Atypical antipsychotics and pituitary tumors.

P rolactin (PRL) secretion is normally inhibited by dopamine and is stimulated by several releasing factors. Unlike the other pituitary hormones, the inhibitory component is dominant, so that if the hypothalamic-pituitary stalk blood flow is impaired, PRL levels rise whereas the other pituitary hormone levels fall. Hypothalamic infiltrative disease such as sarcoidosis and large tumors that interfere with stalk blood flow, such as meningiomas or large pituitary adenomas, can cause hyperprolactinemia. In addition, drugs which either block hypothalamic dopamine generation or block the dopamine D2 receptor present on lactotroph cell membranes can also cause hyperprolactinemia. Some of the most common drugs to cause hyperprolactinemia in this fashion are the classical antipsychotic agents, such as the phenothiazines and butyrophenones, and some of the atypical antipsychotic agents, such as molindone and risperidone. It is currently thought that most pituitary adenomas arise because of a single cell mutation with subsequent monoclonal proliferation and not from underlying hypothalamic dysregulation. However, in animal studies, mutations causing loss of function of the dopamine D2 receptor cause the development of lactotroph hyperplasia and sustained hyperprolactinemia, followed by lactotroph adenomas in aged mice, thereby demonstrating that a chronic loss of neurohormonal dopamine inhibition promotes a hyperplasia-neoplasia sequence in lactotrophs. Thus, it is reasonable to ask the question as to whether continuous dopamine D2 receptor blockade over many years through antipsychotic use could cause prolactinomas to develop initially or stimulate the growth of previously existing prolactinomas. The study reported byMcCarren et al in this issue of the Journal of Clinical Psychopharmacology has attempted to answer this question. The study was carried out in response to two pharmacovigilance studies, one from the FDA Adverse Reporting System and the other from the WHO adverse drug reaction database, which reported disproportionately high numbers of pituitary tumors in patients taking risperidone compared to other antispsychotic agents. Pharmacovigilance studies, of course, can be confounded by an ascertainment bias; in this case, risperidone more commonly causes hyperprolactinemia than many other atypical antipsychotic agents and patients found to have hyperprolactinemia commonly undergo pituitary magnetic resonance imaging (MRI) scans as part of their evaluation. The finding of an adenoma on MRI is nonspecific, as approximately 10% of persons with no clinical evidence of endocrine disease are found to have incidental pituitary adenomas at autopsy and about 40% of such adenomas stain positively for PRL. So what about this study by McCarren et al? They looked at users of risperidone and other antipsychotic agents in two large databases and identified patients harboring pituitary macroadenomas on the basis of the following characteristics: ‘‘pituitary tumor with mass effect, including visual field disturbance, pituitary hormone deficiency, or surgical or radiotherapeutic treatment of the tumor. ’’ Using such criteria, they found no increase in the prevalence of pituitary tumors in patients using risperidone with a prevalence of 13/100,000 patients. Were these prolactinomas? We have no data to show that they were, as neither PRL levels nor surgical pathology reports were reported for these patients. How likely is it that these numbers are truly representative of the number of prolactinomas in this population? The answer is unlikely. Firstly, macroadenomas account for less than 5% of all prolactinomas and an even smaller proportion of macroadenomas cause visual field defects or hypopituitarism. Secondly, almost all prolactinomas are treated with the dopamine agonists, cabergoline and bromocriptine, and therefore would not be treated with either surgery or radiotherapy. Thirdly, pituitary adenomas grow very slowly. Dekkers et al estimated a growth rate of 0.6 mm per year so that over the median 47 months of follow-up of these patients, the 95% that are microadenomas would likely stay microadenomas and certainly would not grow sufficiently to cause visual field defects or hypopituitarism. I think, therefore, that we cannot conclude from this study that any of these drugs can be implicated or exonerated with respect to the development or progression of growth of prolactinomas, as GUEST EDITORIAL