemia diagnosed during investigation of secondary infertility is presented. She was treated for over 2 years with dopamine agonists, with which her prolactin level normalized, but she remained infertile. Subsequent investigations demonstrated that she suffered from macroprolactinemia, not true hyperprolactinemia. The patient is currently not on dopamine agonist therapy, and although her total prolactin levels remain significantly elevated, her free prolactin levels have been in the normal range. Physicians should familiarize themselves with this entity and consider testing for it in patients with hyperprolactinemia to avoid an inappropriate diagnosis and unnecessary treatment.

Key Words: prolactin, hyperprolactinemia, macroprolactin, pituitary adenomas

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Case Report

A 36-year-old Vietnamese female was evaluated for hyperprolactinemia. The couple had been unsuccessful in conceiving for 5 years before assessment. Before that, she had two spontaneous first trimester miscarriages. Her menses were regular, and she denied any galactorrhea, headaches or visual complaints. Her past medical history was significant for hypercalcemia due to primary hyperparathyroidism which was treated surgically. She was on no medications at the time, and her family history was significant for the absence of any pituitary, pancreatic, or parathyroid diseases. Her physical examination was unremarkable; specifically, there were no visual field defects, no expressible galactorrhea, no palpable neck or abdominal masses. The prolactin level was elevated at 102 ng/mL (4-30). An MRI was suggestive of a 3 mm microadenoma. Given the history of primary hyperparathyroidism in the presence of a pituitary adenoma, she was evaluated for multiple endocrine neoplasia (MEN)-I; however, it was ruled out by appropriate biochemical and genetic studies. She was thus diagnosed with hyperprolactinemia due to a microprolactinoma, and treatment was initiated with bromocriptine, and later with cabergoline. Her prolactin levels promptly normalized without restoring fertility.

Despite persistent infertility with normal prolactin levels and regular menses, a reproductive gynecology assessment was sought. The pelvic examination, ultrasound, and hysterosalpingogram were normal. Her husband was found to have oligospermia. A diagnosis of secondary infertility due to oligospermia and hyperprolactinemia was made, and it was decided to continue treatment with cabergoline in addition to clomiphene citrate/HCG induction of ovulation with intrauterine insemination (IUI) of washed motilex sperm. Over the ensuing 2 years, the couple received 5 cycles of IUI but did not successfully conceive. The patient's prolactin level remained normal on 0.5 mg of cabergoline a week.

At her most recent assessment, it was discovered that the patient had not taken the cabergoline for the previous three months. Her menses continued to remain regular. Due to the absence of a history of amenorrhea or galactorrhea, and continued infertility despite normalization of prolactin levels, the diagnosis of macroprolactinemia was entertained. The prolactin level was measured before and after treatment of the serum with polyethylene glycol (PEG) to remove any immunoreactive macroprolactin complex. The prolactin level was 95.2 ng/mL (range 4-30) before incubation with PEG and decreased to 27.4 ng/mL (range 4-30) after PEG precipitation; the recovery of free prolactin in the solution was 29%. These results were consistent with macroprolactinemia. It was subsequently discussed with the patient that in retrospect, she probably never suffered from true hyperprolactinemia, and the macroprolactinemia was not a cause of her infertility. The pituitary microadenoma was most likely an incidental finding; approximately 15 to 20% of "normal" individuals are found to have a pituitary adenoma on MRI. The patient remains without any dopamine agonist treatment, and although her total prolactin levels continue to remain elevated, her free prolactin levels have been in the normal range. There has been no change in her clinical status, and the couple is considering alternate options including IUI with donor sperm or adoption.

Discussion

Human prolactin circulates in at least 3 discreet forms in the serum; monomeric (free) prolactin, which accounts for 85% of the prolactin, a big-prolactin species which accounts for 10 to 15%, and a larger big-big prolactin or macropro-lactin, which is an antigen antibody complex of monomeric prolactin and IgG. (1) In most patients, free prolactin is the predominant form of prolactin present; however, in a significant number of individuals, macroprolactin accounts for the majority of prolactin. When macroprolactin constitutes the predominant form of prolactin in the serum in the presence of normal levels of free prolactin, the condition is referred to as macroprolactinemia. Review articles by Gibney et al and Fahie-Wilson et al, which focus on the clinical and laboratory aspects of macroprolactinemia, will be helpful to readers. (1,2) As macroprolactin remains confined in the vasculature, it does not have any biologic activity and patients with macroprolactinemia do not require treatment with dopamine agonists. The prevalence of macroprolactinemia in patients with hyperprolactinemia has been reported to be between 18 to 45% in various studies. (3-5) There are different methods of detecting macroprolactin, including gel filtration chromatography and PEG precipitation. In PEG precipitation, which is the most commonly used method, prolactin levels are measured before and after incubation of the serum with PEG, a process which removes immunoreactive prolactin-IgG complex. If the prolactin level in the serum falls within the reference range after PEG precipitation, a diagnosis of macroprolactinemia is established. The various commonly used prolactin assays vary widely with respect to sensitivity in detecting macroprolactin. (6) The nature of the prolactin-IgG antibody complex which may mask epitopes recognized by the antibodies in a particular assay may explain these differences. Smith et al sent sera from 10 hyperprolactinemic patients who were known to contain significant amounts of macroprolactin to 18 clinical laboratories in Europe and the US and found significant differences in the prolactin levels reported in the nine different assay systems. (6) In their study, although no assay system provided normal prolactin values in the sera known to contain macroprolactin, the performance of some systems was better than others. The Centaur (Bayer Corp., Pittsburg, PA), ACS: 180 (Bayer Corp.) and the Access (Beckman, Brea, CA) gave elevated readings only in 1 of the 10 samples, whereas the various other systems such as the AxSYM and Architect (Abbott, Abbott, IL), Immuno-1 (Bayer Corp.), DELFIA (Wallac Inc.) and Elecsys (Roche, Indianapolis, IN) gave elevated readings in 8 to 9 of the 10 samples. The laboratory where our patient's specimen was analyzed utilizes Centaur (Bayer Corp.).

As macroprolactin does not have biologic activity and in some respects is a laboratory artifact, it is important that patients with hyperprolactinemia be evaluated for the presence of macroprolactin, as failure to do so will result in inappropriate diagnosis of hyperprolactinemia as well as unnecessary further investigations and treatment. Screening all patients with hyperprolactinemia for the presence of macroprolactinemia offers a simple solution for the avoidance of an incorrect diagnosis, and this approach has also been advocated in the literature. (7) In our case, if the diagnosis of macroprolactinemia had been suspected and made earlier, investigations such as MRI of the pituitary, evaluation for MEN-1, etc., would not have been pursued. Furthermore, treatment with dopamine agonist would not have been prescribed for over 2 years in an attempt to promote fertility, and an alternate cause of the symptomatology would have been investigated and appropriate treatment prescribed at an earlier time.

Conclusion

Given the prevalence of macroprolactinemia, and the significant variability of the various prolactin assay systems, it is important that physicians familiarize themselves with this entity as well as the performance of the assay system being used in their laboratories. It would be advisable to consider testing for macroprolactinemia in patients found to have hyperprolactinemia. Failure to appreciate this entity often leads to establishing an incorrect diagnosis and to additional investigations and treatment. Concerns about pituitary tumor may lead to unnecessary studies, incorrect diagnosis of prolactinoma, and unnecessary medical or neurosurgical intervention. (8,9) In the absence of true hyperprolactinemia, further investigations and dopamine agonist therapy may not be warranted, and alternate diagnoses can be pursued.

References

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

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

3. Fahie-Wilson MN, Soule SG. Macroprolactinaemia: contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol. Ann Clin Biochem 1997;34:252-258.

4. Gibney J, Smith TP, McKenna TJ. The impact on clinical practice of routine screening for macroprolactin. J Clin Endocrinol Metab 2005;90:3927-3932.

5. Vallette Kasic S, Morange Ramos I, Selim A, et al. Macroprolactinemia revisited: a study on 106 patients. J Clin Endocrinol Metab 2002:87:581-586.

6. Smith TP, Suliman AM, Fahie-Wilson MN, et al. 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.

7. Fahie-Wilson M. In hyperprolactinemia, testing for macroprolactin is essential. Clin Chem 2003;49:1434-1436.

8. Cattaneo FA, Fahie-Wilson MN. Concomitant occurrence of macroprolactin, exercise-induced amenorrhea, and a pituitary lesion: a diagnostic pitfall. Case report. J. Neurosurg 2001;95:334-337.

9. Olukoga AO, Dornan TL, Kane JW. Three cases of macroprolactinaemia. J R Soc Med 1999;92:342-344.

Hasnain M. Khandwala, MD, FRCPC 

From the Division of Endocrinology, University of Saskatchewan, Saskatoon. SK, Canada.

Reprint requests to Hasnain M. Khandwala. Royal University Hospital, Division of Endocrinology-Room 3654, 103 Hospital Drive, Saskatoon, SK, S7K 7A9, Canada. Email: [e-mail]

Accepted May 1, 2006.

RELATED ARTICLE: Key Points

* Macroprolactinemia is a condition characterized by elevated total prolactin levels due to a preponderance of big-big prolactin with normal levels of free prolactin.

* Macroprolactinemia may be present in up to 45% of patients with hyperprolactinemia.

* Macroprolactin does not have biologic activity and patients with macroprolactinemia do not require pituitary imaging or treatment with dopamine agonists.

* Physicians should familiarize themselves with this entity and consider further testing for macroprolactinemia in patients with hyperprolactinemia.