A significant proportion of women with BD face emotional challenges during periods of normal hormonal fluctuation . Although it has long been recognized that the postpartum is a period of higher risk of relapse in BD, recent data suggest that the premenstrual phase and menopausal transition are also associated with an elevated risk of a mood episode [2, 3, 16]. Although these findings suggest that the physiological fluctuation of sex hormones may render some women more vulnerable to mood instability, research on the mechanisms behind this association is scarce. The investigation of biological models involving the role of estrogen, progesterone, and other sex steroids has the potential to generate new treatment strategies that could change the course of bipolar disorder in women.
As reviewed above, there is a growing body of literature showing that sex hormones have the ability to regulate intracellular signaling systems that are thought to be abnormal in BD. Thus, it is conceivable to believe that this functional interaction between sex hormones and molecules involved with synaptic plasticity and neurotransmitter systems may be associated with some of the clinical characteristics of women with BD (e.g., higher rates of BD-II, rapid cycling, mixed states, and threshold/subthreshold depressive mood). Another aspect that must be considered here is the fact that mood stabilizers can influence the levels of circulating hormones , or cause menstrual irregularity . Given that the effects of estrogen at the molecular [46, 118] and behavioral [4, 58] level can vary depending on the availability of its endogenous ligands (i.e., hormonal milieu), this may in part explain why some women with BD complain of feeling ‘emotionally worse’ when taking certain medications. Although outside the scope of the present review, it is worth mentioning that sex hormones can also influence other important aspects of BD. For instance, estrogen and progesterone can modulate sleep and circadian rhythms [119, 120], anxiety/fear extinction , as well as processes of learning and memory . Another possible role of progesterone in BD and its impact on mood stability were observed by Johansson et al. [122, 123] in two studies that linked progesterone levels with steroidogenic pathway activity. More specifically, they found that low progesterone levels during euthymia and polymorphisms in the AKR1C4 gene were associated with a history of manic/hypomanic irritability in males but not females . They also observed that polymorphisms in the AKR1C4 gene were associated with less likelihood of paranoid ideation during manic episodes in both genders, and that lower serum levels of progesterone and dehydroepiandrosterone sulfate (DHEA-S) were associated with more paranoid ideation during mania/hypomania in men but not in women . Progesterone and its metabolites can regulate the release of various neurotransmitters through a variety of mechanisms, such as rapid effects on ion channels, as well as through sigma-1, α-1 adrenergic, nicotine, D1, NMDA, and GABA receptors. In addition, DHEA levels are higher in the brain than in peripheral tissues, but the intrinsic mechanisms that regulate DHEA metabolism are not yet fully understood . Plasma DHEA levels in BD patients were found to be higher when compared with controls and lower when compared with subjects with schizophrenia . At least some of the neuroprotective effects of DHEA and its active metabolites occur via modulation of GABA and NMDA receptors and via anti-glucocorticoid activity [126-128]. Studies looking at DHEA's anti-inflammatory profile have found protective effects through the modulation of the microglia response after brain damage , as well as protection against brain oxidative injury in restrained stressed rats . Lastly, there is also preclinical evidence of a possible interaction between DHEA, BDNF, and serotonergic activity in the brain, whereby BDNF would mediate DHEA's neuroprotective effects . Although outside the scope of the present review, it is worth mentioning that other hormones, such as thyrotropin-releasing hormone and prolactin, may be involved in the relationship between BD and female reproductive life events [132, 133]. Furthermore, another fruitful area for future research in women with BD is the role of other neurosteroids (e.g., allopregnanolone) in mood and behavior [134, 135].
In conclusion, clinical data suggest that sex hormones influence some of the psychopathological aspects of BD in women but empirical evidence is still limited. The close relationship between sex hormones and molecular markers of neuroprotection and neurodegeneration (such as BDNF, oxidative stress, and inflammation) can set the stage for future research in this area. Not only could this potentially change the way we understand bipolar illness in women, but, more importantly, it could help in the development of new treatment strategies for this population at risk.