Krystina G. Sorwell

Dehydroepiandrosterone and age-related cognitive decline

In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.

Perimenopausal regulation of steroidogenesis in the nonhuman primate

Human aging is characterized by a marked decrease in circulating levels of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS), hormonal changes associated with cognitive decline. Despite beneficial effects of DHEA supplementation in rodents, studies in elderly humans have generally failed to show cognitive improvement after treatment. In the present study we evaluate the effects of age and estradiol supplementation on expression of genes involved in the de novo synthesis of DHEA and its conversion to estradiol in the rhesus macaque hippocampus. Using reverse transcription polymerase chain reaction (RT-PCR) we demonstrate the expression of genes associated with this synthesis in several areas of the rhesus brain. Furthermore, real-time PCR reveals an age-related attenuation of hippocampal expression level of the genes CYP17A1, STS, and 3BHSD1/2. Additionally, short-term administration of estradiol is associated with decreased expression of CYP17A1, STS, SULT2B1, and AROMATASE, consistent with a downregulation not only of estrogen synthesis from circulating DHEA, but also of de novo DHEA synthesis within the hippocampus. These findings suggest a decline in neurosteroidogenesis may account for the inefficacy of DHEA supplementation in elderly humans, and that central steroidogenesis may be a function of circulating hormones and menopausal status.

Causes and Consequences of Age-Related Steroid Hormone Changes: Insights Gained from Nonhuman Primates

Similar to humans, rhesus macaques (Macaca mulatta) are large, long‐lived diurnal primates, and show similar age‐related changes in the secretion of many steroid hormones, including oestradiol, testosterone, cortisol and dehydroepiandrosterone (DHEA). Consequently, they represent a pragmatic animal model in which to examine the mechanisms by which these steroidal changes contribute to perturbed sleep–wake cycles and cognitive decline in the elderly. Using remote serial blood sampling, we have found the circulating levels of DHEA sulphate, as well as oestradiol and testosterone, decline markedly in old monkeys. Furthermore, using the real‐time polymerase chain reaction, we have shown that the genes for the enzymes associated with the conversion of DHEA to oestradiol and testosterone (3β‐hydroxysteroid dehydrogenase, 17β‐hydroxysteroid dehydrogenase, and aromatase) are highly expressed in brain areas associated with cognition and behaviour, including the hippocampus, prefrontal cortex and amygdala. Taken together, these findings suggest that the administration of supplementary DHEA in the elderly may have therapeutic potential for cognitive and behavioural disorders, although with fewer negative side effects outside of the central nervous system. To test this, we have developed a novel steroid supplementation paradigm for use in old animals; this involves the oral administration of DHEA and testosterone at physiologically relevant times of the day to mimic the circadian hormone patterns observed in young adults. We are currently evaluating the efficacy of this steroid supplementation paradigm with respect to reversing age‐associated disorders, including perturbed sleep–wake cycles and cognitive decline, as well as an impaired immune response.

Testosterone increases circulating dehydroepiandrosterone sulfate levels in the male rhesus macaque.

The adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are two of the most abundant hormones in the human circulation. Furthermore, they are released in a circadian pattern and show a marked age-associated decline. Adult levels of DHEA and DHEAS are significantly higher in males than in females, but the reason for this sexual dimorphism is unclear. In the present study, we administered supplementary androgens [DHEA, testosterone and 5α-dihydrotestosterone (DHT)] to aged male rhesus macaques (Macaca mulatta). While this paradigm increased circulating DHEAS immediately after DHEA administration, an increase was also observed following either testosterone or DHT administration, resulting in hormonal profiles resembling levels observed in young males in terms of both amplitude and circadian pattern. This stimulatory effect was limited to DHEAS, as an increase in circulating cortisol was not observed. Taken together, these data demonstrate an influence of the hypothalamo-pituitary–testicular axis on adrenal function in males, possibly by sensitizing the zona reticularis to the stimulating action of adrenocorticopic hormone. This represents a plausible mechanism to explain sex differences in circulating DHEA and DHEAS levels, and may have important implications in the development of hormone therapies designed for elderly men and women.

Androgen Supplementation During Aging: Development of a Physiologically Appropriate Protocol

Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21-26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained nocturnal elevation of Ts primary bioactive metabolites, DHT and E1 and E2. Plasma DHEAS levels were also significantly elevated after androgen supplementation; DHEAS levels rose in the early morning and gradually declined during the course of the day, closely mimicking the profiles observed in young adults (7-12 years old); in contrast, cortisol levels were unaltered by the supplementation. Together the data demonstrate a non-invasive androgen supplementation paradigm that restores youthful circulating androgen levels in old male primates. Because this paradigm preserves the natural circulating circadian hormone patterns, we predict that it will produce fewer adverse side effects, such as perturbed sleep or cognitive impairment.Abstract Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21–26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained...

Hormone Supplementation During Aging: How Much and When?

Circulating levels of dehydroepiandrosterone, a major adrenal steroid, show a marked age-related decrease in both humans and nonhuman primates. Because this decrease has been implicated in age-related cognitive decline, we administered supplementary dehydroepiandrosterone to perimenopausal rhesus macaques (Macaca mulatta) to test for cognitive benefits. Although recognition memory improved, there was no benefit to spatial working memory. To address the limitations of this study we developed a hormone supplementation regimen in aged male macaques that more accurately replicates the 24-hr androgen profiles of young animals. We hypothesize that this more comprehensive physiological hormone replacement paradigm will enhance cognitive function in the elderly.

Cognition in aged rhesus monkeys: effect of DHEA and correlation with steroidogenic gene expression

Estradiol supplementation has been shown to enhance cognitive performance in old ovariectomized rhesus macaques (Macaca mulatta). To determine if similar benefits could be achieved in perimenopausal animals using alternative hormonal supplements, we administered dehydroepiandrosterone (DHEA) to old ovary‐intact female rhesus macaques for ∼2.5 months. Using computerized touch screen memory tasks, including delayed response (DR) and delayed matching‐to‐sample (DMS), we observed improved performance with time in all of the animals but failed to detect a significant effect of DHEA. On the other hand, gene expression profiling disclosed a significant correlation between cognitive performance and the expression of several steroidogenic and steroid‐responsive genes. The DR performance was positively correlated with hippocampal expression of AKR1C3 and STAR and negatively correlated with the expression of SDRD5A1. A positive correlation was also found between DMS performance and prefrontal cortical expression of AKR1C3 and a negative correlation with STAR, as well as a negative correlation with the hippocampal expression of HSD11B1 and NR3C1. Taken together, the results suggest that steroidogenic gene regulation within the brain may help to maintain cognitive function during the perimenopausal transition period, despite a decline in sex‐steroid levels in the circulation.

Androgen supplementation during aging

Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21-26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained nocturnal elevation of Ts primary bioactive metabolites, DHT and E1 and E2. Plasma DHEAS levels were also significantly elevated after androgen supplementation; DHEAS levels rose in the early morning and gradually declined during the course of the day, closely mimicking the profiles observed in young adults (7-12 years old); in contrast, cortisol levels were unaltered by the supplementation. Together the data demonstrate a non-invasive androgen supplementation paradigm that restores youthful circulating androgen levels in old male primates. Because this paradigm preserves the natural circulating circadian hormone patterns, we predict that it will produce fewer adverse side effects, such as perturbed sleep or cognitive impairment.Abstract Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21–26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained...