title: Deficiencies in estrogen-mediated regulation of cerebrovascular homeostasis may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in menopausal and postmenopausal women.
abstract: Despite the catastrophic consequence of ruptured intracranial aneurysms, very little is understood regarding their pathogenesis, and there are no reliable predictive markers for identifying at-risk individuals. Few studies have addressed the molecular pathological basis and mechanisms of intracranial aneurysm formation, growth, and rupture. The pathogenesis and rupture of cerebral aneurysms have been associated with inflammatory processes, and these have been implicated in the digestion and breakdown of vascular wall matrix. Epidemiological data indicate that the risk of cerebral aneurysm pathogenesis and rupture in women rises during and after menopause as compared to premenopausal women, and has been attributed to hormonal factors. Moreover, experimental evidence supports a role for estrogen in the modulation of each phase of the inflammatory response implicated in cerebral aneurysm pathogenesis and rupture. While the risk of aneurysm rupture in men also increases with age, this increased risk has been attributed to other recognized risk factors including cigarette smoking, use of alcohol, and history of hypertension, all of which are more common in men than women. We hypothesize, therefore, that decreases in both circulating estrogen levels and cerebrovascular estrogen receptor density may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in women during and after menopause. To test our hypothesis, experiments are needed to identify genes regulated by estrogen and to evaluate gene expression and intracellular mechanisms in cells/tissues exposed to varying concentrations and duration of treatment with estrogen, metabolites of estrogen, and selective estrogen receptor modulators (SERMs). Furthermore, it is not likely that the regulation of cerebrovascular homeostasis is due to the actions of estrogen alone, but rather the interplay of estrogen and other hormones and their associated receptor expression. The potential interactions of these hormones in the maintenance of normal cerebrovascular tone need to be elucidated. Additional studies are needed to define the role that estrogen and other sex hormones may play in the cerebrovascular circulation and the pathogenesis and rupture of cerebral aneurysms. Efforts directed at understanding the basic pathophysiological mechanisms of aneurysm pathogenesis and rupture promise to yield dividends that may have important therapeutic and clinical implications. The development of non-invasive tools such as molecular MRI for the detection of specific cells, molecular markers, and tissues may facilitate early diagnosis of initial pathophysiological changes that are undetectable by clinical examination or other diagnostic tools, and can also be used to evaluate the state of activity of cerebral aneurysm pathogenesis before, during, and after treatment.
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 676 St. Clair Street, Suite 2210, Chicago, IL 60611, USA. c-harrod@northwestern.edu
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Harrod
authors.forename: H Hunt
authors.initials: HH
authors.lastname: Batjer
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Bendok
mesh_terms: D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006706:Homeostasis; D006801:Humans; D002532:Intracranial Aneurysm / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D008593:Menopause / Q000378:metabolism*; D017698:Postmenopause / Q000378:metabolism*
chemical_list: D004967:Estrogens