Rhythms of pituitary-adrenal activity during sleep in patients with Cushing's disease.

Previous studies have indicated a dependence of nocturnal pituitary-adrenal secretory activity on central nervous sleep processes in healthy humans: Under normal physiological conditions the release of ACTH/cortisol is inhibited during early sleep and becomes entrained to periods of NonREM sleep during late sleep. Here, we compared nocturnal dynamics in plasma concentrations of ACTH/cortisol in 7 patients with Cushing's disease with those of 7 healthy controls matched in age and sex with the patients. The patients in part were repeatedly tested. The total of 13 nights is composed of 7 nights of hyperpulsatile secretion pattern (5 patients) and 6 nights from hypopulsatile secretion pattern (4 patients). After an adaptation night polysomnographic sleep recordings were obtained and blood was sampled every 15 min between 23.00 and 7.00 h. Controls displayed the typical minimum in ACTH/cortisol concentrations during the early part of the night and maximum concentrations during the late part of the night, whereas ACTH/cortisol levels of Cushing patients indicated a relatively constant elevated pituitary-adrenal activity throughout the night, lacking any circadian variation. Autocorrelation functions revealed the presence of cortisol secretory rhythms with a similar period length in healthy controls (155.6+/-17.4 min) and patients with a hyperpulsatile pattern (142.4+/-6.6 min). In patients displaying hypopulsatility, no significant rhythmicity was observed. However, regardless of the type of secretory pulsatility, adrenal secretory activity started predominantly during periods of NonREM sleep (p<0.01) in healthy controls as well as in patients with Cushing's disease. This data indicates that the normal nocturnal circadian oscillation of pituitary-adrenal activity is absent in Cushing patients, whereas a link between pituitary-adrenal activity and ultradian rhythms of sleep appears to be preserved.

Influence of exogenous atrial natriuretic peptide on the pituitary-adrenal response to corticotropin-releasing hormone and vasopressin in healthy men.

Atrial natriuretic peptide (ANP) has been considered a potential candidate participating in the inhibitory control of pituitary-adrenal secretory activity. Here, we investigated the influence of ANP, infused at two different doses and over infusion intervals of two different durations, on the release of ACTH and cortisol after stimulation with CRH and with combined administration of CRH and vasopressin (VP). In young healthy men, three experiments were conducted. In Exp I, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and after a 45-min period of ANP infusion at a rate of 4.4 microg/min (starting 15 min before CRH injection). In Exp II, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and after a 90-min infusion period of ANP administered at rates of 4.4 and 8.8 microg/min. In Exp III, ANP was infused at a rate of 4.4 microg/min over 90 min, but instead of CRH, a combined administration of CRH (50 microg) and VP (0.5 IU infused within 5 min) was employed to stimulate ACTH/cortisol release. ANP diminished pituitary-adrenal secretory responses within the first hour after stimulation with exogenous secretagogues. Thereafter, the effect of ANP turned in the opposite direction, with distinctly enhanced concentrations of ACTH and cortisol during the third hour after stimulation. The inhibitory effect of ANP during the first hour of the pituitary-adrenal response was more pronounced on concentrations of cortisol than ACTH and was also more pronounced after combined administration of CRH/VP than after stimulation with CRH alone. Increasing the dose of ANP enhanced the late stimulatory effect on ACTH/cortisol release, thereby terminating the early period of inhibited ACTH/cortisol release more abruptly. The late stimulatory effect was enhanced with prolonged infusion of ANP. In addition, it was associated with reduced hematocrit, increased urine volumes collected, increased heart rate, and enhanced plasma VP concentrations. Together, these changes suggest that the late stimulatory effect of ANP on ACTH/cortisol release reflects an effect secondary to its hypovolemic actions. This stimulatory effect originating from peripheral systemic actions of ANP after exogenous administration appears to override a more direct inhibitory action of the peptide on pituitary-adrenal secretory activity. Therefore, we would expect that with localized release into portal hypophyseal blood the inhibitory component of the action of ANP on pituitary-adrenal secretory activity prevails.

Slow wave sleep drives inhibition of pituitary-adrenal secretion in humans.

During the first half of nocturnal sleep, the secretory response of the pituitary-adrenal axis to either CRH or vasopressin (VP) administration is reduced. Two experiments were performed aiming (i) to investigate the impact of sleep on the response to a combined CRH/VP administration and (ii) to specify the onset of sleep associated pituitary-adrenal suppression and its relation to specific sleep stages. In experiment I, we compared the effect of simultaneous administration of VP (0.5 IU i.v., within 6 min) and CRH (50 micrograms bolus i.v., in the third min of VP infusion) on the secretion of ACTH, cortisol and GH in healthy men during the first nocturnal epoch of slow wave sleep (SWS) and during nocturnal wakefulness. The increase of ACTH and cortisol concentrations after combined VP/CRH administration was distinctly higher during wakefulness than sleep (P < 0.01). In experiment II, CRH (30 micrograms/h, after an initial bolus of 30 micrograms) was continuously infused in 7 healthy men on 2 nights. On one of the nights, the men were allowed to sleep (between 23.00 h and 05.00 h) after a 3-h period of wakefulness, on the other night they stayed awake throughout the experiment. In both conditions, CRH enhanced ACTH/cortisol plasma levels. Compared with concentrations during continuous wakefulness, sleep and in particular SWS was associated with a suppression of ACTH/cortisol levels (P < 0.05). The findings further support an inhibitory influence of early nocturnal sleep on pituitary-adrenal activity. The effect appears to be strongest during SWS and is probably mediated via hypothalamic secretion of a release inhibiting factor of ACTH.