Macroprolactin is an
antigen-antibody complex of higher molecular mass than
prolactin (>150kDa), consisting of monomeric
prolactin and
immunoglobulin G. The term 'macroprolactinemia' is used when the concentration of
macroprolactin exceeds 60% of the total serum
prolactin concentration determined by
polyethylene glycol precipitation. The gold standard technique for the diagnosis of macroprolactinemia is gel filtration chromatography. The prevalence of macroprolactinemia in hyperprolactinemic populations varies between 15% and 35%. Although the pathogenesis of these
antibodies is not clear, it is possible that changes in the pituitary
prolactin molecule represent increased antigenicity to the immune system, leading to the production of anti-
prolactin antibodies. Mild
hyperprolactinemia usually occurs because
macroprolactin is not cleared readily from the circulation due to its higher molecular weight. Moreover, the hypothalamic negative feedback mechanism for
autoantibody-bound
prolactin is inactive because
macroprolactin cannot access the hypothalamus, resulting in
hyperprolactinemia. Reduced in-vivo bioactivity of
macroprolactin may be the reason for the lack of hyperprolactinemic symptoms. It also seems that anti-
prolactin autoantibodies may compete with
prolactin molecules for receptor binding, resulting in low bioactivity. Additionally, the large molecular size of
macroprolactin confined in the intravascular compartment prevents its passage through the capillary endothelium to the target cells, which may be the reason for the lack of symptoms. Macroprolactinemia is considered to be a benign clinical condition in patients with normal concentrations of bioactive monomeric
prolactin, with a lack, or low incidence, of hyperprolactinemic symptoms and negative pituitary imaging. In such cases with resistance to anti-prolactinaemic drugs, no pharmacological treatment, diagnostic investigations or prolonged follow-up are required. However, macroprolactinemia may also occur in patients with conventional symptoms of
hyperprolactinemia who cannot be differentiated from patients with true
hyperprolactinemia. These symptoms are mainly attributed to excess levels of monomeric
prolactin, and this is of concern. The diagnosis of macroprolactinemia is misleading and inappropriate. A multitude of physiological, pharmacological and pathological causes, including stress,
prolactinomas,
hypothyroidism, renal and
hepatic failure, intercostal nerve stimulation and polycystic ovary disease, can contribute to increased levels of monomeric
prolactin. It is important for patients with elevated monomeric
prolactin levels to undergo routine evaluation to identify the exact pathological state and introduce adequate treatment, regardless of the presence of
macroprolactin. In addition, macroprolactinemia occasionally occurs due to
macroprolactin associated with
pituitary adenomas, with
biological activity of
macroprolactin comparable with that of monomeric
prolactin. In cases when excess
macroprolactin occurs with clinical manifestations of
hyperprolactinemia, macroprolactinemia should be regarded as a pathological biochemical variant of
hyperprolactinemia. An individualized approach to the management of such patients with macroprolactinemia may be necessary, and pituitary imaging,
dopamine treatment and prolonged follow-up should be applied.