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Testosterone and the brain
This article is made possible thanks to an educational grant from Bayer Schering Pharma AG
Testosterone and the brain Louis Gooren
Keywords Testosterone Cognitive functions Sex difference Depression Alzheimer’s disease Androgen deprivation treatment
Louis Gooren Department of Endocrinology, The Vrije Universiteit Medical Center, Amsterdam, the Netherlands E-mail: [email protected]
Online 20 August 2007
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Abstract The effects of testosterone on sexual appetite are obvious. Furthermore, treatment of hypogonadal men with testosterone leads almost always to unmistakable positive changes in mood, self-esteem and vitality. This testifies to the profound effects testosterone exerts on the brain and the mind. Conversely, hypogonadism and particularly the profound hypogonadism resulting from androgen deprivation treatment in men with prostate cancer, is associated with loss of vitality and mood disorders, if not depression. Several studies have found a role for testosterone on cognition (particularly visuo-spatial abilities), mood and depression, and low testosterone values may predict the development of Alzheimer’s disease. Testosterone administration to hypogonadal men supports this notion. But not all studies have been able to confirm the association between testosterone and mental functions. These discrepancies might be explained by the large variations in design, inclusion criteria with regard to threshold values of testosterone, duration of study and psychometric instruments. It is likely that men with plasma testosterone values below the lower limit of normal will benefit (most). It is presently not justified to prescribe testosterone as a primary treatment for men with impaired cognitive functioning or mood disorders. These complaints are common in elderly men, and one of the diagnostic considerations might be testing for testosterone deficiency as an etiological factor, and if, upon laboratory measurement, testosterone levels are truly hypogonadal, testosterone treatment is warranted. This probably will not only benefit mental functioning but there will be somatic benefits as well as a result of normalization of testosterone levels. ß 2007 WPMH GmbH. Published by Elsevier Ireland Ltd.
Mind–body interaction is evidently fundamental to human existence. But medicine has followed the Cartesian tradition of the split of the body and the mind. The body and the mind have subsequently become the domains of different scientific disciplines, each with different concepts and methodologies and it has been difficult to integrate their insights into one science. However, as a counter current, over the last 50 years psychosomatic medicine has promoted the scientific understanding of the interaction of body and mind, the interaction of brain and mind and the social context we live in. This has contributed to a better understanding of the pathogenesis, course and treatment of disease and has promoted health. This contribution will address the role of testosterone in the interaction of brain and mind, with a focus on the changes occurring in elderly men. The latter might be related to changes in androgen levels with aging. In an attempt to define the role of androgens in these processes, it is accepted that their effects relate to the complexity of the personality
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of the subjects living in their social context. Nevertheless, in spite of the fact that these processes are multifactorial it has been possible to define some elements that can be ascribed to androgens. The relationship between the brain and the endocrine system is now seen to extend far beyond the regulation of somatic hormone production by the hypothalamus and pituitary: the brain itself can be considered both as an endocrine organ, producing hormones that act both within and outside the central nervous system, and as a target for hormones. The brain contains receptors for androgens and estrogens [1–3], and is capable of synthesizing and metabolizing these steroids [4–7]. Hormones direct neurotrophic factors which are involved in neuroplastic changes and affect learning, memory and cognitive behavior (through effects on synaptic plasticity, neurotransmitter and neuropeptide production and excitability). This matter has been the subject of recent reviews [8,9].
ß 2007 WPMH GmbH. Published by Elsevier Ireland Ltd.
This article is made possible thanks to an educational grant from Bayer Schering Pharma AG Sex differences in cognition Androgen effects on cognitive function appear to be domain-specific. Men outperform women in a variety of visuo-spatial skills and women perform better on tests of verbal fluency and fine manual dexterity [10]. The effects of sex steroids on cognitive functioning appear to be related to circulating levels of sex steroids rather than being the result of early imprinting on the brain [11,12]. Observations suggest that androgens enhance visuo-spatial skills. Janowsky et al. [10] tested verbal and visual memory, spatial cognition, motor speed and cognitive flexibility in a group of healthy older men who received three months of testosterone supplementation. Testosterone treatment was associated with a significant improvement in spatial cognition only. Serum testosterone levels were not significantly correlated with spatial performance, but estradiol levels showed a significant inverse relationship with spatial performance suggesting that estradiol might inhibit spatial ability. Barrett-Conner et al. [13] found positive associations between total and bioavailable testosterone levels, and global cognitive functioning and mental control, but not with visuo-spatial skills. Other studies [14] have reported a curvilinear relationship between androgen levels and spatial ability such that females with high testosterone levels and males with mid-normal testosterone levels show the best performance. Women with congenital adrenal hyperplasia with high androgen levels score higher on tests of spatial cognition than their age- and gender-matched siblings. On the contrary, 46 XY individuals with androgen insensitivity syndrome perform worse on tests of spatial cognition than their age-matched male siblings. From this it appears that alterations in circulating sex steroid levels may impact on cognitive functioning.
that many etiological factors play a role in this decline. The attraction of identifying the role of testosterone lies in the fact that testosterone deficiency lends itself to easy correction. Several studies were able to establish a linear [16,17] or non-linear relationship [18,19] between plasma testosterone levels and cognitive functioning in a wide range of ages. An outcome of a non-linear, often curvilinear relationship is the indication that low levels of testosterone are indeed associated with impairment of cognitive functioning but that the highest levels of testosterone measured in a population were not predictive of better functions. There was rather an optimal level of testosterone for optimal cognitive functioning somewhere in the mid-normal range. Studies more specifically directed at the aging male have found that bioavailable testosterone levels were positively associated with scores of general cognitive ability [13,20,21]. Interestingly, a relationship could be established between the metabolic syndrome, cognition and testosterone [22]. In the long-term Baltimore Longitudinal Study of Aging cognitive status and testosterone levels were followed-up for an average duration of 9.7 years in 407 men aged 50–91 years at the beginning of the study. Overall, an increased free testosterone index was associated with improved scores on visual and verbal memory, mental status, and visuospatial function. Men with subnormal plasma testosterone levels had worse scores of visual and verbal memory. However, not all studies confirm the above findings. Fonda et al. [23] analyzing data of the Massachusetts Male Aging Study found an association between free and total testosterone levels with performance on tests of cognitive functioning, but these associations were no longer significant after adjusting for age, education levels and physical health. The authors concluded that their results do not provide evidence that testosterone mediates an age-related cognitive decline.
Aging, cognition and testosterone Cognitive functions such as memory, attention, verbal skill and speed, and visuo-spatial ability decline with aging [15]. This contribution focuses on the potential contribution of the age-related decline of testosterone levels in men. There is probably a parallel with the agerelated decline of erectile function in so far
Testosterone and aggression/ aggressivity Violent behavior occurs more often in men than in women and there is a strong (popular) notion to relate this behavior to testosterone. Yet, there is no serious scientific evidence for
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This article is made possible thanks to an educational grant from Bayer Schering Pharma AG the association. First of all, there is a semantic problem. In the literature pertaining to this subject, aggression is viewed as a normal male trait signifying healthy assertiveness rather than a hostile attitude or action. For the latter the term aggressivity is used. Studies of testosterone treatment of men [24], even with doses producing levels somewhat above normal [25,26], do not induce inappropriately aggressive behavior. Men who abuse anabolicandrogenic steroids may, however, show psychopathological behavior, probably more attributable to their personality disorders than to the use of steroids [27].
Intervention studies with testosterone and cognition If lower-than-normal testosterone levels are associated with cognitive impairment, testosterone administration might have a beneficial effect. And, indeed, some placebo-controlled studies have found that restoring testosterone levels to normal may improve some cognitive functions, in particular spatial ability and memory [10,12,28]. Some studies have attributed a role to the aromatization product of testosterone, estradiol, particularly with regard to the effect of testosterone on verbal fluency [29]. Other placebo-controlled studies report less favorable effects of testosterone administration [30,31]. It is of note that the above studies finding positive and negative outcome of testosterone administration differed in design, duration and mode of testosterone administration, sample size, inclusion of subjects with regard to their baseline testosterone values and also a wide variety of psychometric tests were used. Before any definitive conclusions can be drawn, better designed studies are needed. It may be that age and duration of hypogonadism are factors in the efficacy of testosterone administration.
Estrogens and male brain functions Estrogens have been observed to influence many processes in many regions of the brain throughout the entire life span. These include effects on cognitive function, co-ordination of movement, pain and affective state, involving
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both the estrogen receptor (ER)-a and ER-b genes. Only some of the estrogen actions on the brain are intracellular receptor-mediated, while others take place on the cell membrane, mediated via second messenger mechanisms, neuronal excitability and ion channels [32,33]. Estrogens contribute to explicit (or declarative) memory function through their action on hippocampal neurons. The implication of this estrogen effect is improved (conscious) recall of facts, events and autobiographical memories [32]. Explicit memory is considered the cognitive function that is most vulnerable to loss of estrogen. Women receiving estrogen replacement and men whose estrogen levels are above those of postmenopausal women score better on explicit memory tasks [34]. But not all studies could establish a role for estrogens in men. Yaffe et al. found a correlation between cognitive functioning and bioavailable testosterone, but not with estradiol [20]. In view of the above potential role of estrogens it seems recommendable that androgen deficient men, including the androgen deficient ageing male, receive an aromatizable androgen preparation.
Testosterone and mood and depression Upon observation of the effects of testosterone treatment of hypogonadal men, it is difficult not to be impressed with the vitalizing effects testosterone exerts on the mind. Conversely, depressed mood is a common feature of hypogonadism which usually improves upon testosterone treatment. A recent study demonstrated that when plasma testosterone levels fall below 15 nmol/l (still in the reference range of normal!) there is a loss of libido and vigor. With testosterone levels below 10 nmol/l (hypogonadal range) depression becomes a frequent occurrence [35]. Several recent studies testify to the moodelevating effects in hypogonadal men when testosterone levels are restored to the normal range [36–38]. These effects consist of increases in positive mood and a reduction in negative mood (asthenia, fatigue, irritability). They occur rather rapidly upon testosterone treatment (within three months) and were found to be maintained over an observation period of more than three years [36].
This article is made possible thanks to an educational grant from Bayer Schering Pharma AG Mood disturbances with a severity qualifying as depression have been found to be associated with hypogonadism. The Rancho Bernardo Study showed, first of all, that clinical depression increased with age (age range studied was 50–89 years) but the greater prevalence of depression was also associated with lower bioavailable testosterone levels. This association remained after correction for age, weight change and physical activity [39]. Bioavailable testosterone levels were 17% lower in those men with categorically defined depression than in all other men in the study. One study demonstrated that hypogonadal men are more prone to develop depression than eugonadal controls [40]. But epidemiological studies were less affirmative. The Massachusetts Male Aging Study [41] and the Veteran’s Experience Study [42] could not establish a clear relationship between depression and testosterone at a population level. One reason that it is difficult to relate circulating levels of testosterone to depression might be the link between depression and the number of CAG repeats in the androgen receptor which mediates the biological effects of testosterone in the target tissues. The number of CAG repeats in the androgen receptor varies between subjects. The lower the number of CAG repeats in the androgen receptor, the more pronounced the biological action of testosterone is. Co-activators in the androgen receptor mechanism bind more easily to receptors with fewer CAG repeats thus producing a stronger androgenic stimulus. In men with lower numbers of CAG repeats, total testosterone levels are negatively associated with depressed mood [43]. These men suffer more readily from a decline of testosterone and might also benefit more readily from testosterone treatment. Another study found that men with longer CAG repeats (and consequently a lower efficacy of testosterone action) are more prone to depressed moods [44]. Several intervention studies have found positive effects of restoring subnormal testosterone levels to normal on depression [45,46]. In a study of 22 men with depression refractory to treatment with the more conventional antidepressants, treatment with testosterone gel for 8 weeks produced significantly greater improvements on depression scores than placebo. Administration of testosterone not only produced significant effects on mental aspects of depression (depressed mood, guilt, and anxiety) but also on somatic aspects (appetite,
sleep, libido). Beneficial effects were also noted on depression in men suffering from HIV infection with depressed mood [47]. The latter might also benefit from the anabolic effects of androgens on muscle wasting. Other studies were unable to document a substantial effect of testosterone administration to hypogonadal men with depression [48,49]. These conflicting results may be (partially) explained by the different operational definitions of depression (mood disturbances, dysthymia, severe depression, and even more importantly, by the inclusion criteria with regard to plasma testosterone levels at entry to the study. Often men included in this type of study are not truly hypogonadal which might explain a lack of success of testosterone administration.
Alzheimer’s disease With regard to Alzheimer’s disease, men are relatively protected in comparison to women. A number of studies have found that men with Alzheimer’s disease have lower levels of total or bioavailable testosterone [50,51]. Plasma testosterone was found to be associated with reduced beta-amyloid, a component of senile plaques of Alzheimer’s disease and testosterone might thus protect against Alzheimer’s disease [52]. The Baltimore Longitudinal Study of Aging has provided intriguing evidence with regard to the role of testosterone and the development of Alzheimer’s disease. In this longitudinal study 574 men without Alzheimer’s disease, aged 32–87 years, were followed for a mean of 19 years (4–37 years). The impact of testosterone levels on the risk of developing Alzheimer’s disease was assessed at 2.5 and 10 years. For every 10-unit (nmol/nmol) increase in free testosterone, the risk of developing Alzheimer’s disease appeared to be reduced by 26%. It is thought-provoking that low levels of testosterone could predict the development of Alzheimer’s disease up to 10 years in advance and it shows that testosterone levels are often already low long before Alzheimer’s disease manifests itself, and it may be associated with the mild cognitive impairment which often forebodes Alzheimer’s disease [53]. Not all studies are in agreement. A recent study found no relationship with levels of circulating testosterone but higher estradiol
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This article is made possible thanks to an educational grant from Bayer Schering Pharma AG levels predicted an increased risk for cognitive decline and Alzheimer’s disease [54]. Apo E polymorphism is an important determinant of risk for the development of cardiovascular and Alzheimer diseases, the prevalence of the epsilon 4 allele being increased in both kinds of patients compared with control subjects. The human apolipoprotein (apo) E gene is polymorphic, with three common alleles (epsilon 2, epsilon 3, epsilon 4) coding for three isoforms (E2, E3, E4). The isoforms differ from each other by a single amino acid substitution, and also differ in their binding affinity for the four apo E receptors. A recent study has investigated the interaction between testosterone and apolipoprotein E epsilon4 status on cognition in healthy older men. The study found a significant interaction between free testosterone and apolipoprotein E epsilon4 status on general cognition, verbal and visual memory, working memory and attention. Higher levels of free testosterone were associated with better general cognition in men who were not carriers of apolipoprotein E epsilon4. By contrast, in men who were carriers of apolipoprotein E epsilon4, test results were negatively associated with levels of free testosterone [55]. The finding of low testosterone levels in Alzheimer’s disease in the Baltimore Longitudinal Study of Aging [52] was reason to investigate the effects of testosterone administration in men with mild cognitive impairment of Alzheimer’s disease. The effects were not straightforwardly positive but some gains were noted. Studies found an improvement in visuo-spatial scores [28,56,57] while one study could not detect this effect [30]. In one study testosterone administration prevented the worsening of verbal memory [28]. Overall, there was no improvement of cognitive functioning. The above studies differed in design and inclusion criteria with regard to levels of testosterone, but the improvement in spatial abilities might alleviate spatial disorientation, an important feature of Alzheimer’s disease.
Psychological effects of androgen deprivation therapy in men with prostate cancer Androgen deprivation therapy (ADT) has been introduced as a potential treatment option for
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some men with clinically localized prostate cancer as a means of preventing or delaying progression while avoiding complications associated with surgical or radiation therapies. In the last two decades, safer antiandrogenic agents have been developed, particularly with the introduction of cyproterone acetate and injectable luteinizing hormone-releasing hormone (LHRH) agonists. However, outcomes studies of ADT have shown that androgen deprivation adversely affects quality of life and leads to increased fatigue, depressive feelings, difficulties with erection, and declines in sexual interest and enjoyment. This information is clinically significant because the average general practitioner will encounter several cases of men receiving ADT for prostate cancer. Some studies have reported changes in cognitive functioning in the direction predicted by the above mentioned sex differences in cognitive functioning, with a loss of spatial abilities and an improvement in verbal fluency [12]. These are probably more of academic interest. A study comparing men who received either ADT or no therapy found that men receiving ADT had not only a loss of sexual functions but also a decline in vitality [58]. Measures of psychological well-being were not different between men who had undergone surgical orchiectomy and pharmacological ADT [59]. Similar findings have been reported in other studies [60]. Self-reported health-related quality of life was impaired following ADT [61], also confirmed in another report [62]. Depressive feelings are experienced by some men [63] and others complain of fatigue [64]. Naturally, these findings must be interpreted with some caution. Men who suffer from prostate cancer will be affected by the stress associated with having a potentially lethal disease. Studies have, indeed, found that not only patients but also their spouses and others close to the patient, must develop coping strategies [65]. By contrast, there are also men who find solace and energy in the fact that they are not passively undergoing a malignant disease but are actively undertaking a potentially beneficial treatment [66]. ADT is sometimes an alternative to ‘watchful waiting’ in the management of prostate cancer and the side effects of ADT must be balanced against the potential gain in life expectancy and quality of life [66].
This article is made possible thanks to an educational grant from Bayer Schering Pharma AG Conclusions When treating hypogonadal men with testosterone, clinicians almost always observe remarkable changes in mood, self-esteem and vitality. This and the impressive effects which testosterone has on the sexual appetite, testify to the profound effects testosterone exerts on the brain and the mind. Conversely, hypogonadism and particularly the profound hypogonadism resulting from ADT in men with prostate cancer, are associated with loss of vitality and mood disorders, if not depression. In the literature there is evidence for a role of testosterone on cognition (particularly visuo-spatial abilities), development of Alzheimer’s disease, mood and depression. Studies of hypogonadal men and outcomes of testosterone administration support this notion. But other studies fail to confirm the association
between testosterone and mental functions. These discrepancies might be explained by the large variations in design, inclusion criteria with regard to threshold values of testosterone, duration of study and psychometric instruments. It is likely that men with plasma testosterone values below the lower limit of normal will benefit (most). With this state of affairs it is too early to prescribe testosterone as a primary treatment to men with impaired cognitive functioning or mood disorders. However, encountering men with these complaints might be reason to consider testosterone deficiency as an etiological factor, and if, upon laboratory measurement, testosterone levels are truly hypogonadal, testosterone treatment is warranted, not solely for its potential benefits on mental functioning but also for the somatic benefits that normalization of testosterone levels will have.
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[49] Seidman SN. Normative hypogonadism and depression: does ‘andropause’ exist? Int J Impot Res 2006;18:414–22. [50] Paoletti AM, Congia S, Lello S, Tedde D, Orru M, Pistis M, et al. Low androgenization index in elderly women and elderly men with Alzheimer’s disease. Neurology 2004; 62:301–3. [51] Okun MS, DeLong MR, Hanfelt J, Gearing M, Levey A. Plasma testosterone levels in Alzheimer and Parkinson diseases. Neurology 2004;62:411–3. [52] Gillett MJ, Martins RN, Clarnette RM, Chubb SA, Bruce DG, Yeap BB. Relationship between testosterone, sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia. J Alzheimers Dis 2003;5: 267–9. [53] Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, et al. Free testosterone and risk for Alzheimer disease in older men. Neurology 2004;62: 188–93. [54] Geerlings MI, Strozyk D, Masaki K, Remaley AT, Petrovitch H, Ross GW, et al. Endogenous sex hormones, cognitive decline, and future dementia in old men. Ann Neurol 2006;60:346–55. [55] Burkhardt MS, Foster JK, Clarnette RM, Chubb SA, Bruce DG, Drummond PD, et al. Interaction between testosterone and apolipoprotein E epsilon4 status on cognition in healthy older men. J Clin Endocrinol Metab 2006;91:1168–72. [56] Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol 2006;63:177–85. [57] Tan RS, Pu SJ. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male 2003;6:13–7. [58] Potosky AL, Reeve BB, Clegg LX, Hoffman RM, Stephenson RA, Albertsen PC, et al. Quality of life following localized prostate cancer treated initially with androgen deprivation therapy or no therapy. J Natl Cancer Inst 2002;94:430–7. [59] Potosky AL, Knopf K, Clegg LX, Albertsen PC, Stanford JL, Hamilton AS, et al. Qualityof-life outcomes after primary androgen deprivation therapy: results from the Prostate Cancer Outcomes Study. J Clin Oncol 2001;19:3750–7. [60] Lubeck DP, Grossfeld GD, Carroll PR. The effect of androgen deprivation therapy on health-related quality of life in men with prostate cancer. Urology 2001;58:94–100. [61] Dacal K, Sereika SM, Greenspan SL. Quality of life in prostate cancer patients taking androgen deprivation therapy. J Am Geriatr Soc 2006;54:85–90.
This article is made possible thanks to an educational grant from Bayer Schering Pharma AG [62] Basaria S, Lieb 2nd J, Tang AM, DeWeese T, Carducci M, Eisenberger M, et al. Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol (Oxf) 2002;56:779–86. [63] Pirl WF, Siegel GI, Goode MJ, Smith MR. Depression in men receiving androgen deprivation therapy for prostate cancer: a
pilot study. Psycho-oncology 2002;11: 518–23. [64] Stone P, Hardy J, Huddart R, A’Hern R, Richards M. Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 2000;36:1134–41. [65] Couper JW, Bloch S, Love A, Duchesne G, Macvean M, Kissane DW. The psychosocial
impact of prostate cancer on patients and their partners. Med J Aust 2006;185: 428–32. [66] Higano C. Androgen deprivation therapy: monitoring and managing the complications. Hematol Oncol Clin North Am 2006;20: 909–23.
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Testosterone and the brain Louis Gooren
Keywords Testosterone Cognitive functions Sex difference Depression Alzheimer’s disease Androgen deprivation treatment
Louis Gooren Department of Endocrinology, The Vrije Universiteit Medical Center, Amsterdam, the Netherlands E-mail: [email protected]
Online 20 August 2007
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Abstract The effects of testosterone on sexual appetite are obvious. Furthermore, treatment of hypogonadal men with testosterone leads almost always to unmistakable positive changes in mood, self-esteem and vitality. This testifies to the profound effects testosterone exerts on the brain and the mind. Conversely, hypogonadism and particularly the profound hypogonadism resulting from androgen deprivation treatment in men with prostate cancer, is associated with loss of vitality and mood disorders, if not depression. Several studies have found a role for testosterone on cognition (particularly visuo-spatial abilities), mood and depression, and low testosterone values may predict the development of Alzheimer’s disease. Testosterone administration to hypogonadal men supports this notion. But not all studies have been able to confirm the association between testosterone and mental functions. These discrepancies might be explained by the large variations in design, inclusion criteria with regard to threshold values of testosterone, duration of study and psychometric instruments. It is likely that men with plasma testosterone values below the lower limit of normal will benefit (most). It is presently not justified to prescribe testosterone as a primary treatment for men with impaired cognitive functioning or mood disorders. These complaints are common in elderly men, and one of the diagnostic considerations might be testing for testosterone deficiency as an etiological factor, and if, upon laboratory measurement, testosterone levels are truly hypogonadal, testosterone treatment is warranted. This probably will not only benefit mental functioning but there will be somatic benefits as well as a result of normalization of testosterone levels. ß 2007 WPMH GmbH. Published by Elsevier Ireland Ltd.
Mind–body interaction is evidently fundamental to human existence. But medicine has followed the Cartesian tradition of the split of the body and the mind. The body and the mind have subsequently become the domains of different scientific disciplines, each with different concepts and methodologies and it has been difficult to integrate their insights into one science. However, as a counter current, over the last 50 years psychosomatic medicine has promoted the scientific understanding of the interaction of body and mind, the interaction of brain and mind and the social context we live in. This has contributed to a better understanding of the pathogenesis, course and treatment of disease and has promoted health. This contribution will address the role of testosterone in the interaction of brain and mind, with a focus on the changes occurring in elderly men. The latter might be related to changes in androgen levels with aging. In an attempt to define the role of androgens in these processes, it is accepted that their effects relate to the complexity of the personality
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of the subjects living in their social context. Nevertheless, in spite of the fact that these processes are multifactorial it has been possible to define some elements that can be ascribed to androgens. The relationship between the brain and the endocrine system is now seen to extend far beyond the regulation of somatic hormone production by the hypothalamus and pituitary: the brain itself can be considered both as an endocrine organ, producing hormones that act both within and outside the central nervous system, and as a target for hormones. The brain contains receptors for androgens and estrogens [1–3], and is capable of synthesizing and metabolizing these steroids [4–7]. Hormones direct neurotrophic factors which are involved in neuroplastic changes and affect learning, memory and cognitive behavior (through effects on synaptic plasticity, neurotransmitter and neuropeptide production and excitability). This matter has been the subject of recent reviews [8,9].
ß 2007 WPMH GmbH. Published by Elsevier Ireland Ltd.
This article is made possible thanks to an educational grant from Bayer Schering Pharma AG Sex differences in cognition Androgen effects on cognitive function appear to be domain-specific. Men outperform women in a variety of visuo-spatial skills and women perform better on tests of verbal fluency and fine manual dexterity [10]. The effects of sex steroids on cognitive functioning appear to be related to circulating levels of sex steroids rather than being the result of early imprinting on the brain [11,12]. Observations suggest that androgens enhance visuo-spatial skills. Janowsky et al. [10] tested verbal and visual memory, spatial cognition, motor speed and cognitive flexibility in a group of healthy older men who received three months of testosterone supplementation. Testosterone treatment was associated with a significant improvement in spatial cognition only. Serum testosterone levels were not significantly correlated with spatial performance, but estradiol levels showed a significant inverse relationship with spatial performance suggesting that estradiol might inhibit spatial ability. Barrett-Conner et al. [13] found positive associations between total and bioavailable testosterone levels, and global cognitive functioning and mental control, but not with visuo-spatial skills. Other studies [14] have reported a curvilinear relationship between androgen levels and spatial ability such that females with high testosterone levels and males with mid-normal testosterone levels show the best performance. Women with congenital adrenal hyperplasia with high androgen levels score higher on tests of spatial cognition than their age- and gender-matched siblings. On the contrary, 46 XY individuals with androgen insensitivity syndrome perform worse on tests of spatial cognition than their age-matched male siblings. From this it appears that alterations in circulating sex steroid levels may impact on cognitive functioning.
that many etiological factors play a role in this decline. The attraction of identifying the role of testosterone lies in the fact that testosterone deficiency lends itself to easy correction. Several studies were able to establish a linear [16,17] or non-linear relationship [18,19] between plasma testosterone levels and cognitive functioning in a wide range of ages. An outcome of a non-linear, often curvilinear relationship is the indication that low levels of testosterone are indeed associated with impairment of cognitive functioning but that the highest levels of testosterone measured in a population were not predictive of better functions. There was rather an optimal level of testosterone for optimal cognitive functioning somewhere in the mid-normal range. Studies more specifically directed at the aging male have found that bioavailable testosterone levels were positively associated with scores of general cognitive ability [13,20,21]. Interestingly, a relationship could be established between the metabolic syndrome, cognition and testosterone [22]. In the long-term Baltimore Longitudinal Study of Aging cognitive status and testosterone levels were followed-up for an average duration of 9.7 years in 407 men aged 50–91 years at the beginning of the study. Overall, an increased free testosterone index was associated with improved scores on visual and verbal memory, mental status, and visuospatial function. Men with subnormal plasma testosterone levels had worse scores of visual and verbal memory. However, not all studies confirm the above findings. Fonda et al. [23] analyzing data of the Massachusetts Male Aging Study found an association between free and total testosterone levels with performance on tests of cognitive functioning, but these associations were no longer significant after adjusting for age, education levels and physical health. The authors concluded that their results do not provide evidence that testosterone mediates an age-related cognitive decline.
Aging, cognition and testosterone Cognitive functions such as memory, attention, verbal skill and speed, and visuo-spatial ability decline with aging [15]. This contribution focuses on the potential contribution of the age-related decline of testosterone levels in men. There is probably a parallel with the agerelated decline of erectile function in so far
Testosterone and aggression/ aggressivity Violent behavior occurs more often in men than in women and there is a strong (popular) notion to relate this behavior to testosterone. Yet, there is no serious scientific evidence for
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This article is made possible thanks to an educational grant from Bayer Schering Pharma AG the association. First of all, there is a semantic problem. In the literature pertaining to this subject, aggression is viewed as a normal male trait signifying healthy assertiveness rather than a hostile attitude or action. For the latter the term aggressivity is used. Studies of testosterone treatment of men [24], even with doses producing levels somewhat above normal [25,26], do not induce inappropriately aggressive behavior. Men who abuse anabolicandrogenic steroids may, however, show psychopathological behavior, probably more attributable to their personality disorders than to the use of steroids [27].
Intervention studies with testosterone and cognition If lower-than-normal testosterone levels are associated with cognitive impairment, testosterone administration might have a beneficial effect. And, indeed, some placebo-controlled studies have found that restoring testosterone levels to normal may improve some cognitive functions, in particular spatial ability and memory [10,12,28]. Some studies have attributed a role to the aromatization product of testosterone, estradiol, particularly with regard to the effect of testosterone on verbal fluency [29]. Other placebo-controlled studies report less favorable effects of testosterone administration [30,31]. It is of note that the above studies finding positive and negative outcome of testosterone administration differed in design, duration and mode of testosterone administration, sample size, inclusion of subjects with regard to their baseline testosterone values and also a wide variety of psychometric tests were used. Before any definitive conclusions can be drawn, better designed studies are needed. It may be that age and duration of hypogonadism are factors in the efficacy of testosterone administration.
Estrogens and male brain functions Estrogens have been observed to influence many processes in many regions of the brain throughout the entire life span. These include effects on cognitive function, co-ordination of movement, pain and affective state, involving
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both the estrogen receptor (ER)-a and ER-b genes. Only some of the estrogen actions on the brain are intracellular receptor-mediated, while others take place on the cell membrane, mediated via second messenger mechanisms, neuronal excitability and ion channels [32,33]. Estrogens contribute to explicit (or declarative) memory function through their action on hippocampal neurons. The implication of this estrogen effect is improved (conscious) recall of facts, events and autobiographical memories [32]. Explicit memory is considered the cognitive function that is most vulnerable to loss of estrogen. Women receiving estrogen replacement and men whose estrogen levels are above those of postmenopausal women score better on explicit memory tasks [34]. But not all studies could establish a role for estrogens in men. Yaffe et al. found a correlation between cognitive functioning and bioavailable testosterone, but not with estradiol [20]. In view of the above potential role of estrogens it seems recommendable that androgen deficient men, including the androgen deficient ageing male, receive an aromatizable androgen preparation.
Testosterone and mood and depression Upon observation of the effects of testosterone treatment of hypogonadal men, it is difficult not to be impressed with the vitalizing effects testosterone exerts on the mind. Conversely, depressed mood is a common feature of hypogonadism which usually improves upon testosterone treatment. A recent study demonstrated that when plasma testosterone levels fall below 15 nmol/l (still in the reference range of normal!) there is a loss of libido and vigor. With testosterone levels below 10 nmol/l (hypogonadal range) depression becomes a frequent occurrence [35]. Several recent studies testify to the moodelevating effects in hypogonadal men when testosterone levels are restored to the normal range [36–38]. These effects consist of increases in positive mood and a reduction in negative mood (asthenia, fatigue, irritability). They occur rather rapidly upon testosterone treatment (within three months) and were found to be maintained over an observation period of more than three years [36].
This article is made possible thanks to an educational grant from Bayer Schering Pharma AG Mood disturbances with a severity qualifying as depression have been found to be associated with hypogonadism. The Rancho Bernardo Study showed, first of all, that clinical depression increased with age (age range studied was 50–89 years) but the greater prevalence of depression was also associated with lower bioavailable testosterone levels. This association remained after correction for age, weight change and physical activity [39]. Bioavailable testosterone levels were 17% lower in those men with categorically defined depression than in all other men in the study. One study demonstrated that hypogonadal men are more prone to develop depression than eugonadal controls [40]. But epidemiological studies were less affirmative. The Massachusetts Male Aging Study [41] and the Veteran’s Experience Study [42] could not establish a clear relationship between depression and testosterone at a population level. One reason that it is difficult to relate circulating levels of testosterone to depression might be the link between depression and the number of CAG repeats in the androgen receptor which mediates the biological effects of testosterone in the target tissues. The number of CAG repeats in the androgen receptor varies between subjects. The lower the number of CAG repeats in the androgen receptor, the more pronounced the biological action of testosterone is. Co-activators in the androgen receptor mechanism bind more easily to receptors with fewer CAG repeats thus producing a stronger androgenic stimulus. In men with lower numbers of CAG repeats, total testosterone levels are negatively associated with depressed mood [43]. These men suffer more readily from a decline of testosterone and might also benefit more readily from testosterone treatment. Another study found that men with longer CAG repeats (and consequently a lower efficacy of testosterone action) are more prone to depressed moods [44]. Several intervention studies have found positive effects of restoring subnormal testosterone levels to normal on depression [45,46]. In a study of 22 men with depression refractory to treatment with the more conventional antidepressants, treatment with testosterone gel for 8 weeks produced significantly greater improvements on depression scores than placebo. Administration of testosterone not only produced significant effects on mental aspects of depression (depressed mood, guilt, and anxiety) but also on somatic aspects (appetite,
sleep, libido). Beneficial effects were also noted on depression in men suffering from HIV infection with depressed mood [47]. The latter might also benefit from the anabolic effects of androgens on muscle wasting. Other studies were unable to document a substantial effect of testosterone administration to hypogonadal men with depression [48,49]. These conflicting results may be (partially) explained by the different operational definitions of depression (mood disturbances, dysthymia, severe depression, and even more importantly, by the inclusion criteria with regard to plasma testosterone levels at entry to the study. Often men included in this type of study are not truly hypogonadal which might explain a lack of success of testosterone administration.
Alzheimer’s disease With regard to Alzheimer’s disease, men are relatively protected in comparison to women. A number of studies have found that men with Alzheimer’s disease have lower levels of total or bioavailable testosterone [50,51]. Plasma testosterone was found to be associated with reduced beta-amyloid, a component of senile plaques of Alzheimer’s disease and testosterone might thus protect against Alzheimer’s disease [52]. The Baltimore Longitudinal Study of Aging has provided intriguing evidence with regard to the role of testosterone and the development of Alzheimer’s disease. In this longitudinal study 574 men without Alzheimer’s disease, aged 32–87 years, were followed for a mean of 19 years (4–37 years). The impact of testosterone levels on the risk of developing Alzheimer’s disease was assessed at 2.5 and 10 years. For every 10-unit (nmol/nmol) increase in free testosterone, the risk of developing Alzheimer’s disease appeared to be reduced by 26%. It is thought-provoking that low levels of testosterone could predict the development of Alzheimer’s disease up to 10 years in advance and it shows that testosterone levels are often already low long before Alzheimer’s disease manifests itself, and it may be associated with the mild cognitive impairment which often forebodes Alzheimer’s disease [53]. Not all studies are in agreement. A recent study found no relationship with levels of circulating testosterone but higher estradiol
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This article is made possible thanks to an educational grant from Bayer Schering Pharma AG levels predicted an increased risk for cognitive decline and Alzheimer’s disease [54]. Apo E polymorphism is an important determinant of risk for the development of cardiovascular and Alzheimer diseases, the prevalence of the epsilon 4 allele being increased in both kinds of patients compared with control subjects. The human apolipoprotein (apo) E gene is polymorphic, with three common alleles (epsilon 2, epsilon 3, epsilon 4) coding for three isoforms (E2, E3, E4). The isoforms differ from each other by a single amino acid substitution, and also differ in their binding affinity for the four apo E receptors. A recent study has investigated the interaction between testosterone and apolipoprotein E epsilon4 status on cognition in healthy older men. The study found a significant interaction between free testosterone and apolipoprotein E epsilon4 status on general cognition, verbal and visual memory, working memory and attention. Higher levels of free testosterone were associated with better general cognition in men who were not carriers of apolipoprotein E epsilon4. By contrast, in men who were carriers of apolipoprotein E epsilon4, test results were negatively associated with levels of free testosterone [55]. The finding of low testosterone levels in Alzheimer’s disease in the Baltimore Longitudinal Study of Aging [52] was reason to investigate the effects of testosterone administration in men with mild cognitive impairment of Alzheimer’s disease. The effects were not straightforwardly positive but some gains were noted. Studies found an improvement in visuo-spatial scores [28,56,57] while one study could not detect this effect [30]. In one study testosterone administration prevented the worsening of verbal memory [28]. Overall, there was no improvement of cognitive functioning. The above studies differed in design and inclusion criteria with regard to levels of testosterone, but the improvement in spatial abilities might alleviate spatial disorientation, an important feature of Alzheimer’s disease.
Psychological effects of androgen deprivation therapy in men with prostate cancer Androgen deprivation therapy (ADT) has been introduced as a potential treatment option for
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some men with clinically localized prostate cancer as a means of preventing or delaying progression while avoiding complications associated with surgical or radiation therapies. In the last two decades, safer antiandrogenic agents have been developed, particularly with the introduction of cyproterone acetate and injectable luteinizing hormone-releasing hormone (LHRH) agonists. However, outcomes studies of ADT have shown that androgen deprivation adversely affects quality of life and leads to increased fatigue, depressive feelings, difficulties with erection, and declines in sexual interest and enjoyment. This information is clinically significant because the average general practitioner will encounter several cases of men receiving ADT for prostate cancer. Some studies have reported changes in cognitive functioning in the direction predicted by the above mentioned sex differences in cognitive functioning, with a loss of spatial abilities and an improvement in verbal fluency [12]. These are probably more of academic interest. A study comparing men who received either ADT or no therapy found that men receiving ADT had not only a loss of sexual functions but also a decline in vitality [58]. Measures of psychological well-being were not different between men who had undergone surgical orchiectomy and pharmacological ADT [59]. Similar findings have been reported in other studies [60]. Self-reported health-related quality of life was impaired following ADT [61], also confirmed in another report [62]. Depressive feelings are experienced by some men [63] and others complain of fatigue [64]. Naturally, these findings must be interpreted with some caution. Men who suffer from prostate cancer will be affected by the stress associated with having a potentially lethal disease. Studies have, indeed, found that not only patients but also their spouses and others close to the patient, must develop coping strategies [65]. By contrast, there are also men who find solace and energy in the fact that they are not passively undergoing a malignant disease but are actively undertaking a potentially beneficial treatment [66]. ADT is sometimes an alternative to ‘watchful waiting’ in the management of prostate cancer and the side effects of ADT must be balanced against the potential gain in life expectancy and quality of life [66].
This article is made possible thanks to an educational grant from Bayer Schering Pharma AG Conclusions When treating hypogonadal men with testosterone, clinicians almost always observe remarkable changes in mood, self-esteem and vitality. This and the impressive effects which testosterone has on the sexual appetite, testify to the profound effects testosterone exerts on the brain and the mind. Conversely, hypogonadism and particularly the profound hypogonadism resulting from ADT in men with prostate cancer, are associated with loss of vitality and mood disorders, if not depression. In the literature there is evidence for a role of testosterone on cognition (particularly visuo-spatial abilities), development of Alzheimer’s disease, mood and depression. Studies of hypogonadal men and outcomes of testosterone administration support this notion. But other studies fail to confirm the association
between testosterone and mental functions. These discrepancies might be explained by the large variations in design, inclusion criteria with regard to threshold values of testosterone, duration of study and psychometric instruments. It is likely that men with plasma testosterone values below the lower limit of normal will benefit (most). With this state of affairs it is too early to prescribe testosterone as a primary treatment to men with impaired cognitive functioning or mood disorders. However, encountering men with these complaints might be reason to consider testosterone deficiency as an etiological factor, and if, upon laboratory measurement, testosterone levels are truly hypogonadal, testosterone treatment is warranted, not solely for its potential benefits on mental functioning but also for the somatic benefits that normalization of testosterone levels will have.
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