Article originalThe risks of medical treatment of prolactinomaTraitement medical du prolactinome: quels risques?
Introduction
Prolactinoma is one of the most frequent pituitary adenomas. In most case, first-line treatment is medical rather than surgical [1], [2], [3]. Even optically compressive macroprolactinomas generally benefit from drug therapy with dopamine agonists. This wide use of dopaminergic agonists, occasionally for prolonged periods, obviously raises the question long-term safety. Since the initial publication, 30 years ago, on the efficacy of cabergoline in prolactinomas [4], this treatment has become the first-line drug option. Cabergoline, a dopaminergic D2 receptor agonist, is also used in restless leg syndrome and Parkinson's syndrome, although at much higher doses than those generally used for prolactinoma.
An exhaustive review carried out on PubMed with the search-term “cabergoline” returned 1750 results (for the period between 01/1986 and 05/2020), 122 of which related to prolactinoma treatment tolerance. Over the past 30 years, new side-effects have been described, and others have been disappeared from view. This review will particularly focus on the infrequent side-effects: valvular and pleural fibrosis, addictive or compulsive behavior, and the risks associated with tumor changes induced by treatment (rhinorrhea, apoplexy, campimetric impairment).
Classical side-effects (nausea, reported in up to one third of cases, mediated by interaction with serotonergic 5HT1 receptors; orthostatic arterial hypotension, in one quarter of cases, mediated by dopaminergic D1 receptors; dyskinesia, rarely reported, mediated by interaction with dopaminergic D2 receptors) are generally dose-dependent, and regress when treatment is stopped. They will not be discussed in this review. Likewise, this review will not address the issue of prolactinoma treated medically during pregnancy, or other dopamine agonists such as bromocriptine and quinagolide.
Section snippets
Risk of cardiac valvular fibrosis
Cabergoline can induce serotonergic receptor 5-HT2B activation and consequently vascular interstitial cell proliferation. These cells are very abundant in the structure of heart valves, within which they play the role of fibroblasts. Proliferation generates fibrosis. The risk of cardiac valve fibrosis was first described in the context of use of cabergoline in Parkinson's syndrome [5], [6]. In this context, dose-dependent toxicity was demonstrated, with a risk of moderate to severe mitral valve
Risk of pleural, pericardial and retroperitoneal fibrosis
Cabergoline is associated with risk of pleural, pericardial and retroperitoneal fibrosis in Parkinson's syndrome, at prolonged doses ranging from 1 to 10 mg per day [20]. The mechanism is comparable to that described for heart valve fibrosis. The classic clinical picture of pleural fibrosis associates a dry cough, dyspnea and edema of the lower limbs. Discontinuation of treatment generally allows an improvement in symptoms, without repeating standard investigations. However, the risk seems very
Risk of compulsive/addictive behavior
Addictive and compulsive behaviors such as gambling addiction, hypersexuality, food compulsions, impulsive purchases and “punding” (intense fascination or irresistible attraction toward common objects which are incessantly manipulated, examined, collected, sorted and arranged) have been reported with the use of cabergoline in Parkinson's syndrome or restless leg syndrome [22]. These behaviors are linked to the affinity of cabergoline for dopaminergic D3-receptors that are located in the
Risk of rhinorrhea, apoplexia and visual impairment
Classically, rhinorrhea is linked to a traumatic event (80% of cases), or to pituitary surgery (0.5–15% of cases) [30]. This risk is not present in microprolactinoma, and remains rare in macroprolactinoma. Onset of rhinorrhea under cabergoline involves destruction of the sellar floor by the macroadenoma, and a major anti-tumor effect of cabergoline. Data from the literature are difficult to analyze, being based on case series in which management was heterogeneous [31]. Incidence is estimated to
Conclusion
Despite very frequent use, cabergoline should not be considered as an anodyne treatment that does not require special monitoring. In addition to the classic side-effects (hypotension, nausea), some less well-known side-effects require regular evaluation to screen for suggestive signs, particularly addictive behavior and dyspnea. Cardiac valve impact remains debated, especially due to the low doses employed in the vast majority of prolactinoma patients. However, in the absence of long-term
Disclosure of interest
FC, TC, TB, FA receive consulting fees from Pfizer.
Acknowledgements
This text was presented during the 40th Journees Gueritee on November 20th, 21st in Paris.
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