High serum androstenedione levels correlate with impaired memory in the surgically menopausal rat: a replication and new findings

Abstract

After natural menopause in women, androstenedione becomes the primary hormone secreted by the residual follicle-depleted ovaries. In two independent studies, in rodents that had undergone ovarian follicular depletion, we found that higher endogenous serum androstenedione levels correlated with increased working memory errors. This led to the hypothesis that higher androstenedione levels impair memory. The current study directly tested this hypothesis, examining the cognitive effects of exogenous androstenedione administration in rodents. Middle-aged ovariectomized rats received vehicle or one of two doses of androstenedione. Rats were tested on a spatial working and reference memory maze battery including the water-radial arm maze, Morris water maze (MM) and delay match-to-sample task. Androstenedione at the highest dose impaired reference memory as well as the ability to maintain performance as memory demand was elevated. This was true for both high temporal demand memory retention of one item of spatial information, as well as the ability to handle multiple items of spatial working memory information. We measured glutamic acid decarboxylase (GAD) protein in multiple brain regions to determine whether the gamma-aminobutyric acid (GABA) system relates to androstenedione-induced memory impairments. Results showed that higher entorhinal cortex GAD levels were correlated with worse MM performance, irrespective of androstenedione treatment. These findings suggest that androstenedione, the main hormone produced by the follicle-depleted ovary, is detrimental to working memory, reference memory and memory retention. Furthermore, while spatial reference memory performance might be related to the GABAergic system, it does not appear to be altered with androstenedione administration.

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

“…Thus, intrigued by this correlation, we continued to explore the role of androstenedione on memory in the middle-aged female rat. We found that in middle-aged Ovx rats, a high dose of androstenedione impaired spatial working memory and reference memory (Camp et al, 2012). Androstenedione can be aromatized to estrone, an estrogen that we have shown to impair memory in the Ovx rat model (Engler-Chiurazzi et al, 2012).…”

“…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).…”

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). …”

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

“…Vehicle-treated animals received 0.5ml of polyethylene glycol (PEG) (Sigma-Aldrich, St. Louis, MO, USA) only. All rats receiving androstenedione (Steraloids, Newport, RI, USA) were given 2mg daily dissolved in PEG; this dose of androstenedione was based on previous literature (Lea & Flanagan, 1998; Sprando et al, 2004; Camp et al, 2012) and has been shown to produce working memory impairments in middle-aged Ovx rats (Camp et al, 2012). Animals in the Androstenedione+Anastrozole group received 0.025mg/day anastrozole (Tocris, Minneapolis, MN, USA) co-administered with 2mg androstenedione treatment, in order to block activity of the aromatase enzyme, preventing the conversion of androstenedione to estrone.…”

“…To test this hypothesis, we performed a study in which middle-aged (14 month old) Ovx rats were administered either vehicle or one of two doses of androstenedione, and then tested with a battery of mazes that assess learning and memory. Relative to vehicle treatment, androstenedione administration impaired spatial reference memory on the Morris water maze, was detrimental to performance on the water radial-arm maze (WRAM) when the working memory load was most demanding, and impaired memory retention on a win-stay delay match to sample (DMS) task (Camp et al, 2012). Thus, in several different studies we have shown that androstenedione, released from the follicle-deplete ovary in both women and rats, markedly impairs memory.…”