Gonadal hormone regulation as therapeutic strategy after acute intracerebral hemorrhage

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons AttributionNonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Intracerebral hemorrhage (ICH) constitutes ~15% of strokes subtypes in the United States (US) and results in greater morbidity and mortality than ischemic stroke.1–3 Despite priority reports by the National Institutes of Health and American Heart Association,4,5 ICH remains the only stroke subtype without proven effective therapy. To date, ICH clinical trials have largely focused on hematoma reduction. Despite hematoma volume, robust secondary injury occurs through neuroinflammation, which manifests as cerebral edema after ICH. Prior reports have shown cerebral edema formation6–8 and systemic inflammation9–13 after ICH to be robust and inversely associated with neurological outcome. Strategies that target inflammation in the brain and body may carry high potential for improving ICH outcome. Based on preclinical work, one promising neurotherapeutic strategy may be gonadal hormone regulation. Despite this, results of prior clinical trials for progesterone in acute traumatic brain injury (TBI) and estrogen for ischemic stroke failed to show efficacy. However, treatment benefit in these trials may have been negated by (1) enrolling individuals with normal hormonal production or on oral replacement therapy and (2) lack of data on baseline levels or failure to understand hormonal physiology after the neurologic injury. Thus, effects of endogenous hormones on outcomes after ICH remain to be defined before embarking on an ICH clinical trial. The exact mechanisms underlying relationships between gonadal hormones, brain injury-associated stress response, neurological outcome, and mortality have not been wholly described. Data are needed on the impact of age, sex, and ethnicity on gonadal hormones in human ICH recovery. Brain recovery mechanisms are clearly tied to gonadal hormones physiology. For example, pleiotropic effects of gonadal hormones improve neurological recovery in up to 50% in preclinical central nervous system (CNS) injury studies.14–17 Serum estradiol levels in humans are a robust marker of mortality both in men and women with TBI and subarachnoid hemorrhage, and the relationship changes with age.18 Of course, age and ethnicity influence gonadal hormone regulation.19–21 Finally, gonadal hormones are known to affect coagulation.22–24 However, little of this has been evaluated after ICH. The first steps are (1) characterize gonadal hormone physiology after ICH and (2) define associations between hormone concentrations, pathophysiology, and recovery. These associations will lay the framework for defining if/how these hormones might contribute to neuroprotection in the CNS and/or represent systemic stress that contributes to mortality. The complex interplay among gonadal hormones, gender, and ethnicity provides an opportunity to delineate specific individual and interacting effects of these factors on ICH outcome. For example, compared to Western populations, female patients with ICH in Singapore do not have a lowered mortality and have poorer outcome compared to male patients {Hsieh, 2016 #143}. Defining these effects will inform and improve patient-specific prediction of ICH outcome. Consider the following points: (1) hemostasis is influenced by gonadal hormones, age, and ethnicity,25–30 (2) hematoma volume is a well-known predictor of outcome after ICH,6,31–33 (3) outcome after ischemic stroke is affected by age, gender, and ethnicity,34,35 (4) female gonadal hormones are neuroprotective in a variety of preclinical models,36–42 and (5) temporal changes of these hormones in humans vary by gender, age, and ethnicity.19,20,43 All of these established relationships suggest thorough study of interactive effects of gonadal hormones, gender, and ethnicity on ICH outcome is timely and important. Prior work on sex differences, gonadal hormones, and stroke outcome has focused on overall stroke cases with ICH being excluded or performed as secondary analyses. Investigating ICH as a subtype of all stroke,1,3,44–50 through retrospective reviews1,49,50 or meta-analysis51 of foreign populations suffer from marked limitations of power. Further, Gonadal hormone regulation as therapeutic strategy after acute intracerebral hemorrhage