Chronic Testosterone Deprivation Sensitizes the Middle-Aged Rat Brain to Damaging Effects of Testosterone Replacement

Abstract

Introduction: An increasing number of middle-aged men are being screened for low testosterone levels and the number of prescriptions for various forms of testosterone replacement therapy (TRT) has increased dramatically over the last 10 years. However, the safety of TRT has come into question with some studies suggesting increased morbidity and mortality. Objective: Because the benefits of estrogen replacement in postmenopausal women and ovariectomized rodents are lost if there is an extended delay between estrogen loss and replacement, we hypothesized that TRT may also be sensitive to delayed replacement. Methods: We compared the effects of testosterone replacement after shortterm (2 weeks) and long-term testosterone deprivation (LTTD; 10 weeks) in middle-aged male rats on cerebral ischemia, oxidative stress, and cognitive function. We hypothesized that LTTD would increase oxidative stress levels and abrogate the beneficial effects of TRT. Results: Hypogonadism itself and TRT after short-term castration did not affect stroke outcome compared to intact rats. However, after long-term hypogonadism in middle-aged male Fischer 344 rats, TRT exacerbated the detrimental behavioral effects of experimental focal cerebral ischemia, whereas this detrimental effect was prevented by administration of the freeradical scavenger tempol, suggesting that TRT exacerbates oxidative stress. In contrast, TRT improved cognitive performance in non-stroked rats regardless of the length of hypogonadism. In the Morris water maze, peripheral oxidative stress was highly associated with decreased cognitive ability. Conclusions: Taken together, these data suggest that TRT after long-term hypogonadism can exacerbate functional recovery after focal cerebral ischemia, but in the absence of injury can enhance cognition. Both of these effects are modulated by oxidative stress levels.

Androgens’ effects on cerebrovascular function in health and disease

“…Surprisingly, androgens' effects in animal models of VCID, such as the chronic cerebral hypoperfusion models (e.g., unilateral carotid artery occlusion or bilateral carotid artery stenosis) have yet to be assessed. However, in a rat model of post-stroke dementia, it was found that T replacement after castration increased cognitive deficits following stroke in middle-aged males [122]. It is unclear if the cognitive effect observed was dependent on infarct volume or was independent of stroke severity.…”

“…However, this effect was found to be mediated by increased oxidative stress, as it could be inhibited by a free-radical scavenger. In contrast to the detrimental effects of T in the context of stroke, in sham animals, T actually improved cognitive performance [122]. Therefore, future studies are needed to determine the role of androgens in models of cerebral small vessel disease and chronic cerebral hypoperfusion.…”

Neuroprotective and neurotherapeuticeffects of dihydrotestosterone,17?-estradiol, and pueraria mirifica extract on cognitive impairment in androgen deficient rats

“…With the finer timescale tracking every 2 months in this study, from young adult to middle-aged rats, the impairment in spatial learning and memory could be detected as early as 8 months old (SH-M4) or at the early middle age. This finding partially aligned with the previous studies showing that the deficit in spatial learning and memory on MWM task emerged at the middle age, approximately 12-14 months old (Bizon et al, 2009;Francia et al, 2006;Frick et al, 1995;Frye et al, 2010;Guidi et al, 2014;Smith et al, 2020;Wang et al, 2020). In parallel with the increasing in age and the impairment in spatial learning and memory, male rats had a gradual and marginal decline in serum testosterone levels starting from 8 months old and a significant reduction was detected at 12 months old (or middle age).…”

“…Male animals were induced an androgen deficient condition by castration and their cognitive function, i.e., performances on spatial reference version of learning and memory, was assessed by MWM task (Fang et al, 2017;Frye et al, 2010;Jia et al, 2013;Kang et al, 2014;Moghadami et al, 2016;Pintana et al, 2015;Pintana et al, 2016). However, the results were still inconsistent (Benice and Raber, 2009;Hodosy et al, 2012;Pintana et al, 2016;Sandstrom et al, 2006;Smith et al, 2020;Spritzer et al, 2008;Zhao et al, 2018). The discrepancy between studies might be because of the difference in age of animals recruited into the studies, the ages of animals when they were initiated the castration, and duration of time that the animals were held in androgen deficient condition.…”

“…However, if the animals were recruited at the older age, for example at 13 and 24 months old and kept under androgen deficient condition for 2 weeks (Frey et al, 2010), or kept in a shorter time of androgen deficient condition, for example 2 months of age and kept for only a month after castration (Pintana et al, 2016), the behavioral deficit was not detected. Generally, the deficit of spatial learning and memory was emerged in male testes-intact rodents as early as they entered into the middle age, ranging from 12-14 months old (Bizon et al, 2009;Francia et al, 2006;Frye et al, 2010;Guidi et al, 2014;Smith et al, 2020).…”