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Hormonal influence on the central nervous system
Maturitas 43 Suppl. 1 (2002) S11– S17 www.elsevier.com/locate/maturitas
Hormonal influence on the central nervous system Andrea R. Genazzani *, Patrizia Monteleone, Marco Gambacciani Department of Obstetrics and Gynecology, Uni6ersity of Pisa Via Roma 35, 56100 Pisa, Italy
Abstract Sex steroids play a very important role in female neurobiology. Postmenopausal gonadal hormone withdrawal seems to be of critical importance in mood disorders, reduced libido and cognitive disturbances, which accompany this phase of a woman’s life. Clinical studies have demonstrated that central nervous system (CNS) effects of estrogens are not only limited to resolution of vasomotor instability, they are extended to psychological disturbances like depression, behavioral changes and cognitive dysfunction. Progestins, on the other hand, may have variable effects on the brain, occasionally inducing dysphoric mood and altered behavior. Although their use in hormone replacement therapy (HRT) is widely debated, androgens may help resolve changes in libido experienced by many women after the menopause. It is still, however, difficult to draw guidelines on the use of HRT and postmenopausal CNS disorders as studies present up to date have been carried out with different kinds of molecules and routes of administration. Further studies are required in order to explain the specific role of endogenous and exogenous sex steroids on the CNS. © 2002 Published by Elsevier Science Ireland Ltd. Keywords: Sex steroids; Central nervous system; Hormone replacement therapy (HRT)
1. Introduction The role of sex hormones is not limited to the regulation of reproductive function. Estrogen, progesterone and androgen receptors have been identified in numerous regions of the central nervous system (CNS) indicating that sex steroids are of fundamental importance in female neurobiology. The withdrawal in gonadal hormones occurring at menopause determines CNS disorders such as altered mood, reduced libido and cognitive disturbances [1–3]. In the brain, sex steroid hor* Corresponding author. Tel.: + 39-50-553412; fax: + 3950-553410 E-mail address: [email protected] (A.R. Genazzani).
mones exert, like in other target organs, both genomic and non genomic effects [1–3]. Genomic effects consist of inducing long-term activity by activating specific intracellular receptors that modulate neuronal gene transcription and protein synthesis. In particular, gonadal hormones modulate the synthesis, release and metabolism of many neuropeptides and neuroactive transmitters and the expression of their receptors [1–4]. At menopause, as a consequence of the decline in sex hormones, neuroactive transmitters undergo important modifications, leading to specific symptoms secondary to CNS derangement. Hot flushes, sweating, occurring in over 50–70% of postmenopausal women, are consequences of neuroendocrine changes in the hypothalamus [5,6], in
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particular a temporary derangement of the hypothalamic thermoregulatory centers. Moreover, estrogen deficiency increases the noradrenergic tone and decreases dopaminergic activity, which, in turn, cause vasomotor instability. Finally, there are data showing that, in adult rats, castration determines a reduction in b-endorphin (b-EP) content [7]. Similarly, surgical or spontaneous menopause in women is associated with a fall in circulating b-EP [8,9] while vasomotor symptoms are associated to a sudden surges in plasma b-EP levels caused by the activation of hypothalamus– pituitary axis (GnRH, LH, FSH) [10– 12]. Mood changes, anxiety, depression, insomnia, headaches/migraine, alterations of cognitive functions are related to postmenopausal alterations of the limbic system. In postmenopausal women changes in central serotoninergic and noradrenergic activities may explain mood disorders [1]. Menopausal impairment of opioidergic peptide synthesis and secretion also play a role in the modification of mood, behavior and pain perception during this period of a woman’s life [12– 14]. Hormone replacement therapy (HRT), in most cases, is accompanied by restored levels of these neurotransmitters and an improvement in mood, psychological and cognitive disturbances [15].
2. Estrogens and brain Clinical studies have reported a frequent decrease in cognitive efficiency, including memory, in climacteric women [16]. Estrogen administration improves cognitive functions [17– 20] by exerting a positive effect especially on memory and reaction time tests [18,20– 23]. A recent study reports that estrogens seem to be mostly active within the prefrontal cortex, influencing functions dependant on this area of the brain. In particular, it was shown that estrogen users perform better on spatial and verbal memory tasks than nonusers [24]. Estrogens act as cholinergic agonists by inducing synthesis and activation of choline acetyltransferase (ChAT), the rate-limiting enzyme for acetylcholine formation [25– 27]. Moreover, estrogens seem to be important in the maintenance of
cholinergic neurons projecting to the hippocampus and cortex. Estrogen replacement therapy (ERT) can enhance the functional status of these neurons, as well as reduce cognitive deficits associated with muscarinic cholinergic impairment. Similar effects in humans may help delay the decline in basal forebrain cholinergic function associated with aging and Alzheimer’s disease (AD) and thereby reduce the risk and severity of AD-related dementia in postmenopausal women [28]. There are numerous reports on the positive effects of estrogens on mood and behavior in postmenopausal women. Estrogens seem to affect various brain systems by determining changes in local concentrations of neurotransmitters. Estrogens modulate the noradrenergic and dopaminergic systems of the hypothalamus and of extrahypothalamic regions of the brain controlling movement and behavior in both animals and humans. Evidence of the fact that estrogens modulate the cathecolaminergic system emerges from the fact that, in female rats, the rise in estrogen levels at proestrous determines an increase in norepinephrine and dopamine turnover rates [29,30]. When female rats are castrated. cathecolaminergic activity is, on the other hand, impaired, with an increase in noradrenaline release and a decrease in dopamine [29,30]. The exogenous administration of estrogens decreases hypothalamic noradrenaline release, while it increases dopaminergic neuronal activity with a parallel increase in dopamine release in the medio-basal hypothalamus [30]. In an animal model, estradiol enhances noradrenaline release, leading to an increased excitability of ventromedial hypothalamus neuronal activity and expression of lordosis behavior [30]. In vitro studies have demonstrated that estrogens up-regulate a1adrenergic and down-regulate b-adrenergic receptor activity [30]. Estrogens act as serotoninergic agonists by increasing serotonin (5-HT) synthesis and levels of its main metabolite, 5-hydroxyndolacetic acid (5HTIAA). In women, the levels of circulating estrogens seem to be positively related to mood and behavior [31]. Sex hormones also seem to modulate the serotoninergic system [32]. In female rats, brain serotonin concentration varies during the
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estrous cycle or other periods of ovarian hormone fluctation [33]. Estrogens have positive effects on the serotoninergic system in ovariectomized rats [34]. In particular, they intensify the rate of degradation of monoamino oxidase (MAO), the enzyme that catabolizes serotonin, thus increasing the concentration and the availability of serotonin [35]. These steroids can also render tryptophan more available in the brain for metabolization into serotonin by displacing tryptophan from its binding sites to plasma albumin [36]. A positive role of ERT on vasomotor and subjective psychobehavioral symptoms may be mediated by acting on the opiatergic pathway [37]. Postmenopause is associated to a decrease b-EP levels. Altered b-EP levels seem to be involved in the pathogenesis of mood, behavior and nociceptive disturbances of the postmenopausal period. Oral ERT subsequent to spontaneous or surgically-induced menopause determines by a significant increase in circulating b-EP levels [3]. The majority of studies report that women with climacteric depression may benefit from replacement therapy with conjugated estrogens [15,37– 41], although a few studies do not report a similar response to these molecules [42–44]. The commonly used doses of estrogens do not improve mood in women with major depression but have a strong influence on mood and feeling of well being in healthy nondepressed postmenopausal women [15,30– 32,39 – 42]. However, variable doses or estrogens or the co-administration of certain progestins may determine discrepant findings [45,46].
3. Progestagens and brain In women with an intact uterus undergoing HRT, the administration of progestagens is necessary in order to counteract the proliferative action of estrogens on the endometrium. Progestins used in hormonal replacement therapy may derive from progesterone and from 19nortestosterone. The most commonly used progesterone derivatives are cyproterone acetate, medroxiprogesterone, medrogestone, dehydroges-
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terone, while those deriving from 19-nortestosterone derivatives are norethisterone, norethisterone acetate (NETA) and levonorgestrel. Unfortunately, progesterone and its derivatives can have opposite effects to those exerted by estrogens on the brain, thus inducing dysphoric mood and altered behavior in some women. In contrast to the excitational effects of estrogens, progestins seem to have a depressant effect on the CNS. The depressant action of progesterone is most likely due to its active metabolites such as pregnenolone and allopregnanolone, which can be formed systemically or locally from progesterone [47] and cholesterol [48]. The dampening of mood by progestins has been demonstrated in clinical trials that have used different combinations of estrogen and progestin compounds, conjugated equine estrogens and medroxyprogesterone acetate [49], estrogen implants and norethisterone [50], percutaneous E2 and lynestrenol [51], ethinyl E2 and levonorgestrel [52]. In ovariectomized female rats, the administration of NETA or norgestimate increases hypothalamic and circulating b-EP, while medroxyprogesterone acetate or desogestrel do not induce significant changes [2,53], suggesting that certain progestagens may influence the effects of estrogens [37,53]. Progestins may influence mood negatively by enhancing MAO activity and GABA-inhibitory action and by lowering brain excitability [54,55]. In oophorectomized women, endogenous opioid activity is low. The co-administration of medroxyprogesterone and estrogens, determines an even greater increase in endogenous opioid activity than that obtained with estrogens alone [56], while the administration of nomegestrol acetate, or cyproterone acetate, or vaginal progesterone does not influence the positive effect of estrogens on the opioidergic system in any manner [57]. Although there are very few data regarding the effects of progestins on cognitive functions, an in vitro study suggests that different progestins may have different effects on trophism of neurons. In fact, while progesterone and 19-norprogesterone, alone or in combination with estrogens, increase antiapoptotic bcl-2 expression in neurons,
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MPA blocks the estrogen -induced increase in bcl-2, when coadministered [58].
4. Androgens and brain Androgens play a key role in female sexuality and libido. Their decline probably contributes to the decline in sexual interest experienced by many postmenopausal women [59]. Estrogens improve sexual satisfaction [60,61] by reducing vaginal dryness or dyspareunia, however, they do not seem to induce modifications in libido in women without coital discomfort [62,63]. Several studies have demonstrated that androgen replacement therapy (ART) in surgical postmenopausal women affects libido, sexual performance and feeling of well-being positively [64– 68]. Androgens, however, remain only a little component in the management of menopause replacement therapy. ART is recommended in postmenopausal women, especially younger women with either premature or surgical menopause who suffer from decreased general well-being [69], decreased libido [70] and lack of energy despite adequate estrogen and progestagen administration. Treatment with dehydroepiandosterone (DHEA) or its sulfated ester (DHEAS) is a tool with much potential for ART in older women [71 – 73]. Both D5 androgens are considered neuroactive steroids because they are produced in the CNS and modulate neuronal excitability by blocking GABA-induced chloride transport or current in synaptoneurosomes and neurons in a dose-dependent manner [74,75]. The linear decrease in DHEA and DHEAS plasma levels with age leads to the hypothesize that these steroids are related to life expectancy and aging [73,75,76]. Recent data obtained in our laboratory indicate that the DHEA therapy determines a significant increase in both estradiol and estrone levels [77]. Moreover, DHEA restores basal plasma b-EP levels, marker of neuroendocrine function, and b-EP response to specific neuroendocrine stimuli (clonidine, naloxone and fluoxetine) [77]. Finally, there is a decrease in subjective climacteric symptoms [77,78].
5. Conclusion The effects of HRT on brain seem to be influenced by the type of HRT, the duration of treatment, the nature of the tests, the brain region. Different regimens and routes of estrogen, progestin and androgen administration may exert different effects on brain functions. Gonadal hormones seem to exert a crucial role for the physiological brain functions, acting both on female behavior, cognition. However, at present the available data regarding the implication of sex steroid hormones in the control mechanisms of brain function are insufficient to be conclusive. Further studies are, therefore, required in order to explain the specific role of endogenous and exogenous sex steroids on the CNS.
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Hormonal influence on the central nervous system Andrea R. Genazzani *, Patrizia Monteleone, Marco Gambacciani Department of Obstetrics and Gynecology, Uni6ersity of Pisa Via Roma 35, 56100 Pisa, Italy
Abstract Sex steroids play a very important role in female neurobiology. Postmenopausal gonadal hormone withdrawal seems to be of critical importance in mood disorders, reduced libido and cognitive disturbances, which accompany this phase of a woman’s life. Clinical studies have demonstrated that central nervous system (CNS) effects of estrogens are not only limited to resolution of vasomotor instability, they are extended to psychological disturbances like depression, behavioral changes and cognitive dysfunction. Progestins, on the other hand, may have variable effects on the brain, occasionally inducing dysphoric mood and altered behavior. Although their use in hormone replacement therapy (HRT) is widely debated, androgens may help resolve changes in libido experienced by many women after the menopause. It is still, however, difficult to draw guidelines on the use of HRT and postmenopausal CNS disorders as studies present up to date have been carried out with different kinds of molecules and routes of administration. Further studies are required in order to explain the specific role of endogenous and exogenous sex steroids on the CNS. © 2002 Published by Elsevier Science Ireland Ltd. Keywords: Sex steroids; Central nervous system; Hormone replacement therapy (HRT)
1. Introduction The role of sex hormones is not limited to the regulation of reproductive function. Estrogen, progesterone and androgen receptors have been identified in numerous regions of the central nervous system (CNS) indicating that sex steroids are of fundamental importance in female neurobiology. The withdrawal in gonadal hormones occurring at menopause determines CNS disorders such as altered mood, reduced libido and cognitive disturbances [1–3]. In the brain, sex steroid hor* Corresponding author. Tel.: + 39-50-553412; fax: + 3950-553410 E-mail address: [email protected] (A.R. Genazzani).
mones exert, like in other target organs, both genomic and non genomic effects [1–3]. Genomic effects consist of inducing long-term activity by activating specific intracellular receptors that modulate neuronal gene transcription and protein synthesis. In particular, gonadal hormones modulate the synthesis, release and metabolism of many neuropeptides and neuroactive transmitters and the expression of their receptors [1–4]. At menopause, as a consequence of the decline in sex hormones, neuroactive transmitters undergo important modifications, leading to specific symptoms secondary to CNS derangement. Hot flushes, sweating, occurring in over 50–70% of postmenopausal women, are consequences of neuroendocrine changes in the hypothalamus [5,6], in
0378-5122/02/$ - see front matter © 2002 Published by Elsevier Science Ireland Ltd. PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 1 4 4 - 5
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particular a temporary derangement of the hypothalamic thermoregulatory centers. Moreover, estrogen deficiency increases the noradrenergic tone and decreases dopaminergic activity, which, in turn, cause vasomotor instability. Finally, there are data showing that, in adult rats, castration determines a reduction in b-endorphin (b-EP) content [7]. Similarly, surgical or spontaneous menopause in women is associated with a fall in circulating b-EP [8,9] while vasomotor symptoms are associated to a sudden surges in plasma b-EP levels caused by the activation of hypothalamus– pituitary axis (GnRH, LH, FSH) [10– 12]. Mood changes, anxiety, depression, insomnia, headaches/migraine, alterations of cognitive functions are related to postmenopausal alterations of the limbic system. In postmenopausal women changes in central serotoninergic and noradrenergic activities may explain mood disorders [1]. Menopausal impairment of opioidergic peptide synthesis and secretion also play a role in the modification of mood, behavior and pain perception during this period of a woman’s life [12– 14]. Hormone replacement therapy (HRT), in most cases, is accompanied by restored levels of these neurotransmitters and an improvement in mood, psychological and cognitive disturbances [15].
2. Estrogens and brain Clinical studies have reported a frequent decrease in cognitive efficiency, including memory, in climacteric women [16]. Estrogen administration improves cognitive functions [17– 20] by exerting a positive effect especially on memory and reaction time tests [18,20– 23]. A recent study reports that estrogens seem to be mostly active within the prefrontal cortex, influencing functions dependant on this area of the brain. In particular, it was shown that estrogen users perform better on spatial and verbal memory tasks than nonusers [24]. Estrogens act as cholinergic agonists by inducing synthesis and activation of choline acetyltransferase (ChAT), the rate-limiting enzyme for acetylcholine formation [25– 27]. Moreover, estrogens seem to be important in the maintenance of
cholinergic neurons projecting to the hippocampus and cortex. Estrogen replacement therapy (ERT) can enhance the functional status of these neurons, as well as reduce cognitive deficits associated with muscarinic cholinergic impairment. Similar effects in humans may help delay the decline in basal forebrain cholinergic function associated with aging and Alzheimer’s disease (AD) and thereby reduce the risk and severity of AD-related dementia in postmenopausal women [28]. There are numerous reports on the positive effects of estrogens on mood and behavior in postmenopausal women. Estrogens seem to affect various brain systems by determining changes in local concentrations of neurotransmitters. Estrogens modulate the noradrenergic and dopaminergic systems of the hypothalamus and of extrahypothalamic regions of the brain controlling movement and behavior in both animals and humans. Evidence of the fact that estrogens modulate the cathecolaminergic system emerges from the fact that, in female rats, the rise in estrogen levels at proestrous determines an increase in norepinephrine and dopamine turnover rates [29,30]. When female rats are castrated. cathecolaminergic activity is, on the other hand, impaired, with an increase in noradrenaline release and a decrease in dopamine [29,30]. The exogenous administration of estrogens decreases hypothalamic noradrenaline release, while it increases dopaminergic neuronal activity with a parallel increase in dopamine release in the medio-basal hypothalamus [30]. In an animal model, estradiol enhances noradrenaline release, leading to an increased excitability of ventromedial hypothalamus neuronal activity and expression of lordosis behavior [30]. In vitro studies have demonstrated that estrogens up-regulate a1adrenergic and down-regulate b-adrenergic receptor activity [30]. Estrogens act as serotoninergic agonists by increasing serotonin (5-HT) synthesis and levels of its main metabolite, 5-hydroxyndolacetic acid (5HTIAA). In women, the levels of circulating estrogens seem to be positively related to mood and behavior [31]. Sex hormones also seem to modulate the serotoninergic system [32]. In female rats, brain serotonin concentration varies during the
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estrous cycle or other periods of ovarian hormone fluctation [33]. Estrogens have positive effects on the serotoninergic system in ovariectomized rats [34]. In particular, they intensify the rate of degradation of monoamino oxidase (MAO), the enzyme that catabolizes serotonin, thus increasing the concentration and the availability of serotonin [35]. These steroids can also render tryptophan more available in the brain for metabolization into serotonin by displacing tryptophan from its binding sites to plasma albumin [36]. A positive role of ERT on vasomotor and subjective psychobehavioral symptoms may be mediated by acting on the opiatergic pathway [37]. Postmenopause is associated to a decrease b-EP levels. Altered b-EP levels seem to be involved in the pathogenesis of mood, behavior and nociceptive disturbances of the postmenopausal period. Oral ERT subsequent to spontaneous or surgically-induced menopause determines by a significant increase in circulating b-EP levels [3]. The majority of studies report that women with climacteric depression may benefit from replacement therapy with conjugated estrogens [15,37– 41], although a few studies do not report a similar response to these molecules [42–44]. The commonly used doses of estrogens do not improve mood in women with major depression but have a strong influence on mood and feeling of well being in healthy nondepressed postmenopausal women [15,30– 32,39 – 42]. However, variable doses or estrogens or the co-administration of certain progestins may determine discrepant findings [45,46].
3. Progestagens and brain In women with an intact uterus undergoing HRT, the administration of progestagens is necessary in order to counteract the proliferative action of estrogens on the endometrium. Progestins used in hormonal replacement therapy may derive from progesterone and from 19nortestosterone. The most commonly used progesterone derivatives are cyproterone acetate, medroxiprogesterone, medrogestone, dehydroges-
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terone, while those deriving from 19-nortestosterone derivatives are norethisterone, norethisterone acetate (NETA) and levonorgestrel. Unfortunately, progesterone and its derivatives can have opposite effects to those exerted by estrogens on the brain, thus inducing dysphoric mood and altered behavior in some women. In contrast to the excitational effects of estrogens, progestins seem to have a depressant effect on the CNS. The depressant action of progesterone is most likely due to its active metabolites such as pregnenolone and allopregnanolone, which can be formed systemically or locally from progesterone [47] and cholesterol [48]. The dampening of mood by progestins has been demonstrated in clinical trials that have used different combinations of estrogen and progestin compounds, conjugated equine estrogens and medroxyprogesterone acetate [49], estrogen implants and norethisterone [50], percutaneous E2 and lynestrenol [51], ethinyl E2 and levonorgestrel [52]. In ovariectomized female rats, the administration of NETA or norgestimate increases hypothalamic and circulating b-EP, while medroxyprogesterone acetate or desogestrel do not induce significant changes [2,53], suggesting that certain progestagens may influence the effects of estrogens [37,53]. Progestins may influence mood negatively by enhancing MAO activity and GABA-inhibitory action and by lowering brain excitability [54,55]. In oophorectomized women, endogenous opioid activity is low. The co-administration of medroxyprogesterone and estrogens, determines an even greater increase in endogenous opioid activity than that obtained with estrogens alone [56], while the administration of nomegestrol acetate, or cyproterone acetate, or vaginal progesterone does not influence the positive effect of estrogens on the opioidergic system in any manner [57]. Although there are very few data regarding the effects of progestins on cognitive functions, an in vitro study suggests that different progestins may have different effects on trophism of neurons. In fact, while progesterone and 19-norprogesterone, alone or in combination with estrogens, increase antiapoptotic bcl-2 expression in neurons,
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MPA blocks the estrogen -induced increase in bcl-2, when coadministered [58].
4. Androgens and brain Androgens play a key role in female sexuality and libido. Their decline probably contributes to the decline in sexual interest experienced by many postmenopausal women [59]. Estrogens improve sexual satisfaction [60,61] by reducing vaginal dryness or dyspareunia, however, they do not seem to induce modifications in libido in women without coital discomfort [62,63]. Several studies have demonstrated that androgen replacement therapy (ART) in surgical postmenopausal women affects libido, sexual performance and feeling of well-being positively [64– 68]. Androgens, however, remain only a little component in the management of menopause replacement therapy. ART is recommended in postmenopausal women, especially younger women with either premature or surgical menopause who suffer from decreased general well-being [69], decreased libido [70] and lack of energy despite adequate estrogen and progestagen administration. Treatment with dehydroepiandosterone (DHEA) or its sulfated ester (DHEAS) is a tool with much potential for ART in older women [71 – 73]. Both D5 androgens are considered neuroactive steroids because they are produced in the CNS and modulate neuronal excitability by blocking GABA-induced chloride transport or current in synaptoneurosomes and neurons in a dose-dependent manner [74,75]. The linear decrease in DHEA and DHEAS plasma levels with age leads to the hypothesize that these steroids are related to life expectancy and aging [73,75,76]. Recent data obtained in our laboratory indicate that the DHEA therapy determines a significant increase in both estradiol and estrone levels [77]. Moreover, DHEA restores basal plasma b-EP levels, marker of neuroendocrine function, and b-EP response to specific neuroendocrine stimuli (clonidine, naloxone and fluoxetine) [77]. Finally, there is a decrease in subjective climacteric symptoms [77,78].
5. Conclusion The effects of HRT on brain seem to be influenced by the type of HRT, the duration of treatment, the nature of the tests, the brain region. Different regimens and routes of estrogen, progestin and androgen administration may exert different effects on brain functions. Gonadal hormones seem to exert a crucial role for the physiological brain functions, acting both on female behavior, cognition. However, at present the available data regarding the implication of sex steroid hormones in the control mechanisms of brain function are insufficient to be conclusive. Further studies are, therefore, required in order to explain the specific role of endogenous and exogenous sex steroids on the CNS.
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