Research done thus far supports the hypothesis
Research done thus far supports the hypothesis that MPA has detrimental effects on cognition, alone and in combination with estrogen; there are other FDA-approved progestogens that satisfy the uterus opposing effects that have not been cognitively profiled. An important goal to aid women's health is to find a progestogen that will accomplish uterine protection while not imposing negative cognitive effects. Levonorgestrel (Levo) is a synthetic progestogen used in multiple contraceptives, such as intrauterine devices (i.e., Mirena) and emergency contraception (i.e., Plan B), as well as in combination with estrogens in oral birth control pills such as Lutera, Aviane, Seasonique, and Seasonale. In menopausal hormone therapy, Levo is combined with E2 in the transdermal patch, Climara Pro. The contraceptive efficacy of Levo, and of combination GDC-0994 plus Levo, hormone formulations are well established. However, research has only just begun to address the potential effects of Levo on cognitive performance, and only one preclinical study has evaluated such impact in the context of aging. Our laboratory has demonstrated that daily subcutaneous administration of 0.6-μg Levo, a dose that is approximately equivalent to that clinically available in the Climara Pro patch when accounting for body weight, enhanced working memory performance on the water radial-arm maze (WRAM) relative to administration of the vehicle control in middle-aged, Ovx rats (Braden et al., 2017). This is especially exciting, as this is the first chronically administered progestin shown to benefit memory in a preclinical model of menopause. However, whether these benefits will hold when given in combination with an estrogen is yet to be determined. This question is critically important, given the extensive clinical use of combined regimens for menopausal hormone therapy.
The present study examined the effect of E2 + Levo hormone combination treatment on cognitive function, with interpretations relative to vehicle control treatment, as well as relative to E2 alone and Levo alone treatments. The intent was to study these regimens in the context of older age and ovarian hormone loss. Thus, treatments were administered to middle-aged Ovx rats. The 0.6-μg Levo dose was carefully chosen based on prior work from our laboratory that showed enhancing cognitive effects of Levo alone at this dose (Braden et al., 2017); we were interested in examining whether a cognitively enhancing Levo dose when given alone would also enhance cognitive function when given in combination with E2. First, cognitive function was assessed using a battery of behavioral tasks to test spatial learning and memory using the WRAM (working and reference memory) and the MWM (reference memory), including a control behavioral task (visible platform). Second, after behavioral testing, activated Erk1 and Erk2 levels in brain regions known to be involved in cognitive function were evaluated, including the frontal cortex, dorsal hippocampus, cornu ammonis 1/cornu ammonis 2 (CA1/CA2) ventral hippocampus, entorhinal cortex, and perirhinal cortex. Given that the E2 and Levo regimens tested here were based on our prior effects benefitting cognition, we hypothesized that E2 alone and Levo alone treatments would yield favorable cognitive effects. Because Levo is often used in combination with estrogens in clinical formulations and because Levo is the first progestogen we have shown to initiate beneficial cognitive effects when given alone, we sought to determine whether its beneficial effects would hold when given combined with estrogen. Thus, here, we ask the following: in a surgical menopause model, will the combination of 2 cognitively enhancing hormones result in strengthened beneficial effects, or in null or attenuating effects, on learning and memory performance?
Discussion The present study demonstrated that E2-only and Levo-only treatments enhanced working memory performance during acquisition of the WRAM, as measured by WMI errors collapsed across all trials, and that the combination of E2 + Levo attenuated these beneficial cognitive effects. In fact, at the highest demand working memory load (trial 4) during acquisition, the E2 + Levo combination impaired performance as compared to the E2-only and Levo-only groups. Thus, even a progestin that we have shown here and in prior work (Braden et al., 2017) to enhance the ability to handle an increasing working memory load on the WRAM task when given alone can reverse the beneficial effects of E2 at a high memory demand. In addition, we showed that there was a distinct relationship between activated Erk2 expression in the frontal cortex and working memory performance within the E2-only treatment group, which was mitigated by the addition of Levo to the E2 treatment. However, Levo did not uniformly attenuate the benefits of E2. At a working memory load that was less demanding, the addition of Levo did not reverse the cognitive benefits of E2 relative to vehicle treatment, as determined by trial 3 for WMI errors on the WRAM. Indeed, similar to each hormone treatment given alone, the hormone combination treatment benefitted this moderate working memory load trial performance as compared to the vehicle treatment.