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Are gonadal steroid hormones involved in disorders of brain aging?

Are gonadal steroid hormones involved in disorders of brain aging? <h1>Introduction: gonadal steroids are trophic factors for the brain</h1> Decreasing levels of sex hormones with age are associated with the progression of neurodegenerative disorders, increased depressive symptoms and other psychological disturbances ( Fillit et al ., 1986 ; Paganini-Hill, 1995 ; Paganini-Hill & Henderson, 1996 ; Yaffe et al ., 1998 ; Costa et al ., 1999 ; Saunders-Pullman et al ., 1999 ; Sherwin, 1999 ; Wolf et al ., 1999 ; Hogervorst et al ., 2000 ; Resnick & Maki, 2001 ). This suggests that the decrease in sex steroids with aging may have a negative impact on brain function. Therefore, it has been proposed that gonadal steroid hormone replacement therapies may ameliorate the loss of brain function in old age ( Costa et al ., 1999 ; Hogervorst et al ., 2000 ; Tsang et al ., 2000 ; Resnick & Maki, 2001 ). This proposition is supported by extensive evidence from animal studies indicating that sex steroids are neuroprotective ( Green & Simpkins, 2000 ; Garcia-Segura et al ., 2001 ; Lee & McEwen, 2001 ; Wise et al ., 2001 ). Sex steroids regulate the development of brain areas involved in the control of neuroendocrine function and behaviours related to reproduction, inducing structural and functional sex differences in brain tissue ( Breedlove & Arnold, 1983 ; Arnold & Gorski, 1984 ). In addition, it is well established that sex steroids act on the mature brain to acutely regulate the hypothalamo-pituitary gonadal axis and reproductive behaviour ( Olmos et al ., 1989 ; Gomez & Newman, 1991 ; Naftolin et al ., 1996 ; Russell et al ., 2001 ; Swaab et al ., 2001 ). However, in recent years, there has been an exponential increase in the accumulation of experimental data supporting the idea that sex steroids also act in brain areas that are not considered to be involved in the control of neuroendocrine events or sexual behaviour ( Chowen et al ., 2000 ; Woolley & McEwen, 1992 ). At the same time, a new view of sex steroids as trophic factors for neurones and glial cells has emerged ( Toran-Allerand et al ., 1999 ). Acting via sex steroid receptors and other more recently discovered pathways, these hormones are able to regulate gene expression, neuronal survival and neuronal differentiation in the brain in a way that is not very different from that exerted by neurotrophins and classical growth factors ( Azcoitia et al ., 1999 ; Bi et al ., 2000 ). Receptors for the sex hormones estradiol, progesterone and testosterone are nuclear transcription factors that regulate the expression of specific genes. These receptors are expressed in different brain areas primarily, but not exclusively, in neurones (e.g. DonCarlos et al ., 1989, 1991 ; Simerly, 1993 ; Shughrue et al ., 1997 ; McAbee & DonCarlos, 1998 ; Greco et al ., 2001 ). In addition, sex steroids acting in the brain are able to activate, as in other tissues, the same signalling pathways of tyrosine kinase receptors used by neurotrophin receptors and insulin-like growth factor I receptor ( Moss & Gu, 1999 ; Singh et al ., 1999 ; Toran-Allerand et al ., 1999 ; Bi et al ., 2000 ; Garcia-Segura et al ., 2000 ). The mechanisms involved in the rapid activation by sex steroids of these membrane-associated signalling pathways, as well as those involved in rapid changes in intracellular calcium levels ( Mermelstein et al ., 1996 ; Pozzo-Miller et al ., 1999 ), remain to be elucidated. Progesterone and reduced progesterone metabolites interact with neurotransmitter receptors and may exert rapid actions in the brain by acting as neuromodulators of these classical neurotransmitters ( Majewska et al ., 1986 ; Majewska et al ., 1988 ; Rupprecht et al ., 2001 ). Estradiol may directly inhibit NMDA receptor function ( Weaver et al ., 1997 ). Other rapid actions of sex steroids in the brain may be associated with membrane forms of the sex steroid receptors or with transient association of classical sex steroid receptors with specific membrane compartments ( Pietras et al ., 2001 ; Ramirez et al ., 2001 ; Watson et al ., 2002 ). Synaptosomal mitochondria have been shown to bind estradiol ( Horvat et al ., 2001 ), as does a mitochondrial ATP synthase in the rat brain ( Zheng & Ramirez, 1999 ), and estradiol modifies mitochondrial calcium efflux in the brain ( Horvat et al ., 2001 ), providing another route for sex steroids to modify cellular homeostasis and function. <h1>Sex steroids prevent neuronal death and promote neural regeneration</h1> Experimental data in animal models provide convincing evidence of the neuroprotective properties of sex steroids. Estradiol has been shown to protect brain neurones in vivo and in vitro from a large variety of stressors, neurotoxins and deleterious conditions, including serum or growth factor deprivation, anoxia, excitotoxicity and oxidative damage ( Green & Simpkins, 2000 ; Garcia-Segura et al ., 2001 ; Lee & McEwen, 2001 ; Wise et al ., 2001 ). Estradiol and progesterone are also neuroprotective in experimental models of Parkinson's disease and forebrain ischaemia ( Grandbois et al ., 2000 ; Leranth et al ., 2000 ; Sawada et al ., 2000 ; Wise & Dubal, 2000 ; Stein, 2001 ). A well-documented body of literature shows that testosterone is neuroprotective for motoneurones ( Breedlove & Arnold, 1983 ; Nordeen et al ., 1985 ) and promotes neural regeneration ( Jones et al ., 2001 ). Finally, progesterone has been shown to promote peripheral nerve remyelination and regeneration ( Schumacher et al ., 2001 ). <h1>Synthesis and metabolism of sex steroids by neural tissue: neuroprotective properties</h1> Sex hormones are not produced exclusively in the gonads; among other tissues, the brain has the capacity to synthesize and metabolize sex hormones. Steroids synthesized in the brain directly from cholesterol include gonadal steroids, such as progesterone, and sex steroid metabolites ( Mellon et al ., 2001 ). Some of these steroids act as neuromodulators, regulating the function of ion channels and neurotransmitter receptors, and some are potent antidepressive agents ( Baulieu et al ., 2001 ). Sex steroid synthesis and metabolism by the nervous system may play an important role in the maintenance of neural function and the protection of neural tissue from injury. Dehydroepiandrosterone, a precursor of testosterone and estradiol, is synthesized by glial cells, is neuroprotective and prevents age-associated memory deficits in rodents ( Lapchak et al ., 2000 ; Vallee et al ., 2001 ). In addition, different forms of brain lesion result in induction, in the injured tissue, of the enzyme aromatase, which catalyses the formation of estradiol from testosterone. The enzyme is induced in reactive astrocytes located near neurodegenerative foci and this induction is accompanied by an increased capacity of the injured brain to synthesize oestrogen ( Garcia-Segura et al ., 1999 ). Studies using specific aromatase inhibitors infused in the rat brain, as well as aromatase knock out mice combined with oestrogen replacement, indicate that the induction of brain aromatase after a brain lesion is neuroprotective and reduces neuronal death. Furthermore, it has been shown that this neuroprotective effect of aromatase is specifically mediated by the formation of estradiol ( Azcoitia et al ., 2001 ). Progesterone synthesis and metabolism by the central and peripheral nervous system may also play an important role in neural regeneration. Schwann cells, the glial cells of peripheral nerves, produce and metabolize progesterone into 5-pregnan-3,20-dione (dihydroprogesterone, DHP) ( Melcangi et al ., 1999 ). Progesterone and DHP promote remyelination of the sciatic nerve in young adult rats after injury and increase the expression of myelin proteins such as Po ( Melcangi et al ., 1999 ). Interestingly, in aged rats, where there is a process of demyelination and a decrease in Po expression in the sciatic nerve, progesterone was only mildly effective in increasing Po expression while DHP significantly reversed the age-related deficit in Po ( Melcangi et al ., 2000 ). The different effect of progesterone in young and aged rats may be due to the fact that the activity of 5alpha-reductase, the enzyme that transforms progesterone into DHP, is significantly decreased in the sciatic nerve during aging ( Melcangi et al ., 1998 ). This indicates that progesterone synthesis by Schwann cells and the subsequent metabolism into DHP are protective for the peripheral nerve and that a decreased metabolism of progesterone in the aged nerve may impair remyelination. Therefore, the decreased progesterone metabolism with age may result in increased myelin deficits. <h1>Does gonadal steroid hormone exposure during development alter susceptibility to the degenerative diseases of aging?</h1> Steroid hormone exposure during development alters the neural circuitry of the brain ( Arnold & Gorski, 1984 ; Watson et al ., 1986 ; Matsumoto, 1991 ; Diaz et al ., 1992 ; Lewis et al ., 1995 ; Hutton et al ., 1998 ; Mong et al ., 2001 ). As mentioned above, these effects are not limited to the brain regions that underlie reproduction, but occur in areas involved in cognition, autonomic function and sensorimotor function as well. Among the best documented effects of the sex steroids on developing brain architecture are those related to cell survival and neurite outgrowth. For example, males have more neurones in the visual cortex than do females, and these effects are dependent on exposure to androgens during development ( Nunez et al ., 2000 ). Therefore, it is possible that some of the sex differences observed in the frequency of neurodegenerative diseases are due to an initial sex difference in the numbers of cells or their connectivity within a given region exposed to insult. Maternal infections, either bacterial or viral, during gestation may damage developing neurones in the fetus and alter brain susceptibility to later neurodegenerative diseases, such as Parkinson's or schizophrenia ( Mattock et al ., 1988 ; Mori & Kimura, 2001 ; Borrell et al ., 2002 ). Exposure to the protective effects of steroid hormones, in utero , could partially prevent the damage induced by these infections and may represent an as yet unappreciated source of gender differences in the disorders of brain aging that is independent of sex differences in circulating gonadal steroids in adulthood. The potential relationship between sex hormone exposure during development and susceptibility to damage in brain aging has received little attention to date. <h1>Does aging affect human brain responsiveness to sex steroids?</h1> While the basic studies on animals clearly indicate that sex steroids are neuroprotective, the situation is not so clear when information collected from human studies is analysed. The effect of different steroid replacement therapies has been assessed in men and women. Some studies using the sex steroid precursor dehydroepiandrosterone (DHEA) suggest that this steroid may improve cognition and promote a sense of well-being in normal older men and women, although other studies do not support this conclusion ( Morales et al ., 1994 ; Baulieu et al ., 2000 ; van Niekerk et al ., 2001 ). However, the principal source of information available on the effects of sex steroids in the brain of aged humans has come from studies in which the effect of hormonal replacement therapy (HRT) in post-menopausal women has been analysed ( Saunders-Pullman et al ., 1999 ; Sherwin, 1999 ; Hogervorst et al ., 2000 ; Mulnard et al ., 2000 ; Resnick & Maki, 2001 ). HRT is used to decrease some of the symptoms associated with menopause ( Paganini-Hill, 1995 ) and seems to increase cognitive function in post-menopausal women ( Sherwin, 1999 ; Resnick & Maki, 2001 ). For example, in the Baltimore Longitudinal Study of Aging, non-demented post-menopausal women receiving hormone therapy performed better on tests of verbal and visual memory compared with never-treated women in samples in which both groups of women were comparable with respect to educational attainment, general medical health and performance on a test of verbal knowledge ( Resnick & Maki, 2001 ). HRT may also be an effective treatment of depression for perimenopausal women ( Birkhauser, 2002 ), and in post-menopausal women may reduce negative symptoms in schizophrenia ( Stevens, 2002 ), decrease the risk of stroke ( Paganini-Hill, 1995 ), reduce the motor disability associated with Parkinson's disease ( Cyr et al ., 2002 ) and improve cognition in Alzheimer's disease ( Henderson et al ., 2000 ). However, the evidence for a protective effect of oestrogen in the human brain is not without controversy. Indeed, several studies show that oestrogen replacement therapy has no positive effect for neurodegenerative diseases or stroke and other studies suggest that HRT may have a negative impact on cognition in post-menopausal women with Alzheimer's disease ( Shaywitz & Shaywitz, 2000 ). Therefore, there is an apparent discrepancy between the potent neuroprotective effect of sex steroids in animal models and the high variability of results in human studies, and the question as to the source of these discrepancies naturally arises. One potential source for the discrepancies in the literature is that there is a considerable variation in the exact hormonal composition and pattern of administration in HRT in humans. Usually, a mixture of different natural or synthetic oestrogens and natural progestins is administered. Different hormonal compositions and differences in the age of onset and duration of the treatment may alter the effects of HRT on the human brain. However, there are other possible explanations for the different effects of sex steroids in the brains of experimental animals and in the brains of aged humans. Most studies in animal models use young adult rodents submitted to different forms of brain injury. Very little is known about the effects of sex steroids in the brain of old animals. As mentioned above, the decreased capacity of the aged peripheral nervous tissue to metabolize progesterone may lead to a loss of the protective effect of this steroid in the peripheral nerves of aged rats ( Melcangi et al ., 1999 ). A similar situation may occur in the central nervous system. In addition, neuroprotective effects of sex steroids that depend on the activation of their nuclear receptors may be impaired in the aged brain, because aging may affect the expression of steroid receptors and steroid receptor coactivators ( Jezierski & Sohrabji, 2001 ; Matsumoto & Prins, 2002 ). Therefore, sex steroid receptor signalling may be very different in young and old brains and in consequence the effects of sex steroids in the brain of young animals may not be predictive of the effects of the same molecules in aged brains. A further complication in interpreting clinical studies is that specific allelic variants or mutations of gonadal steroid hormone receptors may cause or confer increased risk for neurodegenerative disorders. For example, the frequency of specific oestrogen receptor alpha gene polymorphisms is higher in women with dementia ( Isoe-Wada et al ., 1999 ; Mattila et al ., 2000 ). Moreover, the risk of Alzheimer's disease has been calculated to be seven-fold greater in individuals that are homozygous for both the apolipoprotein E allele, apoE epsilon 4, and the oestrogen receptor alpha allelle ERα PPXX ( Brandi et al ., 1999 ; Isoe-Wada et al ., 1999 ). A classic example of a neurodegenerative disease that is caused by a variant form of steroid receptor is spinal and bulbar muscular atrophy, in which a CAG repeat expansion in the androgen receptor gene ultimately results in the death of motor neurones ( Merry, 2001 ; Piccioni et al ., 2001 ). Other, as yet unknown, genetically based alterations in steroid hormone sensitivity may contribute in subtle ways to a higher risk of neurodegenerative disorders associated with aging. In addition to alterations in steroid receptor expression and signalling, there is at least one other good reason to explain why neuroprotective effects of sex steroids may be reduced in the aged brain; other substances necessary for the effects of sex steroids may also be depleted by aging. These may include growth factors, neuromodulators, neurotransmitters and their receptors. For example, Forger and colleagues ( Xu et al ., 2001 ) have recently shown that the induction of motoneurone cell survival by testosterone in the developing spinal nucleus of the bulbocavernosus (SNB) of rats is prevented by an acute blockade of the neurotrophin receptors trkB and trkC as well as by the blockade of the ciliary neurotrophic factor receptor-alpha. These findings indicate that endogenously produced trophic factors are necessary for the effect of testosterone on neuronal survival, at least during development. A similar situation may happen in the old brain. Another growth factor involved in the actions of sex steroids is insulin-like growth factor-I (IGF-I). Evidence has accumulated to support the idea that the actions of oestrogen and IGF-I in the brain are interdependent. This interdependence between oestrogen and IGF-I, or between oestrogen receptors and IGF-I receptors, has been documented for neuronal differentiation, synaptic plasticity and neuroprotection ( Cardona-Gomez et al ., 2001 ). Plasma levels of IGF-I decrease with aging and treatment of old rats with IGF-I ameliorates several age-related deficits in the brain ( Lichtenwalner et al ., 2001 ; Lynch et al ., 2001 ). Since brain IGF-I and IGF-I receptor levels are affected by aging ( Sonntag et al ., 1999 ), the effect of oestrogen receptor activation may be very different in young and old brains because aging decreases availability of this key synergist. The limited evidence available suggests that, at least in rodents, sex steroids are still neuroprotective in the aging brain. Sex steroids, and their precursors pregnenolone and DHEA, decrease age-related memory deficits in rodents ( Vallee et al ., 2001 ). In addition, motoneurones of aged male rats retain synaptic plasticity in response to androgens ( Matsumoto, 2001 ). Furthermore, it has been shown that estradiol protects the brain of middle-aged rats (9–12 months) from middle cerebral artery occlusion ( Dubal & Wise, 2001 ). However, other studies suggest that synaptic plasticity in response to oestrogen is abolished in the brain of old rats ( Adams et al ., 2001 ). It is clear that we need more studies to determine to what extent sex steroids are neuroprotective in young vs. old animals. <h1>Opportunities for therapeutic intervention: hormone replacement and beyond</h1> We are still a long way from being able to design rational protocols for HRT to protect the brain from aging. More studies to understand the mechanisms of the action of sex steroids in the aging brain are necessary. We need more information on the interaction of sex steroids with other neuronal survival factors that are affected by the aging process. Moreover, it is not yet clear whether HRT is protective for some types of damage but deleterious in the case of other types of brain insult. Alternative strategies to HRT that may be clinically more effective can be experimentally tested. For instance, it may be useful to exploit the endogenous capacity of the brain to synthesize sex steroids. Possible targets for therapeutic approaches are the proteins that participate in the transport of cholesterol from the cytoplasm to the inner mitochondrial membrane. Cholesterol is converted to pregnenolone in the mitochondria and then pregnenolone is converted to DHEA or progesterone in the endoplasmic reticulum. The transport of cholesterol to the inner mitochondrial membrane is the rate-limiting step for sex steroid synthesis and is highly regulated. Two proteins located in the mitochondrial membrane, the steroidogenic acute regulatory protein (StAR) ( Stocco, 2001 ) and the peripheral-type benzodiazepine receptor (PBR) ( Lacor et al ., 1999 ), are involved in this transport and may represent good candidates for pharmacological treatments to increase steroid synthesis in the aging brain. Other proteins of potential therapeutic interest are the enzymes responsible for sex steroid formation and metabolism, such as 5α-reductase and aromatase. We need more information on the levels of expression of these enzymes in the aged human brain, since a potential mechanism to locally increase sex steroid levels in the brain is to change the expression or the activity of these enzymes specifically in the nervous system. For instance, the aromatase gene is under the control of different tissue-specific promoters ( Honda et al ., 1999 ), and it is conceivable that it will be possible to develop specific selective aromatase modulators that will enhance the expression of this enzyme in the brain but not in other tissues. Finally, other potential candidates for pharmacological targeting are the sex hormone receptors. Selective modulators for androgen and oestrogen receptors are under development. Before the therapeutic use of these drugs as neuroprotectants is considered, it is essential to learn much more about the expression and regulation of sex steroid receptors and their cofactors in the aging brain and also about the impact of aging on the convergence of sex steroid receptor signalling with other signalling pathways. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aging Cell Wiley

Are gonadal steroid hormones involved in disorders of brain aging?

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Publisher
Wiley
Copyright
© Anatomical Society of Great Britain and Ireland 2003
ISSN
1474-9718
eISSN
1474-9726
DOI
10.1046/j.1474-9728.2003.00013.x
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12882332
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Abstract

<h1>Introduction: gonadal steroids are trophic factors for the brain</h1> Decreasing levels of sex hormones with age are associated with the progression of neurodegenerative disorders, increased depressive symptoms and other psychological disturbances ( Fillit et al ., 1986 ; Paganini-Hill, 1995 ; Paganini-Hill & Henderson, 1996 ; Yaffe et al ., 1998 ; Costa et al ., 1999 ; Saunders-Pullman et al ., 1999 ; Sherwin, 1999 ; Wolf et al ., 1999 ; Hogervorst et al ., 2000 ; Resnick & Maki, 2001 ). This suggests that the decrease in sex steroids with aging may have a negative impact on brain function. Therefore, it has been proposed that gonadal steroid hormone replacement therapies may ameliorate the loss of brain function in old age ( Costa et al ., 1999 ; Hogervorst et al ., 2000 ; Tsang et al ., 2000 ; Resnick & Maki, 2001 ). This proposition is supported by extensive evidence from animal studies indicating that sex steroids are neuroprotective ( Green & Simpkins, 2000 ; Garcia-Segura et al ., 2001 ; Lee & McEwen, 2001 ; Wise et al ., 2001 ). Sex steroids regulate the development of brain areas involved in the control of neuroendocrine function and behaviours related to reproduction, inducing structural and functional sex differences in brain tissue ( Breedlove & Arnold, 1983 ; Arnold & Gorski, 1984 ). In addition, it is well established that sex steroids act on the mature brain to acutely regulate the hypothalamo-pituitary gonadal axis and reproductive behaviour ( Olmos et al ., 1989 ; Gomez & Newman, 1991 ; Naftolin et al ., 1996 ; Russell et al ., 2001 ; Swaab et al ., 2001 ). However, in recent years, there has been an exponential increase in the accumulation of experimental data supporting the idea that sex steroids also act in brain areas that are not considered to be involved in the control of neuroendocrine events or sexual behaviour ( Chowen et al ., 2000 ; Woolley & McEwen, 1992 ). At the same time, a new view of sex steroids as trophic factors for neurones and glial cells has emerged ( Toran-Allerand et al ., 1999 ). Acting via sex steroid receptors and other more recently discovered pathways, these hormones are able to regulate gene expression, neuronal survival and neuronal differentiation in the brain in a way that is not very different from that exerted by neurotrophins and classical growth factors ( Azcoitia et al ., 1999 ; Bi et al ., 2000 ). Receptors for the sex hormones estradiol, progesterone and testosterone are nuclear transcription factors that regulate the expression of specific genes. These receptors are expressed in different brain areas primarily, but not exclusively, in neurones (e.g. DonCarlos et al ., 1989, 1991 ; Simerly, 1993 ; Shughrue et al ., 1997 ; McAbee & DonCarlos, 1998 ; Greco et al ., 2001 ). In addition, sex steroids acting in the brain are able to activate, as in other tissues, the same signalling pathways of tyrosine kinase receptors used by neurotrophin receptors and insulin-like growth factor I receptor ( Moss & Gu, 1999 ; Singh et al ., 1999 ; Toran-Allerand et al ., 1999 ; Bi et al ., 2000 ; Garcia-Segura et al ., 2000 ). The mechanisms involved in the rapid activation by sex steroids of these membrane-associated signalling pathways, as well as those involved in rapid changes in intracellular calcium levels ( Mermelstein et al ., 1996 ; Pozzo-Miller et al ., 1999 ), remain to be elucidated. Progesterone and reduced progesterone metabolites interact with neurotransmitter receptors and may exert rapid actions in the brain by acting as neuromodulators of these classical neurotransmitters ( Majewska et al ., 1986 ; Majewska et al ., 1988 ; Rupprecht et al ., 2001 ). Estradiol may directly inhibit NMDA receptor function ( Weaver et al ., 1997 ). Other rapid actions of sex steroids in the brain may be associated with membrane forms of the sex steroid receptors or with transient association of classical sex steroid receptors with specific membrane compartments ( Pietras et al ., 2001 ; Ramirez et al ., 2001 ; Watson et al ., 2002 ). Synaptosomal mitochondria have been shown to bind estradiol ( Horvat et al ., 2001 ), as does a mitochondrial ATP synthase in the rat brain ( Zheng & Ramirez, 1999 ), and estradiol modifies mitochondrial calcium efflux in the brain ( Horvat et al ., 2001 ), providing another route for sex steroids to modify cellular homeostasis and function. <h1>Sex steroids prevent neuronal death and promote neural regeneration</h1> Experimental data in animal models provide convincing evidence of the neuroprotective properties of sex steroids. Estradiol has been shown to protect brain neurones in vivo and in vitro from a large variety of stressors, neurotoxins and deleterious conditions, including serum or growth factor deprivation, anoxia, excitotoxicity and oxidative damage ( Green & Simpkins, 2000 ; Garcia-Segura et al ., 2001 ; Lee & McEwen, 2001 ; Wise et al ., 2001 ). Estradiol and progesterone are also neuroprotective in experimental models of Parkinson's disease and forebrain ischaemia ( Grandbois et al ., 2000 ; Leranth et al ., 2000 ; Sawada et al ., 2000 ; Wise & Dubal, 2000 ; Stein, 2001 ). A well-documented body of literature shows that testosterone is neuroprotective for motoneurones ( Breedlove & Arnold, 1983 ; Nordeen et al ., 1985 ) and promotes neural regeneration ( Jones et al ., 2001 ). Finally, progesterone has been shown to promote peripheral nerve remyelination and regeneration ( Schumacher et al ., 2001 ). <h1>Synthesis and metabolism of sex steroids by neural tissue: neuroprotective properties</h1> Sex hormones are not produced exclusively in the gonads; among other tissues, the brain has the capacity to synthesize and metabolize sex hormones. Steroids synthesized in the brain directly from cholesterol include gonadal steroids, such as progesterone, and sex steroid metabolites ( Mellon et al ., 2001 ). Some of these steroids act as neuromodulators, regulating the function of ion channels and neurotransmitter receptors, and some are potent antidepressive agents ( Baulieu et al ., 2001 ). Sex steroid synthesis and metabolism by the nervous system may play an important role in the maintenance of neural function and the protection of neural tissue from injury. Dehydroepiandrosterone, a precursor of testosterone and estradiol, is synthesized by glial cells, is neuroprotective and prevents age-associated memory deficits in rodents ( Lapchak et al ., 2000 ; Vallee et al ., 2001 ). In addition, different forms of brain lesion result in induction, in the injured tissue, of the enzyme aromatase, which catalyses the formation of estradiol from testosterone. The enzyme is induced in reactive astrocytes located near neurodegenerative foci and this induction is accompanied by an increased capacity of the injured brain to synthesize oestrogen ( Garcia-Segura et al ., 1999 ). Studies using specific aromatase inhibitors infused in the rat brain, as well as aromatase knock out mice combined with oestrogen replacement, indicate that the induction of brain aromatase after a brain lesion is neuroprotective and reduces neuronal death. Furthermore, it has been shown that this neuroprotective effect of aromatase is specifically mediated by the formation of estradiol ( Azcoitia et al ., 2001 ). Progesterone synthesis and metabolism by the central and peripheral nervous system may also play an important role in neural regeneration. Schwann cells, the glial cells of peripheral nerves, produce and metabolize progesterone into 5-pregnan-3,20-dione (dihydroprogesterone, DHP) ( Melcangi et al ., 1999 ). Progesterone and DHP promote remyelination of the sciatic nerve in young adult rats after injury and increase the expression of myelin proteins such as Po ( Melcangi et al ., 1999 ). Interestingly, in aged rats, where there is a process of demyelination and a decrease in Po expression in the sciatic nerve, progesterone was only mildly effective in increasing Po expression while DHP significantly reversed the age-related deficit in Po ( Melcangi et al ., 2000 ). The different effect of progesterone in young and aged rats may be due to the fact that the activity of 5alpha-reductase, the enzyme that transforms progesterone into DHP, is significantly decreased in the sciatic nerve during aging ( Melcangi et al ., 1998 ). This indicates that progesterone synthesis by Schwann cells and the subsequent metabolism into DHP are protective for the peripheral nerve and that a decreased metabolism of progesterone in the aged nerve may impair remyelination. Therefore, the decreased progesterone metabolism with age may result in increased myelin deficits. <h1>Does gonadal steroid hormone exposure during development alter susceptibility to the degenerative diseases of aging?</h1> Steroid hormone exposure during development alters the neural circuitry of the brain ( Arnold & Gorski, 1984 ; Watson et al ., 1986 ; Matsumoto, 1991 ; Diaz et al ., 1992 ; Lewis et al ., 1995 ; Hutton et al ., 1998 ; Mong et al ., 2001 ). As mentioned above, these effects are not limited to the brain regions that underlie reproduction, but occur in areas involved in cognition, autonomic function and sensorimotor function as well. Among the best documented effects of the sex steroids on developing brain architecture are those related to cell survival and neurite outgrowth. For example, males have more neurones in the visual cortex than do females, and these effects are dependent on exposure to androgens during development ( Nunez et al ., 2000 ). Therefore, it is possible that some of the sex differences observed in the frequency of neurodegenerative diseases are due to an initial sex difference in the numbers of cells or their connectivity within a given region exposed to insult. Maternal infections, either bacterial or viral, during gestation may damage developing neurones in the fetus and alter brain susceptibility to later neurodegenerative diseases, such as Parkinson's or schizophrenia ( Mattock et al ., 1988 ; Mori & Kimura, 2001 ; Borrell et al ., 2002 ). Exposure to the protective effects of steroid hormones, in utero , could partially prevent the damage induced by these infections and may represent an as yet unappreciated source of gender differences in the disorders of brain aging that is independent of sex differences in circulating gonadal steroids in adulthood. The potential relationship between sex hormone exposure during development and susceptibility to damage in brain aging has received little attention to date. <h1>Does aging affect human brain responsiveness to sex steroids?</h1> While the basic studies on animals clearly indicate that sex steroids are neuroprotective, the situation is not so clear when information collected from human studies is analysed. The effect of different steroid replacement therapies has been assessed in men and women. Some studies using the sex steroid precursor dehydroepiandrosterone (DHEA) suggest that this steroid may improve cognition and promote a sense of well-being in normal older men and women, although other studies do not support this conclusion ( Morales et al ., 1994 ; Baulieu et al ., 2000 ; van Niekerk et al ., 2001 ). However, the principal source of information available on the effects of sex steroids in the brain of aged humans has come from studies in which the effect of hormonal replacement therapy (HRT) in post-menopausal women has been analysed ( Saunders-Pullman et al ., 1999 ; Sherwin, 1999 ; Hogervorst et al ., 2000 ; Mulnard et al ., 2000 ; Resnick & Maki, 2001 ). HRT is used to decrease some of the symptoms associated with menopause ( Paganini-Hill, 1995 ) and seems to increase cognitive function in post-menopausal women ( Sherwin, 1999 ; Resnick & Maki, 2001 ). For example, in the Baltimore Longitudinal Study of Aging, non-demented post-menopausal women receiving hormone therapy performed better on tests of verbal and visual memory compared with never-treated women in samples in which both groups of women were comparable with respect to educational attainment, general medical health and performance on a test of verbal knowledge ( Resnick & Maki, 2001 ). HRT may also be an effective treatment of depression for perimenopausal women ( Birkhauser, 2002 ), and in post-menopausal women may reduce negative symptoms in schizophrenia ( Stevens, 2002 ), decrease the risk of stroke ( Paganini-Hill, 1995 ), reduce the motor disability associated with Parkinson's disease ( Cyr et al ., 2002 ) and improve cognition in Alzheimer's disease ( Henderson et al ., 2000 ). However, the evidence for a protective effect of oestrogen in the human brain is not without controversy. Indeed, several studies show that oestrogen replacement therapy has no positive effect for neurodegenerative diseases or stroke and other studies suggest that HRT may have a negative impact on cognition in post-menopausal women with Alzheimer's disease ( Shaywitz & Shaywitz, 2000 ). Therefore, there is an apparent discrepancy between the potent neuroprotective effect of sex steroids in animal models and the high variability of results in human studies, and the question as to the source of these discrepancies naturally arises. One potential source for the discrepancies in the literature is that there is a considerable variation in the exact hormonal composition and pattern of administration in HRT in humans. Usually, a mixture of different natural or synthetic oestrogens and natural progestins is administered. Different hormonal compositions and differences in the age of onset and duration of the treatment may alter the effects of HRT on the human brain. However, there are other possible explanations for the different effects of sex steroids in the brains of experimental animals and in the brains of aged humans. Most studies in animal models use young adult rodents submitted to different forms of brain injury. Very little is known about the effects of sex steroids in the brain of old animals. As mentioned above, the decreased capacity of the aged peripheral nervous tissue to metabolize progesterone may lead to a loss of the protective effect of this steroid in the peripheral nerves of aged rats ( Melcangi et al ., 1999 ). A similar situation may occur in the central nervous system. In addition, neuroprotective effects of sex steroids that depend on the activation of their nuclear receptors may be impaired in the aged brain, because aging may affect the expression of steroid receptors and steroid receptor coactivators ( Jezierski & Sohrabji, 2001 ; Matsumoto & Prins, 2002 ). Therefore, sex steroid receptor signalling may be very different in young and old brains and in consequence the effects of sex steroids in the brain of young animals may not be predictive of the effects of the same molecules in aged brains. A further complication in interpreting clinical studies is that specific allelic variants or mutations of gonadal steroid hormone receptors may cause or confer increased risk for neurodegenerative disorders. For example, the frequency of specific oestrogen receptor alpha gene polymorphisms is higher in women with dementia ( Isoe-Wada et al ., 1999 ; Mattila et al ., 2000 ). Moreover, the risk of Alzheimer's disease has been calculated to be seven-fold greater in individuals that are homozygous for both the apolipoprotein E allele, apoE epsilon 4, and the oestrogen receptor alpha allelle ERα PPXX ( Brandi et al ., 1999 ; Isoe-Wada et al ., 1999 ). A classic example of a neurodegenerative disease that is caused by a variant form of steroid receptor is spinal and bulbar muscular atrophy, in which a CAG repeat expansion in the androgen receptor gene ultimately results in the death of motor neurones ( Merry, 2001 ; Piccioni et al ., 2001 ). Other, as yet unknown, genetically based alterations in steroid hormone sensitivity may contribute in subtle ways to a higher risk of neurodegenerative disorders associated with aging. In addition to alterations in steroid receptor expression and signalling, there is at least one other good reason to explain why neuroprotective effects of sex steroids may be reduced in the aged brain; other substances necessary for the effects of sex steroids may also be depleted by aging. These may include growth factors, neuromodulators, neurotransmitters and their receptors. For example, Forger and colleagues ( Xu et al ., 2001 ) have recently shown that the induction of motoneurone cell survival by testosterone in the developing spinal nucleus of the bulbocavernosus (SNB) of rats is prevented by an acute blockade of the neurotrophin receptors trkB and trkC as well as by the blockade of the ciliary neurotrophic factor receptor-alpha. These findings indicate that endogenously produced trophic factors are necessary for the effect of testosterone on neuronal survival, at least during development. A similar situation may happen in the old brain. Another growth factor involved in the actions of sex steroids is insulin-like growth factor-I (IGF-I). Evidence has accumulated to support the idea that the actions of oestrogen and IGF-I in the brain are interdependent. This interdependence between oestrogen and IGF-I, or between oestrogen receptors and IGF-I receptors, has been documented for neuronal differentiation, synaptic plasticity and neuroprotection ( Cardona-Gomez et al ., 2001 ). Plasma levels of IGF-I decrease with aging and treatment of old rats with IGF-I ameliorates several age-related deficits in the brain ( Lichtenwalner et al ., 2001 ; Lynch et al ., 2001 ). Since brain IGF-I and IGF-I receptor levels are affected by aging ( Sonntag et al ., 1999 ), the effect of oestrogen receptor activation may be very different in young and old brains because aging decreases availability of this key synergist. The limited evidence available suggests that, at least in rodents, sex steroids are still neuroprotective in the aging brain. Sex steroids, and their precursors pregnenolone and DHEA, decrease age-related memory deficits in rodents ( Vallee et al ., 2001 ). In addition, motoneurones of aged male rats retain synaptic plasticity in response to androgens ( Matsumoto, 2001 ). Furthermore, it has been shown that estradiol protects the brain of middle-aged rats (9–12 months) from middle cerebral artery occlusion ( Dubal & Wise, 2001 ). However, other studies suggest that synaptic plasticity in response to oestrogen is abolished in the brain of old rats ( Adams et al ., 2001 ). It is clear that we need more studies to determine to what extent sex steroids are neuroprotective in young vs. old animals. <h1>Opportunities for therapeutic intervention: hormone replacement and beyond</h1> We are still a long way from being able to design rational protocols for HRT to protect the brain from aging. More studies to understand the mechanisms of the action of sex steroids in the aging brain are necessary. We need more information on the interaction of sex steroids with other neuronal survival factors that are affected by the aging process. Moreover, it is not yet clear whether HRT is protective for some types of damage but deleterious in the case of other types of brain insult. Alternative strategies to HRT that may be clinically more effective can be experimentally tested. For instance, it may be useful to exploit the endogenous capacity of the brain to synthesize sex steroids. Possible targets for therapeutic approaches are the proteins that participate in the transport of cholesterol from the cytoplasm to the inner mitochondrial membrane. Cholesterol is converted to pregnenolone in the mitochondria and then pregnenolone is converted to DHEA or progesterone in the endoplasmic reticulum. The transport of cholesterol to the inner mitochondrial membrane is the rate-limiting step for sex steroid synthesis and is highly regulated. Two proteins located in the mitochondrial membrane, the steroidogenic acute regulatory protein (StAR) ( Stocco, 2001 ) and the peripheral-type benzodiazepine receptor (PBR) ( Lacor et al ., 1999 ), are involved in this transport and may represent good candidates for pharmacological treatments to increase steroid synthesis in the aging brain. Other proteins of potential therapeutic interest are the enzymes responsible for sex steroid formation and metabolism, such as 5α-reductase and aromatase. We need more information on the levels of expression of these enzymes in the aged human brain, since a potential mechanism to locally increase sex steroid levels in the brain is to change the expression or the activity of these enzymes specifically in the nervous system. For instance, the aromatase gene is under the control of different tissue-specific promoters ( Honda et al ., 1999 ), and it is conceivable that it will be possible to develop specific selective aromatase modulators that will enhance the expression of this enzyme in the brain but not in other tissues. Finally, other potential candidates for pharmacological targeting are the sex hormone receptors. Selective modulators for androgen and oestrogen receptors are under development. Before the therapeutic use of these drugs as neuroprotectants is considered, it is essential to learn much more about the expression and regulation of sex steroid receptors and their cofactors in the aging brain and also about the impact of aging on the convergence of sex steroid receptor signalling with other signalling pathways.

Journal

Aging Cell – Wiley

Published: Feb 1, 2003

Keywords: estradiol; neurodegenerative diseases; neuroprotection; progesterone; testosterone

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