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

Stephanie V Koebele,Zachary M T Plumley,Sarah E Mennenga,Loretta P Mayer,Heather A Bimonte-Nelson,Cheryl A Dyer,Ryoko Hiroi,Catherine Carson,Destiney Kirby,Alesia V Prakapenka,Ryan Melikian,Shruti Patel

doi:10.3389/fnbeh.2021.696838

Stephanie V Koebele, Zachary M T Plumley + Show 10 more

Open Access

https://doi.org/10.3389/fnbeh.2021.696838

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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.

Highlights

During the midlife transition to menopause, a number of symptoms that negatively impact quality of life and wellbeing may occur
Acquisition Phase (Days 2–5) What role does daily E2-only treatment have in spatial learning and memory with transitional menopause? The VCD E2 vs. VCD-Vehicle groups did not differ for Working memory correct (WMC), Working memory incorrect (WMI), or Reference memory (RM) errors during the Early Acquisition Phase, suggesting that daily E2 treatment at the given dose did not affect early task learning in a model of transitional menopause compared to follicle-depleted rats that did not receive hormone treatment
What role does daily combination hormone therapy play for spatial learning and memory with transitional menopause? For RM errors, there was a main effect of Treatment for the VCDE2 vs. VCD-E2 + LEVO comparison [F(1,18) = 4.54, p < 0.05], where follicle-deplete rats treated with a combination of E2 and levonorgestrel made fewer RM errors compared to those treated with E2-only (Figure 3)

Summary

Introduction

During the midlife transition to menopause, a number of symptoms that negatively impact quality of life and wellbeing may occur. If the uterus is intact, a hormone therapy regimen must include a progestogen component (i.e., natural progesterone or one of the many synthetic forms of progesterone; the latter are collectively referred to as progestins) in combination with an estrogen component (e.g., natural 17β-estradiol (E2), synthetic ethinyl estradiol, conjugated equine estrogens). This progestogen component is necessary to mitigate the risk of uterine hyperplasia and cancer (Pinkerton et al, 2017c). Depending on an individual’s circumstance and primary indications for menopausal hormone therapy use, there are a range of possibilities for variations in hormone therapy preparations, including estrogen-only, progestogen-only, or combined estrogen plus progestogen hormone therapy options, which in turn may have variable effects on the brain and periphery

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