Elsevier

Biological Psychiatry

Volume 62, Issue 8, 15 October 2007, Pages 863-869
Biological Psychiatry

Original Article
Sex Specific Associations between Common Glucocorticoid Receptor Gene Variants and Hypothalamus-Pituitary-Adrenal Axis Responses to Psychosocial Stress

https://doi.org/10.1016/j.biopsych.2007.04.013Get rights and content

Background

Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease.

Methods

We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9β) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST).

Results

Male 9β AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9β AG carriers had elevated ACTH levels (sex by genotype interaction p = .03).

Conclusions

We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders.

Section snippets

Subjects

Initially, 601 healthy subjects were recruited from a Trier-based community sample and from students of the University of Trier. These subjects were genotyped for the GR variants under investigation. Subsequently, 206 subjects were selected for phenotyping according to their GR genotype, which resulted in a stratified sample of about equally sized comparison groups (see Results). This sample consisted of 118 females and 88 males (mean age 25.1 with SEM of ± 3.9 years, body mass index [BMI] 24.2

Genotyping

Genotyping of 601 subjects for the four polymorphisms revealed five haplotypes (see Figure 1). Observed haplotype frequencies corresponded to those previously reported (11, 18) and all SNPs were in Hardy Weinberg Equilibrium. The haplotype with the highest frequency (45%) will be referred to as the ‘Most Common Haplotype’ (MCH, Haplotype 1). The GAGAGG to GAAAAG transition at position 22/23 (2.5%) always occurred together with the G allele in exon 9β (Haplotype 2). In 13.5% of the subjects, A/G

Discussion

Variations of the GR gene can modulate the endocrine stress response and possibly represent one factor contributing to vulnerability for psychopathology (13, 18). Therefore, the present study investigated all GR gene polymorphisms, which, at present time, seem to be of functional relevance for the regulation of the HPA axis. The comparison of extreme response groups revealed significant associations between GR gene variants and HPA axis responses to psychosocial stress and one measure of GC

References (47)

  • M.J. Schaaf et al.

    AUUUA motifs in the 3’UTR of human glucocorticoid receptor alpha and beta mRNA destabilize mRNA and decrease receptor protein expression

    Steroids

    (2002)
  • R.H. Oakley et al.

    The dominant negative activity of the human glucocorticoid receptor beta isoformSpecificity and mechanisms of action

    J Biol Chem

    (1999)
  • M.J. Schaaf et al.

    Molecular mechanisms of glucocorticoid action and resistance

    J Steroid Biochem Mol Biol

    (2002)
  • C.M. Bamberger et al.

    Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids

    Endocr Rev

    (1996)
  • E.R. de Kloet et al.

    Stress and the brain: from adaptation to disease

    Nat Rev Neurosci

    (2005)
  • L. Jacobson et al.

    The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis

    Endocrine Rev

    (1991)
  • P. Bjorntorp et al.

    The metabolic syndrome--a neuroendocrine disorder?

    Br J Nutr

    (2000)
  • A.J. Parker et al.

    The neuroendocrinology of chronic fatigue syndrome and fibromyalgia

    Psychol Med

    (2001)
  • R. Yehuda

    Sensitization of the hypothalamic-pituitary-adrenal axis in posttraumatic stress disorder

    Ann N Y Acad Sci

    (1997)
  • I. Fleury et al.

    Characterization of the BclI polymorphism in the glucocorticoid receptor gene

    Clin Chem

    (2003)
  • E.F. van Rossum et al.

    Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index

    Clin Endocrinol (Oxf)

    (2003)
  • E.F. van Rossum et al.

    Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition

    Recent Prog Horm Res

    (2004)
  • S. Wüst et al.

    Common Polymorphisms in the Glucocorticoid Receptor Gene Are Associated with Adrenocortical Responses to Psychosocial Stress

    J Clin Endocrinol Metab

    (2004)
  • Cited by (160)

    • Moving beyond the mean: Promising research pathways to support a precision medicine approach to hormonal contraception

      2023, Frontiers in Neuroendocrinology
      Citation Excerpt :

      For example, HC users exhibit decreased anterior insula activation upon erotic stimulation and enhanced activation during monetary reward expectation (Abler et al., 2013; Bonenberger et al., 2013). Additionally, beyond these differences, research finds that HC use is associated with diminished libido (Boozalis et al., 2016; Casey et al., 2017; Smith et al., 2014), decreased perseverance on cognitive tasks (Bradshaw et al., 2020), and blunting of the HPA axis-mediated stress response (Kirschbaum et al., 1999; Kumsta et al., 2007; Lovallo et al., 2019; Merz, 2017; Nielsen et al., 2013; Rohleder et al., 2003; Roche et al., 2013). Despite the growing body of work demonstrating important psychobehavioral and neurophysiological differences between HC users and non-users, it is also clear that many of these effects are idiosyncratic and can vary considerably between both women and HC products.

    • The clinical significance of the glucocorticoid receptors: Genetics and epigenetics

      2021, Journal of Steroid Biochemistry and Molecular Biology
    • Generalized and tissue specific glucocorticoid resistance

      2021, Molecular and Cellular Endocrinology
      Citation Excerpt :

      The ex vivo studies demonstrated maintained GC-induced up-regulation of GLIZ mRNA via transactivation, but decreased transrepression of IL-2 (van den Akker et al., 2006). Men carrying the GR-9β polymorphism exhibited enhanced ACTH response following the Trier Social Stress Test as well as higher ACTH levels and cortisol awakening response following a DST, suggesting a relative GC resistance (Kumsta et al., 2007). The 3669G allele was associated with reduced central obesity in women and a more favorable lipid profile in men from European origin, but not from South-Asian origin, suggesting an ethnicity-specific attenuation of the undesirable effects of GC on fat metabolism (Syed et al., 2006).

    View all citing articles on Scopus
    View full text