Steroid Hormone Sensitivity in Reproductive Mood Disorders: On the Role of the GABAA Receptor Complex and Stress During Hormonal Transitions

Abstract

Women worldwide are two to three times more likely to suffer from depression in their lifetime than are men. Female risk for depressive symptoms is particularly high during the reproductive years between menarche and menopause. The term “Reproductive Mood Disorders” refers to depressive disorders triggered by hormonal fluctuations during reproductive transitions including the perimenarchal phase, the pre-menstrual phase, pregnancy, the peripartum period and the perimenopausal transition.Here we focus on reproductive mood disorders manifesting in adult life. We propose a research agenda that draws together several reproductive mood disorders and investigates which genetic, endocrinological, neural, and psychosocial factors can explain depressive symptoms during phases of hormonal transitions in women. Based on current research it is assumed that some women experience an increased sensitivity to not only fluctuations in reproductive steroids (estrogen and progesterone), but also stress-related steroids. We integrate both dynamics into the concept of “steroid hormone sensitivity,” expanding on the concept of “reproductive hormone sensitivity.” We suggest that a differential response of the stress steroid system including corticosteroids, neurosteroids, like allopregnanolone and the GABA-A Receptor complex, as well as a differential (epi)genetic risk in serotonergic and GABAergic signaling, are moderators or mediators between changes in the reproductive steroid system and the physiological, affective, and cognitive outcomes manifesting in reproductive mood disorders. We point to the lack of research on the role of psychosocial factors in increasing a woman's stress level and at some point also the sensitivity of her stress steroid system within the etiology of Reproductive Mood Disorders.Drawing together the evidence on various reproductive mood disorders we seek to present a basis for the development of more effective pharmacological, social, and psychological treatment interventions and prevention strategies for women susceptible to these disorders. This could pave the way for new research as well as medical and psychological teaching and practice- such as a new type of Practice for Gynecological Psychoneuroendocrinology- with the aim of working on and ultimately offering more integrative forms of support not yet available to women suffering from depression during hormonal transitions. In medical history women have been left alone with this integrative challenge.

Are alterations in estradiol, cortisol, and inflammatory cytokines associated with depression during pregnancy and postpartum? An exploratory study

“…Interestingly, we found significant correlations between pregnancy estradiol and both pregnancy and postpartum IL-6. This correlation is consistent with emerging evidence of crosstalk between HPG and HPA axes, which has been proposed as a mechanism of reproductive mood disorders ( Schweizer-Schubert et al., 2021 ). It is plausible that inflammation may also contribute to this pathogenic process, but more research is needed to probe the complex interplay between inflammation and neuroendocrine mediation of mood disorders.…”

“…It is well-established that hypothalamic-pituitary-adrenal (HPA) hyperactivation in response to a stressor results in high cortisol levels and inhibits the hypothalamic-pituitary-gonadal (HPG) axis. It is conceivable that dysregulation of both HPA and HPG axes may play a role in the development of mood disorders during reproductive phases, including the perinatal period ( Schweizer-Schubert et al., 2021 ).…”

Reduced Hippocampal GABA+ Is Associated With Poorer Episodic Memory in Healthy Older Women: A Pilot Study

“…Women have a higher prevalence of depression (Pehrson and Sanchez, 2015;Flores-Ramos et al, 2017), with symptom risk peaking during major reproductive events (e.g., perimenopausal transition) when fluctuations in sex steroid hormone levels are high (Soares and Zitek, 2008). These transitional phases are associated with dysregulation of the hypothalamic-pituitary-gonadal axis function (Schweizer-Schubert et al, 2021), which is regulated by GABAergic transmission (Flores-Ramos et al, 2017). Interestingly, individuals with major depression have reduced numbers of somatostatin-expressing neurons (a population of GABAergic interneurons playing a key role in memory), and this reduction is exacerbated in women (Fee et al, 2017).…”

An exploratory assessment of the applicability of direct-to-consumer genetic testing to translational research in Japan

“…In female, hormonal state changes are known to have substantial impact on mood such as postpartum and postmenopausal depressions [ 14 ]. On the other hand, depressive mood caused by hormonal changes is less frequent in male [ 15 ]. The association between GRIN2B and depressive phenotypes was not detected in female potentially because hormonal changes might have a larger impact on depressions in female than GRIN2B , which might be involved in depression by a different mechanism.…”