HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes

AbstractDNA methylation shifts in Hypothalamic–pituitary–adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level ≥ 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.

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The assessment of hypothalamic-pituitary-adrenal (HPA) axis by dexamethasone suppression test in patients with major depression with positive or negative allergic tests results

Biological Psychiatry ◽

10.1016/s0006-3223(97)87059-x ◽

1997 ◽

Vol 42 (1) ◽

pp. 43S

Author(s):

M. Dabkowska

Keyword(s):

Major Depression ◽

Hpa Axis ◽

Dexamethasone Suppression Test ◽

Hypothalamic Pituitary Adrenal ◽

Suppression Test ◽

Dexamethasone Suppression

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In search of the HPA axis activity in unipolar depression patients with childhood trauma: Combined cortisol awakening response and dexamethasone suppression test

Journal of Psychiatric Research ◽

10.1016/j.jpsychires.2016.03.009 ◽

2016 ◽

Vol 78 ◽

pp. 24-30 ◽

Cited By ~ 31

Author(s):

Shaojia Lu ◽

Weijia Gao ◽

Manli Huang ◽

Lingjiang Li ◽

Yi Xu

Keyword(s):

Childhood Trauma ◽

Hpa Axis ◽

Unipolar Depression ◽

Dexamethasone Suppression Test ◽

Cortisol Awakening Response ◽

Suppression Test ◽

Hpa Axis Activity ◽

Dexamethasone Suppression

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Effects of the Introduction of the Dexamethasone Suppression Test on Diagnosis and Treatment of Depression by Psychiatrists

Australian & New Zealand Journal of Psychiatry ◽

10.1080/00048678309160012 ◽

1983 ◽

Vol 17 (4) ◽

pp. 350-353

Author(s):

Geoffrey D. Schrader ◽

Timothy C. Durbridge

Keyword(s):

Psychiatric Disorders ◽

Laboratory Tests ◽

Strong Association ◽

Dexamethasone Suppression Test ◽

Treatment Practice ◽

Treatment Of Depression ◽

Before And After ◽

Management Plans ◽

Suppression Test ◽

Dexamethasone Suppression

A review of case notes before and after the introduction of the DST into clinical psychiatric practice revealed considerable changes in diagnosis and management. Specifically there were increases in the diagnosis of biological depression and treatment with somatic antidepressant therapy. There was no association between DST results and particular management plans. There was a strong association between requesting the DST and management with antidepressants. It is suggested that the introduction of laboratory tests for psychiatric disorders may firm the belief of psychiatrists in the biological basis of some forms of depression and thus alter their diagnostic and treatment practice.

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Childhood traumata, Dexamethasone Suppression Test and psychiatric symptoms: a trans-diagnostic approach

Psychological Medicine ◽

10.1017/s0033291710000115 ◽

2010 ◽

Vol 40 (12) ◽

pp. 2037-2048 ◽

Cited By ~ 19

Author(s):

C. Faravelli ◽

S. Gorini Amedei ◽

F. Rotella ◽

L. Faravelli ◽

A. Palla ◽

...

Keyword(s):

Life Events ◽

Hpa Axis ◽

Salivary Cortisol ◽

Psychiatric Symptoms ◽

Dexamethasone Suppression Test ◽

Diagnostic Approach ◽

Stressful Event ◽

Suppression Test ◽

Hpa Response ◽

Dexamethasone Suppression

BackgroundChildhood traumatic events and functional abnormalities of the hypothalamus–pituitary–adrenal (HPA) axis have been widely reported in psychiatric patients, although neither is specific for any diagnosis. Among the limited number of studies that have evaluated these topics, none has adopted a trans-diagnostic approach. The aim of the present research is to explore the relationship between childhood stressors, HPA axis function and psychiatric symptoms, independent of the diagnosis.MethodA total of 93 moderate to severely ill psychiatric out-patients of Florence and Pisa University Psychiatric Units and 33 healthy control subjects were recruited. The assessment consisted of salivary cortisol pre- and post-low dose (0.5 mg) Dexamethasone, early and recent life events, 121 psychiatric symptoms independent of diagnosis, SCID, BPRS.ResultsIn total, 33.5% of patients were Dexamethasone Suppression Test (DST) non-suppressors, compared with 6.1% of controls (p=0.001). Among patients, non-suppression was associated with particular symptoms (i.e. depressive and psychotic), but not to any specific diagnosis. Early stressful life events were significantly associated with higher salivary cortisol levels, with DST non-suppression and with approximately the same subset of symptoms. A recent stressful event seemed to be associated to the HPA response only in those subjects who were exposed to early traumata.ConclusionsOur report suggests a relationship between life stress, HPA axis and psychopathology. A cluster of specific psychiatric symptoms seems to be stress related. Moreover, it seems that an abnormal HPA response is possibly triggered by an excessive pressure in vulnerable individuals.

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The Dexamethasone Suppression Test in Psychiatric Disorders

Psychiatric Annals ◽

10.3928/0048-5713-19931201-05 ◽

1993 ◽

Vol 23 (12) ◽

pp. 662-670 ◽

Cited By ~ 8

Author(s):

Anthony J Rothschild

Keyword(s):

Psychiatric Disorders ◽

Dexamethasone Suppression Test ◽

Suppression Test ◽

Dexamethasone Suppression

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Hypothalamic–pituitary–adrenal axis function in patients with chronic depression

Psychological Medicine ◽

10.1017/s0033291702005998 ◽

2002 ◽

Vol 32 (6) ◽

pp. 1021-1028 ◽

Cited By ~ 92

Author(s):

S. WATSON ◽

P. GALLAGHER ◽

D. DEL-ESTAL ◽

A. HEARN ◽

I. N. FERRIER ◽

...

Keyword(s):

Hpa Axis ◽

Demographic Variable ◽

Dexamethasone Suppression Test ◽

Chronic Depression ◽

Chronic Patients ◽

Hypothalamic Pituitary Adrenal ◽

Suppression Test ◽

And Control ◽

Dexamethasone Suppression ◽

Pituitary Adrenal Axis

Background. Hypothalamic–pituitary–adrenal (HPA) axis function in patients with chronic depression has previously been shown to be normal when measured using the dexamethasone suppression test (DST). We examined patients with chronic depression using the sensitive dexamethasone/corticotropin releasing hormone (dex/CRH) test and the dexamethasone suppression test (DST) to establish whether HPA axis abnormalities are present in this group. We also compared the sensitivity of the two tests and compared the results with previous studies in depression that have not specifically selected chronic patients.Method. Twenty-nine patients with the chronic subtype of major depressive disorder and 28 matched controls underwent examination of HPA axis function.Results. Neither the cortisol response to the DST or the dex/CRH test differed significantly between the patient and control groups. There was a trend in favour of more patients than controls having an abnormal response to the dex/CRH test (P = 0.052). Neither the patients with an abnormally enhanced response, nor the magnitude of response could be predicted by any illness or demographic variable.Conclusion. The HPA axis is not overtly abnormal in chronic depression. This contrasts with previous findings in acute depression and bipolar disorder and may suggest that the HPA axis abnormalities present in acute depression resolve, but are not accompanied by symptom resolution. Alternatively, a subgroup of depressives with less HPA dysfunction may progress to chronicity. This has implications for treatment and prognosis. The dex/CRH is a more sensitive test of HPA axis function than the DST in patients with chronic depression.

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Dexamethasone Concentrations and the Dexamethasone Suppression Test in Psychiatric Disorders

The British Journal of Psychiatry ◽

10.1192/bjp.148.1.66 ◽

1986 ◽

Vol 148 (1) ◽

pp. 66-69 ◽

Cited By ~ 56

Author(s):

Howard Morris ◽

Vaughan Carr ◽

Judy Gilliland ◽

Michael Hooper

Keyword(s):

Psychiatric Disorders ◽

Clinical Diagnosis ◽

Serum Cortisol ◽

Endogenous Depression ◽

Dexamethasone Suppression Test ◽

Suppression Test ◽

Cortisol Levels ◽

High Concentrations ◽

Dexamethasone Suppression ◽

Low Serum

The dexamethasone suppression test (DST) has been widely used in psychiatry as a laboratory aid for the diagnosis of endogenous depression; failure to suppress serum cortisol levels is interpreted as confirming a clinical diagnosis of endogenous depression. We found that serum dexamethasone concentrations in this test vary widely and are determinants of the DST response: non-suppression of serum cortisol levels is associated with low serum dexamethasone concentrations, and suppression is associated with high concentrations.

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Dexamethasone suppression test in affective and other psychiatric disorders.

The Keio Journal of Medicine ◽

10.2302/kjm.33.161 ◽

1984 ◽

Vol 33 (4) ◽

pp. 161-165

Author(s):

SATORU SHIMA ◽

TOSHINORI KITAMURA ◽

M. R. C. PSYCH ◽

TATSUO SHIKANO ◽

SHOJIRO KANO ◽

...

Keyword(s):

Psychiatric Disorders ◽

Dexamethasone Suppression Test ◽

Suppression Test ◽

Dexamethasone Suppression

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No Postoperative Adrenal Insufficiency in a Patient with Unilateral Cortisol-Secreting Adenomas Treated with Mifepristone before Surgery

Clinical Medicine Insights Endocrinology and Diabetes ◽

10.4137/cmed.s39997 ◽

2016 ◽

Vol 9 ◽

pp. CMED.S39997 ◽

Cited By ~ 3

Author(s):

Rachel M. Saroka ◽

Michael P. Kane ◽

Lawrence Robinson ◽

Robert S. Busch

Keyword(s):

Adrenal Gland ◽

Adrenal Insufficiency ◽

Hpa Axis ◽

Reference Range ◽

Dehydroepiandrosterone Sulfate ◽

Dexamethasone Suppression Test ◽

Normal Range ◽

Free Cortisol ◽

Suppression Test ◽

Dexamethasone Suppression

Background Glucocorticoid replacement is commonly required to treat secondary adrenal insufficiency after surgical resection of unilateral cortisol-secreting adrenocortical adenomas. Here, we describe a patient with unilateral cortisol-secreting adenomas in which the preoperative use of mifepristone therapy was associated with recovery of the hypothalamic–pituitary–adrenal (HPA) axis, eliminating the need for postoperative glucocorticoid replacement. Case Presentation A 66-year-old Caucasian man with type 2 diabetes mellitus, hyperlipidemia, hypertension, and obesity was hospitalized for Fournier's gangrene and methicillin-resistant Staphylococcus aureus sepsis. Abdominal computed tomography scan revealed three left adrenal adenomas measuring 1.4, 2.1, and 1.2 cm and an atrophic right adrenal gland. Twenty-four-hour urinary free cortisol level was elevated (237 µg/24 hours, reference range 0–50 µg/24 hours). Hormonal evaluation after resolution of the infection showed an abnormal 8 mg overnight dexamethasone suppression test (cortisol postdexamethasone 14.5 µg/dL), suppressed adrenocorticotropic hormone (ACTH; <5 pg/mL, reference range 7.2–63.3 pg/mL), and low-normal dehydroepiandrosterone sulfate (50.5 µg/dL, male reference range 30.9–295.6 µg/dL). Because of his poor medical condition and uncontrolled diabetes, his Cushing's syndrome was treated with medical therapy before surgery. Mifepristone therapy was started and, within five months, his diabetes was controlled and insulin discontinued. The previously suppressed ACTH increased to above normal range accompanied by an increase in dehydroepiandrosterone sulfate levels, indicating recovery of the HPA axis and atrophic contralateral adrenal gland. The patient received one precautionary intraoperative dose of hydrocortisone and none thereafter. Two days postoperatively, ACTH (843 pg/mL) and cortisol levels (44.8 µg/dL) were significantly elevated, reflecting an appropriate HPA axis response to the stress of surgery, and two weeks postoperatively, ACTH was within normal range and a repeat dexamethasone suppression test was normal. Six months postoperatively, ACTH was within normal limits and cortisol was approaching normal. The patient has exhibited no postoperative signs or symptoms of adrenal insufficiency in 12 months. Conclusion Preoperative mifepristone therapy was associated with apparent recovery of the HPA axis prior to unilateral adrenalectomy in a patient with unilateral adrenal adenomas. Postoperatively, the patient experienced no signs or symptoms of adrenal insufficiency and no glucocorticoid replacement was required.

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