An update on the cognitive impact of clinically-used hormone therapies in the female rat: models, mazes, and mechanisms

Abstract

In women, ovarian hormone loss associated with menopause has been related to cognitive decline. Hormone therapy (HT) may ameliorate some of these changes. Understanding the cognitive impact of female steroids, including estrogens, progestogens, and androgens, is key to discovering treatments that promote brain health in women. The preclinical literature has presented elegant and methodical experiments allowing a better understanding of parameters driving the cognitive consequences of ovarian hormone loss and HT. Animal models have been a valuable tool in this regard, and will be vital to future discoveries. Here, we provide an update on the literature evaluating the impact of female steroid hormones on cognition, and the putative mechanisms mediating these effects. We focus on preclinical work that was done with an eye toward clinical realities. Parameters that govern the cognitive efficacy of HT, from what we know thus far, include but are not limited to: type, dose, duration, and route of HT, age at HT initiation, timing of HT relative to ovarian hormone loss, memory type examined, menopause history, and hormone receptor status. Researchers have identified intricate relationships between some of these factors by studying their individual effects on cognition. As of late, there is increased focus on studying interactions between these variables as well as multiple hormone types when administered concomitantly. This is key to translating preclinical data to the clinic, wherein women typically have concurrent exposure to endogenous ovarian hormones as well as exogenous combination HTs, which include both estrogens and progestins. Gains in understanding the parameters of HT effects on cognition provide exciting novel avenues that can inform clinical treatments, eventually expanding the window of opportunity to optimally enhance cognition and brain health in aging women. This article is part of a Special Issue entitled Hormone Therapy.

Figure 1

Female steroid hormones can impact the brain and cognition throughout the lifespan. In women, female steroid hormone exposure encompasses both endogenous and exogenous exposures in a lifetime. Endogenous hormone exposure occurs during the prenatal environment, birth, puberty, and menopause, and exogenous hormone exposure occurs from contraceptives during reproductively active years and/or hormone therapy (HT) during menopause. Organizational and activational effects on the brain interact and ultimately impact cognitive outcome. Female steroid-induced effects on cognitive outcome depend on many factors. Putative neurobiological mechanisms underlying hormone-induced alterations in cognition include those listed in the brain schematic in the figure. Regarding research investigating the cognitive effects of various types of HT in middle-aged and aged rats, the plus sign (+) denotes positive effects on cognition and the minus (-) sign denotes detrimental effects on cognition. The numbers under the plus and minus signs refer to the corresponding publication/Reference ID# listed in Table 1.