Glucocorticoid hormones, like other classes of steroid hormones, exert their cellular action by complexing with a specific cytoplasmic receptor which in turn translocates to the nucleus and binds to specific sites on chromatin. The glucocorticoid receptor was the first transcription factor to be isolated and studied in detail (Muller and Renkawitz, 1991). The glucocorticoid receptor (GCCR) is crucial to gene expression. It is a 94-kD polypeptide and according to one model is thought to have distinct steroid-binding and DNA-binding domains.
NCBI Summary:
DISCONTINUED: This record has been withdrawn by NCBI because the model on which it was based was not predicted in a later annotation.
General function
Receptor, Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Unoccupied glucocorticoid receptors are located subcellularly in the cytoplasm; following binding of the hormone, they translocate to the nucleus (Yan et al., 1999).///////
Hypothalamic-pituitary-adrenocortical axis hypersensitivity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome. Milutinović DV et al. (2011) Molecular mechanisms underlying pathophysiology of polycystic ovary syndrome (PCOS), especially those related to cortisol signaling, are poorly understood. We hypothesized that modulation of glucocorticoid receptor (GR) expression and function, may underlie possible PCOS-related impairment of feedback inhibition of hypothalamic-pituitary-adrenocortical (HPA) axis activity and thus contribute to increased adrenal androgen production in women with PCOS. 24 normal-weight and 31 obese women with PCOS were compared to 25 normal-weight controls. Fasting blood samples were collected for measurements of serum concentrations of dehydroepiandrosterone sulfate, testosterone, sex hormone-binding globulin, insulin, basal cortisol and cortisol after oral administration of 0.5 mg dexamethasone. Concentrations of GR mRNA, GR protein, mineralocorticoid receptor (MR) protein and heat shock proteins (Hsps), as well as the number of GR per cell (B(max)) and its equilibrium dissociation constant (K(D)) were measured in isolated peripheral blood mononuclear cells. An increase in HPA axis sensitivity to dexamethasone, an elevation of the GR protein concentration, and unaltered receptor functional status were found in both normal-weight and obese women with PCOS vs. healthy controls. Lymphocyte MR, Hsp90 and Hsp70 concentrations, and MR/GR ratio were similar in all groups. Correlation between B(max) and K(D) was weaker in the group of obese women with PCOS than in the other 2 groups. The results did not confirm the initial hypothesis, but imply that PCOS is associated with increased GR protein concentration and HPA axis sensitivity to dexamethasone.//////////////////
Prenatally administered dexamethasone impairs folliculogenesis in spiny mouse offspring. Hułas-Stasiak M et al. (2015) This study was designed to determine whether prenatal dexamethasone treatment has an effect on follicular development and atresia in the ovary of spiny mouse (Acomys cahirinus) offspring. Dexamethasone (125µg kg-1 bodyweight per day) was administered to pregnant spiny mice from Day 20 of gestation to parturition. The processes of follicle loss were analysed using classical markers of apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling reaction, active caspase-3) and autophagy (Lamp1). The present study indicated that dexamethasone reduced the pool of healthy primordial follicles. Moreover, the oocytes from these follicles showed intensive caspase-3 and Lamp1 staining. Surprisingly, dexamethasone caused an increase in the number of secondary follicles; however, most of these follicles were characterised by extensive degeneration of the oocyte and caspase-3 and Lamp1 labelling. Western-blot analysis indicated that the glucocorticoid receptor as well as apoptosis and autophagy markers were more strongly expressed in the DEX-treated group than in the control. On the basis of these findings, we have concluded that dexamethasone impairs spiny mouse folliculogenesis and enhances follicular atresia through induction of autophagy or combined autophagy and apoptosis.//////////////////
Dexamethasone Induces Germ Cell Apoptosis in the Human Fetal Ovary. Poulain M et al. Context:The 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. Pregnant women presenting a risk of genetic transmission may be treated with synthetic glucocorticoids such as dexamethasone (DEX) to prevent female fetus virilization.Objective:The aim of this study was to assess the potential deleterious effects of DEX exposure on fetal ovarian development.Settings:Human fetal ovaries, ranging from 8-11 weeks after fertilization, were harvested from material available after legally induced abortions. They were cultured in the absence or presence of DEX (2, 10, or 50 m) over 14 d, and histological analyses were performed.Results:The glucocorticoid receptor NR3C1 was present and the signaling pathway active in the fetal ovary as demonstrated by the expression of NR3C1 target genes, such as PLZF and FKBP5, in response to DEX exposure. DEX decreased germ cell density at the 10 and 50 m doses. Exposure to DEX, even at the highest dose, did not change oogonial proliferation as monitored by 5-bromo-2'-deoxyuridine incorporation and significantly increased the apoptotic rate, detected with cleaved caspase 3 staining. Interestingly, the expression of the prosurvival gene KIT was significantly decreased in the presence of DEX during the course of the culture.Conclusion:We have demonstrated for the first time that in vitro exposure to high doses of DEX impairs human fetal oogenesis through an increase in apoptosis. These data are of high importance, and additional epidemiological studies are required to investigate the female fertility of those women who have been exposed to DEX during fetal life.
Jia XC, et al. reported a synergistic effect of glucocorticoids and androgens on the hormonal induction of tissue plasminogen
activator activity and messenger ribonucleic acid levels in granulosa cells.
Adashi EY, et al. reported a synergistic effect of glucocorticoids on the stimulation of progesterone production by follicle-stimulating hormone in cultured rat granulosa cells.
Hsueh AJ, et al reported that treatment with glucocorticoid inhibits FSH-induced estrogen production in cultured rat granulosa cells.
Leptin induces c-Jun expression and attenuates the transcriptional activity of the glucocorticoid receptor (GR) in granulosa cells. A leptin-induced elevation of c-Jun modulates the transcriptional activity of the GR, possibly leading to the observed attenuation of steroidogenesis. (Barkin et al., 1999).
A new concept in reproductive endocrinology is that the status of the ovary as a glucocorticoid target organ alters with follicular development. Evidence for a physiological role of glucocorticoids in the regulation of ovarian folliculogenesis has been strengthened by the discovery that 11beta-hydroxysteroid dehydrogenase (11betaHSD) mRNA expression in human granulosa cells is developmentally regulated (Tetsuka et al.).
Expression regulated by
Comment
Ovarian localization
Granulosa, Theca, Stromal cells
Comment
Schreiber et al identified a
protein in the rat ovary with characteristics of a glucocorticoid receptor and propose that this protein
may be responsible for mediating direct effects of glucocorticoids on the ovary.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Sugino et al. established that the corpus luteum of the rat expressed GR throughout pregnancy and through partuition 1997 .
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: human
Mutation name: Glucocorticoid resistance, familial [NR3C1, ASP641VAL]
type: naturally occurring fertility: fertile Comment: In the kindred originally reported by Vingerhoeds et al. (1976) and studied by Chrousos et al. (1983), (1982) and Lipsett et al. (1985), Hurley et al. (1991),the glucocorticoid receptor gene was sequenced from 3 affected members. A change at nucleotide 2054 predicted substitution of valine for aspartic acid at amino acid residue 641. The propositus was homozygous while the other relatives were heterozygous for the mutation. The point mutation was in the steroid-binding domain of the receptor.
Species: human
Mutation name: Glucorticoid resistance, familial [NR3C1, IVS6DS, 4-BP DEL]
type: naturally occurring fertility: fertile Comment: Affected members had hypercortisolism and approximately half of normal glucocorticoid receptors. The proband was a daughter with manifestations of hyperandrogenism. Furthermore, in the proband, in 1 of her affected brothers, and in her unaffected sister, Karl et al. (1993) found a single nucleotide substitution, asparagine to serine at codon 363 in exon 2 (G1220). Transfection studies indicated that the amino acid substitution did not alter the function of the glucocorticoid receptor. The presence of the null allele in this family was apparently compensated for by increased cortisol production at the expense of concurrent hyperandrogenism.