Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: Tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity

Abstract

Ethinyl estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. Here, we evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory and basal forebrain cholinergic integrity by using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; tonic delivery of low EE, a dose that corresponds to the most popular doses used in the clinic today, did not impact cognition on any measure. Both medium and high doses of EE reduced the number of cholinergic cells in the basal forebrain and cell population estimates in the vertical/diagonal bands negatively correlate with working memory errors.

Effects of age, experience and inter-alpha inhibitor proteins on working memory and neuronal plasticity after neonatal hypoxia-ischemia

“…In addition to the three levels of cognitive demand indicated by the three error types (RM, WMI, WMC), task demand increased on subsequent trials (trials 1-4), within a given testing session, as platforms were removed and working memory load increased [61,64,66,69,71]. Previous studies have shown that HI deficits become more pronounced on tasks with higher working memory load [10,19,66].…”

“…As previously described, orthogonal measures of working and reference memory were used to quantify errors [62,64,66-71]. Three error types were recorded for each daily session.…”

“…Working memory incorrect (WMI) errors were recorded as repeat entries into reference memory arms, which were arms that never contained an escape platform. Working memory correct (WMC) errors represented the number of first and repeat entries into any arm that previously contained an escape platform (removed during preceding trials; [62,64,66-71]). This win-shift strategy of avoiding arms previously used for escape (WMC errors) represented the most challenging aspect of the task, as rats have a natural tendency to return to locations previously used for escape on water-based maze testing [72].…”

“…Planned comparisons using oneway ANOVAs were performed to analyze effects of treatment on total errors within experience groups collapsed across block. Further, analyses of treatment across trial within experience groups were also planned, as treatment-induced differences on later sessions of water-radial-arm maze testing have been observed previously, with the most pronounced effects occurring on trial 4, (highest working memory load; [60, 63-66,69,71]). When appropriate, Tukey's HSD post hoc analyses were used to identify treatment effects within each trial for each experience group.…”

Estrogen–cholinergic interactions: Implications for cognitive aging

“…When cholinergic systems are experimentally destroyed or blocked, estradiol administration is ineffective in enhancing learning (Daniel et al, 2005; Gibbs, 2001), suggesting the cholinergic systems are critical for estradiol to have cognitively enhancing effects. Interestingly, high doses of ethinyl estradiol a synthetic form of 17-β estradiol, the most common estrogen in hormonal contraceptives, appears to negatively impact working memory performance in rodents and this correlates with a decline in measures of cholinergic integrity (Mennenga et al, 2015). …”