Thinking with your gonads: testosterone and cognition.

Sex hormones play a crucial role during brain development, but do they modulate or maintain cognition throughout life? Despite several million prescriptions annually for testosterone supplementation, we do not really know the answer. Here I review recent evidence that testosterone alters neural activity essential for learning and memory, and plays an important role as a neuroprotective agent in aging. In particular, testosterone deprivation is associated with poor memory in men and replacement can enhance memory and spatial cognition. However, there is little evidence that testosterone selectively affects only those cognitive domains where sex differences in performance have been found. There are also gaps in our knowledge surrounding the individual cognitive processes altered by testosterone, their neural basis, and the degree to which testosterone affects cognitive performance in women.

Introduction

The sex hormone testosterone plays a crucial role in the brain organization necessary for sexual development and sexual behavior. However, testosterone is present throughout life in cortical regions important for cognition. This review comes at a crossroad in cognitive neuroscience. Designer pharmaceuticals are in development that are capable of modifying specific cognitive processes and brain systems. New formulations of testosterone make testosterone replacement in men and women a reality, but without a full understanding of its effects on the brain and almost no data on its effects on cognition in women. Here I review neurobiological and cognitive studies that show that testosterone's role as a cognitive modulator is complex but that it could be particularly important for maintaining cognition in aging. There is very little known about cognitive effects of testosterone in women, so much of this review will focus on findings in men. Not reviewed here are studies of the organizational effects of testosterone during early development, the effects on cognition of anabolic steroid abuse, effects in people with congenital endocrine abnormalities or effects of endocrine manipulations in people seeking gender reassignment. Findings in those groups are of great scientific interest, but not likely to be generalizable to testosterone's effects in young and elderly healthy normal adults. In sum, researchers are beginning to gather some knowledge but there is much room for focused, hypothesis-driven studies of this topic in the future.

Cognitive effects of testosterone


Memory effects: animal models

Androgen deprivation by gonadectomy in rodents impairs performance on memory measures that require the hippocampus such as maze learning and fear conditioning. Testosterone replacement normalizes performance. Hippocampal-independent measures such as the ability to balance on a rotating rod are unaffected. The accumulation of beta amyloid, a risk factor for Alzheimer's disease, increases with testosterone deprivation. Blockade of androgen receptors in transgenic mice expressing the apolipoprotein E4 allele, which is a risk gene for Alzheimer's disease in humans, impairs memory on a maze learning task.

Translating between animals and humans

Parallel studies in humans and animal models are not simple. The great majority of the animal studies compare models with complete androgen deprivation (e.g. gonadectomy) to replacement of testosterone or its metabolites. However, in humans the main interest has been in whether native testosterone levels are related to cognitive abilities and whether lower testosterone (but not no testosterone) has cognitive effects. A focus of interest has been whether testosterone can protect people from aging-related cognitive loss, with much of the research focusing on elderly men. By constrast, most studies of the neurobiology and neurobehavioral effects of testosterone use adult but not old rodent or non-human primate models. Thus, the devil is in the details when evaluating what cognitive functions are modified by testosterone, under what circumstances and at what time of life.

Testosterone and cognitive aging

Bioavailable testosterone levels decline with age in men and women. However, unlike menopause when estradiol falls to nearly undetectable levels, testosterone production declines slowly in healthy men such that those in their seventies have approximately 40% lower testosterone than men in their twenties. A precipitous decline in testosterone occurs in women on postmenopausal hormone replacement.

Numerous studies suggest a link between testosterone and cognition in men, particularly with aging, but there have been few studies of women. There is a positive relationship between bioavailable testosterone levels and memory in older men and women. Two recent studies show positive relationships between endogenous testosterone and memory, and processing speed in men, and attention in men and women, but they suggest that this relationship is particularly true in aging. By contrast, other studies show that age but not testosterone is related to mental rotation or digit span when several common covariates are considered in the analysis.

Placebo-controlled and dose-response studies suggest that testosterone supplementation can modify cognition, particularly in older men. Testosterone supplementation improves spatial cognition and working memory in healthy older men. Visual-spatial cognition improves in older men with testosterone replacement in a dose-dependent manner, but similar effects are not found in young men. Spatial memory performance improves in men with testosterone supplementation regardless of whether pharmacological manipulations (aromatase inhibitors) permit its conversion to estradiol. However, verbal memory improves only if conversion to estradiol occurs, suggesting estradiol mediates testosterone's role in verbal memory in men.

There are weak associations between testosterone levels in older men and performance on the Trails-B test which assesses switching between cognitive sets as well as psychomotor speed, but supplementation in men with testosterone levels within the range of younger men does not significantly alter performance. Testosterone replacement has few effects in men with low or no testosterone throughout life (congenital hypogonadism) with the exception that verbal fluency is worse and improves with replacement, in comparison with men with normal testosterone levels. By contrast, in another study word-list learning does not improve in supplemented hypogonadal men, nor is verbal and nonverbal memory, or mental rotation affected after a single injection of testosterone in men.

Testosterone and neurodegenerative disease

Lower premorbid testosterone levels are associated with a higher risk for Alzheimer's disease. Although controversial some studies suggest that low testosterone is associated with increased beta amyloid deposition in men, which is considered a major risk factor for the disease. Supplementation with testosterone in men who have Alzheimer's disease or mild cognitive impairment, a precursor to Alzheimer's disease, results in improvement in spatial memory or spatial cognition but results are not consistent across studies. The findings of positive effects on spatial cognition and memory are in contrast to studies showing no effect of estrogen supplementation in women with Alzheimer's disease, despite similar epidemiological evidence in women that long-term estrogen replacement decreases the risk for Alzheimer's disease, at least if initiated many years before the onset of the disease.

Testosterone in women

Few studies of testosterone supplementation are available for women. However, a series of related studies show that mental rotation, and object location memory improve, and attentional bias is reduced towards fearful faces but not happy faces within hours of a single injection of testosterone in young women.

Do sex differences signal testosterone effects?

Two kinds of information can be brought to bear on this question: (i) Studies that show a relationship between testosterone and performance on measures that also show sex differences but no relationship on measures that do not; and (ii) studies that examine sex steroid levels in normal men and women who perform at the limits of the range for their sex on tasks that show sex differences. The reasoning is that if men show an advantage on a task over women, then testosterone should relate to performance and men with higher testosterone should outperform men with lower testosterone. For example, men on average outperform women on tasks of spatial cognition, particularly, mental rotation. Indeed several studies cited above show effects of testosterone on mental rotation or a relationship between testosterone levels and performance, but some do not. When a single measure of testosterone is related to a single instance of cognitive performance, particularly in high functioning young adults with normal testosterone levels, few consistent results are found. In addition, sex differences in performance are maintained in aging when radical sex steroid changes have occurred, suggesting that circulating sex steroids are not the source of maintained sex differences in cognition in adulthood. Probably more important is that other cognitive domains, that show little or no sex differences are affected by testosterone loss or replacement, notably memory. Thus, sex differences in performance are not reliable signals of cognitive processes that will be influenced by testosterone in adulthood.

Summary

The effects of testosterone on cognition are not nearly as dramatic as the advertisements for the products suggest. This is true even in the most severe cases of testosterone deprivation or testosterone replacement in hypogonadal older men. However, the findings thus far are by no means piffle. The pattern across studies suggests that testosterone can have effects in adulthood when conditions make cognition fragile, such as when working and long-term memory decline in aging, or when testosterone levels are significantly modified, such as in replacement or hypogonadism. Reliable relationships between testosterone and cognition when both are optimal are less likely. This might be because testosterone has a subtle neuromodulatory role in adulthood but can be neuroprotective with brain aging when both cognition and testosterone levels decline. The specific cognitive and neural processes where testosterone plays a chronic but subtle neuromodulatory role have not been isolated even within domains such as memory and spatial cognition, where testosterone effects have been found. The isolation of testosterone's relationship to figural encoding, initiation of transformation or decision making but not the rotation process itself is one example of specifying modulated processes