Abstract
Although results of animal research show that interactions between stress and sex hormones are implicated in the development of affective disorders in women, translation of these findings to patients has been scarce. As a basic step toward advancing this field of research, we analyzed findings of studies which reported circulating cortisol levels in healthy women in the follicular vs. luteal phase of the menstrual cycle. We deemed this analysis critical not only to advance our understanding of basic physiology, but also as an important contrast to the findings of future studies evaluating stress and sex hormones in women with affective disorders. We hypothesized that cortisol levels would be lower in the follicular phase based on the proposition that changes in levels of potent GABAergic neurosteroids, including allopregnanolone, during the menstrual cycle dynamically change in the opposite direction relative to cortisol levels. Implementing strict inclusion criteria, we compiled results of high-quality studies involving 778 study participants to derive a standardized mean difference between circulating cortisol levels in the follicular vs. luteal phase of the menstrual cycle. In line with our hypothesis, our meta-analysis found that women in the follicular phase had higher cortisol levels than women in the luteal phase, with an overall Hedges' g of 0.13 (p < 0.01) for the random effects model. No significant between-study difference was detected, with the level of heterogeneity in the small range. Furthermore, there was no evidence of publication bias. As cortisol regulation is a delicate process, we review some of the basic mechanisms by which progesterone, its potent metabolites, and estradiol regulate cortisol output and circulation to contribute to the net effect of higher cortisol in the follicular phase.
Highlights
Women exhibit high prevalence of stress-related disorders, such as major depressive disorder (MDD) and anxiety spectrum disorder [1,2,3,4,5,6,7,8,9]
Of the 221 studies, 44 were excluded based on the self-report nature of menstrual cycle phase determination, and 40 were excluded because they either didn’t mention cortisol collection time, or the morning sample was collected at times
Implementing a comprehensive search of high-quality studies spanning a period of almost 50 years of research, we show that circulating cortisol levels are higher in the follicular vs. luteal phase
Summary
Women exhibit high prevalence of stress-related disorders, such as major depressive disorder (MDD) and anxiety spectrum disorder [1,2,3,4,5,6,7,8,9]. The increase in prevalence of these disorders is observed during periods of drastic hormonal changes, such as puberty, the pre-menstrual period, pregnancy, postpartum and menopause [10,11,12] These observations suggest that interactions between sex hormones, regulated by the hypothalamic-pituitary-gonadal (HPG). Results of studies comparing reactivity to psychosocial stress in healthy women suggest that cortisol output is higher in the luteal vs follicular phase of the menstrual cycle [14, 15] Their small sample size and opposite findings from other studies [16,17,18,19] indicate that more research needs to be completed before a conclusion can be drawn. Additional studies, implementing strict verification of menstrual cycle phase, stress manipulation and participants’ healthy status, are needed
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