ObjectiveMacroprolactinaemia is a condition in which serum prolactin (PRL) consists mainly of large molecular weight PRL (macroPRL). The aim of this study was to examine the natural history of macroprolactinaemia.Design and participantsSix hundred and fifty-four hospital workers participated in this study, including 27 subjects with macroprolactinaemia and 627 controls. MacroPRL and serum PRL concentrations were evaluated over a 4-year period. The ratio of macroPRL was examined by the polyethylene glycol (PEG) method and gel filtration chromatography. IgG-bound PRL and anti-PRL autoantibodies were examined by protein G and 125I-PRL binding studies respectively.ResultsOver the 4 years of the study, all 27 macroprolactinaemic subjects had persistent macroprolactinaemia without the development of raised free PRL, while none of the 627 controls developed macroprolactinaemia. The ratios of PEG–precipitable PRL and IgG-bound PRL did not significantly change, but 125I-PRL binding ratios significantly increased. As a whole, total and free serum PRL concentrations did not significantly change in subjects with macroprolactinaemia over the 4-year period. However, hyperprolactinaemia developed in five of the 18 macroprolactinaemic subjects who were initially normoprolactinaemic along with an increase in anti-PRL autoantibody titres. One of the remaining nine macroprolactinaemic subjects who were initially hyperprolactinaemic showed a decrease in serum PRL concentrations, which occurred concomitantly with a decrease in the anti-PRL autoantibody titre.ConclusionsMacroprolactinaemia may develop before middle age and is likely a chronic condition leading to hyperprolactinaemia.