scholarly journals Chronic Insomnia Is Associated with Nyctohemeral Activation of the Hypothalamic-Pituitary-Adrenal Axis: Clinical Implications

2001 ◽  
Vol 86 (8) ◽  
pp. 3787-3794 ◽  
Author(s):  
Alexandros N. Vgontzas ◽  
Edward O. Bixler ◽  
Hung-Mo Lin ◽  
Paolo Prolo ◽  
George Mastorakos ◽  
...  
Keyword(s):  
Sleep Disturbance ◽  
Sleep Disturbances ◽  
Sleep Time ◽  
Hypothalamic Pituitary Adrenal Axis ◽  
Chronic Insomnia ◽  
Cortisol Secretion ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Chronic Anxiety ◽  
Pituitary Adrenal Axis

Although insomnia is, by far, the most commonly encountered sleep disorder in medical practice, our knowledge in regard to its neurobiology and medical significance is limited. Activation of the hypothalamic-pituitary-adrenal axis leads to arousal and sleeplessness in animals and humans; however, there is a paucity of data regarding the activity of the hypothalamic-pituitary-adrenal axis in insomniacs. We hypothesized that chronic insomnia is associated with increased plasma levels of ACTH and cortisol. Eleven young insomniacs (6 men and 5 women) and 13 healthy controls (9 men and 4 women) without sleep disturbances, matched for age and body mass index, were monitored in the sleep laboratory for 4 consecutive nights, whereas serial 24-h plasma measures of ACTH and cortisol were obtained during the fourth day. Insomniacs, compared with controls, slept poorly (significantly higher sleep latency and wake during baseline nights). The 24-h ACTH and cortisol secretions were significantly higher in insomniacs, compared with normal controls (4.2 ± 0.3 vs. 3.3 ± 0.3 pm, P = 0.04; and 218.0 ± 11.0 vs. 190.4 ± 8.3 nm, P = 0.07). Within the 24-h period, the greatest elevations were observed in the evening and first half of the night. Also, insomniacs with a high degree of objective sleep disturbance (% sleep time < 70), compared with those with a low degree of sleep disturbance, secreted a higher amount of cortisol. Pulsatile analysis revealed a significantly higher number of peaks per 24 h in insomniacs than in controls (P < 0.05), whereas cosinor analysis showed no differences in the temporal pattern of ACTH or cortisol secretion between insomniacs and controls. We conclude that insomnia is associated with an overall increase of ACTH and cortisol secretion, which, however, retains a normal circadian pattern. These findings are consistent with a disorder of central nervous system hyperarousal rather than one of sleep loss, which is usually associated with no change or decrease in cortisol secretion or a circadian disturbance. Chronic activation of the hypothalamic-pituitary-adrenal axis in insomnia suggests that insomniacs are at risk not only for mental disorders, i.e. chronic anxiety and depression, but also for significant medical morbidity associated with such activation. The therapeutic goal in insomnia should be to decrease the overall level of physiologic and emotional arousal, and not just to improve the nighttime sleep.

Decreased glucocorticoid receptor activity following glucocorticoid receptor antisense RNA gene fragment transfection

1991 ◽  
Vol 11 (3) ◽  
pp. 1647-1653
Author(s):  
M C Pepin ◽  
N Barden
Keyword(s):  
Glucocorticoid Receptor ◽  
Antisense Rna ◽  
Cellular Response ◽  
Hypothalamic Pituitary Adrenal Axis ◽  
Cortisol Secretion ◽  
Promoter Element ◽  
Gene Fragment ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Pituitary Adrenal Axis

Depression is often characterized by increased cortisol secretion caused by hyperactivity of the hypothalamic-pituitary-adrenal axis and by nonsuppression of cortisol secretion following dexamethasone administration. This hyperactivity of the hypothalamic-pituitary-adrenal axis could result from a reduced glucocorticoid receptor (GR) activity in neurons involved in its control. To investigate the effect of reduced neuronal GR levels, we have blocked cellular GR mRNA processing and/or translation by introduction of a complementary GR antisense RNA strand. Two cell lines were transfected with a reporter plasmid carrying the chloramphenicol acetyltransferase (CAT) gene under control of the mouse mammary tumor virus long terminal repeat (a glucocorticoid-inducible promoter). This gene construction permitted assay of the sensitivity of the cells to glucocorticoid hormones. Cells were also cotransfected with a plasmid containing 1,815 bp of GR cDNA inserted in the reverse orientation downstream from either a neurofilament gene promoter element or the Rous sarcoma virus promoter element. Northern (RNA) blot analysis demonstrated formation of GR antisense RNA strands. Measurement of the sensitivity of CAT activity to exogeneous dexamethasone showed that although dexamethasone increased CAT activity by as much as 13-fold in control incubations, expression of GR antisense RNA caused a 2- to 4-fold decrease in the CAT response to dexamethasone. Stable transfectants bearing the GR antisense gene fragment construction demonstrated a 50 to 70% decrease of functional GR levels compared with normal cells, as evidenced by a ligand-binding assay with the type II glucocorticoid receptor-specific ligand [3H]RU 28362. These results validate the use of antisense RNA to GR to decrease cellular response to glucocorticoids.

HYPOTHALAMIC-PITUITARY-ADRENAL FUNCTION IN OBESITY AND THE CORTISOL SECRETION RATE FOLLOWING PROLONGED STARVATION

1970 ◽  
Vol 63 (3) ◽  
pp. 415-422 ◽  
Author(s):  
Ivor M. D. Jackson ◽  
Joy I. Mowat
Keyword(s):  
Diurnal Rhythm ◽  
Plasma Cortisol ◽  
Hypothalamic Pituitary Adrenal Axis ◽  
Adrenal Function ◽  
Secretion Rate ◽  
Cortisol Secretion ◽  
Prolonged Starvation ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Pituitary Adrenal Axis

ABSTRACT Evaluation of the hypothalamic-pituitary-adrenal axis was undertaken in obesity. Abnormality of diurnal rhythm of plasma cortisol, elevated cortisol secretion rate (CSR) and, to a lesser extent, excessive response to adrenal stimulation, were found in a proportion of cases. Adequate hypoglycaemia invariably produced a significant cortisol rise and 80% of cases responded to L.8 vasopressin at 5 units im. A significant fall in CSR, urinary 17-OHCS and 17-KS occurred with starvation. The significance of these findings in relation to Cushing's syndrome is discussed.

scholarly journals Hypothalamic-Pituitary-Adrenal Axis Activity in Obese Men with and without Sleep Apnea: Effects of Continuous Positive Airway Pressure Therapy

2007 ◽  
Vol 92 (11) ◽  
pp. 4199-4207 ◽  
Author(s):  
A. N. Vgontzas ◽  
S. Pejovic ◽  
E. Zoumakis ◽  
H.-M. Lin ◽  
C. M. Bentley ◽  
...  
Keyword(s):  
Sleep Apnea ◽  
Airway Pressure ◽  
Positive Airway Pressure ◽  
Hypothalamic Pituitary Adrenal Axis ◽  
Sleep Laboratory ◽  
Cortisol Secretion ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Low Cortisol ◽  
Pituitary Adrenal Axis

Abstract Context: Previous studies on the association between the hypothalamic-pituitary-adrenal axis activity and sleep apnea (SA) and obesity are inconsistent and/or limited. Objective: In this study, we evaluated the activity of the hypothalamic-pituitary-adrenal axis in nonpsychologically distressed obese subjects with and without SA and examined the impact of continuous positive airway pressure (CPAP) in SA patients. Design and Participants: In study I, four-night sleep laboratory recordings and serial 24-h plasma measures of cortisol were obtained in 45 obese men with and without apnea and nonobese controls. Sleep apneic patients were reassessed after 3 months of CPAP use. In study II, 38 obese men with and without sleep apnea and nonobese controls were challenged with ovine CRH administration after four nights in the sleep laboratory. Results: The sleep patterns were similar between obese and nonobese controls. Twenty-four-hour plasma cortisol levels were highest in nonobese controls, intermediate in obese apneic patients, and lowest in obese controls (8.8 ± 0.4 vs. 8.1 ± 0.3 vs. 7.5 ± 0.3 μg/dl, P < 0.05). CPAP tended to reduce cortisol levels in the apneic patients (difference −0.7 ± .4 μg/dl, P = 0.1). CRH administration resulted in a higher ACTH response in both obese groups, compared with nonobese controls; the three groups were not different in cortisol response. Conclusions: Nonpsychologically distressed, normally sleeping, obese men had low cortisol secretion. The cortisol secretion was slightly activated by SA and returned to low by CPAP use. The low cortisol secretion in obesity through its inferred hyposecretion of hypothalamic CRH might predispose the obese to sleep apnea.

STIMULATING ACTION OF CALCIUM ON THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

1972 ◽  
Vol 71 (4) ◽  
pp. 677-683 ◽  
Author(s):  
Herluf Jensen ◽  
Harly Toft
Keyword(s):  
Intravenous Infusion ◽  
Plasma Calcium ◽  
Hypothalamic Pituitary Adrenal Axis ◽  
Glucose Infusion ◽  
Cortisol Secretion ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Adrenal System ◽  
Calcium Infusion ◽  
Pituitary Adrenal Axis

ABSTRACT The effect of calcium on the hypothalamic-pituitary-adrenal system was studied in 10 subjects – 9 with normal adrenal function and in 1 adrenalectomized patient – by giving an intravenous infusion of calcium during 4 hours. In all the subjects with intact hypothalamic-pituitary-adrenal axis the level of plasma 11-OHCS either was increased or the fall was diminished as compared to the fall in plasma 11-OHCS during an intravenous infusion of glucose. However, no correlation was found between the plasma calcium and the 11-OHCS. Furthermore the excretion of 17-KGS in the urine was unaltered during the calcium infusion experiments. In the adrenalectomized patient no difference in the plasma 11-OHCS was found during calcium or glucose infusion. It is concluded that calcium stimulates the hypothalamic-pituitary-adrenal system, resulting in an increased cortisol secretion. The level at which this stimulation occurs remains unknown.

scholarly journals Decreased glucocorticoid receptor activity following glucocorticoid receptor antisense RNA gene fragment transfection.

1991 ◽  
Vol 11 (3) ◽  
pp. 1647-1653 ◽  
Author(s):  
M C Pepin ◽  
N Barden
Keyword(s):  
Glucocorticoid Receptor ◽  
Antisense Rna ◽  
Cellular Response ◽  
Hypothalamic Pituitary Adrenal Axis ◽  
Cortisol Secretion ◽  
Promoter Element ◽  
Gene Fragment ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Pituitary Adrenal Axis

Depression is often characterized by increased cortisol secretion caused by hyperactivity of the hypothalamic-pituitary-adrenal axis and by nonsuppression of cortisol secretion following dexamethasone administration. This hyperactivity of the hypothalamic-pituitary-adrenal axis could result from a reduced glucocorticoid receptor (GR) activity in neurons involved in its control. To investigate the effect of reduced neuronal GR levels, we have blocked cellular GR mRNA processing and/or translation by introduction of a complementary GR antisense RNA strand. Two cell lines were transfected with a reporter plasmid carrying the chloramphenicol acetyltransferase (CAT) gene under control of the mouse mammary tumor virus long terminal repeat (a glucocorticoid-inducible promoter). This gene construction permitted assay of the sensitivity of the cells to glucocorticoid hormones. Cells were also cotransfected with a plasmid containing 1,815 bp of GR cDNA inserted in the reverse orientation downstream from either a neurofilament gene promoter element or the Rous sarcoma virus promoter element. Northern (RNA) blot analysis demonstrated formation of GR antisense RNA strands. Measurement of the sensitivity of CAT activity to exogeneous dexamethasone showed that although dexamethasone increased CAT activity by as much as 13-fold in control incubations, expression of GR antisense RNA caused a 2- to 4-fold decrease in the CAT response to dexamethasone. Stable transfectants bearing the GR antisense gene fragment construction demonstrated a 50 to 70% decrease of functional GR levels compared with normal cells, as evidenced by a ligand-binding assay with the type II glucocorticoid receptor-specific ligand [3H]RU 28362. These results validate the use of antisense RNA to GR to decrease cellular response to glucocorticoids.

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