Deciphering the Dichotomy: The Role of Glucocorticoid Receptor Isoforms in Cortisol’s Paradoxical Impact on Reproduction and Pregnancy

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis and associated changes in circulating levels of glucocorticoids are integral to an organism's response to stressful stimuli. Glucocorticoids acting via glucocorticoid receptors (GR) play a role in fertility, reproduction, placental function, and fetal development. GRs are ubiquitously expressed throughout the female reproductive system and regulate normal reproductive function. Stress induced glucocorticoids have been shown to inhibit reproduction and affect female gonadal function by supressing the hypothalamic-pituitary-gonadal (HPG) axis at each level. Furthermore, during pregnancy, a mother's exposure to prenatal stress or external glucocorticoids can result in long-lasting alterations to the fetal HPA and neuroendocrine function. Several GR isoforms generated via alternative splicing or translation initiation from the GR gene have been identified in the mammalian ovary and uterus. The GR isoforms identified include the splice variants, GRα and GRβ, GRγ and GR-P. Glucocorticoids can exert both stimulatory and inhibitory effects and both pro- and anti-inflammatory functions in the ovary, in vitro. In the placenta, thirteen GR isoforms have been identified in human, guinea pig, sheep, rat and mouse indicating it is conserved across species and may be important in mediating a differential response to stress. Distinctive responses to glucocorticoids, differential birth outcomes in pregnancy complications, and sex-based variations in the response to stress could all potentially be dependent on a particular GR expression pattern. This review provides an overview of the structure and function of the GR in relation to female fertility and reproduction and discusses the changes in GR and glucocorticoid signalling during pregnancy. This review will delve into the existing understanding of GR isoforms and explore the possible roles that these distinct isoforms may have in regulating glucocorticoid signalling, along with their impact on gonadal activity, placental function, and fetal growth.