The role of sex steroids in prevention of post-ischaemic brain injury
Department of Anaesthesiology, Intensive Therapy and Emergency Medicine, Pomeranian Medical University in Szczecin
Sex steroids play an important role in neuroprotection following brain injury. Although their protective action has been found to be effective in many experimental animal models, their use in humans remains controversial. Many authors have shown that the frequency and extent of post-ischaemic damage is sex-dependent, and even low concentrations of estrogens are neuroprotective, but not therapeutic.
The authors have summarized the current knowledge of neuroprotection by sex steroids in experimental and clinical settings. They conclude that direct extrapolation from animals to humans is not possible, and so far, widespread clinical use of sex steroids in humans is not justified.
Numerous recent and ongoing studies are focused on guidelines and indications for the use of sex hormones for prevention and treatment of severe traumatic or post-ischaemic brain injury. The role of sex hormones in the repair processes after traumatic brain injury is unquestionable. According to Bramlett and Dietrich , already the basic levels of female sex hormones reduce the extent of traumatic brain damage in female animals. In animals subjected to surgical sterilization before trauma, histopathological brain changes have been found to be markedly larger than in healthy animals, irrespective of the ovulation cycle stage on trauma.
Sex hormones are used to diminish the extent of brain injury and to improve the neurological status. Such protective effects are exerted by the endogenous hormones, produced by the ovaries and within the brain. For instance, testosterone is the source of endogenous estradiol. In brain ischaemia, the local production of endogenous estradiol increases, which is caused by ischaemia-related stimulation of the activity of aromatase P 450, present in brain tissues . Endogenous estrogens act protectively by increasing the brain blood flow. Their neuroprotective action depends on the direct influence on the neurons and glial cells .
The majority of researchers agree that estrogens play an extremely important, probably essential neuroprotective role in various neurodegenerative diseases, trauma, cerebral stroke and other ischaemic brain changes. However, the comprehensive review of literature regarding their efficacy and its dependence on the time of administration shows that the opinions differ. Although neuroprotective effects of estrogens have been confirmed in many experimental models of CNS ischaemia, their use in the treatment of ischaemia causes remains controversial . The exogenous administration of 17β-estradiol limits the rate of development and extent of ischaemic stroke in the cerebral cortex and in the striatum after reversible occlusion of the middle cerebral artery in rats of both genders. However, its protective action is dose- and treatment duration-dependent, in favour of small physiological serum concentrations of estradiol and long-term therapy [3, 5, 6].
During treatment of adult women after brain injury, protective effects of estrogens are visible already at their low blood concentrations. The administration of 17β-estradiol slows downs the progression of destructive brain changes and inhibits apoptosis . Similar findings have been reported in patients with Alzheimer’s disease and other advanced neurodegenerative processes; such effects of estrogens result from alleviated activation of the microglia . Moreover, it has been demonstrated that high doses of estrogens increase the brain injury by stimulating the pro-apoptotic activities and up-regulating N-methyl-D-aspartate (NMDA) receptor-dependent activity. The more advanced the ageing process, the stronger the effect .
The neuroprotective effects of estrogens have been demonstrated in rats, when administered both immediately before trauma and after post-ischaemic brain injury [10,11]. The prerequisite is the use of 17β-estradiol within the three post-ischaemic hours . Some other experimental studies report different results, showing explicitly that estrogens protect CNS against sequelae of brain injury yet are not involved in the repair processes and reparation. The protective action of estrogens in prevention of neurodegenerative diseases in women depends on the time of therapy onset and the neurological status on treatment institution. The expected therapeutic effect is observed only when estrogens are administered before the development of CNS changes, in the early stage of menopause. If the first clinical symptoms of Alzheimer’s or Parkinson’s disease have developed before the onset of estrogen therapy or more than 10 years after menopause, the hormone supply will have no positive effects . 17β-estradiol exerts neuroprotective effects only when used before injury. Irrespective of the dose used, its pre-injury administration diminishes the extent of ischaemic brain changes by 50%. Once administered after exposure to the injuring factor and/or ischaemia, its protective action is not observed . According to the findings of experimental studies in male rats, the action of estrogens is time-dependent and effective only in prevention of brain injury. 17β-estradiol shows protective effects if administered pre-emptively .
According to Kalita and Szymczak , the lack of estrogen efficacy in the treatment of various CNS diseases is likely to be related to the genomic mechanism of their neuroprotective action. The activation of this mechanism takes several hours. For this reason, to exert their neuroprotective effects, estrogens would have to be administered several hours before the exposure to the injuring factor.
After administration, exogenous estrogens increase the blood flow through the ischaemic area, i.e. where the brain barriers have stopped to function. The non-genomic mechanism induces significant activation of endothelial nitric nitrous oxide synthase (eNOS) and the mitogen-activated protein kinase (MAPK) pathway . In rats with symptoms of brain injury, exogenous estrogens increase the extent of damage in females and have protective effects in males . The supply of estrogens has no effect on the size of regional blood flow in ischaemia-intact brain regions. Estrogens are to decide about lower risk of ischaemic sequelae of stroke or injury and their potential vascular effects are to be the first-line defence against the development of severe and irreversible brain changes. Such conclusions can be drawn from experimental studies in various animals. In humans, however, the expected beneficial effects of estrogen therapy have not been observed. The use of repeated doses of estrogens to treat brain oedema
and other consequences of severe craniocerebral injuries or brain stroke can lead to uncontrolled cerebral congestion. The final, often critical effect of exogenous action of estradiol depends on its interaction with other potentially vasodilating factors. Besides increased activity of eNOS, the activation of cyclic guanosine monophosphate (c-GMP), prostacyclin, carbon dioxide and many others, are involved . The study findings prove that estrogens are important for prevention yet not treatment of post-traumatic brain injury. Thus, inefficacy of estrogen therapy in the treatment of post-traumatic intracranial pathologies corresponds to ineffectiveness, or even harmful effects, of steroid therapy .
As far as the role of estrogens in maintaining the stability of brain structures in sickness and in health is concerned, the opinions presented are inconsistent. Opinions about gestagens are much more favourable. Experimental and clinical studies indicate beneficial action of progesterone and its derivatives for prevention and treatment of severe CNS pathologies. Maternik and Walczak [19, 20] have confirmed that progesterone provides protection against excessive transfer of high and medium molecular weight compounds through the brain barrier system. There is a direct relation between the serum concentration of progesterone and brain water content. The higher the serum progesterone concentration, the lower the water content, hence the lower the brain oedema is . Progesterone exerts its protective effects on prevention and treatment of brain oedema indirectly, through its derivative allopregnanolon. This proves complete inefficacy of promegestone in the treatment of brain oedema, as it is not metabolised to allopregnanolon .
The oedema-reducing action of gestagens is indisputable . Under experimental conditions in rats of both genders, the use of progesterone or allopregnanolon within the first hours after post-traumatic brain injury and continuation of therapy for the next several days has positive effects on morphology of injury-endangered nervous cells and on the return of neurological functions, including the earlier acquired behaviour [22, 24]. Thanks to their effects, which stabilise the cell membranes and inhibit lipid peroxidation, progesterone and its derivatives promote the maintenance of brain barrier system, despite the injury sustained, and decrease the extent and progression rate of brain vascular oedema, once the barrier system has been injured [1, 25]. Progesterone, as a free radical scavenger, is also capable of reducing cytotoxic brain oedema . Reduced brain oedema is observed in all animals when progesterone is supplied one hour after experimental head injury. The anti-oedematous effects are increasingly strong during the subsequent days of therapy. Progesterone can reduce the brain oedema even in cases of delayed administration. The study results suggest that progesterone derivatives should be administered to patients with severe brain injuries during the first post-injury day and continued for at least 5 days. This management decreases the risk of sequelae of the first post-traumatic phase of brain oedema and prevents the development of the equally dangerous second phase .
The beneficial effect of progesterone has been confirmed in cases of ischaemic brain injury. Alkayed and co-workers  have reported that progesterone administered in experimental ischaemic cerebral stroke, like estrogens, reduces the extent of changes within the cerebral cortex. Unlike estrogens, progesterone does not exert any positive effects on ischaemic lesions within the sub-cortical centres. Another relevant finding is that progesterone does not change the extent or redistribution of cerebral blood flow.
The destructive changes in the brain caused by the primarily acting injuring factor and secondarily progressing degenerative changes in neurons develop at different times depending on the concentration of gestagens. Thanks to that the therapeutic window for neuroprotective action of progesterone is prolonged in women , encouraging to use progesterone derivatives as the anti-oedematous and CNS protective drugs. The concentration of progesterone in blood serum and brain markedly differs according to gender, age, some physiological states (menstrual cycle, pregnancy) and pathological conditions (strong stress) , which is particularly important in women as the menstrual cycle day during which they have sustained brain injury is likely to be essential for prognosis.
Neuroprotective effects of progesterone and its derivatives have been successively confirmed in all the studies carried out. Some reports regarding estrogens praise them, some are more balanced and some definitely critical. The literature review shows that wide neuroprotective effects of estrogens have been mainly confirmed in experimental animal studies and in cell models. In human studies, neuroprotection of estrogens has not been confirmed.
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