Frequent Misdiagnosis and Mismanagement of Hyperprolactinemic Patients before the Introduction of Macroprolactin Screening: Application of a New Strict Laboratory Definition of Macroprolactinemia

Abstract

Background: Macroprolactin (big big prolactin) has reduced bioactivity and is measured by immunoassays for prolactin when it accumulates in the plasma of some individuals. We applied normative data for serum prolactin after treatment of sera to remove macroprolactin to elucidate the contribution of macroprolactin to misleading diagnoses, inappropriate investigations, and unnecessary treatment. Methods: We reviewed records of women attending a tertiary referral center who had prolactin >1000 mIU/L. Application of a reference interval to polyethylene glycol (PEG)-treated hyperprolactinemic sera identified 21 patients in whom hyperprolactinemia was accounted for entirely by the presence of macroprolactin. Presenting clinical features, diagnoses, and treatment were compared in these patients and 42 age-matched true hyperprolactinemic patients.

Importance of macroprolactinemia in hyperprolactinemia

“…However, further, more comprehensive serial investigations of patients with macroprolactinemia reported a mild symptomatology with a lower incidence of clinical symptoms and abnormal imaging findings in the pituitarry gland than in patients with true hyperprolactinemia [3,5,10,15,[19][20][21][22]. During prolonged follow-up of a cohort of 51 patients with macroprolactinemia headache had been experienced in 12 patients (24%), oligomenorrhea in five (10%) and galactorrhea was present in only two cases (4%) with no symptomatic progression in any of the patients [5].…”

“…However, when serum free PRL concentrations exceed normal PRL concentrations, negative feedback mechanisms begin operating to normalize free PRL levels which are usually in sera from most macroprolactinemic patients within normal range [14,37]. Therefore the biochemical findings of serum estradiol and luteinizing hormone (LH) may be significantly higher in individuals with macroprolactinemia compared with those with true hyperprolactinemia [10,18,37].…”

“…Although the majority of macroprolactinemia cases are asymptomatic, a number of patients experienced the main hyperprolactinemia-related symptoms due to the rise in the levels of monomeric PRL, that could not be differentiated from those with true hyperprolactinemia [7][8][9][10][11].…”

“…However, not all patients with macroprolactinemia lack clinical symptoms because there are a number of reports regarding the overlapping of the main hyperprolactinemic symptoms due to the rise in the levels of monomeric PRL in subjects with true hyperprolactinemia and those with macroprolactinemia [7][8][9][10][11]. Moreover, no laboratory features in addition to clinical features could reliably differentiate macroprolactinemic patients from those with monomeric hyperprolactinemia [8].…”

“…Although oligomenorrhea and galactorrhea occurred more frequently in patients with true hyperprolactinemia, they also occurred in 57% and 29%, respectively, of macroprolactinemic patients and these differences were not sufficient to distinguish between the two groups on the basis of clinical symptoms alone. Moreover, hyperprolactinemia due to macroprolactin led to diagnostic confusion, unnecessary investigations, and unsuitable treatment before the introduction of macroprolactin screening by application of a reference interval to polyethylene glycol (PEG)-treated hyperprolactinemic sera [10]. Therefore, it is important that laboratories introduce screening programmes to examine samples with elevated total immunoreactive PRL for the presence of macroprolactin and to determine the monomeric PRL component which is responsible for bioactivity in vivo [11].…”