Laboratory and clinical significance of macroprolactinemia in women with hyperprolactinemia

Abstract

The role of macroprolactinemia in women with hyperprolactinemia is currently controversial and can lead to clinical dilemmas, depending upon the origin of macroprolactin, the presence of hyperprolactinemic symptoms and monomeric prolactin (PRL) levels. Macroprolactinemia is mostly considered an extrapituitary phenomenon of mild and asymptomatic hyperprolactinemia associated with normal concentrations of monomeric PRL and a predominance of macroprolactin confined to the vascular system, which is biologically inactive. Patients can therefore be reassured that macroprolactinemia should be considered a benign clinical condition, resistant to antiprolactinemic drugs, and that no diagnostic investigations or prolonged follow-up should be necessary. However, a significant proportion of macroprolactinemic patients appears to suffer from hyperprolactinemia-related symptoms and radiological pituitary findings commonly associated with true hyperprolactinemia. The symptoms of hyperprolactinemia are correlated to the levels of monomeric PRL excess, which may be explained as coincidental, by dissociation of macroprolactin, or by physiological, pharmacological and pathological causes. The excess of monomeric PRL levels in such cases is of primarily importance and the diagnosis of macroprolactinemia is misleading or inadequate. However, macroprolactinemia of pituitary origin associated with radiological findings of pituitary adenomas may rarely occur with similar hyperprolactinemic manifestations, exclusively due to bioactivity of macroprolactin. Therefore, in such cases with hyperprolactinemic signs and pituitary findings, macroprolactinemia should be considered a pathological biochemical condition of hyperprolactinemia. Accordingly, individualized diagnostic investigations with the introduction of dopamine agonists, or other treatment with prolonged follow-up, should be mandatory. The review analyses the laboratory and clinical significance of macroprolactinemia in hyperprolactinemic women suggesting clinically useful diagnostic and treatment strategies.

Hyperprolactinaemia

“…Detection of macroprolactin is clinically important to avoid incorrect diagnosis and unnecessary investigations [83]. Gel filtration chromatography is regarded as the "gold standard" technique, however, it is labour-intensive and expensive [83,84,86]. Polyethylene glycol (PEG) precipitation is the most widely used method, as it is simple, fast, and cost effective [25,83,84,86].…”

“…Gel filtration chromatography is regarded as the "gold standard" technique, however, it is labour-intensive and expensive [83,84,86]. Polyethylene glycol (PEG) precipitation is the most widely used method, as it is simple, fast, and cost effective [25,83,84,86]. It involves mixing and incubating the serum with 25% PEG which is then centrifuged and the precipitating PRL complexes are subsequently quantified [83,84,86].…”

“…Polyethylene glycol (PEG) precipitation is the most widely used method, as it is simple, fast, and cost effective [25,83,84,86]. It involves mixing and incubating the serum with 25% PEG which is then centrifuged and the precipitating PRL complexes are subsequently quantified [83,84,86]. Recovery of free PRL > 60% of the total is suggestive of monomeric hyperprolactinaemia, whereas recovery <40% is consistent with macroprolactinaemia [33,86].…”

“…Despite the general view that macroprolactin does not have significant biological activity, in recent years, this has been a matter of debate [83,85]. Thus, it has been proposed that macroprolactin can dissociate into biologically active monomeric isoforms; nonetheless, studies assessing the biological activity of macroprolactin in vitro have yielded conflicting results [83,85,86]. Kalsi et al [87] in a study of 102 hyperprolactinaemic individuals, found that 68.8% of those with macroprolactinaemia had reproductive manifestations that could not be otherwise explained.…”

Cardiometabolic risk factors in young women with macroprolactinaemia

“…Apart from monomeric prolactin, being the most abundant (60-90%) and biologically active form of prolactin, this hormone occurs in the circulation in two other molecular forms: big-prolactin, consisting of prolactin dimers, and big-big prolactin, also referred to as macroprolactin. Macroprolactin comprises mainly high-molecular-mass complexes of 23 kDa prolactin and IgG autoantibodies [1][2][3]. Less frequently occurring forms of big-big prolactin include: complexes of prolactin with IgA or IgM, highly glycosylated monomeric prolactin, as well as covalent or non-covalent aggregates of monomeric prolactin [4,5].…”