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Toward the Establishment of a Clinical Prediction Rule for Response of Prolactinomas to Cabergoline

Department of Internal Medicine and Endocrinology Université Catholique de Louvain at Mont-Godinne University Hospital B-5530 Yvoir, Belgium

We read with interest the article by Verhelst et al. (1) published in the July 1999 issue of the journal. The authors confirmed in a large group of patients the already well documented effectiveness of the dopamine agonist cabergoline in the treatment of hyperprolactinemic states. However, their attempt to define the baseline predictors of response to treatment, the statistical methods used, and the conclusions drawn may be subject to discussion.

Six parameters potentially predicting success of treatment were studied: initial tumor volume, gender, basal PRL levels, bromocriptine resistance or intolerance, and previous treatment with bromocriptine. The effect of a previous treatment with bromocriptine will be of little help in the future to predict the response to cabergoline therapy because this medication will be increasingly used as a first-line treatment. Moreover, the interpretation of the results presented in bromocriptine-resistant patients is difficult because the criteria of resistance were not clearly defined. Other potentially important predictors of the response to treatment, such as age or invasiveness, were not considered. Indeed, in male patients, young age (<30 yr) might be associated with a higher rate of resistance to dopamine agonists (2). On the contrary, some authors (3) consider that older (>40 yr) female patients present more aggressive and, thus, presumably less responsive tumors. Invasion of the cavernous sinuses might also influence the response to treatment. In a previous series (4) including 37 men with prolactinomas, whose response to bromocriptine could be assessed, bromocriptine-resistant tumors were more frequently invasive (10 of 11) than bromocriptine-responsive tumors (9 of 26; P = 0.003).

The authors conclude that gender has no independent influence on the response of prolactinomas to treatment and that the smaller success rate observed in male patients is due only to the sex-related difference in tumor size, macroprolactinomas being more frequent among men and less responsive to dopamine agonists. However, the results in males compared with females with macroprolactinomas have not been studied. The similar results observed in males and females with microprolactinomas can hardly be taken into account because only about 10 men were concerned and the criteria for diagnosis of a presumed microprolactinoma were not given. Altogether, a multivariate analysis should have been performed to assess the respective roles of gender and tumor size.

Finally, the authors quoted one of our papers (4) when stating that the worst results observed in macroadenomas reflect the known difference in biological behavior between micro- and macroprolactinomas. However, our article demonstrated gender-based (and not only size-based) differences in the biological behavior of prolactinomas. Even considering macroprolactinomas only, the tumoral growth potential seemed greater in males than females.

In conclusion, the development of a clinical prediction rule for response of prolactinomas to cabergoline would probably have been possible on the basis of the large study presented by Verhelst et al. (1) but would have necessitated a skillful selection, a precise definition of the predictors, and the establishment of a reliable regression model (5). Thus, additional studies using such models are still needed to define the main potential predictors of the response of prolactinomas that should include age, gender, tumor size, and invasion of the cavernous sinuses.

Footnotes

¹ Received August 27, 1999. Accepted September 20, 1999. Address correspondence to: Etienne Delgrange, M.D., Internal Medicine and Endocrinology, Université Catholique de Louvain at Mont-Godinne University Hospital, B-5530 Yvoir, Belgium.

References

1. Verhelst J, Abs R, Maiter D, et al. 1999 Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab. 84:2518–2522.[Abstract/Free Full Text]
2. Delgrange E, Maiter D, Donckier J, Tourniaire J. 1999 Influence of age on the clinical presentation of prolactinomas in male patients. Gerontology. 45:160–164.[Medline]
3. Calle-Rodrigue RDP, Giannini C, Scheithauer BW, et al. 1998 Prolactinomas in male and female patients: a comparative clinicopathologic study. Mayo Clin Proc. 73:1046–1052.[Medline]
4. Delgrange E, Trouillas J, Maiter D, Donckier J, Tourniaire J. 1997 Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab. 82:2102–2107.[Abstract/Free Full Text]
5. Wasson JH, Sox HC, Neff RK, Goldman L. 1985 Clinical prediction rules. Applications and methodological standards. N Engl J Med. 313:793–799.[Abstract]

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