Several important studies have evaluated the effect of estrogen replacement on the age related decline in learning and memory. In a recent study, Maki et al (2001) concluded that non-demented postmenopausal women receiving estrogen replacement therapy possessed better learning and verbal memory than did women who had never received estrogen replacement therapy. Although cognitive function is influenced by many factors, including education and exercise, loss of estrogen appears to be an important and independent determinant of certain aspects of cognition in postmenopausal women.
Observational studies also suggest that estrogen may delay or prevent the onset of Alzheimer’s disease [AD]. A study conducted by Tang et al (1996) determined that the age of onset for AD was significantly later in women who had used estrogen supplements than among those who had not. Women who used estrogen for more than one year remained free of AD for significantly more years than did women who used estrogen for less than one year or those who had not used it at all (Tang et al 1996)
One mechanism by which estrogen may slow or prevent the onset of AD is by reducing the production and deposition of beta-amyloid protein, which is involved in the pathogenesis of AD. Seven to 10 days of therapy with physiological levels of estrogen, reduced the amount of beta-amyloid generated by human embryonic neurons (Xu et al 1998).
While research on the role that hormone replacement therapy (estrogen supplements) may play in preventing or delaying AD appears promising, most studies investigating the affect of estrogen therapy on symptoms and progression of disease in women with existing AD have not shown a benefit (Henderson et al 2000) (Mulnard et al 2000). There is growing awareness that the past use of estrogen, particularly at the time of menopause, may have a disproportionate effect on age-related cognitive decline and dementia. Women experiencing a more rapid loss of estrogen, as with a surgical menopause, may be more vulnerable. For example, women undergoing a surgical menopause have 3 times the risk of developing Parkinson’s disease as those experiencing a natural menopause (Benedetti et al 2001).
These finding show that the hormone estrogen has a variety of physiological and anatomical functions in the areas on the CNS involved with cognition. Furthermore the findings show that HRT prevents the decline, particularly in verbal memory, associated with estrogen loss at the onset of the menopause. If these finding suggest that the sex hormone estrogen improves cognitive function in women and delays the onset of Alzheimer’s disease than what about the effects of the male hormone testosterone?
Although both hormones are produced by both sexes in some measure, estrogen levels are considerably higher in women and testosterone levels are higher in men (Christiansen 1993). Estrogen, not surprisingly, tends to promote “female” mental skills, such as verbal articulation, fine motor control and perceptual speed, while it depresses “males” skills, such as spatial analysis and deductive reasoning. These finding are based on studies of women at different points in the menstrual cycle, as well as comparisons of postmenopausal women who either do or do not take estrogen replacement therapy. Estrogen is highest just before ovulation and the lowest in the first few days of menstruation, so it would seem that while women are menstruating their abilities appear to resemble cognitive characteristics exhibited by males and towards the middle of their cycle more female cognitive characteristics(Christiansen 1993).
The effects of testosterone on cognition are more complex than those demonstrated by estrogen. Higher levels of testosterone are associated with better mathematical and spatial skills (Geschwind et al 1985). As might be expected men tend to outperform women on these skill and women tend to outperform men in verbal abilities. Geschwind and Galaburda (1985) proposed that concentration of testosterone are responsible for alterations in the central nervous system. They predicted that elevated levels of testosterone slow the growth of the left hemisphere, which consequently leads to an enhancement of certain cognitive abilities (spatial, musical or ,mathematical abilities) hypothesised to be dependent on right hemispheric functioning (Geschwind et al 1985).
A few studies have so far indicated that there is a curvilinear relationship between levels of testosterone and spatial abilities. An earlier study by Shute et al (1983)found that females with the highest plasma androgen (male that is involved in expressing secondary male characteristics) levels performd better in spatial tests than females with the lowest androgen levels, whereas males with the highest androgen levels performed worse than males with the lowest androgen concentrations (Shute et al 1983).
Gouchie and Kimura confirmed Shute’s study, finding a non-linear relationship between testosterone levels and spatial performance (Gouchie et al 1991). Males with lower testosterone levels performed better than males with higher levels, while female’s performed better in spatial tests than those with lower testosterone levels. It was proposed that testosterone functions at optimal levels that have lower physiological values for men and higher for women (Gouchie et al 1991).
However not all studies investigating the relationship between testosterone and spatial ability have found a curvilinear effect. Christiansen et al (1993) reported a positive relationship between testosterone and spatial ability in men. However, Mc Keever et al failed to find any relationship between plasma testosterone levels and spatial visualisation tests in both male and female students (McKeever et al 1990)
Other work suggests that testosterone, like estrogen, may help prevent the development of AD and its resulting memory decline. A study conducted by Yonker (2003) found that compared with healthy men those with AD have lower levels of testosterone. They also found that testosterone supplements improved verbal and spatial memory in a small group of men with AD. (Yonker 2003). The implication of these findings suggests that testosterone may prevent AD by warding off the brain destruction that marks the disease. Studies of rat brain cells found that the hormone limits the production of beta-amyloid peptide, thought to be a prime contributor to AD. (Xu et al 1998)
Similarly, testosterone may also help ward off AD by directly preventing brain cell death. Research led by Gelfand et al (2001) were the first to show that testosterone protects neurons against cell death, suggesting the male sex hormone may also have potential as a preventative therapy for both men and women. Gelfand et al manipulated human brain cells and caused them to die prematurely. The results showed that by adding doses of testosterone this limited the cell death (Gelfand et al 2001).
While together the results show a positive side to testosterone, scientists say that more research needs to be conducted before they would encourage people to take testosterone supplements to aid cognition. However, with its benefits, testosterone may also cause negative effects. For example, some believe that it may spur the development of prostate cancer in certain individuals. (Halmos et al 2000). The additional studies on large groups of people will help researchers evaluate whether the pluses of testosterone outweigh the minuses.
Researchers also plan to define the specific mechanisms that carry out certain brain benefits. Specialists in the field are currently using brain imaging techniques and molecular methods to track how testosterone induces its actions. Morrison (2001) demonstrated how testosterone can convert to estrogen in the brain (Morrison 2001), so as part of this work, further research was spurred to discover whether the cognitive benefits shown are directly from testosterone or the mechanisms that occur after its conversion. Researchers have developed a method to test this, by effectively blocking an enzyme that converts testosterone to see if it would still create positive effects (Halmos et al 2000). Specific information about such uncertainties will not only provide scientists with the tools on how testosterone functions, but further research into this area could help formulate a drug that only activates the positive effects but also without unwanted side effects (Halmos et al 2000).
Cognitive impairment such as Alzheimer’s disease is a growing and as of yet, an inevitable disease as our population ages. As a result, the role of hormone replacement therapy to regulate cognitive functioning is therefore crucial in treatment. While estrogen replacement therapy shows promise in helping post-menopausal women preserve important cognitive abilities, such as memory, its effectiveness is still being questioned.
In conclusion the last ten years has shown a significant number of studies which have been conducted to explore the possibility of a connection between sex hormones and cognitive decline such as dementia. The potential role of estrogen in the prevention of Alzheimer’s disease (AD) and other forms of dementia is an exciting area of research. Evidence to date provides a rationale for considering the role of estrogen in preventing or treating AD. The evidence suggests that estrogen improves performance of selected memory tasks in otherwise healthy women who are estrogen deficient (Sherwin 1997). Retrospective case-studies have yielded mixed results. Some studies showed a protective effect of ERT on the development of AD (Xu et al 1998), while others have not demonstrated this benefit (Benedetti et al 2001). On the other hand a small number of trials in women with AD have suggested benefits in cognition (Xu H, et al 1998).
Similarly other work suggests that testosterone, like estrogen, may help prevent the development of AD and its resulting memory decline. Scientists found that compared with healthy men, those with AD have lower levels of testosterone (Yonker 2003). Furthermore, research findings on estrogen and testosterone has argued sex hormones may have an impact on those cognitive tasks that typically exhibit sex differences; namely, high levels of testosterone may have a negative impact on visuospatial ability in men, whereas estrogen may positively influence episodic memory in women(Yonker 2003).Since estrogen promotes neuronal sprouting and enhances cholinergic activity in the brain, researcher’s rationalise that its use may prevent or adequately treat Alzheimer’s disease.
However, in spite of numerous clinical trials, definitive findings that support or question the role of the benefits of estrogen and testosterone (in delaying the onset, preventing or diminishing the symptoms) of Alzheimer’s disease have not yet been reached. But it is evident that our hormonal system effects our cognitive functioning in a number of ways and researchers are now hoping to develop techniques which cause selected benefits from hormones, mainly estrogen. Once the hormone’s mechanisms are better understood, the next step for scientists would be to develop hormonal type drugs that target specific brain actions. This step could revolutionaries’ medical practice and treatment forever.
Reference page
- Osterlund MK, et al. Neuroscience.2000; 95:333-42.
- Sughrue PJ, et al. Neuroscience. 2000; 96:41-9.
- Orikasa C, et al. Brain Res Dev Brain Res. 2000; 120:245-54.
- Birge SJ. Menopause Management. 2000; 13-21.
- Maki PM,et al. American journal of psychiatry. 2001; 158:227-33.
- Behl C, et al. Molecular Pharmacology. 1997; 535-41.
- Resnick SM, et al. Hormonal behaviour. 1998 34:171-82.
- Shaywitz SE, et al. JAMA. 1999; 281: 1197-202.
- Tang M-X, et al. Lanct. 1996; 348: 429-32.
- Xu H, et al. Natures Medicine. 1998; 4:447-51.
- Henderson VW, et al.JAMA. 2000; 54:295-301.
- Mulnard RA, et al. JAMA. 2000; 283:1007-15.
- Benedetti MD, et al. Movement disorder. 2001; 16:830-7.
- Christiansen K. Sex hormone and cognitive function in men. Neuropsychobiology 1993;2797-107
- Geschj, wind N, et al. Cerebral lateralisation. Arch Neurol., 1985; 42:428-459.
-
Shute VJ, et al. The relationship between andogen levels and human spatial abilities. Bulletin of the Psychonomic Society. 1983; 21:465-468.
- Gouchie C, Kimura D. The relationship between testosterone levels and cognitive ability patterns. Psychoendocrinology 1991; 16: 323-34.
- McKeever WF,Deyo RA. Testosterone, dihydrotestosterone and spatial task performance of males. Bull Psychonom Soc 1990; 28:305-308.
- Yonker JE. 2003. http://www.su.se/forskning/disputationer/spikblad/JulieYonker.pdf
-
Gelfan M, et al.: Testosterone -mediated neuroprotection through the androgen receptor in human primary neurons. Journal of Neurochemistry 2001; 77:1319-1326
- . Sherwin BB. Estrogen effects on cognition in menopausal women. Neurology. 1997; 48(Suppl 7): 21-26
- Halmos et al. Medical Sciences. 2000 Vol. 93, Issue 6, 2398-2402
- Morrison MF. Hormones, Gender and the aging brain. (2001)
- Yonker JE. 2003. Abstract can be found at http://www.su.se/forskning/disputationer/spikblad/JulieYonker.pdf
