In the brain E can modulate the mitogen activated
In the brain, E2 can modulate the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway, which is involved in the formation of different memory types (Atkins et al., 1998, Blum et al., 1999, Schafe et al., 2000). When the MAPK/ERK signaling pathway is activated, the signal travels from a cell receptor (e.g., estrogen receptors) to the nucleus DNA via a sequence of proteins, including the activated extracellular signal–regulated kinase 1 and 2 (Erk1/2) (Ciccarelli and Giustetto, 2014, Koebele and Bimonte-Nelson, 2017, Witty et al., 2012). Research indicates that, in the dorsal hippocampus, MAPK/ERK activation is essential for long-term memory formation, as well as for E2-induced beneficial effects on memory consolidation (Blum et al., 1999, Fan et al., 2010, Fernandez et al., 2008, Harburger et al., 2009). Indeed, there is increased expression of activated Erk2 in the dorsal hippocampus after E2 treatment (Fernandez et al., 2008, Harburger et al., 2009, Witty et al., 2013). Blocking this E2-induced increase in Erk2 activation attenuated the beneficial cognitive effects of E2 on the object recognition task (Fan et al., 2010, Fernandez et al., 2008). E2 treatment can also increase the expression of neurotrophins that are associated with learning and memory, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3, in regions of the RG-108 that are involved in cognitive function (i.e., the entorhinal cortex and hippocampus) (Bimonte-Nelson et al., 2004, Kiss et al., 2012, Zhou et al., 2005). Thus, both the MAPK/ERK pathway and neurotrophins have been implicated in learning and memory, and notable work has been done identifying effects on neuroplasticity as well (Bechara et al., 2014, Gooney et al., 2002, McGauran et al., 2008). Taken together, these studies highlight the significant role of E2 in cognitive functions mediated through its role in several defined pathways associated with neuroplasticity and memory. For women with an intact uterus, estrogen-based hormone therapies must also include a progestogen component to offset the increased risk for developing endometrial hyperplasia and cancer following exposure to unopposed estrogens (NAMS, 2012). Progestogens are a class of steroid hormones, and include natural progesterone and progestins (synthetic progestogens), which bind to the progesterone receptor. There is preclinical evidence that some progestogens can also offset the cognitive benefits of E2 (Bimonte-Nelson et al., 2006, Harburger et al., 2007, Harburger et al., 2009, Lowry et al., 2010). For instance, studies testing combination hormone therapies have shown that the addition of progesterone to E2 treatment reversed the enhancing cognitive effects of E2 on the spatial reference memory MWM task in Ovx rodents (Bimonte-Nelson et al., 2006, Harburger et al., 2007, Lowry et al., 2010). There is also preclinical evidence that the addition of progesterone can attenuate E2-induced changes in several neuromolecular mechanisms in the brain that are essential for cognitive function. For example, in the entorhinal cortex, the E2-induced increases in brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 levels were obviated with the addition of progesterone (Bimonte-Nelson et al., 2004). In the dorsal hippocampus, progesterone in combination with E2 treatment attenuated the E2-induced increase in activated Erk2 expression (Harburger et al., 2009). These collective findings indicate that the addition of a progesterone component in hormone therapy to oppose undesired E2 stimulation in the periphery may not be cognitively beneficial, and that it can attenuate associated E2-induced benefits. Because progesterone has low systemic bioavailability with oral and transdermal delivery, synthetic progestogens are often used for both contraceptive and hormone therapy purposes (Du et al., 2013, Kuhl, 2005, Pickar et al., 2015). Medroxyprogesterone acetate (MPA) is a synthetic progestogen that is commonly prescribed for birth control (Depo-Provera) as well as used in combination with an estrogen for menopausal hormone therapy. Our laboratory found that exogenous treatment with MPA alone in female rats impaired cognitive function (Braden et al., 2010, Braden et al., 2011, Braden et al., 2017). Furthermore, a study testing the effects of a tonic MPA and E2 hormone combination showed that subcutaneous MPA (via a pellet) plus oral E2 (via drinking water) treatment resulted in impaired learning on the MWM in middle-aged Ovx rats compared to chronic E2, chronic E2 plus progesterone, or cyclic E2 (Lowry et al., 2010). In addition, subcutaneous tonic administration of progesterone or of MPA in adult Ovx rats blocked the neuroprotective effects of E2 after excitotoxic lesion with kainate (Rosario et al., 2006). These studies further indicate that the role of E2 on the brain and cognitive function can be altered by the addition of a progestogen, and that the magnitude of this effect may be governed by the type of progestogen administered (e.g., progesterone vs. MPA).