Aneurysmal subarachnoid hemorrhage (aSAH) continues to be a devastating neurological disease with few viable therapeutic treatments. Inflammation has been shown to increase the risk of complications associated with aSAH such as vasospasm and brain injury in human and animal models. The goal of this review is to explore sex hormones as therapeutic agents to prevent inflammation induced by aSAH, and to investigate potential risk factors that predispose patients to complications. Studies have shown that administration of sex steroids such as progesterone and estrogen at early stages in the inflammation process can lower the risk and magnitude of subsequent pathologies. The exact mechanism how these hormones act on the brain, as well as their role in the inflammatory cascade is not fully understood. Moreover, conflicting results have been published on the use of sex hormone therapy in animal and human trials. This review will scrutinize the variations in these studies in order to provide a more detailed understanding of these sex hormones as therapeutic agents.
Patients surviving an aneurysmal subarachnoid hemorrhage (aSAH) often develop cerebral vasospasm and delayed ischemic neurological injury. About two-thirds of patients with aSAH develop angiographic vasospasm 3-14 days after rupture of an aneurysm . Following aSAH, inflammatory cells enter the CNS leading to a decrease in cerebral blood flow and endothelial cell death [1, 2]. Inflammation, increase in endothelin-1, and depletion of nitric oxide from endothelial dysfunction are associated with onset of vasospasm [2, 3]. Sex steroids such as estrogen and progesterone, on the other hand, have been shown to have some beneficial effects on inflammation and edema   [6, 7]. Treatment with estrogen has been shown to reverse these effects by decreasing endothelin-1 and increasing nitric oxide (NO) . Mortality has been shown to be significantly reduced in progesterone treated animals when compared to placebo . There have been conflicting results on the different gender outcomes associated with aSAH; however, the incidence of SAH is generally found to be higher in females . The purpose of this review is to explore the relationship between inflammation and vasospasm in the setting of aSAH, and the potential benefits of sex hormones as a therapeutic anti-inflammatory intervention.
Role of Inflammation on Aneurysm Formation and Cerebral Vasospasm after SAH
CSF Inflammatory Markers
Several studies have investigated various inflammatory mediators in cerebrospinal fluid (CSF) following aSAH, with some conflicting reports [10, 11]. Many studies point to the prominent role of tumor necrosis factor-alpha (TNF-α)-, though other studies have found increased levels of interleukin (IL)-6 and IL-8 but not TNFα [11-13]. One recent study found detectable levels of TNFα in 30% of patients after SAH, this suggests that the amount and type of inflammation may very considerably in different patients . In animal models of SAH, blockage of TNF-α has been shown to reduce apoptosis in the hippocampus after SAH . Another inflammatory marker found throughout many studies is endothelin-1 (ET-1) [16, 17]. As with many other pro-inflammatory molecules, the expression of ET-1 is highly variable. In one study, ET-1 levels were found to be present in 46% of patients with SAH versus none detectable in the CSF of control subjects . A study from a different group, however, failed to detect ET-1 after SAH . The variation found in these inflammatory markers reflects the similar heterogeneity of complications associated with aSAH [19, 20]. The conflicting findings in these studies may stem from the time following injury that CSF levels were measured or the method of injury experienced by each subject.
Inflammation has also been suggested to play a role in aneurysm formation due to endothelial injury and remodeling based on human and animal studies [21, 22]. One such study showed increased levels of cyclooxygenase within the walls of ruptured and unruptured aneurysms, as well as a reduction in rate of rupture with aspirin administration [23-25].
Peripheral Inflammatory Markers
Inflammatory markers increase in the systemic circulation as well as in CSF following SAH and are predictive of poor outcomes [10, 26, 27]. This has led to an increasing interest in the development of biomarkers to predict the outcome of SAH, with conflicting results . High body temperature and leukocytosis have also been correlated with worse outcomes after SAH, though no causal relationship was established between intracerebral and peripheral inflammation [29, 30]. This relationship, however, may be the result of the global inflammation expected in critically ill patients suffering from SAH complications. SAH patients may experience cardiopulmonary complications as part of the systemic reaction . In a rat model of SAH, anti-inflammatory treatment administered systemically was able to reduce lung injury after SAH .
Evidence for inflammation as cause of vasospasm
Several clinical studies have attempted to correlate fever and inflammation in the absence of infection with vasospasm [33-42]. Pro-inflammatory agents, such as lipopolysaccharide (LPS) , have been administered using the intracisternal route to show that vasospasm can occur in the absence of blood. This has demonstrated that the presence of red blood cells (RBCs) or hemoglobin (Hgb) are not necessary for the induction of vasospasm. Among the cellular adhesion molecules, E-selectin has also been shown to correlate well with the patients’ response to SAH. E-selectin was found to be in higher concentrations in the CSF of SAH patients who develop moderate or severe vasospasm . Additionally, inhibition of E-selectin with an inhibitory antibody was shown to decrease vasospasm in rodent models . Other adhesion molecules have been implicated as well. In one study Mac-1 monoclonal antibodies and anti-LFA-1 antibodies were administered systemically, and shown to reduce vasospasm in rat , rabbit , and primate  SAH models. Similar results have been shown with anti-ICAM1 monoclonal antibodies in a rodent model . Among other pro-inflammatory cytokines, TNF-α levels in patients with lower grade SAH were shown to correlate with severity of vasospasm . This has been further studied as TNF-α inhibitors were shown to attenuate vasospasm in animal models . Similar results were described for other inflammatory cytokines including: IL-1B, IL-6, IL-8, and MCP-1 [13, 52-59]. Signaling pathways have been examined as well in the induction of vasospasm, namely mitogen-activated protein-kinase (MAPK) and nuclear factor kappa-B (NfKB) . Other studies have suggested oxidative stress , and complement pathway activation  could play a large role in the induction of vasospasm as well.
Recent work has been done to explore a possible genetic predisposition to vasospasm. One promising avenue has been the study of haptoglobin proteins, which are responsible for removal of free hemoglobin from CSF that may be the cause of inflammation. hHaptoglobin (Hp) have three known distinct phenotypes in humans: Hp 1-1, Hp 2-1, and Hp 2-2  In humans, the haptoglobin proteins with α-2 subunits are associated with higher rates of vasospasm as compared to other haptoglobin types (α1- α1) . This is consistent with animal models that demonstrate more severe vasospasm and worst outcome after SAH in genetically altered hp 2-2 rodents .
Changes in nitric oxide (NO) have been extensively studied in the induction of vasospasm as well. Increase in endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) levels were detected in mice after SAH, and this physiological response to SAH is decreased in pro-inflammatory Hp 2-2 transgenic mice compared with Hp 1-1 mice [66, 67]. This further supports the evidence that Hp 2-2 genotypes are associated with a worse outcome in SAH, as these subjects would have less NO, which is involved in signaling pathways that lead to vasodilation and cytoprotection . Studies have also suggested that an alteration dubbed “eNOS uncoupling” may lead to production of superoxides instead of NO following SAH . ET-1, a potent vasoconstrictor is thought to play a role in the inflammatory response after SAH [69-71]. Increase in ET-1 levels in in patients with SAH and symptomatic vasospasm has been documented in several studies, and he amount of blood found within the cisterns corolated well with the level of ET-1 in CSF [69-71]. Other studies, however, found no significant elevation of ET-1 after SAH and similarly, no correlation between ET-1 levels and vasospasm . Similarly, administration of anti-ET-1 monoclonal antibodies were effective in decreasing vasospasm in some studies  [73, 74]. A rodent study suggested that transgenic mice over-expressing ET-1 experienced more severe vasospasm and edema . Some studies have attempted the use of clasozentan, a synthetic endothelin receptor antagonist (ETRA)c, to reduce vasospasm in aSAH models of rodents, but the overall morbidity from vasospasm was unchanged .
Sex Steroids for the Treatment of Subarachnoid Hemorrhage
Estrogen is found in both females and males, but it is the primary female sex hormone that is responsible for the development and regulation of the female reproductive system . Estrogens readily diffuse across the cell membrane because of their steroidal characteristics. Once inside the cell, they bind to and activate estrogen receptors . At the molecular level, two main genes, estrogen receptor-alpha (ER-) and estrogen receptor-beta (ER-), encode the vascular estrogen receptors (ER) inside the nuclear membrane. The binding of the estrogen to the ER ligand binding domain induces a receptor conformational change and dimerization.
Evidence obtained from animal studies suggests that continuous estrogen treatment in SAH-induced rats may decrease rate and severity of vasospasm by inhibiting endothelin-1 production, increasing iNOS expression and preserving eNOS expression. Mechanistically, estrogen’s attenuation of cerebral vasospasm may be related to its potent vasodilatory action, described in detail by Ding, et al. .
Progesterone (PROG), a neurosteroid synthesized in the CNS, is therapeutic in several experimental models of traumatic brain injury (TBI), transient and permanent ischemic stroke, neonatal hypoxic brain injury, diabetic neuropathy and demyelinating disorders.[80-85] Besides its hypothalamic receptors, PROG receptors are constitutively expressed in cerebral cortex, basal ganglia, hippocampus, midbrain and cerebellum. A growing body of evidence suggests that PROG and its metabolite allopregnanolone have strong anti-inflammatory, anti-apoptotic and neuroprotective properties [80-82, 84, 85, 87] and is effective in improving functional outcomes.[81-84, 88]
Progesterone has also been shown to prevent vasospasm in SAH rat models using a similar mechanism . In rats treated with progesterone one hour after experimental SAH, greater levels of eNOS were seen when compared to the control group . The mechanisms for progesterone-mediated elevation of eNOS were multifactorial, but involved the Akt signaling pathway, which has also been implicated in estrogen-mediated vasodilation. Moreover, administration of progesterone was shown to be effective at increasing appetite scores of induced SAH rats and decreased intestinal levels of proinflammatory cytokines such as IL-1b, TNF-a, and IL-6 as well as ameliorating the gut structure thereby possibly preventing secondary complications of SAH . Progesterone treated animals showed a significantly reduced mortality when compared to vehicle treated animals .
Testosterone, another gonadal sex steroid, also plays important roles in the CNS, but its direct role is still unclear . Testosterone is physiologically secreted by the testes and adrenal glands and transported by the sex hormones binding globulins (SHBG) and albumins [91, 92]. It acts via the activation of androgen receptors (AR) , which are found in neurons throughout the brain . The cellular effect of testosterone is divided into two categories, genomic and non-genomic. Nongenomic pertains the ion movements and initiation of signal transduction and occurs rapidly. On the other hand, genomic effect involves transcription and translation of new gene products, hence requires longer duration .
Pike’s study suggest that AR-dependent neuroprotection occurs through inhibition of apoptotic and rapid cell signaling pathways . In male rodents, testosterone is also associated with increase in neuronal somal size, neuritic growth, and plasticity and synaptogenesis of motor neurons . In the setting of SAH, testosterone was shown to be beneficial at preventing vasospasm in rabbits with induced SAH . On the contrary, Myers et al’s findings suggest that testosterone does not have any neuroprotective effect against methamphetamine-induced neurotoxicity on the dopaminergic system in mice .
Translation from animal data to human trials
Though there is promising data alluding to sex hormones as a potential therapeutic agent for vasospasm in aSAH patients, the gap between animal and human trials is still very large. Growing concern for surrounding the failure of clinical trials in humans calls for more precise outcome measures . A study by the SAHIT investigators discusses potential reasons for failure of randomized clinical trials in SAH including: functional ineffectiveness of the tested therapies, timing and dose of the treatment, inadequate sample size, insensitive or inappropriate outcome measures, the confounding effect of rescue therapies in placebo groups, treatment-associated side effects, and variations in practice across different centers. Another study of phase III progesterone trials following TBI suggests that the testing parameters used to evaluate the efficiency of the drug are inadequate, and that outcome measures used in humans for neurological diseases need to improved . Some studies have attempting to correlate human
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