Clinically Used Hormone Formulations Differentially Impact Memory, Anxiety-Like, and Depressive-Like Behaviors in a Rat Model of Transitional Menopause

Abstract

A variety of U.S. Food and Drug Administration-approved hormone therapy options are currently used to successfully alleviate unwanted symptoms associated with the changing endogenous hormonal milieu that occurs in midlife with menopause. Depending on the primary indication for treatment, different hormone therapy formulations are utilized, including estrogen-only, progestogen-only, or combined estrogen plus progestogen options. There is little known about how these formulations, or their unique pharmacodynamics, impact neurobiological processes. Seemingly disparate pre-clinical and clinical findings regarding the cognitive effects of hormone therapies, such as the negative effects associated with conjugated equine estrogens and medroxyprogesterone acetate vs. naturally circulating 17β-estradiol (E2) and progesterone, signal a critical need to further investigate the neuro-cognitive impact of hormone therapy formulations. Here, utilizing a rat model of transitional menopause, we administered either E2, progesterone, levonorgestrel, or combinations of E2 with progesterone or with levonorgestrel daily to follicle-depleted, middle-aged rats. A battery of assessments, including spatial memory, anxiety-like behaviors, and depressive-like behaviors, as well as endocrine status and ovarian follicle complement, were evaluated. Results indicate divergent outcomes for memory, anxiety, and depression, as well as unique physiological profiles, that were dependent upon the hormone regimen administered. Overall, the combination hormone treatments had the most consistently favorable profile for the domains evaluated in rats that had undergone experimentally induced transitional menopause and remained ovary-intact. The collective results underscore the importance of investigating variations in hormone therapy formulation as well as the menopause background upon which these formulations are delivered.

Evaluating the Cognitive Impacts of Drospirenone, a Spironolactone-Derived Progestin, Independently and in Combination With Ethinyl Estradiol in Ovariectomized Adult Rats

“…These group differences may have been due, in part, to an overall change in locomotor activity induced by the high EE dose; as such, these findings should be interpreted with caution in the context of being solely related to anxiety-like alleviation by the high dose of EE alone and in combination with drospirenone, specifically. E2 levels are known to impact locomotor and anxiety-like behavior, and thus this finding is concordant with prior research in surgical and transitional menopause models ( Blizard et al, 1975 ; Lund et al, 2005 ; Hiroi et al, 2006 ; Hiroi and Neumaier, 2006 ; McLaughlin et al, 2008 ; Koebele et al, 2021a ). The investigation of effects of EE on anxiety assessments are currently limited, although dose-dependent beneficial effects of EE have been reported in ovary-intact rats ( Simone et al, 2015 ).…”

“…The OFT was a 100 cm × 100 cm × 30 cm black plexiglass arena. Although some paradigms use a bright light in the center of the maze, this assay was completed in red light (i.e., darkness for rats), as we have previously published ( Koebele et al, 2021a ). This is because rats with significant anxiety-like phenotypes tend not to move at all if the center of the arena is lit.…”

“…For Experiment 2, each DRSP, EE, and DRSP + EE group was compared to Vehicle using two-group comparisons. Additionally, we compared EE-Low and EE-High groups to each other to assess dose-dependent effects, as well as compared EE-Low, EE-High, and DRSP groups to the combinations of DRSP + EE to assess effects of the hormones alone vs in combination with one another to evaluate differential cognitive effects when hormone treatments are co-administered ( Prakapenka et al, 2018 ; Koebele et al, 2021a ). Alpha level was set to 0.05 for all analyses.…”

“…Water radial-arm maze data were separated into three phases based on error-making patterns in the learning curve, as we have previously published ( Mennenga et al, 2015b ; Braden et al, 2017 ; Prakapenka et al, 2018 ; Koebele et al, 2019 , 2021a ). Day 1 was considered training and was excluded from the analysis.…”

“…For example, the progestin levonorgestrel has null or beneficial effects on spatial working memory when given alone ( Braden et al, 2017 ; Prakapenka et al, 2018 ), but its beneficial effect is attenuated when combined with E2 in middle-aged ovariectomized (Ovx; surgical ovary removal) rats ( Prakapenka et al, 2018 ). Yet, when E2 and levonorgestrel were co-administered to middle-aged rats with intact but follicle-depleted ovaries, this combined treatment regimen benefited spatial memory, anxiety-like, and depressive-like behaviors ( Koebele et al, 2021a ). Our laboratory has also reported spatial memory impairments associated with the progestins segesterone acetate ( Woner et al, 2019 ) and medroxyprogesterone acetate ( Braden et al, 2010 , 2011 ).…”