Context: Macroprolactinomas (MPRL) may result in non-surgical (spontaneous or dopamine-agonist-induced) cerebrospinal rhinorrhoea; however, the incidence of and mechanisms underlying this phenomenon are poorly understood.

Objective: To determine the incidence of non-surgical rhinorrhoea. To identify biochemical, radiological and histopathological factors associated with leakage.

Design, Setting and Participants: Retrospective review of MPRL patients (n=114) compared with patients with non-functioning pituitary adenoma (NFA) (n=181) seen over a 19-year period (1985-2004).

Main Outcome Measures: Incidence of CSF rhinorrhoea, factors predictive of leakage and differential expression of candidate markers of invasiveness.

Results: Non-surgical CSF rhinorrhoea occurred in 8.7% of MPRLs (10/114) (2.6% spontaneous (3/114), 6.1% dopamine-agonist-induced (7/114)) whereas no NFAs developed non-surgical rhinorrhoea.

There was a clear male preponderance in MPRLs with non-surgical rhinorrhoea (M:F, 9:1, p= 0.008).

Dopamine-agonist resistance was more frequent in MPRLs with rhinorrhoea than with MPRL without rhinorrhoea (30% (n=10) vs. 5% (n=104) p=0.003).

Baseline prolactin levels, rate of prolactin decline in response to dopamine-agonists and tumour volume at diagnosis did not predict CSF leakage.

Candidate markers of invasiveness, specifically, the protease-activated receptor1 (PAR1) and E-cadherin expression scores and tumour macrophage density were not significantly different between groups; MPRL+CSF rhinorrhoea (n=6), MPRL without CSF rhinorrhoea (n=9) and NFAs (n=9).

Conclusions: The incidence of non-surgical CSF rhinorrhoea in MPRL patients (8.7%) is higher than expected. Dopamine-agonist resistance is commoner in MPRL with CSF rhinorrhoea; however, whether this is a mechanistic relationship requires further study. PAR1 expression, e-cadherin expression and macrophage infiltration rates do not distinguish tumours with from those without CSF rhinorrhoea.