Comprehensive article on the sex hormones and womens' mental health.
Excerpt:
Although the levels of sex hormones do not differ between PMDD and healthy women, there might be an altered genetic susceptibility to affective dysregulation induced by normal sex hormone levels. Preliminary genetic findings state an association between allelic variants in the estrogen receptor alpha gene (ESR2) and PMDD (Woods et al., 2000). As PMDD is a heritable disorder with non-Mendelian pattern (Bayer and Hausmann, 2010), elucidating the underlying genetic variations and the multiple interacting genes that confer increased susceptibility may improve our understanding of how PMDD symptoms develop.
Evidence for an interaction between the altered ESR2 in PMDD and catechol-o-methyltransferase (COMT) Val/Val genotype has been reported in a human haplotype analysis of 91 women with PMDD and 56 controls (Woods et al., 2000). COMT is an enzyme involved in multiple functions, such as estrogen metabolism (Hay et al., 1994) and has been hypothesized to tune prefrontal cortical activation through the regulation of dopamine levels (Belelli et al., 2006). The Val/Val genotype has been associated with decreased dopamine levels in the PFC and tuning efficiency (Soares, 2014). Thus, the authors speculate that a Val/Val genotype accompanied by an ESR2 variation might be a factor that could increase the susceptibility toward a dysphoric state via decreased PFC efficiency and disinhibited subcortical activity. Replication of this finding in a larger sample size, as well as the implementation of a neuroimaging protocol to explore the PFC-amygdala circuit in parallel with a detailed assessment of PMDD symptoms will be needed to further test this hypothesis.
While the magnitude of hormonal fluctuation does not seem significantly altered in women suffering from PMDD, an altered brain response to normal hormonal fluctuation could explain the changes in mood and behavior. Several lines of evidence support this concept: preliminary in vivo evidence from a small pilot (PET) study in five women with PMDD has shown that relative to healthy controls, women with PMDD experience a smaller change in 5-HT-receptor 1A binding throughout the menstrual cycle (Jovanovic et al., 2006). In animal models of hormonally induced depression via progesterone withdrawal, depression-like behavior can be modulated through specific serotonergic mechanisms or receptor subtypes respectively. Li and colleagues report that activation of 5-HT1A receptors or inhibition of 5-HT3 receptors rapidly decreases immobility in the forced swim test (FST), a prominent model for assessing antidepressant-like behavior in rodents. The FST differentiates between active (swimming and climbing) and passive (immobility) behavior when rodents are forced to swim in a cylinder with no escape options. Conversely, blocking 5-HT1A receptors, activating 5-HT3 receptors, or 5-HT7 receptors increased depression-like behavior in rats in the FST (Li et al., 2013).
The 5-HTT mediates the recapture of serotonin from the synaptic cleft back into the cell. It is the therapeutic target of the currently most widely prescribed class of antidepressants: the SSRI. SSRIs have been found to be more effective in treating premenstrual symptoms than other non-SSRI drugs or a placebo (Dimmock et al., 2000; Shah et al., 2008). It is of particular interest that the pattern of response to drug therapy is different in patients with PMDD compared to patients suffering from a MDE. PMDD patients respond within the first menstrual cycle to SSRI-treatment (Halbreich and Kahn, 2003), suggesting that an imbalance in the serotonergic system may be of particular relevance to the development of PMDD symptoms.
In the context of serotonergic alternations in PMDD, BDNF has also been implicated. Depression has been shown to be associated with decreased BDNF expression, which can be reversed by antidepressant treatment (Lopez et al., 2013). In a study by Oral and colleagues, PMDD women are associated with increased BDNF levels and increased heat-shock protein 70 (HSP70) levels in the luteal phase compared with controls (Oral et al., 2013). These findings seem contrary to the previous findings by Lopez et al. However, Oral et al. discuss the possibility that increased HSP70 levels, as a molecular defense mediator against proteotoxic stress, might reflect cellular distress in PMDD women and that the respectively increased BDNF levels could be a compensatory mechanism potentially leading to resolved PMDD symptoms in the follicular phase. These compensatory mechanisms seem to fail in depressed patients. Findings of a recent study suggest a relationship between a specific BDNF polymorphism (BDNF Val66Met) and impaired fronto-cingulate cortex activation in response to an emotion processing task displaying angry or fearful emotions in the luteal phase of PMDD women (Comasco et al., 2014). As this interaction just appears to be present in the luteal phase, Comasco and colleagues suggest declining progesterone levels to trigger this phenomenon and discuss these changing progesterone levels to act via direct or chloride pump-mediated influence of BDNF on the GABAergic system. Furthermore, the BDNF Met allele lowers the sensitivity to 5-HT signaling (Martinowich and Lu, 2008), which may influence antidepressant efficacy in PMDD women (Comasco et al., 2014). Martinowich and Lu hypothesize that an increase in extracellular 5-HT, for instance after SSRI use, might increase BDNF levels because inhibition of 5-HTT facilitates serotonergic transmission through 5-HT4,6,7 receptor subtypes (Martinowich and Lu, 2008).
Progesterone withdrawal associated with allopregnanolone increase in the luteal phase of the menstrual cycle has been hypothesized to be implicated in PMDD (Backstrom et al., 2011, 2014). Allopregnanolone is known for its similarities with benzodiazepines (Majewska et al., 1986), which can cause drowsiness, poor concentration, and memory impairment (Holbrook et al., 2000). Therefore, heightened allopregnanolone levels have been hypothesized to exhibit similar effects in the brain (Backstrom et al., 2014). Contrary to this hypothesis, a study by Girdler and colleagues found lower luteal phase allopregnanolone levels in PMDD patients with higher anxiety and irritability scores (Girdler et al., 2001). Furthermore, greater luteal phase allopregnanolone concentrations have been shown to be associated with improved symptom ratings in PMDD patients (Wang et al., 1996). A possible explanation for these unexpected findings has been proposed by Backstrom and colleagues: PMDD symptom severity seems to be related to allopregnanolone serum concentration in an inverted U-shaped curve (Backstrom et al., 2011). Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood (Backstrom et al., 2014). This recent hypothesis is extended by the suggestion that negative mood symptoms in women with PMDD could be caused by an increased GABAA receptor sensitivity to allopregnanolone (Backstrom et al., 2014). Allopregnanolone levels have also been reported to increase in the brain after acute and chronic treatment with SSRIs (Lovick, 2013), providing evidence for a direct or indirect connection of allopregnanolone with the serotonergic system. The mechanism by which SSRIs increases allopregnanolone levels is thought to involve direct stimulation of 3a-hydroxysteroid dehydrogenase (3a-HSD), an important enzyme in the allopregnanolone biosynthesis (Compagnone and Mellon, 2000). Not only the susceptibility of the GABAergic system toward allopregnanolone seems to be altered in PMDD, GABA levels might also be abnormal. For instance, Epperson and colleagues found a reduction in the cortical GABA levels during the follicular phase in those with PMDD compared with healthy controls (Epperson et al., 2002). In healthy women, cortical GABA levels fluctuate across the menstrual cycle with decreasing levels from the follicular phase to the luteal phase, whereas the opposite occurred in PMDD women (Epperson et al., 2002).
