Dose-Related Neuroprotective versus Neurodamaging Effects of Estrogens in Rat Cerebral Ischemia: A Systematic Analysis

Abstract

Numerous studies of the effects of estrogens for stroke prevention have yielded conflicting results in human and animal studies alike. We present a systematical analysis of study design and methodological differences between 66 studies where estrogens' impact on ischemic brain damage in rat models has been investigated, providing evidence that the differences in results may be explained by high estrogen doses produced by slow-release pellets. These pellets have been used in all studies showing increased neurologic damage because of estrogens. Our data indicate that the increased neurologic damage is related to the pellets' plasma concentration profile with an early, prolonged, supraphysiological peak. Neither the method of inducing the ischemic brain lesions, the choice of variables for measuring outcome, the measured plasma concentrations of estrogens at the time of ischemia nor rat population attributes (sex, strain, age, and diseases) are factors contributing to the discrepancies in results. This suggests that the effects of estrogens for stroke prevention are concentration related with a complex dose-response curve, and underscores the importance of carefully validating the experimental methods used. Future studies of hormonereplacement therapy in women may have to take dosage and administration regimens into account.

Neuronal Estrogen Receptor-α Mediates Neuroprotection by 17β-Estradiol

“…The neuroprotective effect of estrogens in physiologic doses is well established (Gibson et al, 2006;Strom et al, 2009), but the molecular and cellular mechanisms remain controversial. Although receptor-independent effects of E 2 have been reported (Culmsee et al, 1999), there is ample evidence that suggests that ERs mediate most of the neuroprotective effect.…”

Long-term cerebral cortex protection and behavioral stabilization by gonadal steroid hormones after transient focal hypoxia

“…Since many stroke studies have been performed under a short-term protection paradigm, it is not fully clear to which extent these activated individual pathways contribute to an improved functional longterm outcome. Moreover, long-term protection studies were often performed using repeated steroid applications for up to several weeks, and it also turned out that the method of administration and dosage is causally linked to the study outcome [12]. We assume that the multitude of beneficial steroid effects act in concert to achieve sufficient neuroprotection but are aware that each hormone also transmits selective cellular actions.…”

Challenges in experimental stroke research : The 17β-estradiol example

“…Although the narrative reviews are numerous [67][68][69][70][71], the studies actually utilizing a systematic and/or meta-analytical approach are few. To our knowledge, only three such studies exist: one by Gibson et al from 2006 [72] and two from our lab, Ström et al from 2009 [73], and Paper III of the current thesis.…”

“…Paper III was a sequel to a previous systematic analysis [73] performed in our lab in which the same question was investigated, namely the effect of administration method and estrogen treatment dose on ischemic stroke in rat studies. The statistical shortcomings of the previous systematic analysis, the continuing debate on the matter and the publication of several additional original studies encouraged us to perform this updated and improved study.…”

“…These silastic capsules were in the abovementioned administration studies shown to produce lower and more stable hormone concentrations than the slow-release pellets. Further, in a systematic analysis of all studies on the effects of estrogens on cerebral ischemia in rats it was found that the slow-release pellets had been used in all studies showing detrimental effects [73].…”