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Abstract

Although the cognitive benefits of estrogen therapies have been extensively studied in women, understanding of the cognitive benefits of androgen therapies in men has lagged behind. This review synthesizes current clinical research and animal research on the effects of testosterone and its major metabolites on spatial memory in young and aged males. Spatial memory and associated hippocampal function show age-related decline, and current research indicates that testosterone treatments may ameliorate some of the cognitive effects of aging. This review highlights testosterone dose, long-term versus working memory, place versus response strategies, and estrogen versus androgen pathways as key variables that influence the relative impact of testosterone on spatial memory. Despite inconsistencies, there is considerable evidence from rodent and clinical research that testosterone can improve spatial memory. The cognitive benefits are most consistent when testosterone is given to hypogonadal males for a prolonged period.

Introduction

A decline in some forms of memory is a well-known consequence of aging.¹ Normal aging is associated with deficits in episodic memory, attention, and working memory, with other cognitive domains remaining relatively intact.^2,3 By age 50, the prevalence of memory impairment is more than three times greater than the general population, at 5.8% and 18.5%, respectively.⁴ This decline in cognitive function may be partially due to decreasing levels of sex steroid hormones with aging, pointing to an important clinical role for testosterone.^5,6 Aging also increases the risk for pathological memory loss, including mild cognitive impairment and dementia, and there is evidence that risk of both these conditions increases with reduced testosterone.^6,7 This review will summarize evidence from human and rodent research that testosterone influences memory in both young and aged males.

Although aging leads to a general decline in learning and memory, spatial memory is particularly vulnerable.^3,8 Spatial memory, broadly defined, is the ability to perceive, encode, store, visualize, retrieve, manipulate, transform, and integrate spatial information drawn from one or multiple environmental cues.^9,10 This important cognitive ability is nurtured through an organism's typical exploration of its environment and is critical in acquiring new information to inform later navigational decisions. Similar to all forms of memory, spatial memory can be further subdivided into long-term, short-term, and working memory.¹¹ Long-term spatial memory is typically classified as a type of episodic memory: explicit memories about personal experiences that do not easily decay over time.¹² In the context of rodent research, long-term spatial memory is often referred to as “reference memory,”¹³ but we will use “long-term memory” for this review to maintain consistency. Short-term memory is distinct from long-term memory in that it decays more rapidly over time and has limited capacity.¹¹ Working memory involves actively applying a memory to attend to a specific task for as long as it is useful to complete the task.¹¹ These distinctions between forms of spatial memory are important, as testosterone's effects vary depending on the type of memory. Among the forms of memory, short-term is the most difficult to characterize and has been rarely assessed in the context of testosterone studies, so our focus will be the distinction between working and long-term memory.

When an individual is navigating through space to reach a goal, one of two strategies can be employed: a place strategy or a response strategy.¹⁴ A place strategy involves using knowledge about the positions of environmental cues relative to a goal and relative to one's own position to locate the goal,^15,16 whereas a response strategy involves using stimulus–response associations to locate a goal.^15,16 There is considerable evidence that the ability to effectively use a place strategy relies on the hippocampus, whereas use of a response strategy relies on the striatum.^15,17–19 For example, acetylcholine release in the hippocampus predicted use of a place strategy for adult male rats in a T-maze, whereas acetylcholine release in the striatum predicted use of a response strategy.²⁰ The terms allocentric strategy and egocentric strategy are also sometimes used,²¹ and these are roughly equivalent to place and response strategies, respectively.

When considering the effects of sex steroids on the various forms for spatial memory, the distinction is often made between organizational and activational effects. The steroidal conditions in which the brain develops have a profound effect on the long-term organization of the brain in terms of both neuroanatomy and neurochemistry.^22,23 These organizational effects occur during critical periods of brain development (e.g., neonatal period and puberty), whereas the more transient effects of sex steroids on the adult brain are referred to as activational. Numerous experiments with humans and rats have demonstrated that testosterone has organizational effects on the brain early in development that lead to enhanced spatial learning and memory in adulthood.^24–28 In one experiment, testosterone was given to male and female rats in the first week after birth.²⁸ Testosterone-treated females performed better than control females and comparable with control males on the Morris water maze (MWM), which assesses long-term spatial memory. In contrast, testosterone treatment during early development had minimal effect on male spatial memory. Although these organizational effects of testosterone are important developmentally, the focus of this review will be on the activational effects of testosterone. It should also be acknowledged that the adult brain is more plastic than was once believed, and the activational effects of sex steroids can influence many forms of neuroplasticity in the adult (e.g., synaptogenesis and neurogenesis), as described hereunder.

Sex Differences in Spatial Memory

A sex difference in a physiological or behavioral trait suggests that it may be regulated by sex steroids, and the same is true for cognitive traits. A male advantage for spatial ability is one of the best characterized human sex differences in human cognition.^29–32 This sex difference is most apparent for the mental rotation task, which tests participants' ability to mentally rotate a two- or three-dimensional object.³¹ Brain-imaging studies indicate that this task relies heavily on cortical brain regions, with males relying more on the parietal cortex and females relying more on the frontal cortex.^33–37 Males also outperform females on some other spatial tasks, including object location memory,³⁸ route-learning,^39,40 and maze navigation.^41–46 Based on functional magnetic resonance imaging (fMRI) studies, maze navigation tasks rely heavily on the hippocampus and parietal lobes, with males generally showing greater activation of the hippocampus than females.^47,48

Among rats, males have better working and long-term spatial memory based on performance in the MWM,^49–52 radial-arm maze (RAM),^53,54 and object location memory task.⁵⁵ For example, one study demonstrated that female rats performed better than males on the novel object recognition task, whereas males performed better than females on the object location memory task.⁵⁶ The object location task relies more on the hippocampus than does the novel object task,⁵⁷ suggesting a sex difference in hippocampal function. A meta-analysis of experiments conducted with rats and mice also concluded that there is a male advantage on spatial tasks.⁵⁸ It is important to note, however, that human females consistently outperform males on tasks that involve remembering the relative position of objects in an array.^59–61 Similarly, one experiment found that female rats had longer memory retention than males on a task that involved remembering the relative positions of two objects in an array of four objects.⁵⁵

When solving spatial tasks, men preferentially use a place strategy involving Euclidian cues, whereas women preferentially use a response strategy involving local landmarks,^62–65 and some studies have found that men perform better than women on tasks that require a place strategy.^66,67 For example, in a virtual reorientation task, females were more likely to use a response strategy to find a goal, whereas males were more likely to use a place strategy (i.e., create a mental map of the virtual environment).⁶⁸ Similar sex differences in spatial strategy use have been demonstrated with rodent experiments. In a classic study, Williams et al.⁶⁹ found that altering the geometry of the testing room impaired performance of male but not female rats on the RAM. In contrast, rearranging landmark cues impaired the performance of females but not males.⁶⁹ Thus, males relied on a place strategy and females relied on a response strategy. Similarly, female rats show a strong bias for using local landmarks to find the escape platform in water maze tasks,^49,70,71 whereas males rely more heavily on extra-maze cues.^72,73 Male rats outperformed females in the water maze when a place strategy was required to solve the task, but no sex difference was observed when response strategies (local cues or a turn bias) could be used to solve the task.⁷⁴ Similarly, female rats made more errors than males when they had to switch from a response strategy to a place strategy.¹⁶

There is considerable evidence that the activational effects of sex steroids play a causal role in sex differences in spatial strategy preferences as well as spatial learning and memory more broadly. Meta-analyses indicate that sex differences in various spatial abilities become more apparent after puberty in humans.^29,31 However, a female bias for locating and using landmarks for navigation seems to arise before puberty,⁷⁵ and some studies have found a sex difference in route learning in children as young as 6 years old.^76,77 No sex differences were observed on the water maze among juvenile rats (18–24 days old),⁷⁸ and one study found that unlike adult rats, juvenile rats did not show a sex difference in spatial strategy preference.⁷¹ Thus, at least some sex differences in spatial memory seem to be due to the activational effects of sex steroids, whereas others may be established early in development.

Human Research with Younger Males

Some reviews have concluded that elevated circulating testosterone levels do not consistently improve spatial memory in men.^79,80 Despite inconsistencies, however, past research indicates that testosterone levels in males correlate with improved mental rotation ability,^81–83 route-learning,⁸⁴ and performance on a block design task.⁸⁵ Discrepancies among studies seem to be at least partially due to dose-dependent effects of testosterone. The relationship between circulating testosterone levels and spatial memory has often been described as an “inverted U” or negative parabolic relationship. Shute et al.⁸⁶ conducted two studies on free circulating testosterone in healthy adults. They found that males with relatively low levels of circulating testosterone performed better on spatial tests than males with higher levels. This trend was reversed for females—those with relatively high levels of circulating testosterone performed better on spatial tests than females with lower levels. This relationship has been replicated several times,^87,88 suggesting that relatively high circulating testosterone levels improve spatial abilities in females but impair spatial abilities in males. In support of this conclusion, females given a single administration of testosterone made fewer errors on a mental rotation task than did those given a placebo.^89,90 Interestingly, there is evidence for a similar negative parabolic relationship between perinatal androgen exposure and masculine sexual behavior from both human and rodent research.⁹¹

There are also some studies with all-male populations that have supported the optimum-testosterone hypothesis.^44,92 For example, one study observed the effects of testosterone on spatial memory among eugonadal and hypogonadal males of approximately the same age.⁹³ In this study, supraphysiological testosterone levels were induced by injecting eugonadal males with testosterone. Spatial memory performance decreased in the testosterone-supplemented group relative to a eugonadal placebo group, whereas the hypogonadal group performed worse than either eugonadal group.⁹³ Some studies have demonstrated that long-term use of anabolic-androgenic steroids impairs spatial memory,^94,95 supporting the conclusion that supraphysiological levels of androgens have negative effects on memory. The dose-dependent effects of testosterone were also demonstrated by a study that analyzed both circulating testosterone and androgen receptor genotype.⁴⁴ The androgen receptor gene has a trinucleotide (cytosine-adenine-guanine [CAG]) sequence repeat on exon 1, and longer repeats are associated with weaker receptor activation.⁹⁶ Among males with the genotype for lower androgen receptor activity, higher testosterone levels predicted poorer performance on a virtual water maze task, whereas no relationship between testosterone level and performance was observed among males with high androgen receptor activity.⁴⁴ A more recent study with younger males found a positive relationship between number of CAG repeats and performance on a spatial visualization task.⁹⁷ Thus, although testosterone dose is clearly a critical variable, it may interact with other variables such as sex and genotype to determine the effects of testosterone on spatial memory.

Experimental manipulation of testosterone levels in younger men has primarily involved populations undergoing treatment for prostate cancer. Androgen deprivation therapy is a common treatment for prostate cancer because it reduces the rate that the cancer spreads.⁹⁸ Androgen deprivation therapy is sometimes followed up by testosterone treatment, but the therapeutic benefits of testosterone therapy remain controversial.^99,100 Among patients with prostate cancer, androgen deprivation therapy caused significant cognitive impairments, including impaired spatial memory, which were associated with changes in the right parietal–occipital regions of the brain.^101–105 However, in an experiment in which testosterone was given to hypogonadal young to middle-aged males (20–59 years old), no changes in spatial ability were observed.¹⁰⁶ Similarly, a short-term androgen deprivation treatment was found to have no effect on spatial cognition in both healthy younger (25–35 years old) and healthy older (60–80 years old) males.¹⁰⁷ In a study in which 2 years of testosterone treatment was given to hypogonadal young to middle-aged males without prostate cancer, regular testosterone injections resulted in improvements in attention, visual scanning ability, executive function, and psychomotor speed.¹⁰⁸ The opposite effect was found in eugonadal males, with subjects who received testosterone biweekly for 8 weeks performing worse than the placebo group.⁹³ In summary, studies in which testosterone levels were manipulated in young males provide only mixed evidence to indicate an activational role for androgens on spatial memory, with testosterone dose, duration of treatment, and possibly health status (i.e., with or without cancer) being key variables.

Few human studies have tested the effects of testosterone on the use of specific spatial strategies. A study of male and female college students found that higher levels of circulating testosterone in males, but not females, were associated with more use of a place strategy.⁸⁴ However, for a judgment of line orientation task, the addition of landmarks, which facilitates the use of a response strategy, helped males to solve the task if they also had relatively high circulating testosterone levels.⁶⁶ Given that the results of these two experiments are somewhat contradictory, further study is needed in this area.

Rodent Research with Younger Males

Given the lack of consistent results from human studies, it is useful to look to rodent research, which allows for better control of variables and easier use of testosterone manipulation. Multiple tasks are commonly used to test spatial learning and memory in rodents, varying in the type of memory tested and the motivator. The MWM requires rodents to escape a cold pool of water by navigating toward a hidden platform in opaque water using only external visual cues, with testing typically occurring over multiple days to measure long-term memory.¹⁰⁹ The Barnes maze is another aversively motivated task, which involves training subjects to find an escape hole among many holes around the edge of a circular platform, and this task is also most frequently used to measure long-term memory.¹¹⁰ The RAM is another commonly used spatial task, consisting of straight arms (8, 12, or 16) radiating out from a single central platform, with food rewards placed at the ends of specific arms. Arm entries can be used to score both working memory and long-term memory.¹³ Finally, the object location memory task relies on a rodent's natural tendency to explore novelty. Subjects are first allowed to explore two objects, and then one of the objects is moved and the subjects are re-exposed to the objects after a retention interval. Increased exploration of the moved object relative to the unmoved object is indicative of good spatial memory.¹¹¹ Various T-maze and Y-maze tasks have also been devised, with exploration of novelty and food reward being used as motivators.

The effects of testosterone on spatial memory among rodents are most clear for spatial working memory. In various versions of the RAM, T-maze tasks, and Barnes maze, castration impaired spatial working memory.^53,112–117 Furthermore, testosterone given to castrated male rats improved spatial working memory on the RAM and T-maze.^117–119 Thus, there is considerable evidence that testosterone improves spatial working memory, corroborating some findings from human research.

The effects of testosterone on long-term spatial memory among male rodents have been less consistent than the effects on spatial working memory. Experiments using the RAM suggest that testosterone either impairs long-term spatial memory^53,113 or has no effect.¹²⁰ Studies employing the MWM have shown that testosterone improves,^{118,121–123} impairs,^124–126 or has no effect^{113,127–130} on long-term spatial memory. Both the MWM and the RAM typically involve a 24-h retention interval. Experiments with the object location memory task have consistently shown that testosterone improves long-term spatial memory,^120,131,132 with the key distinction compared with the MWM being that relatively short (30–120 min) retention periods were used. Thus, testosterone may act primarily on working memory and long-term memories of shorter duration, but there are exceptions to this conclusion. Hawley et al.¹³³ studied the role of testosterone on long-term memory using a version of the Y-maze that is comparable to the object location task in that it relies on a rat's interest in exploring a novel location. They found that castration impaired performance after a 48-h retention interval and that performance was restored by testosterone implants. Similarly, one experiment using the Barnes maze demonstrated that castration impaired and testosterone implants restored long-term spatial memory (7-day interval).¹¹⁵ Procedural differences among tasks, possibly involving relative stress levels, may explain the inconsistent effects, but there is growing evidence that testosterone can enhance long-term spatial memory.

Supporting the previously mentioned results of human studies, experiments with rodents have shown that the effects of testosterone on spatial memory vary with dose. A number of studies using the MWM demonstrating a negative effect of testosterone or no effect on long-term spatial memory have involved supraphysiological doses.^{125,127,130,134–136} In contrast, Spritzer et al.¹¹⁸ found that testosterone doses ranging from low physiological to slightly supraphysiological resulted in better long-term spatial memory on the MWM relative to castrated controls. A subsequent experiment showed that both high and low physiological doses of testosterone improved spatial working memory (RAM) and long-term spatial memory (object location memory) in castrated male rats, but an intermediate dose did not.¹²⁰ These results suggest that the dose–response relationship for testosterone and spatial memory may be even more complex than the negative parabolic relationship that has been suggested by human research. Other experiments with male rats provide some support for this conclusion. Hawley et al.¹³³ gave castrated rats two doses of testosterone followed by testing on a Y-maze, and they found that the higher dose of testosterone, but not the lower dose, restored long-term spatial memory. This suggests that doses of testosterone that elevate serum testosterone levels slightly above a physiological baseline are sufficient to restore long-term spatial memory in castrated males. Jia et al.¹²² documented a negative parabolic relationship between testosterone dose and long-term spatial memory using the MWM. Thus, dose influences the effects of testosterone on both spatial working memory and long-term spatial memory, but the nature of the dose–response relationship is still being clarified.

Another critical variable that has not been considered in most previous studies with rodents is whether a spatial task is testing place memory, response memory, or some combination of the two. Place and response memory are assessed in rodents using various versions of a T-maze (Fig. 1), with a dual-solution task used to assess strategy preference and specific place and response tasks used to assess ability to use a particular strategy. The effects of estrogens on spatial strategies have been extensively tested using female rats.¹³⁷ Ovariectomized females given estradiol performed fewer errors than did ovariectomized females without estradiol on tasks requiring a place strategy, whereas for tasks requiring a response strategy, females without estradiol performed better than did females given estradiol.^138–140 In addition, intrahippocampal infusions of estradiol improved place learning in females rats¹⁴¹ and intrastriatal infusions of estradiol impaired response learning.^141,142 Testosterone has also been shown to mediate the bias between place and response strategies in a dose-dependent manner. In particular, a low dose of testosterone biased castrated male rats toward using a response strategy and a high dose biased them toward using a place strategy.¹⁴³ When the task required the use of a particular strategy, male rats given a low dose of testosterone made fewer errors on a response task, whereas a high dose of testosterone resulted in fewer errors on a place task.¹⁴⁴ Another study also found that male rats administered a low dose of testosterone performed worse compared with intact males when they were unable to use a response strategy on a working memory version of the RAM.⁵³ Interestingly, an intermediate dose provided no benefit for performance of either strategy,¹⁴⁴ which may explain why rats receiving this dose perform poorly on spatial tasks where they could make use of either strategy (Fig. 2).¹⁴³ Specifically, whereas a low dose of testosterone may activate the striatum and a high dose may activate the hippocampus, the intermediate dose is ineffective in activating either brain region, possibly due to a conflict between memory systems.^15,145 It could be that the striatum is more sensitive to testosterone than the hippocampus.¹⁴⁴ There are more androgen receptors in the striatum than in the hippocampus of male rats,¹⁴⁶ and low levels of circulating testosterone have been shown to downregulate androgen receptor expression in the hippocampus of male rats.¹²³ Failure to consider the interplay between testosterone dose and spatial strategy helps to explain why broad reviews of human research have concluded that testosterone has no effect on spatial memory.^79,80

FIG. 1.

Examples of plus-maze protocols used to test place and response memory. Arrows indicate correct choices for each version of the task. (A) For the place version of the task, the rat is released from three different arms and rewarded for entering the same arm (the west arm in this example). (B) For the response version of the task, the rat is released from any one of the four arms and rewarded for making the same directional turn (left in this example). Both the place and response task involve a predetermined number of trials (typically 80–100) conducted consecutively on the same day and the number of trials needed to reach a criterion (e.g., 9 out of 10 correct trials) is used as an index of memory. (C) A modified plus-maze is used for the dual-solution task. The dashed line indicates the location of a sliding door that converts the plus-maze to a T-maze. During training trials, rats are consistently released from the same start arm and receive a reward pellet in the same goal arm. Whether rats use a place (P) or response (R) strategy to solve the task is assessed during the probe trial conducted immediately after a set number of training trials. The dual-solution task assesses which strategy a rat is using to solve a task without forcing them to use a particular strategy.

FIG. 2.

Graphical model of the relationship between circulating testosterone levels and spatial working memory. Based on experiments with male rats,^{120,143,144,203} low and high serum testosterone leads to good performance on spatial tasks that require the use of a response strategy and a place strategy, respectively. Intermediate levels of testosterone are associated with poor use of both place and response strategies.

Human Research with Older Males

In men, testosterone levels begin to decline by age 30 at a rate of about 2% per year.^147,148 This decline leads to hypogonadism (serum testosterone levels consistently <325 ng/dL), which occurs in about 20% of men 60–69 years old and in about 50% of men >80 years old.¹⁴⁸ Andropause refers to this age-associated hypogonadism and related symptoms in males¹⁴⁹ and is thought to be due to impaired feedforward and feedback functions of the hypothalamic–pituitary–gonadal (HPG) axis.¹⁵⁰ Specifically, age is associated with a disruption of either the production of testosterone within the testes or impaired hypothalamic secretion of gonadotropin-releasing hormone (GnRH). Impaired GnRH regulation results in inadequate release of luteinizing hormone (LH) from the anterior pituitary, which in turn reduces the conversion of cholesterol to testosterone by Leydig cells of the testes.¹⁵¹ There is also evidence that a lack of negative feedback inhibition from testosterone by the testes in aged males can lead to unusually high levels of circulating LH,¹⁵² which may be a causative factor in the progression of Alzheimer's disease (AD).^153,154 In addition, longer CAG repeat sequences in the androgen receptor were shown to predispose males to hypogonadism in older age.¹⁵⁵ Thus, andropause involves dysfunction of the entire HPG axis.

Andropause can lead to many negative clinical implications: decreased muscle tone and strength, increased fat mass, decreased bone mineral density contributing to osteoporosis, decreased insulin sensitivity, impaired glucose tolerance, and negatively affected mood.^156–158 Given that this decline in testosterone parallels the age-related decline in cognitive ability, there has been much speculation regarding a causal link between the two.^5,32 Both human and rodent studies indicate that memory tasks involving the hippocampus and the prefrontal cortex are most severely affected during both normal aging and by pathological aging.^3,159–161 Spatial ability, in particular, is negatively affected, with older males exhibiting impaired learning and memory on a variety of spatial tasks.^3,79,162

Cross-sectional studies have shown a positive correlation between testosterone levels and cognitive ability in older men.^163,164 In a longitudinal study involving 407 nondemented older men followed for 10 years, higher testosterone levels were associated with better spatial ability and a reduced rate of decline in visual memory.¹⁶⁵ Testosterone-supplementation studies with healthy older males have produced mixed results, with some results showing improved spatial ability in males receiving testosterone,^166,167 and others showing no effect of testosterone on cognition.^168,169 One month of testosterone supplementation was shown to significantly improve working memory in healthy older men (61–75 years old) to a level comparable with that of younger men (23–34 years old),¹⁷⁰ but this experiment did not specifically test spatial memory. Similar to studies with younger males, androgen deprivation therapy for prostate cancer has been shown to impair memory in older males.^171,172 Discrepancies among studies may be due to differences in the duration of hormone exposure and the specific doses used. Cherrier et al.¹⁷³ found that a moderate dose of testosterone (100 mg) injected weekly for 6 weeks caused healthy older males to perform better on spatial memory tasks than those injected with either low or high testosterone doses (50 or 300 mg). Thus, moderate testosterone supplementation may be best at improving memory in older males.

A nonquantitative review of four clinical trials (conducted 2003–2006) involving testosterone treatment in older males concluded that testosterone supplementation had moderate positive effects on selective cognitive domains, including spatial abilities.⁶ However, a more recent review of clinical trials concluded that testosterone treatment had minimal effect on cognitive abilities and the authors suggested that prolonged, rather than acute, treatments with testosterone may be needed to see positive effects.¹⁷⁴ Two recent meta-analyses of clinical trials involving testosterone supplementation came to opposite conclusions. Buskbjerg et al.¹⁷⁵ synthesized 23 randomized clinical trials, mainly involving older subjects, and concluded that testosterone supplementation had no effect on cognitive functioning among eugonadal males. In contrast, Tan et al.⁷ synthesized 14 randomized clinical trials and concluded that testosterone supplementation resulted in improved executive function and improvement on a cognitive composite score. Key differences between the two meta-analyses were that: (1) Tan et al. used only trials involving healthy older males, whereas Buskbjerg et al. included studies with a wider age range and included studies on males with dementia at the time of treatment; (2) the Tan et al. study only included clinical trials with a documented increase in circulating testosterone due to treatment, whereas the Buskbjerg et al. study did not. Thus, testosterone supplementation may be most beneficial when given for prolonged periods to elderly males before the onset of any cognitive impairments and it should result in a quantifiable increase in circulating testosterone. Somewhat surprisingly, Tan et al. did not find that baseline testosterone was predictive of post-treatment cognitive abilities; rather, final circulating testosterone levels after treatment was the key predictor.⁷ It should also be added that both of the meta-analyses included studies that assessed a broad range of cognitive functions, although some form of visuospatial memory was commonly included in testing batteries.

Aging has been shown to lead to increased use of a striatum-dependent response strategy rather than a hippocampus-dependent place strategy in males and females,^21,176,177 which suggests that neurodegeneration within the hippocampus, specifically, plays an important role in age-related memory loss. A study in which both sexes navigated through a virtual 8-arm maze showed that 84% of children (8 years old), 46% of young adults (19–40 years old), and 39% of older adults (53–85 years old) employed a place strategy to solve the task.¹⁷⁷ Another study showed a similar decrease in the use of a place strategy by both sexes with increasing age.¹⁷⁸ Some studies have shown that this increased preference for a response strategy among aged individuals is due to an impaired ability to employ a place strategy.^176,179,180 For example, when participants were asked to explain changes in the position of an object in a virtual room, younger subjects performed better than older subjects when distal cues were changed (place learning), whereas there was no age effect when only the relative position of the observer was changed (response learning).¹⁸¹ One study examined the neurological correlates of the age-related shift in spatial strategy using fMRI and demonstrated that younger adults showed more activation of the hippocampus than did older adults when solving a spatial navigation task and, as expected, older adults showed greater activation of the striatum.¹⁸² In combination with the studies demonstrating age-related hippocampal atrophy,^2,159,183 these results suggest that hippocampal deficits force elderly individuals to rely more heavily on the striatum for spatial memory.

AD shows similar incidence between the sexes up to age 80, when women show greater incidence than men.¹⁸⁴ In addition, men show earlier mortality than women after developing AD.^184,185 These results suggest that sex steroids may play a role in the progression of AD. Deficits in spatial memory are symptomatic of AD, and decreased spatial working memory seems to be particularly useful in diagnosis.¹⁸⁶ Two cross-sectional studies have shown that males with AD have significantly lower serum testosterone levels than nonsymptomatic control subjects.^187,188 A long-term longitudinal study (subjects followed 4–37 years) demonstrated that baseline testosterone levels were lower in males who developed AD later in life.¹⁸⁹ Another large longitudinal study followed 4069 males over an average of 10.5 years and found that low baseline testosterone levels were a significant predictor for developing dementia later in life.¹⁹⁰ A shorter (1-year) study also found the low baseline testosterone levels predicted increased risk of developing AD.¹⁹¹

Studies involving males with AD or mild cognitive impairment showed that testosterone supplementation improved cognitive abilities in general and improved spatial memory in particular.^166,192 In contrast, one study found no effect of testosterone on males with mild cognitive impairment,¹⁹³ and another found that testosterone improved “quality of life” in AD patients but had no effect on cognition.¹⁹⁴ Some of these varied results may be due whether or not individuals are carriers for the APOE4 allele of the APOE gene, which codes for the lipid-transport protein apolipoprotein E. In healthy older males without the APOE4 allele, circulating free testosterone levels were positively correlated with cognitive function, whereas in males with the APOE4 allele, testosterone level was negatively correlated with cognitive function.¹⁹⁵ One short-term study found that androgen deprivation increased levels of anxiety and depression as well as circulating amyloid-β levels.¹⁹⁶ In a study that encompassed 9272 males with prostate cancer, it was found that androgen deprivation therapy led to a significant increase in the likelihood of developing AD.¹⁹⁷ The absolute increase was only 4.4%, but this involved a doubling of risk from 3.5% in patients not receiving therapy to 7.9% among those receiving androgen deprivation therapy (hazard ratio = 2.17).¹⁹⁷ Two even larger studies (23,651 and 154,089 subjects) also concluded that androgen deprivation therapy increases risk of developing AD and other forms of dementia, although with smaller hazard ratios (1.34 and 1.14, respectively).^198,199 A recent meta-analysis of 13 studies concluded that androgen deprivation therapy, regardless of method, leads to a 21% increased risk of dementia in patients with prostate cancer.²⁰⁰ Thus, hypogonadism is associated with increased risk of AD, and androgen therapies hold promise for treating and possibly preventing the development of AD and other forms of dementia.

Rodent Research with Older Males

As with humans, male rats show an age-related decline in testosterone^201–203 and aging impairs spatial memory. In a mouse model (SAMP8) that shows early memory decline (8 months old), circulating testosterone levels were found to drop significantly more with aging relative to wild-type mice.²⁰⁴ Older male rats performed worse than young rats on the Barnes maze.^205,206 Similarly, increased age has been shown to impair both long-term spatial memory and spatial working memory on a variety of tasks, including the MWM,^124,160,207 water-escape RAM,²⁰⁸ and the traditional RAM.^203,207 Aging also impaired long-term spatial memory on the object location memory task.²⁰³

Castration alone has been shown to have no effect on spatial memory in aged male rats tested using a variety of tasks,^203,206 but this is not unexpected as testosterone levels are already quite low in aged males before castration.²⁰³ Testosterone supplementation, however, improves spatial memory in aged males. Using a water-escape RAM, Bimonte-Nelson et al.²⁰⁸ found that testosterone supplementation given to intact aged males improved spatial working memory but not long-term spatial memory. An experiment with a traditional food-reward RAM showed that testosterone injections caused dose-dependent improvement in spatial working memory among aged male rats, with both high and low doses of testosterone improving memory in a manner similar to that demonstrated for young males.²⁰³ In contrast, an intermediate dose of testosterone was optimal for improving long-term spatial memory on an object-location memory task, suggesting differences in the optimal dose for working and long-term memory.²⁰³ A study with mice showed that testosterone injections improved spatial working memory (RAM) similarly in both aged (18 months old) and young (29 days old) mice.²⁰⁹ Thus, growing evidence indicates that testosterone supplementation can improve multiple forms of spatial memory in aged male rodents.

As with humans, aging influences spatial strategy use among rodents. Young male rats are significantly more likely than aged males to use a place strategy rather than a response strategy on a dual-solution task.^110,206 A study using various water maze tasks showed that aged male rats performed significantly worse than young males on a place task and that there was no effect of age on performance on a response task.²¹⁰ These results parallel the general findings with aged human subjects. An interesting experiment divided aged male rats into those with impaired or unimpaired spatial memory based on preliminary performance on the MWM, and then aged and young subjects were tested on place and response tasks.²¹¹ Memory-impaired aged males made fewer errors on a response task and young males made fewer errors on a place task. Interestingly, memory-unimpaired aged males performed well on both place and response tasks, and the authors suggest that this may be due to reduced competition between the hippocampus and striatum within this group.²¹¹ As all the subjects in this experiment were males, it is possible that the memory-impaired and memory-unimpaired groups had differences in circulating testosterone levels, but this was not measured. The potential role of testosterone in regulating the age-related transition from a place strategy to a response strategy should be explored further.

Some studies have tested the therapeutic benefits of testosterone in rodent models of AD. An androgen receptor antagonist (hydroxyflutamide) given to a transgenic male mouse model of AD (NSE-apoE) caused significant memory deficits on the MWM, suggesting a neuroprotective role for androgens.²¹² This conclusion was supported by a follow-up experiment in which the NSE-apoE mice also lacking androgen receptors were found to have impaired memory relative to mice with normal androgen receptor levels.⁴² In a triple-transgenic mouse model of AD, castration increased the rate of amyloid-β accumulation in the brain and treatment with the androgen-receptor agonist dihydrotestosterone (DHT) reversed this effect.²¹³ Jia et al.¹²² gave rats intrahippocampal injections of amyloid-β to model AD and found a negative parabolic relationship between long-term spatial memory (MWM) and testosterone dose. In a follow-up experiment using the same rat model, testosterone injections improved long-term spatial memory and flutamide (androgen-receptor antagonist) blocked this effect.²¹⁴ However, one study found that neither testosterone nor DHT supplementation had an effect on amyloid-β levels in aged male rats,²⁰⁸ suggesting that the memory-restoring effects of testosterone may not involve direct changes in amyloid-β. Overall, however, rodent experiments indicated memory-enhancing benefits of testosterone treatments for AD.

Metabolites of Testosterone: DHT and Estradiol

As alluded to previously, testosterone either binds directly to androgen receptors or is converted to DHT or estradiol to bind androgen or estrogen receptors, respectively. The enzyme 5α-reductase catalyzes the conversion of testosterone into DHT,²¹⁵ which has been shown to have about twice the binding affinity to androgen receptors and a fivefold slower dissociation constant from these receptors compared with testosterone.²¹⁶ The classic androgen receptor is a 110-kDa ligand-activated protein, which binds to DNA to act as a transcription factor.²¹⁷ Although poorly characterized, there are also membrane-bound androgen receptors that can have more rapid (nongenomic) effects on cellular functions.²¹⁸ Alternatively, testosterone can be converted into estradiol in the brain through P450 aromatase.^219,220 Estradiol acts through two known intracellular receptors (ERα and ERβ) to have genomic effects as well as through a G-protein-coupled estrogen receptor to have more rapid nongenomic effects.²²¹ Estrogens have been shown to regulate spatial memory in women, and these effects have been extensively reviewed.^32,222,223 Although steroidal mechanisms of action in the male brain have not been fully characterized, both estrogen receptors and androgen receptors have been localized to the hippocampus and striatum among male rodents.^{123,224–227} Thus, testosterone may influence male spatial memory through an androgen-dependent pathway, an estrogen-dependent pathway, or some combination of the two.

In support of a role for an androgen-dependent pathway, male rats with nonfunctional androgen receptors exhibited poorer spatial memory, as assessed by the MWM.²²⁸ Systemic DHT administration also restored long-term spatial memory among castrated male mice.²²⁹ Furthermore, DHT, but not estradiol, has been shown to enhance synaptic density and neurogenesis within the hippocampus of adult male rats,^230,231 and intrahippocampal injections of DHT improved long-term spatial memory among male rats.²³² In contrast, a study with aged male rats found no effect of DHT on spatial memory (neither working nor long-term), suggesting that testosterone improves memory through an estrogen-dependent pathway.²⁰⁸

In support of an estrogen-dependent pathway, two studies found that estradiol implants improved spatial working memory in castrated young male rats.^119,233 However, estradiol implants given to aged males had little effect on working memory but improved memory when there was a 2- to 3-h delay between choices,²³³ suggesting a role for estrogens in long-term spatial memory among aged males. Similarly, intrahippocampal injections of estradiol enhanced long-term spatial memory among young male rats,²³⁴ and young males given estradiol injections showed increased hippocampal spine density within 30–60 min of injection and improved performance on an object location memory task.¹³² Alejandre-Gomez et al.²³⁵ used letrozole, an aromatase inhibitor, to block the conversion of testosterone into estradiol in adult male rats. They found that rats given letrozole exhibited fewer errors on a spatial working memory task (plus maze) than did either untreated controls or rats administered a letrozole vehicle control. This suggests that estradiol may actually interfere with spatial working memory in some cases, potentially providing insights regarding the dose-dependent effects of testosterone. However, letrozole injections impaired performance by male mice on the water maze,¹²⁹ leading to the interesting possibility that androgens facilitate working memory and estrogens facilitate long-term memory. In summary, there is evidence that testosterone acts through both estrogen- and androgen-dependent pathways to improve spatial memory in males, and the relative importance of these pathways likely depends on the form of spatial memory and may change with age.

Lakshman et al.²³⁶ compared the kinetics of testosterone conversion with its major metabolites in older and younger human males given weekly doses of testosterone for 5 months. Interestingly, they found no effects of age on DHT levels, but estradiol levels were elevated in the older males relative to the younger males. The authors suggest that this effect may be due to higher percent body fat in older males, as aromatase is highly expressed in adipose tissue.²³⁶ It is possible, therefore, that the differences between older and younger men in the effects of testosterone on memory may be due to increased conversion of testosterone to estradiol in older men. However, Laskshman et al. measured hormone levels peripherally, and the kinetics of steroidogenesis in the brain, particularly in humans, is much more poorly understood than the kinetics in blood. Indeed, there is evidence from rodent studies that the rate of estradiol production in the hippocampus depends on the level of neural activity.²³⁷

Neuroplasticity and Neuroprotection

Numerous forms of neuroplasticity are modified by testosterone, and these may be the cellular substrate for memory formation. For example, castrated male mice exhibited a reduction in dendritic spine density among CA1 cells of the hippocampus, and testosterone treatment reversed this effect.^129,238 Similar results have been obtained using male rats,^132,230,239 and this effect was replicated with DHT,^230,240 suggesting an androgen-dependent pathway. Surprisingly, DHT also enhanced CA1 spine density among testicular-feminization mutant rats that have nonfunctional androgen receptors,²⁴¹ which indicates that DHT is either acting on membrane-bound androgen receptors to increase spine density or is acting through another molecular pathway involving one of its metabolites.²⁴² Both castration and letrozole (aromatase blocker) were shown to reduce a variety of molecular markers of synaptic plasticity in male mice,¹²⁹ suggesting that estrogens also enhance neuroplasticity in males. The therapeutic value of testosterone was supported in an experiment in which testosterone treatment given to an AD rat model caused both an increase in CA1 spine density and improved spatial memory.²¹⁴ Within the CA3 region of the hippocampus, castration caused a similar reduction synaptic spine density but, interestingly, this was accompanied by an increase mossy fiber density in the hippocampus of male rats, suggesting a neurological trade-off.²³⁹ There is also considerable evidence that testosterone upregulates adult neurogenesis within the hippocampus, specifically increasing the survival of new neurons, while having minimal effect on cell proliferation.^231,243 Finally, electrophysiology studies with rat hippocampus slices (CA1 region) have produced somewhat divergent results: castration impaired excitatory postsynaptic field potentials in temporal slices,²⁴⁴ but testosterone administration impaired long-term potentiation in the dorsal hippocampus.²⁴⁵ In summary, there is evidence that testosterone influences many forms of neuroplasticity through both estrogen- and androgen-dependent pathways.

Although there are many unexplored downstream effects of activated testosterone receptors,²⁴⁶ brain-derived neurotrophic factor (BDNF) has become a molecule of particular interest because of its importance in regulating neuroplasticity.^247,248 A number of studies have shown that testosterone upregulates the expression of BDNF in the spinal cord and the peripheral nervous system.^249,250 Hill et al.²⁵¹ showed that surges of testosterone early in development among male mice increased BDNF expression in both the PFC and the striatum, but not the hippocampus. A number of studies have also shown that castration decreases total BDNF protein levels in the hippocampus of adult male rats.^252–254 Similarly, castration caused a decrease in BDNF mRNA (as well as other mRNA markers of neuroplasticity) in the hippocampus of male rats.²⁵³ More refined analyses have shown that castration increased BDNF levels specifically within the mossy fibers extending from the dentate gyrus to the CA3 layer of the hippocampus,^255,256 but castration decreased BDNF production within CA1 layer of the hippocampus, again indicating a trade-off.²³⁸ Zhang et al.¹⁴⁴ recently demonstrated that a low dose of testosterone increased BDNF levels in the striatum of male rats and that a high dose increased BDNF levels in the hippocampus. The same experiment demonstrated that the low dose improved response learning and the high dose improved place learning, implying a functional significance for these changes.¹⁴⁴ Testosterone implants increased both BDNF and CA1 spine density in SAMP8 mice, and flutamide blocked this effect, suggesting that testosterone enhances BDNF through an androgen-dependent pathway.²⁵⁷ Although many details need to be clarified, considerable evidence indicates that testosterone enhances BDNF levels, which may in turn improve memory through increased neuroplasticity.

Importantly, the ability of testosterone to upregulate BDNF seems to be lost in aged males. Two studies have shown that testosterone supplementation has no effect on BDNF levels in the hippocampus or striatum of aged male rats.^203,208 This suggests that the molecular effects of testosterone may differ between the young and aged male brain, and perhaps a disconnect between testosterone and BDNF is partially responsible for age-related memory loss.

In addition to enhancing various forms of neuroplasticity, the neuroprotective effects of testosterone are well established. Testosterone prevents the apoptotic effects induced by oxidative stress and a variety of neurotoxins.^258,259 This effect seems to be dose dependent, as relatively high doses of testosterone induce apoptosis.^260–262 Although some of the neuroprotective properties of testosterone may occur through aromatization to estradiol,²⁶³ evidence suggests that neuroprotection occurs mainly through androgen-dependent pathways.^262,264 For example, DHT implants caused a significant reduction in neuronal loss in the hippocampus after kainate lesions among castrated male rats.²⁶⁵ Similarly, DHT decreased apoptosis among cultured rat hippocampal neurons.²⁵⁹ The neuroprotective properties of androgens involve activation of the mitogen-activated protein kinase (MAPK) pathway.^261,266 Specifically, Gatson et al.²⁶¹ found that DHT induced phosphorylation of MAPK through a genomic pathway and activated the phosphatide 3-kinase pathway through membrane-bound receptors. In addition, testosterone implants given to castrated male rats were found to upregulate MAPK1 (one protein in the pathway) within the hippocampus.²⁶⁷ Androgens also rapidly phosphorylate cyclic-AMP response element binding protein (CREB) in cultured hippocampal neurons, which can have neuroprotective effects, but this effect was found to involve the protein kinase C pathway rather than the MAPK pathway.²⁶⁸

Testosterone application also reduces β-amyloid production in neurons^269,270 and blocks formation of neurofibrillary tangles,²⁷¹ both distinctive symptoms of AD. There is evidence that this neuroprotective effect against Aβ neurotoxicity occurs through both the MAPK pathway and by upregulating the enzyme neprilysin.²⁷² Caspase proteins have a well-established role in inducing apoptosis,^273,274 and increased caspase activity has been identified as having a causal role in AD pathology.²⁷⁵ There is a tentative link between testosterone and caspase-3 activity in the hippocampus: castration increased the number of caspase-3 positive cells within the dentate gyrus region of the hippocampus, while simultaneously downregulating both BDNF and its primary receptor (tyrosine receptor kinase B).²⁵² In summary, multiple intracellular pathways are activated by androgens that lead to enhanced neuroprotection.

One way that testosterone may act as a neuroprotectant is by blocking the neurotoxic effects of the hormonal stress response, and interactions between the HPG axis and the hypothalamic–pituitary–adrenal axes have been extensively documented using rodent experiments.^276,277 Chronic stress, acting through glucocorticoids (i.e., cortisol and corticosterone), impairs spatial memory and hippocampal plasticity.^278–280 For example, castration resulted in a reduction in hippocampal neurons among rats that were also exposed to an acute stressor (restraint and water immersion).²⁸¹ Furthermore, intrahippocampal injections of an androgen-receptor antagonist caused an increase in anxiety-like behavior in male rats,²⁴² suggesting that testosterone reduces the stress response by acting directly on the brain. Interestingly, higher testosterone doses were found to reduce anxiety on a burying task, whereas a lower dose did not,²⁸² which indicates that the dose-dependent effects of testosterone may involve suppression of the stress response. Direct experimental tests of the relative impact of stress and testosterone on spatial memory would be a useful line of research.

Conclusion

Sex differences on some spatial tasks piqued interest in studying the activational effects of sex steroids on spatial memory. Despite variable results from both clinical trials and animal experiments, current research indicates an activational role for testosterone in sustaining spatial memory in young males and potentially restoring memory in aging males. Discrepancies among studies are likely due to uncontrolled variables. Dose of testosterone used for androgen therapies is of particular importance, as there is considerable evidence that the relationship between circulating testosterone levels and memory is nonlinear. Human studies indicate an inverted-U relationship,⁹³ and some research with rats suggests an even more complex relationship (Fig. 2).^120,203 Testosterone dose has been shown to influence which strategy male rats use to solve spatial tasks, with low doses improving response learning and high doses improving place learning.^143,144 Considering that aging leads to increased use of a striatum-dependent response strategy rather than a hippocampus-dependent place strategy in both humans and rodents,^177,211 it is reasonable to hypothesize that impaired androgen activity within the hippocampus, specifically, is responsible for some cognitive deficits associated with aging. Human studies have demonstrated the most consistent beneficial effects of testosterone when given to hypogonadal rather than eugonadal males, likely due to low physiological doses being more beneficial than supraphysiological doses.^86,93 This may explain why the cognitive benefits of testosterone therapies seem to be more consistent for older males, as they are more likely to be hypogonadal.⁷ Similarly, prolonged testosterone deprivation has been shown to consistently increase risk of developing dementia.²⁰⁰ This demonstrates a need to carefully consider the costs and benefits of prolonged androgen deprivation for the treatment of prostate cancer. Rodent research suggests that testosterone has a stronger effect on spatial working memory than long-term memory,¹¹⁸ but this distinction has not been systematically tested in human research. Another important variable is whether testosterone is influencing cognition through an androgen- or estrogen-dependent pathway. Current evidence indicates that both estrogens and androgens can enhance spatial memory in males, but increased aromatization of testosterone to estradiol in aged males is an intriguing effect that should be researched further.²³⁶ The molecular mechanisms by which testosterone influences spatial memory are likely diverse, but current evidence points to enhancement of neuroplasticity through elevated BDNF levels and neuroprotection by blocking apoptotic pathways.

Particularly important is a potential role for testosterone therapies in preventing or treating AD, as supported by both clinical and animal research.^7,200,214 In 2021, an estimated 6.2 million people aged ≥65 years in the United States were living with AD, which accounts for one in nine Americans in this age range.²⁸³ Globally, an estimated 50 million people have dementia.²⁸⁴ As this number is expected to increase with aging global populations, there is urgent need for new therapies, and androgens provide a promising direction for further research.

Footnotes

Authors' Contributions

Conception and design by M.D.S.; drafting and approval of the article by all authors.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Abbreviations Used

References

Nyberg

, Lövdén

, Riklund

, et al. Memory aging and brain maintenance. Trends Cogn Sci. 2012; 16(5):292–305.

Driscoll

, Hamilton

, Petropoulos

, et al. The aging hippocampus: Cognitive, biochemical and structural findings. Cereb Cortex 1991. 2003; 13(12):1344–1351.

Cansino

. Episodic memory decay along the adult lifespan: A review of behavioral and neurophysiological evidence. Int J Psychophysiol. 2009; 71(1):64–69.

Barker

, Jones

, Jennison

. A prevalence study of age-associated memory impairment. Br J Psychiatry. 1995; 167(5):642–648.

Holland

, Bandelow

, Hogervorst

. Testosterone levels and cognition in elderly men: A review. Maturitas. 2011; 69(4):322–337.

Beauchet

. Testosterone and cognitive function: Current clinical evidence of a relationship. Eur J Endocrinol. 2006; 155773–155781.

Tan

, Sohrabi

, Weinborn

, et al. Effects of testosterone supplementation on separate cognitive domains in cognitively healthy older men: A meta-analysis of current randomized clinical trials. Am J Geriatr Psychiatry. 2019; 27(11):1232–1246.

Grady

, Craik

FIM

. Changes in memory processing with age. Curr Opin Neurobiol. 2000; 10(2):224–231.

Moscovitch

, Nadel

, Winocur

, et al. The cognitive neuroscience of remote episodic, semantic and spatial memory. Curr Opin Neurobiol. 2006; 16(2):179–190.

10.

Ecuyer-Dab

, Robert

. Have sex differences in spatial ability evolved from male competition for mating and female concern for survival?. Cognition. 2004; 91(3):221–257.

11.

Cowan

. What are the differences between long-term, short-term, and working memory? In: Progress in Brain Research ( Sossin

, Lacaille

J-C

, Castellucci

, et al., eds). Amsterdam, Netherlands: Elsevier. 2008; pp 323–338.

12.

Sharma

, Rakoczy

, Brown-Borg

. Assessment of spatial memory in mice. Life Sci. 2010; 87(17):521–536.

13.

Olton

, Papas

. Spatial memory and hippocampal function. Neuropsychologia. 1979; 17(6):669–682.

14.

Eichenbaum

, Stewart

, Morris

RGM

. Hippocampal representation in place learning. J Neurosci. 1990; 10(11):3531–3542.

15.

Packard

, McGaugh

. Inactivation of the hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. Neurobiol Learn Mem. 1996; 65(1):65–72.

16.

Schmidt

, Jacobson

, Markus

. Hippocampal and striatal dependent navigation: Sex differences are limited to acquisition. Horm Behav. 2009; 56(2):199–205.

17.

McDonald

, White

. A triple dissociation of memory systems: Hippocampus, amygdala, and dorsal striatum. Behav Neurosci. 1993; 107(1):3–22.

18.

Chersi

, Burgess

. The cognitive architecture of spatial navigation: Hippocampal and striatal contributions. Neuron. 2015; 88(1):64–77.

19.

Jarrard

. On the role of the hippocampus in learning and memory in the rat. Behav Neural Biol. 1993; 60(1):9–26.

20.

McIntyre

, Marriott

, Gold

. Patterns of brain acetylcholine release predict individual differences in preferred learning strategies in rats. Neurobiol Learn Mem. 2003; 79(2):177–183.

21.

Colombo

, Serino

, Tuena

, et al. Egocentric and allocentric spatial reference frames in aging: A systematic review. Neurosci Biobehav Rev. 2017; 80:605–621.

22.

Gladue

, Clemens

. Androgenic influences on feminine sexual behavior in male and female rats: Defeminization blocked by prenatal antiandrogen treatment. Endocrinology. 1978; 103(5):1702–1709.

23.

Yamanouchi

, Arai

. Female lordosis pattern in the male rat induced by estrogen and progesterone: Effect of interruption of the dorsal inputs to the preoptic area and hypothalamus. Endocrinol Jpn. 1975; 22(3):243–246.

24.

Bull

, Davidson

, Nordmann

. Prenatal testosterone, visual-spatial memory, and numerical skills in young children. Learn Individ Differ. 2010; 20(3):246–250.

25.

Hines

, Fane

, Pasterski

, et al. Spatial abilities following prenatal androgen abnormality: Targeting and mental rotations performance in individuals with congenital adrenal hyperplasia. Psychoneuroendocrinology. 2003; 28(8):1010–1026.

26.

Isgor

, Sengelaub

. Prenatal gonadal steroids affect adult spatial behavior, CA1 and CA3 cell morphology in rats. Horm Behav. 1998; 34(2):183–198.

27.

Mueller

, Temple

, Oh

, et al. Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH). Psychoneuroendocrinology. 2008; 33(7):973–980.

28.

Roof

, Havens

. Testosterone improves maze performance and induces development of a male hippocampus in females. Brain Res. 1992; 572(1–2):310–313.

29.

Voyer

, Voyer

, Bryden

. Magnitude of sex differences in spatial abilities: A meta-analysis and consideration of critical variables. Psychol Bull. 1995; 117(2):250–270.

30.

Hyde

. Gender similarities and differences. Annu Rev Psychol. 2014; 65(1):373–398.

31.

Linn

, Petersen

. Emergence and characterization of sex differences in spatial ability: A meta-analysis. Child Dev. 1985; 56(6):1479–1498.

32.

Hamson

, Roes

, Galea

LAM

. Sex hormones and cognition: Neuroendocrine influences on memory and learning. Compr Physiol. 2016; 6(3):1295–1337.

33.

Thomsen

, Hugdahl

, Ersland

, et al. Functional magnetic resonance imaging (fMRI) study of sex differences in a mental rotation task. Med Sci Monit. 2000; 6(6):1186–1196.

34.

Griksiene

, Arnatkeviciute

, Monciunskaite

, et al. Mental rotation of sequentially presented 3D figures: Sex and sex hormones related differences in behavioural and ERP measures. Sci Rep. 2019; 9(1):18843.

35.

Semrud-Clikeman

, Fine

, Bledsoe

, et al. Gender differences in brain activation on a mental rotation task. Int J Neurosci. 2012; 122(10):590–597.

36.

Schöning

, Engelien

, Kugel

, et al. Functional anatomy of visuo-spatial working memory during mental rotation is influenced by sex, menstrual cycle, and sex steroid hormones. Neuropsychologia. 2007; 45(14):3203–3214.

37.

Gizewski

, Krause

, Wanke

, et al. Gender-specific cerebral activation during cognitive tasks using functional MRI: Comparison of women in mid-luteal phase and men. Neuroradiology. 2006; 48(1):14–20.

38.

Postma

, Jager

, Kessels

RPC

, et al. Sex differences for selective forms of spatial memory. Brain Cogn. 2004; 54(1):24–34.

39.

Galea

LAM

, Kimura

. Sex differences in route-learning. Pers Individ Differ. 1993; 14(1):53–65.

40.

McGuiness

, Sparks

. Cognitive style and cognitive maps: Sex differences in representations of a familiar terrain. J Ment Imag. 1983; 7(2):91–100.

41.

Woolley

, Vermaercke

, de Beeck

, et al. Sex differences in human virtual water maze performance: Novel measures reveal the relative contribution of directional responding and spatial knowledge. Behav Brain Res. 2010; 208(2):408–414.

42.

Rizk-Jackson

, Acevedo

, Inman

, et al. Effects of sex on object recognition and spatial navigation in humans. Behav Brain Res. 2006; 173(2):181–190.

43.

Buckley

, Bast

. A new human delayed-matching-to-place test in a virtual environment reverse-translated from the rodent watermaze paradigm: Characterization of performance measures and sex differences. Hippocampus. 2018; 28(11):796–812.

44.

Nowak

, Diamond

, Land

, et al. Contributions of sex, testosterone, and androgen receptor CAG repeat number to virtual Morris water maze performance. Psychoneuroendocrinology. 2014; 41(1):13–22.

45.

Astur

, Ortiz

, Sutherland

. A characterization of performance by men and women in a virtual Morris water task: A large and reliable sex difference. Behav Brain Res. 1998; 93(1):185–190.

46.

Moffat

, Hampson

, Hatzipantelis

. Navigation in a “Virtual” maze: Sex differences and correlation with psychometric measure of spatial ability in humans. Evol Hum Behav. 1998; 19(1):73–87.

47.

Grön

, Wunderlich

, Spitzer

, et al. Brain activation during human navigation: Gender-different neural networks as substrate of performance. Nat Neurosci. 2000; 3(4):404–408.

48.

Persson

, Herlitz

, Engman

, et al. Remembering our origin: Gender differences in spatial memory are reflected in gender differences in hippocampal lateralization. Behav Brain Res. 2013; 256(1):219–228.

49.

Jonasson

, Cahill

JFX

, Tobey

, et al. Sexually dimorphic effects of hippocampal cholinergic deafferentation in rats. Eur J Neurosci. 2004; 20(11):3041–3053.

50.

Harris

, D'Eath

, Healy

. Sex differences, or not, in spatial cognition in albino rats: Acute stress is the key. Anim Behav. 2008; 76(5):1579–1589.

51.

Markowska

. Sex dimorphisms in the rate of age-related decline in spatial memory: Relevance to alterations in the estrus cycle. J Neurosci. 1999; 19(18):8122–8133.

52.

Roof

, Stein

. Gender differences in Morris water maze performance depend on task parameters. Physiol Behav. 1999; 68(1–2):81–86.

53.

Gibbs

, Johnson

. Sex-specific effects of gonadectomy and hormone treatment on acquisition of a 12-arm radial maze task by Sprague Dawley rats. Endocrinology. 2008; 149(6):3176–3183.

54.

Seymoure

, Dou

, Juraska

. Sex differences in radial maze performance: Influence of rearing environment and room cues. Psychobiology. 1996; 24(1):33–37.

55.

Cost

, Williams–Yee

, Fustok

, et al. Sex differences in object-in-place memory of adult rats. Behav Neurosci. 2012; 126(3):457–464.

56.

Sutcliffe

, Marshall

, Neill

. Influence of gender on working and spatial memory in the novel object recognition task in the rat. Behav Brain Res. 2007; 177(1):117–125.

57.

Oliveira

AMM

, Hawk

, Abel

, et al. Post-training reversible inactivation of the hippocampus enhances novel object recognition memory. Learn Mem. 2010; 17(3):155–160.

58.

Jonasson

. Meta-analysis of sex differences in rodent models of learning and memory: A review of behavioral and biological data. Neurosci Biobehav Rev. 2005; 28(8):811–825.

59.

Silverman

, Choi

, Peters

. The hunter-gatherer theory of sex differences in spatial abilities: Data from 40 countries. Arch Sex Behav. 2007; 36(2):261–268.

60.

Duff

, Hampson

. A sex difference on a novel spatial working memory task in humans. Brain Cogn. 2001; 47(3):470–493.

61.

Levy

, Astur

, Frick

. Men and women differ in object memory but not performance of a virtual radial maze. Behav Neurosci. 2005; 119(4):853–862.

62.

Cherney

, Brabec

, Runco

. Mapping out spatial ability: Sex differences in way-finding navigation. Percept Mot Skills. 2008; 107(3):747–760.

63.

Dabbs Jr. JM, Chang E-L, Strong RA, et al. Spatial ability, navigation strategy, and geographic knowledge among men and women. Evol Hum Behav. 1998; 19(2):89–98.

64.

Lawton

. Gender differences in way-finding strategies: Relationship to spatial ability and spatial anxiety. Sex Roles. 1994; 30(11/12):765–779.

65.

Silverman

, Choi

. Non-Euclidean navigational strategies of women: Compensatory response or evolved dimorphism?. Evol Psychol. 2006; 4(1):75–84.

66.

Goyette

, McCoy

, Kennedy

, et al. Sex differences on the judgment of line orientation task: A function of landmark presence and hormonal status. Physiol Behav. 2012; 105(4):1045–1051.

67.

Sandstrom

, Kaufman

, Huettel

. Males and females use different distal cues in a virtual environment navigation task. Brain Res. 1998; 6(4):351–360.

68.

Picucci

, Caffò

, Bosco

. Besides navigation accuracy: Gender differences in strategy selection and level of spatial confidence. J Environ Psychol. 2011; 31(4):430–438.

69.

Williams

, Barnett

, Meck

. Organizational effects of early gonadal secretions on sexual differentiation in spatial memory. Behav Neurosci. 1990; 104(1):84–97.

70.

Kanit

, Taşkiran

, Furedy

, et al. Nicotine interacts with sex in affecting rat choice between “look-out” and “navigational” cognitive styles in the Morris water maze place learning task. Brain Research Bull. 1998; 46(5):441–445.

71.

Kanit

, Taskiran

, Yilmaz

, et al. Sexually dimorphic cognitive style in rats emerges after puberty. Brain Res Bull. 2000; 52(4):243–248.

72.

Sava

, Markus

. Intramaze cue utilization in the water maze: Effects of sex and estrous cycle in rats. Horm Behav. 2005; 48(1):23–33.

73.

Rodríguez

, Torres

, Mackintosh

, et al. Sex differences in the strategies used by rats to solve a navigation task. J Exp Psychol Anim Behav Process. 2010; 36(3):395–401.

74.

Blokland

, Rutten

, Prickaerts

. Analysis of spatial orientation strategies of male and female Wistar rats in a Morris water escape task. Behav Brain Res. 2006; 171(2):216–224.

75.

Bocchi

, Palermo

, Boccia

, et al. Object recognition and location: Which component of object location memory for landmarks is affected by gender? Evidence from four to ten year-old children. Appl Neuropsychol Child. 2020; 9(1):31–40.

76.

Choi

, Silverman

. Processes underlying sex differences in route-learning strategies in children and adolescents. Pers Individ Differ. 2003; 34(7):1153–1166.

77.

Merrill

, Yang

, Roskos

, et al. Sex differences in using spatial and verbal abilities influence route learning performance in a virtual environment: A comparison of 6- to 12-year old boys and girls. Front Psychol. 2016; 7(1):258.

78.

Akers

, Hamilton

. Comparison of developmental trajectories for place and cued navigation in the Morris water task. Dev Psychobiol. 2007; 49(6):553–564.

79.

Gazova

, Vlcek

, Laczó

, et al. Spatial navigation—A unique window into physiological and pathological aging. Front Aging Neurosci. 2012; 4(1):16.

80.

Ulubaev

, Lee

, Purandare

, et al. Activational effects of sex hormone on cognition in men. Clin Endocrinol (Oxf). 2009; 71(5):607–623.

81.

Christiansen

, Knussmann

. Sex hormones and cognitive functioning in men. Neuropsychobiology. 1987; 18(1):27–36.

82.

Hooven

, Chabris

, Ellison

, et al. The relationship of male testosterone to components of mental rotation. Neuropsychologia. 2004; 42(6):782–790.

83.

Silverman

, Kastuk

, Choi

, et al. Testosterone levels and spatial ability in men. Psychoneuroendocrinology. 1999; 24(8):813–822.

84.

Choi

, Silverman

. The relationship between testosterone and route-learning strategies in humans. Brain Cogn. 2002; 50(1):116–120.

85.

Thilers

, MacDonald

SWS

, Herlitz

. The association between endogenous free testosterone and cognitive performance: A population-based study in 35 to 90 year-old men and women. Psychoneuroendocrinology. 2006; 31(5):565–576.

86.

Shute

, Pellegrino

, Hubert

, et al. The relationship between androgen levels and human spatial abilities. Bull Psychon Soc. 1983; 21(6):465–468.

87.

Moffat

, Hampson

. A curvilinear relationship between testosterone and spatial cognition in humans: Possible influence of hand preference. Psychoneuoendocrinology. 1996; 21(3):323–337.

88.

Gouchie

, Kimura

. The relationship between testosterone levels and cognitive ability patterns. Psychoneuroendocrinology. 1991; 16(4):323–334.

89.

Aleman

, Bronk

, Kessels

RPC

, et al. A single administration of testosterone improves visuospatial ability in young women. Psychoneuroendocrinology. 2004; 29(5):612–617.

90.

Pintzka

CWS

, Evensmoen

, Lehn

, et al. Changes in spatial cognition and brain activity after a single dose of testosterone in healthy women. Behav Brain Res. 2016; 298(Pt B):78–90.

91.

Swift-Gallant

, Monks

. Androgenic mechanisms of sexual differentiation of the nervous system and behavior. Front Neuroendocrinol. 2017; 46(1):32–45.

92.

Muller

, Aleman

, Grobbee

, et al. Endogenous sex hormone levels and cognitive function in aging men. Neurology. 2005; 64(5):866–871.

93.

O'Connor

, Archer

, Hair

, et al. Activational effects of testosterone on cognitive function in men. Neuropsychologia. 2001; 39(13):1385–1394.

94.

Kanayama

, Kean

, Hudson

, et al. Cognitive deficits in long-term anabolic-androgenic steroid users. Drug Alcohol Depend. 2013; 130(1–3):208–214.

95.

Kaufman

, Janes

, Hudson

, et al. Brain and cognition abnormalities in long-term anabolic-androgenic steroid users. Drug Alcohol Depend. 2015; 152(1):47–56.

96.

Chamberlain

, Driver

, Miesfeld

. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994; 22(15):3181–3186.

97.

Sankar

, Hampson

. Androgen receptor polymorphism, mental rotation, and spatial visualization in men. Psychoneuroendocrinology. 2021; 129(1):105239.

98.

Gee

, Holtgrewe

, Albertsen

, et al. Practice trends in the diagnosis and management of prostate cancer in the United States. J Urol. 1995; 154(1):207–208.

99.

Lenfant

, Leon

, Cancel-Tassin

, et al. Testosterone replacement therapy (TRT) and prostate cancer: An updated systematic review with a focus on previous or active localized prostate cancer. Urol Oncol. 2020; 38(8):661–670.

100.

Polchert

, Voznesensky

, Soubra

, et al. Updated review of testosterone replacement therapy in the setting of prostate cancer. Androg Clin Res Ther. 2021; 2(1):36–45.

101.

Cherrier

, Aubin

, Higano

. Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer. Psychooncology. 2009; 18(3):237–247.

102.

Cherrier

, Borghesani

, Shelton

, et al. Changes in neuronal activation patterns in response to androgen deprivation therapy: A pilot study. BMC Cancer. 2010; 10(1):1.

103.

Salminen

, Portin

, Koskinen

, et al. Associations between serum testosterone fall and cognitive function in prostate cancer patients. Clin Cancer Res. 2004; 10(22):7575–7582.

104.

Cherrier

, Rose

, Higano

. The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. J Urol. 2003; 170(5):1808–1811.

105.

Beer

, Bland

, Bussiere

, et al. Testosterone loss and estradiol administration modify memory in men. J Urol. 2006; 175(1):130–135.

106.

Alexander

, Swerdloff

, Wang

, et al. Androgen–behavior correlations in hypogonadal men and eugonadal men. Horm Behav. 1998; 33(2):85–94.

107.

Young

, Neiss

, Samuels

, et al. Cognition is not modified by large but temporary changes in sex hormones in men. J Clin Endocrinol Metab. 2010; 95(1):280–288.

108.

Lašaitė

, Čeponis

, Preikša

, et al. Effects of two-year testosterone replacement therapy on cognition, emotions and quality of life in young and middle-aged hypogonadal men. Andrologia. 2017; 49(3):n/a–n/a.

109.

Morris

, Garrud

, Rawlins

, et al. Place navigation impaired in rats with hippocampal lesions. Nature. 1982; 297(5868):681–683.

110.

Barnes

. Spatial memory deficit in senescent rats. Can J Psychol. 1980; 34(1):29; 29–39; 39.

111.

Becker

, Olton

, Anderson

, et al. Cognitive mapping in rats: The role of the hippocampal and frontal systems in retention and reversal. Behav Brain Res. 1981; 3(1):1–22.

112.

Daniel

, Winsauer

, Moerschbaecher

. Castration in rats impairs performance during acquisition of a working memory task and exacerbates deficits in working memory produced by scopolamine and mecamylamine. Psychopharmacology (Berl). 2003; 170(3):294–300.

113.

Spritzer

, Gill

, Weinberg

, et al. Castration differentially affects spatial working and reference memory in male rats. Arch Sex Behav. 2008; 37(1):19–29.

114.

Locklear

, Bhamidipaty

, Kritzer

. Local N-methyl-d-aspartate receptor antagonism in the prefrontal cortex attenuates spatial cognitive deficits induced by gonadectomy in adult male rats. Neuroscience. 2015; 288(1):73–85.

115.

Locklear

, Kritzer

. Assessment of the effects of sex and sex hormones on spatial cognition in adult rats using the Barnes maze. Horm Behav. 2014; 66(2):298–308.

116.

Hasegawa

, Mochizuki

. Improved effect of pycnogenol on impaired spatial memory function in partial androgen deficiency rat model. Phytother Res. 2009; 23(6):840–843.

117.

Kritzer

, McLaughlin

, Smirilis

. Gonadectomy impairs T-maze acquisition in adult male rats. Horm Behav. 2001; 39(2):167–174.

118.

Spritzer

, Daviau

, Coneeny

, et al. Effects of testosterone on spatial learning and memory in adult male rats. Horm Behav. 2011; 59(4):484–496.

119.

Gibbs

. Testosterone and estradiol produce different effects on cognitive performance in male rats. Horm Behav. 2005; 48(3):268–277.

120.

Wagner

, Braddick

, Batson

, et al. Effects of testosterone dose on spatial memory among castrated adult male rats. Psychoneuroendocrinology. 2018; 89(1):120–130.

121.

Khalil

, King

, Soliman

MRI

. Testosterone reverses ethanol-induced deficit in spatial reference memory in castrated rats. Pharmacology. 2005; 75(2):87–92.

122.

Jia

, Kang

, Li

, et al. Amelioratory effects of testosterone treatment on cognitive performance deficits induced by soluble Aβ1–42 oligomers injected into the hippocampus. Horm Behav. 2013; 64(3):477–486.

123.

Moghadami

, Jahanshahi

, Sepehri

, et al. Gonadectomy reduces the density of androgen receptor-immunoreactive neurons in male rat's hippocampus: Testosterone replacement compensates it. Behav Brain Funct. 2016; 12(1):5.

124.

Goudsmit

, Vandepoll

, Swaab

. Testosterone fails to reverse spatial memory decline in aged rats and impairs retention in your and middle-aged animals. Behav Neural Biol. 1990; 53(1):6–20.

125.

Emamian

, Naghdi

, Sepehri

, et al. Learning impairment caused by intra-CA1 microinjection of testosterone increases the number of astrocytes. Behav Brain Res. 2010; 208(1):30–37.

126.

Naghdi

, Majlessi

, Bozorgmehr

. The effect of intrahippocampal injection of testosterone enanthate (an androgen receptor agonist) and anisomycin (protein synthesis inhibitor) on spatial learning and memory in adult, male rats. Behav Brain Res. 2005; 156(2):263–268.

127.

Hodosy

, Pales

, Ostatnikova

, et al. The effects of exogenous testosterone on spatial memory in rats. Cent Eur J Biol. 2010; 5(4):466–471.

128.

Sandstrom

, Kim

, Wasserman

. Testosterone modulates performance on a spatial working memory task in male rats. Horm Behav. 2006; 50(1):18–26.

129.

Zhao

, Bian

, Liu

, et al. Orchiectomy and letrozole differentially regulate synaptic plasticity and spatial memory in a manner that is mediated by SRC-1 in the hippocampus of male mice. J Steroid Biochem Mol Biol. 2018; 178(1):354–368.

130.

Naghdi

, Mohaddess

, Khamnei

, et al. No significant difference between intact and testosterone depleted or administrated male rats in spatial learning and memory. Iran J Pharm Res. 2005; 1(1):29–32.

131.

McConnell

SEA

, Alla

, Wheat

, et al. The role of testicular hormones and luteinizing hormone in spatial memory in adult male rats. Horm Behav. 2012; 61(4):479–486.

132.

Jacome

, Barateli

, Buitrago

, et al. Gonadal hormones rapidly enhance spatial memory and increase hippocampal spine density in male rats. Endocrinology. 2016; 157(4):1357–1362.

133.

Hawley

, Grissom

, Martin

, et al. Testosterone modulates spatial recognition memory in male rats. Horm Behav. 2013; 63(4):559–565.

134.

Khorshidahmad

, Tabrizian

, Vakilzadeh

, et al. Interactive effects of a protein kinase AII inhibitor and testosterone on spatial learning in the Morris water maze. Behav Brain Res. 2012; 228(2):432–439.

135.

Naghdi

, Nafisy

, Majlessi

. The effects of intrahippocampal testosterone and flutamide on spatial localization in the Morris water maze. Brain Res. 2001; 897(1–2):44–51.

136.

Moradpour

, Naghdi

, Fathollahi

. Anastrozole improved testosterone-induced impairment acquisition of spatial learning and memory in the hippocampal CA1 region in adult male rats. Behav Brain Res. 2006; 175223–232.

137.

Korol

. Role of estrogen in balancing contributions from multiple memory systems. Neurobiol Learn Mem. 2004; 82(3):309–323.

138.

Korol

, Kolo

. Estrogen-induced changes in place and response learning in yough adult female rats. Behav Neurosci. 2002; 116(3):411–420.

139.

Daniel

, Lee

. Estrogen replacement in ovariectomized rats affects strategy selection in the Morris water maze. Neurobiol Learn Mem. 2004; 82(2):142–149.

140.

Davis

, Jacobson

, Aliakbari

, et al. Differential effects of estrogen on hippocampal- and striatal-dependent learning. Neurobiol Learn Mem. 2005; 84(2):132–137.

141.

Zurkovsky

, Brown

, Boyd

, et al. Estrogen modulates learning in female rats by acting directly at distinct memory systems. Neuroscience. 2007; 144(1):26–37.

142.

Zurkovsky

, Serio

, Korol

. Intra-striatal estradiol in female rats impairs response learning within two hours of treatment. Horm Behav. 2011; 60(5):470–477.

143.

Spritzer

, Fox

, Larsen

, et al. Testosterone influences spatial strategy preferences among adult male rats. Horm Behav. 2013; 63(5):800–812.

144.

Zhang

, Ramdev

, Tuta

, et al. Dose-dependent effects of testosterone on spatial learning strategies and brain-derived neurotrophic factor in male rats. Psychoneuroendocrinology. 2020; 121(1):104850.

145.

Chang

, Gold

. Switching memory systems during learning: Changes in patterns of brain acetylcholine release in the hippocampus and striatum in rats. J Neurosci. 2003; 23(7):3001–3005.

146.

Feng

, Weijdegård

, Wang

, et al. Spatiotemporal expression of androgen receptors in the female rat brain during the oestrous cycle and the impact of exogenous androgen administration: A comparison with gonadally intact males. Mol Cell Endocrinol. 2010; 321(2):161–174.

147.

Feldman

, Longcope

, Derby

, et al. Age trends in the level of serum testosterone and other hormone in middle-aged men: Longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002; 87(2):589–598.

148.

Harman

, Metter

, Tobin

, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab. 2001; 86(2):724–731.

149.

Hijazi

, Cunningham

. Andropause: Is androgen replacement therapy indicated for the aging male?. Annu Rev Med. 2005; 56(1):117–137.

150.

Liu

, Pincus

, Takahashi

, et al. Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: Analyses via a model of graded GnRH receptor blockade. Am J Physiol Endocrinol Metab. 2006; 290(1):E34–E41.

151.

Golan

, Scovell

, Ramasamy

. Age-related testosterone decline is due to waning of both testicular and hypothalamic-pituitary function. Aging Male. 2015; 18(3):201–204.

152.

Morley

, Kaiser

, Perry

, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997; 46(4):410–413.

153.

Bowen

, Verdile

, Liu

, et al. Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-B precursor protein and amyloid-B deposition. J Biol Chem. 2004; 279(19):20539–20545.

154.

Gregory

, Atwood

, Smith

, et al. Antigonadotropins: A novel strategy to halt Alzheimer's disease progression. Curr Pharm Des. 2006; 12(6):685–690.

155.

Kim

, Bae

, Ahn

, et al. Androgen receptor CAG repeat length as a risk factor of late-onset hypogonadism in a Korean Male Population. Sex Med. 2018; 6(3):203–209.

156.

Basaria

, Dobs

. Risks versus benefits of testosterone therapy in elderly men. Drugs Aging. 1999; 15(2):131–142.

157.

Matsumoto

. Andropause: Clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci. 2002; 57(2):M76–M99.

158.

Arver

, Lehtihet

. Current guidelines for the diagnosis of testosterone deficiency. Front Horm Res. 2009; 37(1):5–20.

159.

Bettio

LEB

, Rajendran

, Gil-Mohapel

. The effects of aging in the hippocampus and cognitive decline. Neurosci Biobehav Rev. 2017; 79(1):66–86.

160.

Bizon

, LaSarge

, Montgomery

, et al. Spatial reference and working memory across the lifespan of male Fisher 344 rats. Neurobiol Aging. 2009; 30(4):646–655.

161.

Burke

, Barnes

. Neural plasticity in the ageing brain. Nat Rev Neurosci. 2006; 7(1):30–40.

162.

Erickson

, Barnes

. The neurobiology of memory changes in normal aging. Proc 6th Int Symp Neurobiol Neuroendocrinol Aging. 2003; 38(1–2):61–69.

163.

Barrett-Connor

, Goodman-Gruen

, Patay

. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab. 1999; 84(10):3681–3685.

164.

Yaffe

, Lui

L-Y

, Zmuda

, et al. Sex hormones and cognitive function in older men. J Am Geriatr Soc. 2002; 50(4):707–712.

165.

Moffat

, Zonderman

, Metter

, et al. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab. 2002; 87(11):5001–5007.

166.

Cherrier

, Matsumoto

, Amory

, et al. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology. 2005; 64(12):2063–2068.

167.

Janowsky

, Oviatt

, Orwll

. Testosterone influences spatial cognition in older men. Behav Neurosci. 1994; 108(2):325–332.

168.

Vaughan

, Goldstein

, Tenover

. Exogenous testosterone alone or with finasteride does not improve measurements of cognition in older men with low serum testosterone. J Androl. 2007; 28(6):875–881.

169.

Wolf

, Preut

, Hellhammer

, et al. Testosterone and cognition in elderly men: A single testosterone injection blocks the practice effect in verbal fluency, but has no effect on spatial or verbal memory. Biol Psychiatry. 2000; 47(7):650–654.

170.

Janowsky

, Chavez

, Orwoll

. Sex steroids modify working memory. J Cogn Neurosci. 2000; 12(3):407–414.

171.

Bussiere

, Beer

, Neiss

, et al. Androgen deprivation impairs memory in older men. Behav Neurosci. 2005; 119(6):1429–1437.

172.

Janowsky

. The role of androgens in cognition and brain aging in men. Neuroscience. 2006; 138(3):1015–1020.

173.

Cherrier

, Matsumoto

, Amory

, et al. Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men. Psychoneuroendocrinology. 2007; 32(1):72–79.

174.

Lisco

, Giagulli

, De Tullio

, et al. Age-related male hypogonadism and cognitive Impairment in the elderly: Focus on the effects of testosterone replacement therapy on cognition. Geriatr Basel Switz. 2020; 5(4):76.

175.

Buskbjerg

, Gravholt

, Dalby

, et al. Testosterone supplementation and cognitive functioning in men-a systematic review and meta-analysis. J Endocr Soc. 2019; 3(8):1465–1484.

176.

Wiener

, de Condappa

, Harris

, et al. Maladaptive bias for extrahippocampal navigation strategies in aging humans. J Neurosci. 2013; 33(14):6012–6017.

177.

Bohbot

, McKenzie

, Koniski

, et al. Virtual navigation strategies from childhood to senescence: Evidence for changes across the life span. Front Aging Neurosci. 2012; 4(1):e28.

178.

Rodgers

, Sindone III

, Moffat

. Effects of age on navigation strategy. Neurobiol Aging. 2012; 33(1):202.e15–202.e22.

179.

Head

, Isom

. Age effects on wayfinding and route learning skills. Behav Brain Res. 2010; 209(1):49–58.

180.

Harris

, Wiener

, Wolbers

. Aging specifically impairs switching to an allocentric navigational strategy. Front Aging Neurosci. 2012; 4(1):e29.

181.

Montefinese

, Sulpizio

, Galati

, et al. Age-related effects on spatial memory across viewpoint changes relative to different reference frames. Psychol Res. 2015; 79(4):687–697.

182.

Antonova

, Parslow

, Brammer

, et al. Age-related neural activity during allocentric spatial memory. Mem Hove Engl. 2009; 17(2):125–143.

183.

Persson

, Pudas

, Lind

, et al. Longitudinal structure-function correlates in elderly reveal MTL dysfunction with cognitive decline. Cereb Cortex. 2012; 22(10):2297–2304.

184.

Dubal

. Chapter 16—Sex difference in Alzheimer's disease: An updated, balanced and emerging perspective on differing vulnerabilities. In: Handbook of Clinical Neurology ( Lanzenberger

, Kranz

, Savic

, eds). Amsterdam, Netherlands: Elsevier. 2020; pp 261–273.

185.

Baum

. Sex, hormones, and Alzheimer's disease. J Gerontol Ser Biol Sci Med Sci. 2005; 60(6):736–743.

186.

Iachini

, Iavarone

, Senese

, et al. Visuospatial memory in healthy elderly, AD and MCI: A review. Curr Aging Sci. 2009; 2(1):43–59.

187.

Hogervorst

, Bandelow

, Combrinck

, et al. Low free testosterone is an independent risk factor for Alzheimer's disease. Exp Gerontol. 2004; 39(1–2):1633–1639.

188.

Paoletti

, Congia

, Lello

, et al. Low androgenization index in elderly women and elderly men with Alzheimer's disease. Neurology. 2004; 62(2):301–303.

189.

Moffat

, Zonderman

, Metter

, et al. Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004; 62(2):188–193.

190.

Ford

, Yeap

, Flicker

, et al. Sex hormones and incident dementia in older men: The health in men study. Psychoneuroendocrinology. 2018; 98(1):139–147.

191.

Chu

L-W

, Tam

, Wong

RLC

, et al. Bioavailable testosterone predicts a lower risk of Alzheimer's disease in older men. J Alzheimers Dis. 2010; 21(4):1335–1345.

192.

Tan

, Pu

. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer's disease. Aging Male. 2003; 6(1):13–17.

193.

Kenny

, Fabregas

, Song

, et al. Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol. 2004; 59A(1):75–78.

194.

, Mosterman

, Mulnard

, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006; 63(2):177–185.

195.

Burkhardt

, Foster

, Clarnette

, et al. Interaction between testosterone and apolipoprotein E epsilon4 status on cognition in healthy older men. J Clin Endocrinol Metab. 2006; 91(3):1168–1172.

196.

Almeida

, Waterreus

, Spry

, et al. One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology. 2004; 29(8):1071–1081.

197.

Nead

, Gaskin

, Chester

, et al. Association between androgen deprivation therapy and risk of dementia. JAMA Oncol. 2017; 3(1):49–55.

198.

Huang

W-K

, Liu

C-H

, Pang

S-T

, et al. Type of androgen deprivation therapy and risk of dementia among patients with prostate cancer in Taiwan. JAMA Netw Open. 2020; 3(8):e2015189.

199.

Jayadevappa

, Chhatre

, Malkowicz

, et al. Association between androgen deprivation therapy use and diagnosis of dementia in men with prostate cancer. JAMA Netw Open. 2019; 2(7):e196562.

200.

Cui

, Wang

, Li

, et al. Quantifying observational evidence for risk of dementia following androgen deprivation therapy for prostate cancer: An updated systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 24(1):15–23.

201.

Chen

, Hardy

, Huhtaniemi

, et al. Age-related decreased Leydig cell testosterone production in the brown Norway rat. J Androl. 1994; 15(6):551–557.

202.

Wang

, Leung

, Sinha-Hikim

. Reproductive aging in the male brown Norway rat: A model for the human. Endocrinology. 1993; 133(6):2773–2781.

203.

Jaeger

ECB

, Miller

, Goins

, et al. Testosterone replacement causes dose-dependent improvements in spatial memory among aged male rats. Psychoneuroendocrinology. 2020; 113(1):104550.

204.

Flood

, Farr

, Kaiser

, et al. Age-related decrease of plasma testosterone in SAMP8 mice: Replacement improves age-related impairment of learning and memory. Physiol Behav. 1995; 57(4):669–673.

205.

Barnes

. Memory deficits associated with senescence: A neurophysiological and behavioral study in the rat. J Comp Physiol Psychol. 1979; 93(1):74–104.

206.

Jiménez-Rubio

, Herrera-Pérez

, Martínez-Becerril

, et al. Age-dependent effects of testosterone on spatial memory in male rats. Horm Behav. 2020; 122104748.

207.

Stewart

, Mitchell

, Kalant

. The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes. Neurobiol Aging. 1989; 10(6):669–675.

208.

Bimonte-Nelson

, Singleton

, Nelson

, et al. Testosterone, but not nonaromatizable dihydrotestosterone, improves working memory and alters nerve growth factor levels in aged male rats. Exp Neurol. 2003; 181(2):301–312.

209.

Onaolapo

, Onaolapo

, Omololu

, et al. Exogenous testosterone, aging, and changes in behavioral response of Gonadally Intact Male Mice. J Exp Neurosci. 2016; 1059–70.

210.

Begega

, Cienfuegos

, Rubio

, et al. Effects of ageing on allocentric and egocentric spatial strategies in the Wistar rat. Behav Processes. 2001; 53(1–2):75–85.

211.

Tomás Pereira

, Gallagher

, Rapp

. Head west or left, east or right: Interactions between memory systems in neurocognitive aging. Neurobiol Aging. 2015; 36(11):3067–3078.

212.

Raber

, Bongers

, LeFevour

, et al. Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci Off J Soc Neurosci. 2002; 22(12):5204–5209.

213.

Rosario

, Carroll

, Oddo

, et al. Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease. J Neurosci. 2006; 26(51):13384–13389.

214.

Yan

X-S

, Yang

Z-J

, Jia

J-X

, et al. Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer's disease. Neural Regen Res. 2019; 14(4):649–657.

215.

Pelletier

, Luu-The

, Labrie

. Immunocytochemical localization of 5 alpha-reductase in rat brain. Mol Cell Neurosci. 1994; 5(5):394–399.

216.

Grino

, Griffin

, Wilson

. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology. 1990; 126(2):1165–1172.

217.

Jänne

, Palvimo

, Kallio

, et al. Androgen receptor and mechanism of androgen action. Ann Med. 1993; 25(1):83–89.

218.

Losel

, Falkenstein

, Feuring

, et al. Nongenomic steroid action: Controversies, questions, and answers. Physiol Rev. 2003; 83(3):965–1016.

219.

Meinhardt

, Mullis

. The essential role of the aromatase/p450arom. Semin Reprod Med. 2002; 20(3):277–284.

220.

Hojo

, Hattori

T-A

, Enami

, et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons. Proc Natl Acad Sci U S A. 2004; 101(3):865–870.

221.

Frick

, Kim

, Tuscher

, et al. Sex steroid hormones matter for learning and memory: Estrogenic regulation of hippocampal function in male and female rodents. Learn Mem. 2015; 22(9):472–493.

222.

Paletta

, Sheppard

PAS

, Matta

, et al. Rapid effects of estrogens on short-term memory: Possible mechanisms. Horm Behav. 2018; 10488–99.

223.

Taxier

, Gross

, Frick

. Oestradiol as a neuromodulator of learning and memory. Nat Rev Neurosci. 2020; 21(10):535–550.

224.

Beyenburg

, Watzka

, Clusmann

, et al. Androgen receptor mRNA expression in the human hippocampus. Neurosci Lett. 2000; 294(1):25–28.

225.

Fernandez-Guasti

, Swaab

, Rodríguez-Manzo

. Sexual behavior reduces hypothalamic androgen receptor immunoreactivity. Psychoneuroendocrinology. 2003; 28(4):501–512.

226.

, Schwartz

, Rissman

. Distribution of estrogen receptor- β-like immunoreactivity in rat forebrain. Neuroendocrinology. 1997; 66(2):63–67.

227.

Pérez

, Chen

E-Y

, Mufson

. Distribution of estrogen receptor alpha and beta immunoreactive profiles in the postnatal rat brain. Brain Res Dev Brain Res. 2003; 145(1):117–139.

228.

Jones

, Watson

. Spatial memory performance in androgen insensitive male rats. Physiol Behav. 2005; 85(2):135–141.

229.

Benice

, Raber

. Dihydrotestosterone modulates spatial working-memory performance in male mice. J Neurochem. 2009; 110(3):902–911.

230.

Leranth

, Petnehazy

, MacLusky

. Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci. 2003; 23(5):1588–1592.

231.

Spritzer

, Galea

LAM

. Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats. Dev Neurobiol. 2007; 67(10):1321–1333.

232.

Babanejad

, Naghdi

, Haeri Rohani

. Microinjection of dihydrotestosterone as a 5α-reduced metabolite of testosterone into CA1 region of hippocampus could improve spatial learning in the adult male rats. Iran J Pharm Res. 2012; 11(2):661–669.

233.

Luine

, Rodriguez

. Effects of estradiol on radial arm maze performance of young and aged rats. Behav Neural Biol. 1994; 62(3):230–236.

234.

Packard

, Kohlmaier

, Alexander

. Posttraining intrahippocampal estradiol injections enhance spatial memory in male rats: Interaction with cholinergic systems. Behav Neurosci. 1996; 110(3):626–632.

235.

Alejandre-Gomez

, Garcia-Segura

, Gonzalez-Burgos

. Administration of an inhibitor of estrogen biosynthesis facilitates working memory acquisition in male rats. Neurosci Res. 2007; 58(3):272–277.

236.

Lakshman

, Kaplan

, Travison

, et al. The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men. J Clin Endocrinol Metab. 2010; 95(8):3955–3964.

237.

Di Mauro

, Tozzi

, Calabresi

, et al. Different synaptic stimulation patterns influence the local androgenic and estrogenic neurosteroid availability triggering hippocampal synaptic plasticity in the male rat. Eur J Neurosci. 2017; 45(4):499–509.

238.

, Masugi-Tokita

, Takanami

, et al. Testosterone has sublayer-specific effects on dendritic spine maturation mediated by BDNF and PSD-95 in pyramidal neurons in the hippocampus CA1 area. Brain Res. 2012; 1484(1):76–84.

239.

Mendell

, Atwi

, Bailey

CDC

, et al. Expansion of mossy fibers and CA3 apical dendritic length accompanies the fall in dendritic spine density after gonadectomy in male, but not female, rats. Brain Struct Funct. 2017; 222(1):587–601.

240.

Hatanaka

, Hojo

, Mukai

, et al. Rapid increase of spines by dihydrotestosterone and testosterone in hippocampal neurons: Dependence on synaptic androgen receptor and kinase networks. Brain Res. 2015; 1621(1):121–132.

241.

MacLusky

, Hajszan

, Johansen

, et al. Androgen effects on hippocampal CA1 spine synapse numbers are retained in Tfm male rats with defective androgen receptors. Endocrinology. 2006; 147(5):2392–2398.

242.

Edinger

, Frye

. Testosterone's analgesic, anxiolytic, and cognitive enhancing effects may be due in part to actions of its 5a-reduced metabolites in the hippocampus. Behav Neurosci. 2004; 118(6):1352–1364.

243.

Spritzer

, Roy

. Testosterone and adult neurogenesis. Biomolecules, 2020; 10(2):225.

244.

Smith

, Jones

, Wilson

. Sex differences in hippocampal slice excitability: Role of testosterone. Neuroscience. 2002; 109(3):517–530.

245.

Harley

, Malsbury

, Squires

, et al. Testosterone decreases CA1 plasticity in vivo in gonadectomized male rats. Hippocampus. 2000; 10(6):693–697.

246.

Quintela

, Marcelino

, Gonçalves

, et al. Gene expression profiling in the hippocampus of orchidectomized rats. J Mol Neurosci. 2015; 55(1):198–205.

247.

Waterhouse

, Xu

. New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci. 2009; 42(2):81–89.

248.

McAllister

, Katz

, Lo

. Neurotrophins and synaptic plasticity. Annu Rev Neurosci. 1999; 22:295.

249.

Ottem

, Beck

, Jordan

, et al. Androgen-dependent regulation of brain-derived neurotrophic factor and tyrosine kinase B in the sexually dimorphic spinal nucleus of the bulbocavernosus. Endocrinology. 2007; 148(8):3655–3665.

250.

Yang

, Arnold

. Interaction of BDNF and testosterone in the regulation of adult perineal motoneurons. J Neurobiol. 2000; 44(3):308–319.

251.

Hill

, Wu

YWC

, Kwek

, et al. Modulatory effects of sex steroid hormones on brain-derived neurotrophic factor-tyrosine kinase B expression during adolescent development in C57Bl/6 mice. J Neuroendocrinol. 2012; 24(5):774–788.

252.

Shin

M-S

, Chung

, Ko

I-G

, et al. Effects of surgical and chemical castration on spatial learning ability in relation to cell proliferation and apoptosis in hippocampus. Int Urol Nephrol. 2016; 48(4):517–527.

253.

Fainanta

, Jaroenporn

, Wititsuwankul

, et al. Chronological molecular changes in neuronal communication in androgen-deficient rats. J Mol Neurosci. 2019; 69(1):83–93.

254.

Ebrahimzadeh

, Shahabi

, Mohaddes

, et al. Effect of testosterone on memory and BDNF levels of hippocampus in gonadectomized diabetic rats. Biosci Biotechnol Res Asia. 2015; 12(3):2433–2440.

255.

Skucas

, Duffy

, Harte-Hargrove

, et al. Testosterone depletion in adult male rats increases mossy fiber transmission, LTP, and sprouting in area CA3 of hippocampus. J Neurosci. 2013; 33(6):2338–2355.

256.

Atwi

, McMahon

, Scharfman

, et al. Androgen modulation of hippocampal structure and function. Neuroscientist. 2016; 22(1):46–60.

257.

Jia

J-X

, Cui

C-L

, Yan

X-S

, et al. Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice. J Toxicol Environ Health A. 2016; 79(19):849–855.

258.

Ahlbom

, Prins

, Ceccatelli

. Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism. Brain Res. 2001; 892(2):255–262.

259.

Nguyen

, Jayaraman

, Quaglino

, et al. Androgens selectively protect against apoptosis in hippocampal neurones. J Neuroendocrinol. 2010; 22(9):1013–1022.

260.

Estrada

, Varshney

, Ehrlich

. Elevated testosterone induces apoptosis in neuronal cells. J Biol Chem. 2006; 281(35):25492–25501.

261.

Gatson

, Kaur

, Singh

. Dihydrotestosterone differentially modulates the mitogen-activated protein kinase and the phophoinositide 3-kinase/Akt pathways through the nuclear and novel membrane androgen receptor in C6 cells. Endocrinology. 2006; 147(4):2028–2034.

262.

Hammond

, Le

, Goodyer

, et al. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem. 2001; 77(5):1319–1326.

263.

Heyer

, Hasselblatt

, von Ahsen

, et al. In vitro gender differences in neuronal survival on hypoxia and in 17beta-estradiol-mediated neuroprotection. J Cereb Blood Flow Metab. 2005; 25(4):427–430.

264.

Pike

. Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons. Brain Res. 2001; 919(1):160–165.

265.

Ramsden

, Shin

, Pike

. Androgens modulate neuronal vulnerability to kainate lesion. Neuroscience. 2003; 122(3):573–578.

266.

Nguyen

, Yao

, Pike

. Androgens activate mitogen-activated protein kinase signaling: Role in neuroprotection. J Neurochem. 2005; 941639–1651.

267.

Carrier

, Kabbaj

. Extracellular signal-regulated kinase 2 signaling in the hippocampal dentate gyrus mediates the antidepressant effects of testosterone. Biol Psychiatry. 2012; 71(7):642–651.

268.

Nguyen

, Yao

, Pike

. Dihydrotestosterone activates CREB signaling in cultured hippocampal neurons. Brain Res. 2009; 1298(1):1–12.

269.

Gouras

, Xu

, Gross

, et al. Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci U S A. 2000; 97(3):1202–1205.

270.

Zhang

, Champagne

, Beitel

, et al. Estrogen and androgen protection of human neurons against intracellular amyloid β1–42 toxicity through heat shock protein 70. J Neurosci. 2004; 24(23):5315–5321.

271.

Papasozomenos

, Shanavas

. Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3 beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: Implications of Alzheimer's disease. Proc Natl Acad Sci U S A. 2002; 99(3):1140–1145.

272.

Pike

, Nguyen

T-VV

, Ramsden

, et al. Androgen cell signaling pathways involved in neuroprotective actions. Horm Behav. 2008; 53(5):693–705.

273.

Cryns

, Yuan

. Proteases to die for. Genes Dev. 1998; 12(11):1551–1570.

274.

Thornberry

, Lazebnik

. Caspases: Enemies within. Science. 1998; 281(5381):1312–1316.

275.

, Zhao

, Anderson

, et al. Activated caspase-3 expression in Alzheimer's and aged control brain: Correlation with Alzheimer pathology. Brain Res. 2001; 898(2):350–357.

276.

Viau

. Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes. J Neuroendocrinol. 2002; 14(6):506–513.

277.

Viau

, Meaney

. The inhibitory effect of testosterone on hypothalamic-pituitary-adrenal responses to stress in mediated by the medial preoptic area. J Neurosci. 1996; 16(5):1866–1876.

278.

de Quervain

DJ-F

, Roozendaal

, McGaugh

. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature. 1998; 394(6695):787–789.

279.

Hölscher

. Stress impairs performance in spatial water maze learning tasks. Behav Brain Res. 1999; 100(1–2):225–235.

280.

Garcia

. Stress, hippocampal plasticity, and spatial learning. Synapse. 2001; 40(3):180–183.

281.

Mizoguchi

, Kunishita

, Chui

, et al. Stress induces neuronal death in the hippocampus of castrated rats. Neurosci Lett. 1992; 138(1):157–160.

282.

Fernández-Guasti

, Martínez-Mota

. Anxiolytic-like actions of testosterone in the burying behavior test: Role of androgen and GABA-benzodiazepine receptors. Psychoneuroendocrinology. 2005; 30(8):762–770.

283.

2021 Alzheimer's disease facts and figures. Alzheimers Dement. 2021;17(3):327–406.

284.

Dementia. https://www.who.int/news-room/fact-sheets/detail/dementia (accessed June 29, 2021).

Testosterone and Spatial Memory: Rodent Models and Clinical Applications

Abstract

Introduction

Sex Differences in Spatial Memory

Human Research with Younger Males

Rodent Research with Younger Males

Human Research with Older Males

Rodent Research with Older Males

Metabolites of Testosterone: DHT and Estradiol

Neuroplasticity and Neuroprotection

Conclusion

Footnotes

Authors' Contributions

Author Disclosure Statement

Funding Information

Abbreviations Used

References