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 associated with 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.

Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it?

“…That is, one dose and duration might be optimal for one woman, but suboptimal or even detrimental to another woman. In addition, the animal work indicates that there are a considerable number of potentially interactive factors to bear in mind, including, but certainly not limited to, the type of estrogen given, route of hormone administration, status of reproductive senescence/follicular depletion, age at which hormone is administered, presence or absence of a progestogen, and the presence or absence of ovaries (Acosta et al, 2013; Chisholm and Juraska, 2013; Luine, 2014; Mennenga and Bimonte-Nelson, 2013), as well as the appropriate battery of assessments to tap into estrogen-modulated systems.…”

“…A critical period hypothesis regarding the timing of hormone therapy administration and its cognitive outcome has gained substantial support in the rodent and human literature, garnering much discussion and consideration (Acosta et al, 2013; Daniel and Bohacek, 2010; Maki, 2013; Rocca et al, 2011, 2010; Singh et al, 2013; Singh and Su, 2013b). One of the first reports indicating the importance of the timing of hormone therapy in an animal model comes from the laboratory of Robert Gibbs, stemming in part from data showing that weekly injections of 17β-estradiol and progesterone administered shortly after Ovx improved spatial memory task acquisition, but the same treatment administered several months after Ovx did not produce this benefit (Gibbs, 2000a).…”

Distinct cognitive effects of estrogen and progesterone in menopausal women

“…The majority of evidence for cognitive effects of natural progesterone comes from studies of postmenopausal women using combined hormone formulations (estrogen + progestin versus progesterone), studies of circulating progesterone levels or fluctuations in endogenous progesterone levels across a menstrual cycle, and progesterone administration in animals. Evidence from these studies suggest an effect of progesterone in cognitive processing brain regions, distinct from the effects of estrogen, and indicate the need for closer investigation of progesterone effects in postmenopausal women (Acosta et al, 2013; Chisholm and Juraska, 2012; Drake et al, 2000; Farage et al, 2008; Gibbs, 2000; Nilsen and Brinton, 2002b; Rapp et al, 2003; Stanczyk et al, 2013). …”

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

“…Nevertheless, it is important that investigators consider the possible effects of sex steroid hormones on neural function and behavior in their experimental designs and data interpretation. However, when thinking about sex differences in brain function or behavior, it is important to note whether differences are due to the activational effects of circulating hormones in adulthood or from organizational effects of hormones in early development, as it has been argued that only the latter can be construed as a true sex difference (McCarthy and Konkle 2005).Numerous recent reviews have discussed the effects of E 2 on learning and memory in females (Korol 2002;Foster 2005;Daniel 2006Daniel , 2013Sherwin and Henry 2008;Barha and Galea 2010;Bimonte-Nelson et al 2010;Gibbs 2010;Kim and Casadesus 2010;Choleris et al 2012;Foster 2012;Frick 2012;Acosta et al 2013;Chisolm and Juraska 2013;Ervin et al 2013;Galea et al 2013;Hogervorst 2013;Luine and Frankfurt 2013;Maki 2013;Bean et al 2014;Luine 2014;Frankfurt and Luine 2015;Tuscher et al 2015). As such, this review will not attempt to provide a comprehensive discussion of all effects of E 2 on learning and memory.…”