Laboratory and Clinical Experience in 55 Patients with Macroprolactinemia Identified by a Simple Polyethylene Glycol Precipitation Method

Abstract

PRL exists in different forms in human serum. The predominant form is little PRL (molecular mass 23 kDa) with smaller amounts of big PRL (molecular mass 50--60 kDa) and at times big big or macroprolactin (molecular mass 150--170 kDa). The frequency and clinical consequences of macroprolactinemia have not been clearly established, mainly because of difficulty in identifying these patients biochemically. This previously required the use of gel filtration chromatography, which could not be used routinely. Recently, a screening test using polyethylene glycol (PEG) has been used to identify macroprolactin in serum. Consequently, this study was designed to examine the use of PEG precipitation in the identification of patients with a predominance of macroprolactin and to establish the clinical characteristics of such a cohort. Over 12 months, 18,258 requests for serum PRL were received and of these 1225 patients had a serum PRL more than 700 mU/L. A total of 322 of these patients (26%) had a percentage recovery after PEG precipitation of less than 40%, thus indicating the presence of a predominance of macroprolactin. Fifty-five of these patients were referred for detailed clinical assessment. Symptoms typical of hyperprolactinemia were not common in this cohort. None had sustained amenorrhea and eight have had oligomenorrhea at age less than 40 yr. One had galactorrhea. All had pituitary imaging, and four had a microadenoma with none having a macroadenoma. PEG precipitation allows easy identification of macroprolactin in routine clinical practice. As the clinical consequences of this entity at this stage seem relatively benign, referral and intensive investigation of these patients may not be necessary. However, follow-up of a large cohort is required to ensure that the long-term outlook is likewise benign. This would have important implications for both patients and healthcare systems.

Clinical and biological characterization of macroprolactinemia with and without prolactin-IgG complexes

“…In accord with previous, albeit smaller studies, the majority of them were young to middle-aged adult females (7,15,16). Menstrual disorders, infertility and galactorrhea are the classic symptoms observed in previous published series of women with macroprolactinemia (7,9,15,16,20). Although most of the macroprolactinemic women in our survey consulted for infertility, this feature may have only initiated the PRL evaluation.…”

Importance of macroprolactinemia in hyperprolactinemia

“…Among 113 patients with hyperprolactinemia clinical symptoms were more likely to occur in individuals with true hyperprolactinemia than in patients with macroprolactinemia (90% vs.54%) [15]. Out of 55 patients with macroprolactinemia none of the patients had sustained amenorrhea, one had galactorrhea and eight have had oligomenorrhea at age bellow 40 years [19].…”

“…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].…”

“…A number of studies have shown that PEG induced precipitation of macroprolactin in serum sample represents a simple, inexpensive, accessible, rapid and reproducible screening technique for hyperprolactinemic sera [19,26,27]. The method is based on different precipitation of proteins according to their molecular weight and solubility in different concentrations of PEG solution.…”

“…Therefore macroprolactinemia develops due to the delayed clearance of PRL rather than increased production. These PRL autoantibodies are stable with time and long-term follow-up (>10 years) revealed that macroprolactinemia might be a longlasting condition in humans [3,4,19,28]. The second reason for the asymptomatic presentation of macroprolactinemia includes binding of anti-PRL autoantibodies to their binding sites (epitopes) in both N-and C-terminal residues of the PRL molecule which are located near the binding site 1 to PRL receptors.…”