Contrasting effects of individual versus combined estrogen and progestogen regimens as working memory load increases in middle-aged ovariectomized rats: one plus one does not equal two

Abstract

Most estrogen-based hormone therapies are administered in combination with a progestogen, such as Levonorgestrel (Levo). Individually, the estrogen 17β-estradiol (E2) and Levo can improve cognition in preclinical models. However, although these hormones are often given together clinically, the impact of the E2 + Levo combination on cognitive function has yet to be methodically examined. Thus, we investigated E2 + Levo treatment on a cognitive battery in middle-aged, ovariectomized rats. When administered alone, E2 and Levo treatments each enhanced spatial working memory relative to vehicle treatment, whereas the E2 + Levo combination impaired high working memory load performance relative to E2 only and Levo only treatments. There were no effects on spatial reference memory. Mitogen-activated protein kinases/extracellular signal-regulated kinases pathway activation, which is involved in memory formation and estrogen-induced memory effects, was evaluated in 5 brain regions implicated in learning and memory. A distinct relationship was seen in the E2-only treatment group between mitogen-activated protein kinases/extracellular signal-regulated kinases pathway activation in the frontal cortex and working memory performance. Collectively, the results indicate that the differential neurocognitive effects of combination versus sole treatments are vital considerations as we move forward as a field to develop novel, and to understand currently used, exogenous hormone regimens across the lifespan.

The middle-aged brain: biological sex and sex hormones shape memory circuitry

“…In contrast, the largest randomized clinical trial of hormone replacement therapy (HT) in postmenopausal women found no benefit of HT for slowing the rate of cognitive decline and found an increased risk of dementia (Shumaker et al, 2003), although more recent work in midlife women challenges this finding (see Daniel et al, 2015; McCarrey and Resnick, 2015; Henderson et al, 2016; and Prakapenka et al, 2017). Reconciling long-standing discrepancies between basic animal studies and large-scale clinical trials on estradiol’s neural and cognitive effects is essential for advancing women’s health (Morrison et al, 2006; Hara et al, 2015; Maki & Henderson, 2012; Boulware, Kent and Frick, 2012; Brinton et al, 2015).…”

The Role of Estrogen in Anxiety-Like Behavior and Memory of Middle-Aged Female Rats

“…Similarly, there are numerous data showing anxiogenic effect of ovariectomy in several tests, such as open field, elevated plus maze or light-dark box (16)(17)(18)(19)(20). On the other hand, estradiol replacement in the surgical model of menopause may improve cognitive functions and decrease anxiety-like behavior in rodents (14,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Premarin has opposing effects on spatial learning, neural activation, and serum cytokine levels in middle-aged female rats depending on reproductive history

“…In addition, the ability of HT to improve cognition in middle-age depends on the specific formulation of HT in animals (Baxter et al, 2013;Prakapenka et al, 2018). Furthermore, the effects of HT on cognition in women may be dependent on the timing of when HTs were prescribed (early or late in menopause), with a greater proportion of studies finding detrimental outcomes, or fewer positive outcomes, when HT is initiated 10 or more years after menopause (Espseland et al, 2017;Hogevorst et al, 2000;Ryan et al, 2008), although other studies find no such effect (Henderson et al, 2016).…”