Pharmacological blockade of the aromatase enzyme, but not the androgen receptor, reverses androstenedione-induced cognitive impairments in young surgically menopausal rats

Abstract

Androstenedione, the main circulating ovarian hormone present after menopause, has been shown to positively correlate with poor spatial memory in an ovary-intact rodent model of follicular depletion, and to impair spatial memory when administered exogenously to surgically menopausal ovariectomized rats. Androstenedione can be converted directly to estrone via the aromatase enzyme, or to testosterone. The current study investigated the hormonal mechanism underlying androstenedione-induced cognitive impairments. Young adult ovariectomized rats were given either androstenedione, androstenedione plus the aromatase inhibitor anastrozole to block conversion to estrone, androstenedione+the androgen receptor blocker flutamide to block androgen receptor activity, or vehicle treatment, and were then administered a battery of learning and memory maze tasks. Since we have previously shown that estrone administration to ovariectomized rats impaired cognition, we hypothesized that androstenedione's conversion to estrone underlies, in part, its negative cognitive impact. Here, androstenedione administration impaired spatial reference and working memory. Further, androstenedione did not induce memory deficits when co-administered with the aromatase inhibitor, anastrozole, whereas pharmacological blockade of the androgen receptor failed to block the cognitive impairing effects of androstenedione. Anastrazole alone did not impact performance on any cognitive measure. The current data support the tenet that androstenedione impairs memory through its conversion to estrone, rather than via actions on the androgen receptor. Studying the effects of aromatase and estrogen metabolism is critical to elucidating how hormones impact women's health across the lifespan, and results hold important implications for understanding and optimizing the hormone milieu from the many endogenous and exogenous hormone exposures across the lifetime.

Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory

“…Serum was collected after centrifugation for 20 minutes at 2,000 rpm at 4°C and stored at −20°C until measurement by radioimmunoassay. Steroid hormone levels for 17β-estradiol, estrone, androstenedione, and progesterone were determined by radioimmunoassay using previously described methods (Acosta et al, 2010; Camp et al, 2012; Mennenga et al, 2015a, 2015b). …”

The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory

“…The aromatase enzyme converts androstenedione to estrone and 17β-estradiol; androstenedione can also be converted to testosterone via the enzyme17β-HSD; both of these androgens and their metabolites can impact the brain and cognition (Bimonte-Nelson et al, 2003; Camp et al, 2012; Mennenga et al, 2015b). In the context of menopause, research shows that, while estrogen and progesterone production declines substantially with reproductive senescence, the postmenopausal ovary continues to produce androgens in rodents (Mayer, 2004) and in humans (Fogle et al, 2007).…”

“…Consequently, our laboratory systematically evaluated whether the apparent detrimental effects of androstenedione on memory were due to binding to the androgen receptor or androstenedione’s conversion to estrone via the aromatase enzyme. Results indicated that blocking aromatase enzymatic activity via anastrozole reversed androstenedione-induced spatial memory impairments in young Ovx rats, but blocking the androgen receptor did not prevent detrimental effects on memory, suggesting that the conversion of androstenedione to estrone influences cognitive performance (Mennenga et al, 2015b). Collectively, these findings point to a crucial role of androgens, a long ignored yet ostensibly critical factor in understanding the role of the hormone milieu on cognition in the menopausal woman.…”

Nature, Calcigender, Nurture: Sex-dependent differential Ca2+ homeostasis as the undervalued third pillar

“…rats. [20,[35][36][37] Information was also obtained from studying neurodegenerative diseases, e.g. Alzheimer.…”