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In this issue of the Annals Eijsbouts and coworkers1 show that the prolactin (PRL) response to hypoglycaemia is lower in patients with early untreated rheumatoid arthritis (RA) than in healthy controls. Furthermore, the unique design of their study allowed the authors to compare the PRL response before the test, after 2 weeks of treatment with a non-steroidal anti-inflammatory drug (NSAID) and, then again, after 6 months of conventional antirheumatic treatment with NSAIDs and disease modifying antirheumatic drugs (DMARDs). After 6 months they found that the PRL response to hypoglycaemia was significantly normalised, which correlated positively with the Disease Activity Score. The results of the study1 suggest that disease activity and/or treatment with DMARDs significantly affects the central regulation of PRL secretion resulting from stimulation in patients with RA.
A possible involvement of PRL in the pathogenesis of inflammatory diseases has been intensively studied, including a hypothesis about dysregulated secretion of this pituitary hormone in patients with RA.2 It has been shown that about one third of patients with RA are hyperprolactinaemic under basal conditions.2 However, controversy remains about whether stimulated secretion of PRL is up regulated or down regulated. Using the same stress stimulus as in the study of Eijsbouts et al,1 we showed that the PRL response to hypoglycaemia was decreased in 38 patients with long term RA with moderate disease activity who were receiving treatment with NSAIDs or DMARDs.3 In line with others,4,5 we observed a PRL response to thyrotropin releasing hormone stimulation comparable to the response in healthy subjects in the same cohort of patients,3 suggesting a normal pituitary gland but altered central neuroendocrine regulatory mechanisms in patients with moderately active RA. The disease activity rather than the treatment itself seems have a more important effect on the PRL response to hypoglycaemia.
The PRL response to insulin-induced hypoglycaemia, unlike that of other pituitary hormones (for example, growth hormone), is not usually triggered in all healthy subjects, at least in a dose of 0.1 IU/kg of rapid acting insulin and may depend on an individual person’s threshold for PRL release.6
In our most recent study we observed a lower PRL response to hypoglycaemia in glucocorticoid naive premenopausal patients with RA. When we analysed the data we found during hypoglycaemia that a double or higher increase of plasma PRL occurred only in 5/15 (33%) patients with RA but in 8/14 (57%) controls. PRL responses were irrespective of any clinical (disease activity, disease duration) or biochemical (tumour necrosis factor α, interleukin 6, C reactive protein, erythrocyte sedimentation rate) variables. The prevalence of PRL responders was not significantly different in patients with RA and controls, probably owing to the small sample size; however, the area under the response curve of PRL in patients with RA was significantly lower than in healthy controls.7 Nevertheless, we suggest that patients with RA may have a tendency towards a higher threshold for PRL release in response to hypoglycaemia, which deserves further investigation.
To test our proposal we would be interested in having the authors’ view of their data in patients with RA and finding out whether the improvement in the PRL response in their study1 was due to a quantitatively higher response in individual patients or rather a qualitative shift from being a PRL non-responding subject to a PRL responding subject.
We thank the authors for their interest in our work and opportunity for discussion of this interesting but still puzzling subject. Published reports are contradictory, possibly because of different study subjects, different methods of stimulating prolactin (PRL) secretion, and large variation of PRL levels between individual subjects.
Indeed the study mentioned by the authors1 showed that about one third of patients with rheumatoid arthritis (RA) were hyperprolactinaemic under basal conditions, and in our article we refer to other studies reporting hypersecretion of prolactin in RA. However, by now we have performed three studies in which we could not confirm this: (a) the study that is now being discussed, including a total of 50 patients with RA; (b) a former smaller study in patients before and after undergoing total hip replacement,3 in which 10 patients with RA were compared with patients with osteoarthritis; and (c) a study in which we treated nine patients with RA with quinagolide, a dopamine agonist, which suppresses PRL secretion.4 None of these patients had raised PRL levels under basal conditions.
In our current study,2 17/20 (85%) healthy subjects had a double or higher increase in PRL levels in response to hypoglycaemia-induced stress, unlike the findings of the authors in their study, who found that only 57% of controls had a double or higher increase of PRL. They found PRL responses in patients with RA irrespective of disease activity, whereas in our study, as mentioned in the article, we found a negative correlation of PRL response and disease activity (DAS). We agree with the authors that it seems likely that disease activity is a more important factor in the changed PRL response than the treatment itself.
To answer the last question of the authors. In patients with RA we found that eight (40%) patients did not show a double or higher increase of PRL levels, and after treatment for 6 months only four did not show such a response, which could be consistent with the suggestion of Dr Imrich that more patients become PRL responding. However, 15/20 patients showed a marked increase in PRL levels after 6 months in response to hypoglycaemia-induced stress, and so we conclude that the improvement of the PRL response that we observed was due to a general quantitatively higher response in most patients, and not a shift towards more patients being PRL responding.