An appropriate diagnostic evaluation is essential for the most appropriate treatment to be performed. Currently, macroprolactinemia is the third most frequent cause of nonphysiological
hyperprolactinemia after drugs and
prolactinomas. Up to 40% of macroprolactinemic patients may present with
hypogonadism symptoms,
infertility, and/or
galactorrhea. Thus, the screening for
macroprolactin is indicated not only for asymptomatic subjects but also for those without an obvious cause for their
prolactin (PRL) elevation. Before submitting patients to
macroprolactin screening and pituitary magnetic resonance imaging, one should rule out pregnancy,
drug-induced
hyperprolactinemia,
primary hypothyroidism, and
renal failure. The magnitude of PRL elevation can be useful in determining the etiology of
hyperprolactinemia. PRL values >250 ng/mL are highly suggestive of
prolactinomas and virtually exclude nonfunctioning
pituitary adenomas (NFPAs) and other sellar masses as the etiology of
hyperprolactinemia. However, they can also be found in subjects with macroprolactinemia,
drug-induced hyper-prolactinemia or
chronic renal failure. By contrast, most patients with NFPAs,
drug-induced
hyperprolactinemia, macroprolactinemia, or systemic diseases present with PRL levels <100 ng/mL. However, exceptions to these rules are not rare. Indeed, up to 25% of patients harboring a
microprolactinoma or a cystic
macroprolactinoma may also have PRL <100 ng/mL. Falsely low PRL levels may result from the so-called "hook effect," which should be considered in all cases of large (≥3 cm)
pituitary adenomas associated with normal or mildly elevated PRL levels (≤250 ng/mL). The hook effect may be unmasked by repeating PRL measurement after a 1:100 serum sample dilution.