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.