Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells

Abstract

Chronic stress has a negative impact on many fertility-related functions; thus, the recent decline in female fertility seems to be at least partially associated with increased stress. The secretion of glucocorticoids is a typical endocrine response to chronic stress and indirectly reduces uterine receptivity through the hypothalamus-pituitary-gonadal (HPG) axis. However, in addition to its well-known canonical role, the direct effects of chronic stress-induced glucocorticoids on various uterine functions and their underlying molecular mechanisms are complex and have not yet been revealed. Recent studies have found that resident stem cell deficiency is responsible for the limited regenerative potential of the endometrium (the innermost lining of the uterine cavity) during each menstrual cycle, which subsequently increases infertility rates. In this context, we hypothesized that stress-induced glucocorticoids directly damage endometrial stem cells and consequently negatively affect endometrial reconstruction, which is important for uterine receptivity. In addition to its well-known canonical roles, we identified for the first time that cortisol, the most abundant and potent glucocorticoid in humans, directly suppresses the multiple beneficial functions (self-renewal, transdifferentiation, and migratory potential) of human endometrial stem cells through its functional receptor, glucocorticoid receptor (GR). Glucocorticoids inhibit well-known survival signals, such as the PI3K/Akt and FAK/ERK1/2 pathways. More importantly, we also found that immobilization of stress-induced glucocorticoids suppresses the various beneficial functions of tissue resident stem cells in vivo. To the best of our knowledge, this is the first study to investigate the direct effects of glucocorticoids on the regenerative capacity of endometrial stem cells, and the findings will facilitate the development of more promising therapeutic approaches to increase female fertility.

Glucocorticoid involvement in reproductive biology

“…The failure of an oestrus cycle probably prevents the cyclical proliferation and apoptosis of uterine lining, leading to an accumulation of BrdU-stained cells. Recently, glucocorticoids have been shown to limit the regenerative capacity of endometrial stem cells (22)…”

Cyclic processes in the uterine tubes, endometrium, myometrium, and cervix: pathways and perturbations

“…Glandular AR expression has been detected in the late secretory and decidualized endometrium ( Milne et al , 2005 ). In addition, there is the potential for effects of glucocorticoids via endometrial GR expression, as well as the recognized effects via the hypothalamic–pituitary–gonadal (HPG) axis, with recent research suggesting direct effects on endometrial stem cell function ( Park et al , 2021 ); of interest, are the potential direct effects of adrenal hormone production (via a stress response) on endometrial cyclicity, particularly during the menstrual phase.…”

Reliability and validity of the Chinese version of the COMPI Fertility Problem Stress Scale—Short Form for infertile women

“…5 Cortisol produced by the stress endocrine response inhibits various beneficial functions of human endometrial stem cells, indirectly reduces the receptivity of the uterus and has a serious negative impact on fertility. 6 Therefore, paying attention to the various stresses faced by infertility patients is important for improving quality of life and treatment compliance and reducing the impairment of reproductive function.…”

“…The inability to conceive naturally can lead to poor mental health in women, 3 making them prone to negative emotions such as fertility‐related stress, anxiety, depression, and stigma, which seriously affect their quality of life 4 and can even lead them to withdraw from fertility treatment 5 . Cortisol produced by the stress endocrine response inhibits various beneficial functions of human endometrial stem cells, indirectly reduces the receptivity of the uterus and has a serious negative impact on fertility 6 . Therefore, paying attention to the various stresses faced by infertility patients is important for improving quality of life and treatment compliance and reducing the impairment of reproductive function.…”