Your brain and your hormones
The brain represents an important target for estrogen and progesterone effects, ranging from learning, memory, emotion, cognition, motivation and motor control. Interestingly, the classical estrogen and progesterone receptors are highly expressed in brain areas involved in emotion and cognition, namely the amygdala and hippocampus (Barth, Villringer, & Sacher, 2015). “Ovarian hormones can act on multiple receptor types, such as voltage-gated ion channels, including GABA, NMDA, serotonin and dopamine” (Barth et al., 2015). Ovarian hormones can also affect neurotrophins such as BDNF, since there has been evidence demonstrating that estrogen treatment can increase BDNF expression in several brain regions such as the hippocampus, amygdala and cortex (Barth et al., 2015). In fact, brain structural changes due to hormone replacement therapy (HRT) seem to be prominent in the hippocampus. “Women using HRT showed an increased hippocampal volume compared to men and women who never used HRT” (Barth et al., 2015).
In addition, cyclical changes in endogenous sex hormones, such during monthly menstrual cycles, are also associated with mood changes. This is often observed in PMDD, which is categorized by core symptoms such as anxiety, irritability and depressed mood, which occur 2-3 days before the onset of menses and resolve after the onset of menstruation. Interestingly, PMDD does not seem to be related to the amount of ovarian hormones as much as it may be associated with a heightened vulnerability of the CNS to normal ovarian function and physiological changes, rather than hormone imbalance. “In the pathology of premenstrual dysphoric disorder (PMDD), the normal functional of predominantly two main NT systems, the serotonergic and dopaminergic system seems to be impaired” (Barth et al., 2015). Some studies report negative premenstrual changes in mood as common (among healthy women) and suggest that the majority of women of reproductive age describe a cycle-dependent increase in negative emotions, such as irritability, impulsivity, fear, and low mood.
There may be a genetic component involved as well, such as the COMT SNP in predisposition to PMDD. COMT is an enzyme involved in multiple functions, such as estrogen metabolism and has been hypothesized to tune prefrontal cortical activation through the regulation of dopamine levels. The Val/Val genotype has been associated with decreased dopamine levels in the prefrontal cortex and tuning efficiency, and could be associated with altered ESR2 (estrogen receptor alpha gene), “might be a factor that could increase the susceptibility toward a dysphoric state via decreased PFC efficiency and disinhibited subcortical activity” (Barth et al., 2015). In the context of serotonergic alternations in PMDD, BDNF has also been implicated. Depression has been shown to be associated with decreased BDNF expression.
Recent studies have also shown that progesterone, progestin or progestin metabolites could have the capacity to induce or inhibit neuroplastic changes by preventing microglia from releasing harmful free radicals or by stimulating myelin production (Barth et al., 2015). Progesterone has been suggested to increase serotonergic neurotransmission via the regulation of the expression of SERT-related genes and proteins. The anger or fearful emotions in the luteal phase of PMDD women is also associated with declining progesterone levels that may influence the BDNF on the GABAergic system.
Barth, C., Villringer, A., & Sacher, J. (2015). Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front Neurosci, 9, 37. doi:10.3389/fnins.2015.00037