Vasculogenic hyperprolactinemia: severe prolactin excess in association with internal carotid artery aneurysms

Purpose: Internal carotid artery (ICA) aneurysms have rarely been found in association with marked hyperprolactinemia in the absence of prolactinoma; the cause of hyperprolactinemia has never been investigated. We aimed to determine if the observed hyperprolactinemia is due to a vascular-derived or known prolactin secretagogue from the injured ICA, analogous to pregnancy-associated hyperprolactinemia putatively due to placental factors. Methods: We conducted a case series and literature review of individuals with severe hyperprolactinemia in association with ICA aneurysms. In two affected patients at our institutions, we performed RT-PCR and ELISA of prolactin secretagogues that are produced by vascular tissue and/or upregulated in pregnancy: AGT (encoding angiotensinogen), TAC1 (encoding substance P), HDC (encoding the enzyme responsible for conversion of histidine to histamine), and prolactin-releasing hormone (PRLH). Patient blood samples were compared to pregnancy blood samples (positive controls) and middle-aged male blood samples (negative controls). Results: Two men presented with serum prolactin >100-fold normal associated with cavernous ICA aneurysms and no pituitary adenoma. Aneurysm stenting in one man more than halved his serum prolactin. In both men, dopamine agonist therapy markedly reduced serum prolactin. RT-PCR and ELISA showed no differences between patients and controls in AGT, TAC1 or HDC expression or PRLH titre, respectively. Literature review revealed 11 similar cases. Conclusions: We propose the term ‘vasculogenic hyperprolactinemia’ to encompass the hyperprolactinemia associated with ICA aneurysms. This may be mediated by an endothelial factor capable of paracrine stimulation of lactotrophs; however, angiotensin II, substance P, histamine and PRLH appear unlikely to be causative.