Glucocorticoids and Their Receptor Isoforms: Roles in Female Reproduction, Pregnancy, and Foetal Development

Abstract

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 (GRs) play a role in fertility, reproduction, placental function, and foetal 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 suppressing 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 foetal 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, and 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 humans, guinea pigs, sheep, rats, and mice, indicating they are 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 comprehensive review provides an overview of the structure and function of the GR in relation to female fertility and reproduction and discusses the changes in the GR and glucocorticoid signalling during pregnancy. To generate this overview, an extensive non-systematic literature search was conducted across multiple databases, including PubMed, Web of Science, and Google Scholar, with a focus on original research articles, meta-analyses, and previous review papers addressing the subject. This review integrates the current understanding of GR variants and their roles in glucocorticoid signalling, reproduction, placental function, and foetal growth.

Keywords: glucocorticoid receptor; pregnancy; reproduction; stress.

Figure 2

Splice and translation initiation isoforms of the glucocorticoid receptor. Exons of the glucocorticoid receptor gene with the subsequent splice (left) and translation initiation (right) isoforms. AF-1—transcriptional activation function 1; DBD—DNA binding domain; GR—glucocorticoid receptor; LBD—ligand-binding domain; NTD—N-terminal domain. Created on bio render. Adapted from Ramamoorthy and Cidlowski [45].

Figure 1

Hypothalamic–pituitary–adrenal axis. Cells in the paraventricular nucleus produce CRH in response to physical or psychological stress. CRH binds to cells in the anterior pituitary gland to stimulate the production of ACTH, which acts on the adrenal glands to increase the production of glucocorticoids, which, in turn, regulates the stress response. Glucocorticoids can also exert their negative effects on CRH and ACTH via a negative feedback mechanism. PVN—paraventricular nucleus; CRH—corticotrophin-releasing hormone; ACTH—adrenocorticotrophic hormone. Created on bio render. Adapted from [6].

Figure 3

Genomic action of a glucocorticoid receptor (GR). The GR binds to glucocorticoids in the cytoplasm, leading to the dislocation of its chaperone protein complex and translocation into the nucleus. In the nucleus, the GR can either directly induce or repress gene expression by binding to GREs or nGREs, respectively. It can also interact with other TFs by tethering or composite actions. GR—glucocorticoid receptor; Hsp90—heat shock protein 90; Fkbp51—FK506-binding protein 51; GRE—glucocorticoid response element; nGRE—negative GRE; TF—transcription factor. Created on bio render. Adapted from [45].

Figure 4

Steroidogenesis pathway, illustrating the key factors involved in the conversion of cholesterol into progesterone and cortisol. STAR, steroidogenic acute regulatory protein; CYP11A1, cytochrome P450 family 11 subfamily A member 1; CYP17A1, cytochrome P450 family 17 subfamily A member 1; HSD3B, hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase; CYP21A2, cytochrome P450 family 21 subfamily A member 2; CYP11B1, cytochrome P450 family 11 subfamily B member 1; HSD11B1, hydroxysteroid 11-beta dehydrogenase 1; HSD11B2, hydroxysteroid 11-beta dehydrogenase 2. Created on bio render. Adapted from [111].

Figure 5

Stress axis during pregnancy. Under stress, the maternal HPA axis produces cortisol, which can act on the placenta to stimulate the production of pCRH. Most of the cortisol is metabolised by placental 11β-HSD 2, with 20% crossing over to the foetus. Increased levels of cortisol crossing over to the foetal compartment can over-activate the foetal HPA, leading to long-lasting effects on its growth and development. CRH—corticotrophin releasing hormone; ACTH—adrenocorticotropic hormone; 11β-HSD 2—type 2 11-beta hydroxysteroid dehydrogenase; pCRH—placental CRH; HPA—hypothalamus—pituitary—adrenal. Created on bio render. Adapted from [178].