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  • Several large scale clinical studies have


    Several large-scale clinical studies have set out with the common goal to further understand the cognitive impact of menopause and hormone therapies taken by women (Gleason et al., 2015, Greendale et al., 2011, Karlamangla et al., 2017, Rapp et al., 2003, Shumaker et al., 2003). Only one human study thus far has specifically evaluated the impact Calpain Inhibitor II, ALLM and Levo have on cognitive function. In this study, the estradiol valerate plus Levo oral hormone therapy, Klimonorm, was assessed; after 2 months, Klimonorm improved concentration, speed of cognitive function, and short-term memory in perimenopausal and postmenopausal women that either had received a hysterectomy (n = 6), Ovx (n = 14), hysterectomy plus Ovx (n = 6), or no surgical manipulations (n = 52) (Rudolph et al., 2000). In the present study, we showed that the cognitive effects of the estrogen plus Levo treatment in surgically menopausal rats are contingent on the level of cognitive demand and memory type evaluated. Thus, systematically designed studies of clinically relevant hormone formulations and their effects in animal models of menopause are critical; information gained from such studies can inform future human study designs as steps are taken to further understand the complex interactions between hormones and various memory domains.
    Conclusion To our knowledge, this study is the first to examine the effect of an E2 + Levo hormone combination treatment, as well as E2-only and Levo-only treatments, on cognitive function in a preclinical model of surgical menopause. Hormone therapy, which can contain only estrogens, only progestogens, or an estrogen plus progestogen combination, is used to decrease the onset and severity of undesired changes associated with menopause. Thus, it is critical to not only examine the individual effects of hormones on symptoms associated with menopause, including the impact on learning and memory, but also how the combination of both an estrogen and a progestogen impacts these symptoms. Our results showed that E2 and Levo each have beneficial effects on spatial working memory when administered separately, replicating our prior studies (Bimonte and Denenberg, 1999, Bimonte-Nelson et al., 2006, Braden et al., 2017, Talboom et al., 2008). However, the E2 + Levo hormone combination impaired spatial working memory relative to either of the hormones alone when the spatial working memory task was highly taxing. Furthermore, a relationship between activated Erk2 levels in the frontal cortex and spatial working memory after E2-only treatment was observed. These findings are significant as they highlight opposing effects of an estrogen and progestogen hormone combination treatment and raise further questions regarding which underlying neurobiological mechanisms are responsible for the individual cognitive enhancements of E2-only and Levo-only, and for the negating effects when the 2 hormones are administered together. This study illustrates that although an estrogen and a progestogen can be cognitively beneficial when administered alone, the clinically used combination of the same estrogen and progestogen does not necessarily result in added benefits and can in fact yield impairments. Indeed, in the context of hormone therapy, 1 plus 1 does not always equal 2.
    Disclosure statement
    Introduction While the role of progestogens in endometrial protection has been well accepted in studies of hormone replacement therapy (HRT), whether progestogens reduce or enhance the risk of breast cancer remains controversial. Recently, the Women's Health Initiative (WHI) study, the first randomized, prospective, controlled trial, reported a 26% increase in the relative risk of breast cancer for combined estrogen–progestogen when compared with a placebo [1]. The Million Women Study, the largest observational study reported to date, also reported a significant increase in breast cancer risk with the estrogen–progestogen combination [2]. However, another arm of WHI study, the estrogen trial, showed that estrogen alone administered to hysterectomized women did not increase the risk of breast cancer [3], although the precise effect of estrogen-alone remains unclear. Thus, there is clearly a need to urgently reevaluate the role of progestogens in HRT with regard to breast cancer risk. Although a number of in vitro studies using breast cancer cell lines have been reported, results have been inconsistent as it appears that whether progestogens inhibit or stimulate cancer cell proliferation can depend on the culture conditions, cell type, and the specific progestogen tested [4], [5], [6], [7], [8], [9], [10], [11]. One of the major confounding factors is that while most of the large-scale clinical trials have used medroxyprogesterone acetate (MPA) as the progestogen, the studies have not necessarily compared differences between progestogen types, duration of use, and specific regimens.