**4. Gender differences in pathophysiology and outcome**

slightly higher incidence of ICH in older women was attributable to higher life expectancy in women and increasing incidence of amyloid angiopathy with age. In another population-based study in Shibata province of Japan, the investigators studied 97 patients with primary ICH during the time period 1976-1978. The investigators noted incidence in men of 80 as compared

In a large multicenter study conducted across 10 different provinces in China during the years 1991-2000, the investigators identified a total of 16,031 cases of new onset stroke. Out of these cases, 23.9 percent were ICH. The investigators found no difference in incidence of ICH across

In the Northern Manhattan Stroke study [25,26] the investigators found that the annual incidence of ICH in the urban population of New York City was 30.9. Incidence was the same in men (81) as compared to 74 in women. Risk of ICH in men was higher than in women overall with a relative risk of 1.5 (95% CI=1.2-1.8) for ICH in men as compared to women. Below age 65, men were at significantly greater risk than women (RR=3.4, 95% CI=2.7-4.3) but age 65 and above men and women had a similar risk (RR=0.8, 95% CI=0.5-1.2). Men were at significantly greater risk of deep ICH than women (RR=1.8, 95% CI=1.4–2.3) but there was no difference in

Kissela et al. [27] conducted a hospital-based observational study of 3136 stroke patients during the time period of January 1, 1993, to June 30, 1994, to evaluate racial differences in clinical features of strokes. The investigators noted that the incidence of primary ICH was 37 (95 CI, 28–46) in blacks as compared to 18 (95 CI, 16–20) in whites. Further, the incidence of ICH was higher in black men in age group 65-74, (225) as compared to black women in the same age group (100). There was no significant gender difference in the incidence of ICH in white

There have been few studies from South America in this regard. The PISCIS stroke project, a community-based prospective study in Iquique, Chile noted that the incidence of ICH was higher in men as compared to women with nearly two thirds of the total study cohort being men. Minelli et al. [28] in a population-based study in Brazil noted similar findings. They studied overall incidence of various types of strokes in the assigned population and found the overall incidence of ICH was 14.7. Incidence in men (18.7) was nearly twice as much in women (10.7). The majority of women were older (above 75 years of age) at presentation as compared

In STROMA study, slightly higher incidence of ICH in men was found as compared to women [29]. These findings are similar to the Australian study, NEMESIS, completed over

to men who most commonly were between 55-74 years of age.

**3.5. Studies from Australia and New Zealand**

to 44 in women. [18,19,21-23].

**3.3. Studies from North America**

risk of lobar ICH (RR=1, 95% CI=0.8-1.2).

**3.4. Studies from South America**

gender. [24]

14 Intracerebral Hemorrhage

population.

While gender differences in clinical features of aneurismal subarachnoid hemorrhage has been studied [35,36], a relative paucity of data exists regarding gender difference in similar charac‐ teristics after ICH.

In the Northern Manhattan study [25,26], the incidence of ICH in men was 81 as compared to 74 in women (RR=1.5, 95% CI=1.2-1.8). The incidence of deep ICH was 58 in men as compared to 43 in women (RR=1.8, 95% CI=1.4–2.3). On the other hand, the incidence of lobar ICH was 21 in men as compared to 28 in women (RR=1, 95% CI 0.7–1.4).

Inagawa et al. [20] evaluated incidence of ICH across gender and anatomical location during 8-year period 1991 to 1998 in Izumo City, Japan. Though ICH occurred more commonly in men as opposed to women, the investigators did not find any significant difference regards to the anatomical hematoma location across genders. Taken together, these findings suggest a potential interaction between gender and race/ethnicity in determining the site of ICH.

Mean arterial pressure (MAP) may be associated with mortality in first 24 hours after presen‐ tation of ICH. Qureshi et al. [37] carried out a retrospective chart review of 105 patients with a diagnosis of primary ICH, and looked at the effect of rapid lowering of MAP on mortality in the first 24 hours after ICH. The rate of decline in MAP (slope) was independently associated with increased mortality (p=0.04), i.e., a faster rate of MAP decline was associated with higher mortality. This effect was independent of other known predictors of mortality, i.e., hematoma volume, presence of ventricular blood, and initial GCS score. While not powered to examine gender-specific interaction, MAP lowering effects on mortality were nearly greater in men as compared to women. (p=0.08). These findings may highlight gender differences in suscepti‐ bility to changes in MAP and its potential contribution to mortality.

Gender differences may exist in formation of deep venous thrombosis (DVT) in patients with primary ICH. Kawase et al. [38] prospectively evaluated 81 patients with primary ICH for risk of developing DVT. After adjustment for age and relevant confounders, female sex was the only independent predictor for DVT (odds ratio 6.89, 95% confidence interval, CI, 1.56-36.34, p=0.014). Female patients with an initial NIHSS score ≥ 12 had 19 times the risk for DVT compared to men with an NIHSS score <12 (95% CI 2.61-213.77, p=0.007). Development of DVT could add significantly to the morality and morbidity, especially in patients with ICH, as these patients are not routine candiates for anticoagulation in the acute phase.

Perihematomal edema (PHE) formation after ICH may affect mortality and long-term neuro‐ logical function in this patient population. Wagner et al. [39] looked at the role of gender in perihematomal edema in cases of primary ICH. PHE development was assessed over a 14-day period on follow-up CT scans in 387 subjects and was compared between men and women. The investigators found that starting at days 2-4, women showed lower PHE values (P<0.05; days 2-4 and 8-11). The mechanism and ultimate effect on outcome of these findings is unclear.

cerebral edema at 2 days after ICH. These observations are supported by work from Gu et al. [47] The investigators evaluated the role of estrogen pretreatment in reducing brain edema and neuronal survival in iron induced injury in murine models of ICH. The investigators found that estrogen pretreatment in male rats reduced brain edema (p < 0.01) as well as reduced

Gender Differences in Incidence, Pathophysiology, and Outcome of Primary Intracerebral Hemorrhage

http://dx.doi.org/10.5772/58469

17

Further, accumulation of iron and free radicals is proposed as one of the mechanisms of neuronal injury after ICH. Chen et al. [48] evaluated the molecular mechanisms underlying estrogen-mediated neuroprotective effect against iron induced neuronal injury in cases of ICH. The investigators found that ferrous citrate induced greater brain injury in male rats than female rats. Further, they observed that estrogen pretreatment was protective in iron-induced brain injury in both sexes but the effect was more pronounced in female rats as compared to male rats. The protective effect in female rats was attributed to higher concentrations of estrogen receptor alpha in the brain regions involved. These observations suggest a direct receptor mediated neuroprotective effect of estrogens against iron-induced free radical injury

Findings from work with estrogen may be partialy extended to other gonadal hormones. Chen et al. [49] evaluated progesterone and testosterone effects on ICH-induced brain injury in male rats. There was significant reduction of PHE in progesterone-treated rats (p < 0.05) as well as improved functional outcome following ICH (p < 0.05), as compared to vehicle-treated rats. However, testosterone treatment did not affect PHE and was associated with worse functional outcome (p < 0.05) as compared to vehicle-treated rats. These observations suggest a differen‐

Finally, Lei et al. [50] evaluated the role of sex and APOE polymorphism in modifying outcomes in murine models of ICH. The investigators found that female mice had better functional outcome as compared to male mice after ICH, as measured by neurobehavioral and cognitive tests. Further, female mice showed rapid rates of recovery as compared to male mice after comparable ICH injury. Interestingly, both male and female mice showed functional benefits after administartion of apoE mimetic peptide. Thus, sex differences may exist in

Several general conclusions can be made from the above observations. Gender differences in incidence of ICH appear to exist in Asian and South American populations, where men seem to suffer a higher incidence. Gender differences in incidence of ICH are not as obvious in Northern America, European, or Australian-New Zealand populations. Interestingly, there appears to be an interaction between age and gender in many of these populations, with ICH occurring at a younger age in men. Differences in access to preventative treatment, prevalence of known risk factors (e.g., hypertension, alcohol consumption, use of sympathomimetic

pharmacogenomic interactions for drug therapy to improve recovery after ICH.

drugs), and genetic variance may explain some of these disparities.

tial effect between female and male sex hormones after ICH.

neuronal death *in vitro* suggesting a broader neuroprotective effect of etrogen.

in murine models of ICH.

**6. Conclusions**

To further support the neuroprotective role of female sex hormones, menopause may alter the risk of primary ICH in women. Feldman et al. [40] carried out a prospective observational study of 1714 patients with a diagnosis of ICH, and evaluated various risk factors for devel‐ oping primary ICH. The investigators found that post-menopausal women had signifcantly higer incidence of ICH as compared to premenopausal women. Thus, menopause was significantly associated with development of primary ICH (adjusted OR, 2.50; 95% CI, 1.06 to 5.88). This observation may support role of female sex hormones in modifying the risk of developing ICH. Clearly, more studies are necessary in this regard.

Five studies provide information about the fatality of ICH in both genders. In a cross sectional study done by Kimura et al. [41], investigators found no difference in ICH mortality in men vs. women at 28 days. The case fatality was 17.6% overall, with 18.8% in men and 16.2% in women. These findings were similar to subsequent studies. Data from the Arcadia stroke registry [16] showed a slightly higher rate of case fatality in women (51.8%) as compared to men (44%) at 4 weeks after ICH. There was no difference in the case fatality rates in men as compared to women from the observations in STROMA study. [29] The investigators found that case fatality rate was 23.9% in men and 22.7% in women at 4 weeks after UCG. These findings were supported by a large multicenter study from China, where the case fatality rate was 48.4 percent in men, similar to 50.7 percent in women at 4 weeks after ICH. [24] Strikingly different were the observations made by Thrift et al. [30] from Australia. The investigators found that case fatality was higher in women (50.6%) as compared to men (29.2%). Finally, women had better survival than men after first-ever primary ICH in a prospective stroke register from Sweden, largely explained by a higher 28-day mortality in male patients over 75 years. [42]

## **5. Preclinical observations of the role of sex in ICH**

Data from preclinical models of ICH suggest response to the estrogen therapy. Nakamura et al. [43] studied sex differences in rat model of ICH. They observed that brain edema and neurological deficits at 24 hours after ICH were less in female rats as compared to male rats. The investigators then studied the role of an estrogen derivative on edema as well as functional outcome in male and female rats. They observed that administration of exogenous estrogen decreased edema as well as neurological deficits in male rats, but made no difference in female rats. Other studies support these findings. [44,45] These observations may also extend to pretreatment. Auriat et al. [46] found that estrogen pretreatment significantly reduced hemorrhagic blood volume at 12 hours after ICH in male rats; however estrogen did not lessen cerebral edema at 2 days after ICH. These observations are supported by work from Gu et al. [47] The investigators evaluated the role of estrogen pretreatment in reducing brain edema and neuronal survival in iron induced injury in murine models of ICH. The investigators found that estrogen pretreatment in male rats reduced brain edema (p < 0.01) as well as reduced neuronal death *in vitro* suggesting a broader neuroprotective effect of etrogen.

Further, accumulation of iron and free radicals is proposed as one of the mechanisms of neuronal injury after ICH. Chen et al. [48] evaluated the molecular mechanisms underlying estrogen-mediated neuroprotective effect against iron induced neuronal injury in cases of ICH. The investigators found that ferrous citrate induced greater brain injury in male rats than female rats. Further, they observed that estrogen pretreatment was protective in iron-induced brain injury in both sexes but the effect was more pronounced in female rats as compared to male rats. The protective effect in female rats was attributed to higher concentrations of estrogen receptor alpha in the brain regions involved. These observations suggest a direct receptor mediated neuroprotective effect of estrogens against iron-induced free radical injury in murine models of ICH.

Findings from work with estrogen may be partialy extended to other gonadal hormones. Chen et al. [49] evaluated progesterone and testosterone effects on ICH-induced brain injury in male rats. There was significant reduction of PHE in progesterone-treated rats (p < 0.05) as well as improved functional outcome following ICH (p < 0.05), as compared to vehicle-treated rats. However, testosterone treatment did not affect PHE and was associated with worse functional outcome (p < 0.05) as compared to vehicle-treated rats. These observations suggest a differen‐ tial effect between female and male sex hormones after ICH.

Finally, Lei et al. [50] evaluated the role of sex and APOE polymorphism in modifying outcomes in murine models of ICH. The investigators found that female mice had better functional outcome as compared to male mice after ICH, as measured by neurobehavioral and cognitive tests. Further, female mice showed rapid rates of recovery as compared to male mice after comparable ICH injury. Interestingly, both male and female mice showed functional benefits after administartion of apoE mimetic peptide. Thus, sex differences may exist in pharmacogenomic interactions for drug therapy to improve recovery after ICH.
