Gonadal hormone regulation as therapeutic strategy after acute intracerebral hemorrhage

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 formation^6–8 and systemic inflammation^9–13 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 reviews^1,49,50 or meta-analysis ⁵¹ of foreign populations suffer from marked limitations of power. Further, little is known regarding gonadal hormone physiology and effects specific to ICH. The neurologic injury from ICH differs from ischemic stroke in at least two ways: (1) the mass effect of the hematoma contributes substantially to neurologic injury and (2) blood is known to induce specific inflammatory/apoptotic pathways.

Preclinical data strongly support the hypothesis that gender differences both in survival and recovery exist after ICH;^52–56 however, limited data exist on the effects on hematoma evolution and cerebral edema formation.^57,58 Hemostatic sex differences in ischemic stroke are present in preclinical models and in humans.^59–63 Since hematoma volume is held constant in preclinical models of ICH, sex differences have been extended to include neuroinflammatory modulation after ICH: Female mice consistently demonstrate up to 50% improvement in neurological recovery after ICH with reduction in cerebral edema and markers of inflammation. ⁶⁴ As a possible mechanism for gender-specific differences, studies for people with ICH will be enhanced by understanding hormone-specific mechanisms of hemostasis and inflammation.

Insight into the role of gonadal hormones may be gained from preclinical studies in ischemic stroke ¹⁶ and TBI. ⁶⁵ These studies indicate that gonadal hormones are key factors in sex differences in outcome. However, these findings have not yet been translated to effective therapy in human disease.^66–71 Failed translation may be related to incomplete understanding of gonadal influence on brain pathophysiology. In stroke and TBI, gonadal hormones are pleiotropic, including roles in coagulation and inflammation, with both beneficial and injurious effects.^{14,15,39,41,71–88} These findings have repeatedly found beneficial effects of gonadal hormones in reducing injury after preclinical ICH.^{17,53,55,56,58,89} Administration of exogenous gonadal hormones improves neurological recovery by up to 75% in models of ICH, but no published data evaluate the role of gonadal hormones on hematoma evolution, cerebral edema, or outcome after ICH in humans, and the impact of the critical illness period after ICH on hormone physiology is not known.

Influence of gonadal hormones on ICH pathophysiological mechanisms, such as hematoma and edema evolution, may not have been fully considered in major clinical trials.^90–94 For instance, pathophysiologic mechanisms after ICH, such as blood pressure response, hemostasis, and edema formation, may be different between men and women.^{95 –97} While hormonal modulation of coagulation and hemostasis have been reported after systemic injuries^25,27 and ischemic stroke,^98,99 such data are limited after ICH. Further, influences of hormone replacement therapy (HRT) after ICH are unknown. While early single-center investigations found that the risk of unfavorable outcome for women increased with age at a greater rate than for men,^100,101 other multicenter investigations found sex differences in outcomes that did not hold up after covariate adjustment ¹⁰² or failed to persist over time from ICH onset. ¹⁰³ Finally, using the largest cohort of ICH cases to date, the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) ¹⁰⁴ study examined long-term outcomes after ICH in a multiethnic cohort from 19 US centers. In this study, no sex-age interaction effect was found for mortality or modified Rankin Score (mRS) at 90 days after ICH. In racial/ethnic subgroups, only the non-Hispanic black cohort provided possible evidence of a sex-age interaction on 90-day mRS (James et al. Neurology 2017. Publication pending). However, the lack of direct serum or brain hormone measurement should be emphasized in all of these studies, yet hormone concentration, irrespective of patient sex, is likely to be a critical component to explaining these conflicting findings.

Even more poorly understood are testosterone effects in the brain. While preclinical data suggest androgens may have both neurotoxic and neuroprotective properties,^{105 –107} no published studies measure or test for testosterone’s effects on ICH recovery. Testosterone declines slowly in men as they age and supplementation is increasingly common. ¹⁰⁸ Thus, testosterone may contribute more to physiology in older men, relative to estrogen in older women. However, little is known about the effects of testosterone in the brain, especially after ICH. The sole preclinical study demonstrated that exogenous administration of testosterone did not affect brain edema in male rats but worsened forelimb placement at 24 hours after ICH. ¹⁰⁹ There is a single human study in 20 individuals that demonstrated that serum testosterone is altered but measurable in men and women after ICH, but did not have power to detect meaningful associations. ¹¹⁰ This fundamental lack of knowledge blocks (1) assessment of testosterone regulation as a potential ICH therapy, (2) appropriate advice on testosterone replacement continuation after ICH, and (3) optimal ICH clinical trial design. Discovering effects of testosterone concentrations during the acute-to-subacute phase after ICH would provide novel insights into associations between these hormones, hemorrhage formation, and outcome after ICH.

Future research should directly address gonadal hormone associations with ICH pathophysiology and outcome to guide (1) HRT use after ICH, (2) patient-specific outcome prediction by defining the gonadal hormone range at which patients are most at risk for poor outcome after ICH, and (3) clinical trial design regarding relevance of hormonal status. Once accomplished, the framework for evaluating longitudinal changes in gonadal hormone physiology after ICH may be measured in serum, cerebrospinal fluid, and brain through serial sampling. After clearly defining hormone changes and their correlations with ICH pathophysiology and outcome, testing targeted, personalized hormonal modulation as a therapy to improve recovery can begin for people after ICH.