Neuroendocrinological investigations during sleep deprivation in depression. II. Longitudinal measurement of thyrotropin, TH, cortisol, prolactin, GH, and LH during sleep and sleep deprivation

Thyrotropin (TSH), thyroxin (T4), triiodothyronine (T3), free T3 (fT3), cortisol, prolactin, and human growth hormone (HGH) were measured every 2 hr during a night of sleep, the following day, and a night of sleep deprivation (SD) in 14 patients with major depressive disorder. In subgroups fT4 (n = 5), reverse T3 (rT3), and luteinizing hormone (LH) (n = 6) were also investigated. Significant increases in TSH, T4, fT4, T3, fT3, rT3, and cortisol and decreases in prolactin levels occurred during the night of SD, compared to the pattern during the night of sleep. The pre-SD T4 and T3 levels of the responders to SD were already higher than in the nonresponders, and increased less during SD. The cortisol and HGH concentrations of the responders rose higher during SD than those of the nonresponders. Changes in TSH and prolactin were not correlated to clinical response. Analysis of possible neurochemical mechanisms underlying this "pattern" of changes in different endocrine profiles suggests that enhanced noradrenergic activity might play a role in the changes in TSH, cortisol, thyroid hormones, and possibly HGH secretion during SD, and increased dopaminergic tone probably induced the decline in prolactin levels. Additional effects of the serotonergic system cannot be excluded at present. In conclusion, the data suggest that enhanced noradrenergic activity of the locus coeruleus stimulates alpha and/or beta adrenergic receptors in depressed patients during SD. This mechanism could well be involved in the antidepressant effect of this therapy.     

Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression

BACKGROUND: One night of sleep deprivation induces a brief remission in about half of depressed patients. Subclinical hypothyroidism may be associated with depression, and changes in hypothalamic-pituitary-thyroid function may affect the mood response to sleep deprivation. We wished to define precisely the status of the hypothalamic-pituitary-thyroid axis of depressed patients during sleep deprivation and the possible relationship of hypothalamic-pituitary-thyroid function to the mood response. METHODS: We studied 18 patients with major depressive disorder and 10 normal volunteers. We assessed mood before and after sleep. We measured serum thyrotropin every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity, the thyrotropin response to protirelin the next afternoon, and other indexes of hypothalamic-pituitary-thyroid function. To determine if the changes were limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol, which also has a circadian secretory pattern. RESULTS: Nocturnal serum thyrotropin concentrations were consistently higher in responders, entirely because of elevated levels in the women reponders. Responders had exaggerated responses to protirelin the next afternoon. The bioactivity of thyrotropin in nonresponders was significantly greater than in responders (F(1,8. 99) = 7.52; P =.02). Other thyroid indexes and serum cortisol concentrations were similar among groups. CONCLUSIONS: Depressed patients have mild compensated thyroid resistance to thyrotropin action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation responders compensate by secreting more thyrotropin with normal bioactivity; nonresponders compensate by secreting thyrotropin with increased bioactivity.     

Effects of ECT on prolactin, LH, FSH and testosterone in males with major depressive illness

Fourteen males with major depressive illness (DSM-III) received a course of electroconvulsive therapy (ECT). Serum prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone (T), were measured 15 minutes before and 15 minutes after each treatment. The severity of depression was assessed with the Hamilton Rating Scale for Depression (HRSD) two to three days before the first and two to three days following the last treatment. Post-ECT levels of PRL and LH were significantly higher than pre-ECT levels across every treatment. Changes in FSH and testosterone were not significant. There were no relationships between hormone levels (first versus last ECT) and severity of depression, including sexual functioning. It is argued that the relatively greater increases of LH than FSH is due to an acute antidopaminergic action of ECT which acts selectively on the secretion of the former. The blunted testosterone response to the increase of gonadotropins may be due to ECT-induced hyperprolactinemia.     

Blunted prolactin response to fentanyl in depression. Normalizing effect of partial sleep deprivation

There is some evidence that sleep deprivation (SD) might exert its antidepressant properties by involving endogenous opioid mechanisms. The authors investigated the effects of mu-receptor agonist administration on prolactin release in depressed patients before and after partial SD. Medication-free female depressed inpatients (N=18) were participating in two fentanyl challenge tests after partial SD and undisturbed sleep, 3 days apart in random order. Healthy volunteer women (N=10) were enrolled after full night sleep as comparison subjects. Five of them had placebo trials. Participants were given an intravenous injection of 0.1 mg/70 kg fentanyl at 9:00 AM. The prolactin secretory response to the opiate agonist was investigated for 1 h with serial blood sampling. After a night of undisturbed sleep, fentanyl administration prompted increases in plasma prolactin concentrations with blunted responses found in the depressed group. Following partial SD, the stimulated prolactin secretion of depressed patients increased significantly and was comparable to the response of comparison subjects. These findings suggest that SD acts via an opioid/dopamine-related mechanism. An alternative explanation, based on serotonin involvement is addressed in the discussion.     

Early morning cortisol response and emotional processing in adults exposed to postnatal depression in infancy

Emotional processing and cortisol were investigated in non-depressed young adults whose mothers experienced PND. PND-exposed participants (n = 11) had higher waking salivary cortisol and slower performance on an emotional categorization task than controls (n = 15). This supports the hypothesis that early exposure to maternal depression is associated with characteristics reminiscent of vulnerability to depression.     

Effects of competition and its outcome on serum testosterone, cortisol and prolactin.

In various species, competitive encounters influence hormonal responses in a different way depending on their outcome, victory or defeat. This study aimed to investigate the effects of sports competition and its outcome on hormonal response, comparing it with those displayed in situations involving non-effort and non-competitive effort. To this end, serum testosterone (T), cortisol (C) and prolactin (PRL) were measured in 26 judoists who participated in three sessions (control, judo fight and ergometry). The relationship between hormonal changes and psychological variables before and after the fight were also analysed. Our results showed a hormonal response to competition, which was especially characterized by an anticipatory rise of T and C. Depending on outcome, significant higher C levels were found in winners in comparison to losers through all the competition but not in T or PRL, both groups expending a similar physical effort. Furthermore, similar hormonal responses to the fight and to a non-competitive effort with the same caloric cost were found, other than with PRL. Winners showed a higher appraisal of their performance and satisfaction with the outcome, and perceived themselves as having more ability to win than losers, although there were no significant differences in motivation to win. Finally, the relationships found between T changes in competition and motivation to win, as well as between C response and self-efficacy suggest that in humans hormonal response to competition is not a direct consequence of winning and losing but rather is mediated by complex psychological processes.     

Chronic stress during paradoxical sleep deprivation increases paradoxical sleep rebound: association with prolactin plasma levels and brain serotonin content

Previous studies suggest that stress associated to sleep deprivation methods can affect the expression of sleep rebound. In order to examine this association and possible mechanisms, rats were exposed to footshock stress during or immediately after a 96-h period of paradoxical sleep deprivation (PSD) and their sleep and heart rate were recorded. Control rats (maintained in individual home cages) and paradoxical sleep-deprived (PS-deprived) rats were distributed in three conditions (1) no footshock - NF; (2) single footshock - SFS: one single footshock session at the end of the PSD period (6-8 shocks per minute; 100ms; 2mA; for 40min); and (3) multiple footshock - MFS: footshock sessions with the same characteristics as described above, twice a day throughout PSD (at 7:00h and 19:00h) and one extra session before the recovery period. After PSD, animals were allowed to sleep freely for 72h. Additional groups were sacrificed at the end of the sleep deprivation period for blood sampling (ACTH, corticosterone, prolactin and catecholamine levels) and brain harvesting (monoamines and metabolites). Neither SFS nor MFS produced significant alterations in the sleep patterns of control rats. All PS-deprived groups exhibited increased heart rate which could be explained by increased dopaminergic activity in the medulla. As expected, PS deprivation induced rebound of paradoxical sleep in the first day of recovery; however, PSD+MFS group showed the highest rebound (327.3% above the baseline). This group also showed intermediate levels of corticosterone and the highest levels of prolactin, which were positively correlated with the length of PS episodes. Moreover, paradoxical sleep deprivation resulted in elevation of the serotonergic turnover in the hypothalamus, which partly explained the hormonal results, and in the hippocampus, which appears to be related to adaptive responses to stress. The data are discussed in the realm of a prospective importance of paradoxical sleep for processing of traumatic events.     

Role of the septum on LH, FSH and prolactin secretion in male rats

Serum concentrations of luteinizing hormone (LH) follicle-stimulating hormone (FSH), prolactin (PRL) and testosterone were measured by radioimmunoassay in male Wistar rats:

1. (a) Four days after a septal lesion (n = 19) and

2. (b) Just following electrical stimulation of the septum (n = 15). Septal lesions induced a significant decrease in serum LH (16.37 ± 2.01 vs. 30.27 ± 2.08 ng/ml; p < 0.001) and testosterone concentrations (0.53 ± 0.05 vs. 1.01 ± 0.14 ng/ml; p < 0.02). No significant changes were observed for FSH or PRL levels. Electrical septal stimulation induced an increase in serum levels of LH (211.5 ± 46.4 vs. 29.6 ± 11.5 ng/ml; p < 0.01) and FSH (703 ± 83 vs. 378 ± 57 ng/ml;p < 0.01), without changes in PRL or testosterone concentrations. From these data we conclude that in male rats the septum may play a role in the mechanisms controlling gonadotropins release by the anterior pituitary gland.

Cyclic alternating pattern and interictal epileptiform discharges during morning sleep after sleep deprivation in temporal lobe epilepsy

PurposeSleep deprivation (SD) increases the occurrence of interictal epileptiform discharges (IED) compared to basal EEG in temporal lobe epilepsy (TLE). In adults, EEG after SD is usually performed in the morning after SD. We aimed to evaluate whether morning sleep after SD bears additional IED-inducing effects compared with nocturnal physiological sleep, and whether changes in sleep stability (described by the cyclic alternating pattern-CAP) play a significant role.MethodsAdult patients with TLE underwent in-lab night polysomnography (n-PSG) and, within 7 days from n-PSG, they underwent also a morning EEG after night SD (SD-EEG). We included only TLE patients in which both recordings showed IED. SD-EEG consisted of waking up patients at 2:00 AM and performing video EEG at 8:00 AM. For both recordings, we obtained the following markers for the first sleep cycle: IED/h (Spike Index, SI), sleep macrostructure, microstructure (NREM CAP rate; A1, A2 and A3 Indices), and SI association with CAP variables.ResultsThe macrostructure of the first sleep cycle was similar in n-PSG and morning SD-EEG, whereas CAP rate and SI were significantly higher in SD-EEG. SI increase was selectively associated with CAP phases.ConclusionsSD increases the instability of morning recovery sleep compared with n-PSG, and particularly enhances CAP A1 phases, which are associated with the majority of IED. Thus, higher instability of morning recovery sleep may account at least in part for the increased IED yield in SD-EEG in TLE patients.     

Hexarelin decreases slow-wave sleep and stimulates the secretion of GH, ACTH, cortisol and prolactin during sleep in healthy volunteers

Ghrelin, the endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor and some GHSs exert different effects on sleep electroencephalogram (EEG) and sleep-related hormone secretion in humans. Similar to GH-releasing hormone (GHRH) ghrelin promotes slow-wave sleep in humans, whereas GH-releasing peptide-6 (GHRP-6) enhances stage 2 nonrapid-eye movement sleep (NREMS). As GHRP-6, hexarelin is a synthetic GHS. Hexarelin is superior to GHRH and GHRP-6 in stimulating GH release. The influence of hexarelin on sleep-endocrine activity and the immune system is unknown. We investigated simultaneously the sleep EEG and nocturnal profiles of GH, ACTH, cortisol, prolactin, leptin, tumor necrosis factor (TNF)-alpha, and soluble TNF-alpha receptors in seven young normal volunteers after repetitive administration of 4 x 50 microg hexarelin or placebo at 22.00, 23.00, 24.00 and 01.00 h. Following hexarelin, stage 4 sleep during the first half of the night, and EEG delta power during the total night decreased significantly. Significant increases of the concentrations of GH and prolactin during the total night, and of ACTH and of cortisol during the first half of the night were found. Leptin levels, TNF-alpha and soluble TNF receptors remained unchanged. We hypothesize that sleep is impaired after hexarelin since the GHRH/corticotropin-releasing hormone (CRH) ratio is changed in favour of CRH. There are no hints for an interaction of hexarelin and the immune system.     

Body core temperature and depression during total sleep deprivation in depressives

Endogenously depressed patients were subjected to a total sleep deprivation (TSD) schedule of sleep-TSD-sleep-TSD. They were simultaneously treated with the antidepressant drug clomipramine. Self- and observer-rated depression was measured daily. Continuously measured rectal temperature (RT) data were available for the second TSD. It was found that a higher nocturnal minimum RT during this TSD was associated with a positive clinical response.     

双相障碍与单相抑郁患者雌二醇和催乳素水平对照研究

目的探讨双相障碍、单相抑郁患者与健康人群之间雌二醇、催乳素水平差异以及性激素水平与躁狂、抑郁症状之间的相关性。方法选取2014年1月-2015年5月收住北京回龙观医院的符合《国际疾病分类(第10版)》(ICD-10)双相情感障碍、抑郁发作诊断标准的患者99例(男性55例,女性44例)。采用汉密尔顿抑郁量表24项版(HAMD-24)、蒙哥马利-艾森贝格抑郁量表(MADRS)评估抑郁症状,采用贝克-拉范森躁狂量表(BRMS)评估躁狂症状;选取与患者组性别、年龄及受教育程度相匹配的42例健康人作为对照组。采用化学发光免疫分析法检测研究对象周围血中雌二醇、催乳素水平。结果催乳素水平在双相障碍组、单相抑郁组以及健康对照组之间差异有统计学意义(F=6.575,P0.05),而三组雌二醇水平差异无统计学意义(P0.05),催乳素水平与BRMS评分呈正相关(r=0.361,P=0.033),雌二醇水平与抑郁症状及躁狂症状评分相关均不显著(P0.05)。结论心境障碍患者存在性激素水平的改变;性激素水平与情感症状严重程度存在相关性。     

Dopaminergic augmentation of sleep deprivation effects in bipolar depression.

Total sleep deprivation (TSD) has been used in association with lithium salts and with serotonergic and noradrenergic antidepressants, leading to sustained improvements in patients affected by major depression. Current theories on the neurobiological mechanism of action of TSD propose a major role for enhanced dopamine activity. To test the clinical relevance of dopaminergic enhancement in TSD, we treated a homogeneous sample of 28 bipolar depressed patients with three cycles of TSD combined with placebo or with the dopaminergic antidepressant amineptine. Changes in mood over time were rated with self-administered visual analogue scales and with the Montgomery-Asberg Depression Rating Scale. Patients showed improved mean daily-mood scores after TSD, an effect that was highest at the first cycle and decreased with treatment repetition. Amineptine enhanced the effects of TSD on perceived mood during the first two TSD cycles, but patients in the placebo and amineptine groups showed comparable results at the end of the treatment. Despite its theoretical importance, the clinical usefulness of combining TSD with a dopaminergic agent must be questioned.     

睡眠癲痫发作时血清促肾上腺皮质激素和皮质醇的变化

目的探讨睡眠癫痫患者临床发作时血清促肾上腺皮质激素（adrenoconicotropic hormone,ACTH）和皮质醇的变化及其与脑电波变化之间的联系。方法采用24导video—EEG对睡眠癫痫患者进行脑电监测,并对其发作前瞬时的EEG进行分析,采用化学发光免疫法在清醒时、睡眠时、发作前瞬间、发作时和发作后的5个时间点测定血清中ACTH和皮质醇的浓度。在36例睡眠癫痫患者中,28例为自然发作,8例为贝美格诱发发作。用11例假性心因性癫痫发作患者作为对照组。结果睡眠癫痫发作前、中、后血清ACTH和皮质醇的浓度有显著差异（P〈0．001）,发作前瞬间降低,发作时升高,发作后明显升高;假性癫痫发作对照组的血清ACTH和皮质醇浓度在发作时无明显变化（P〉0．05）;贝美格诱发发作组与自然发作组间ACTH和皮质醇比较无显著差异（P〉0．05）。结论睡眠癫痫患者血清ACTH和皮质醇与癫痫发作前和发作时的脑电变化有密切关系。     

Effect of hypoglycaemia,TRH and levodopa on plasma growth hormone,prolactin, thyrotropin and cortisol in Parkinson's disease before and during therapy

Summary Thirteen drug-free and not severely affected patients with idiopathic Parkinson's disease underwent an insulin-hypoglycaemia test, a TRH test and a levodopa test. The responses of growth hormone, prolactin, cortisol and thyrotropin were measured, and retested under stable therapy with levodopa and benserazide. Mean basal and stimulated hormonal concentrations were in the normal range before and during therapy. Minor abnormalities were observed in individual cases, but did not indicate a hypothalamic dopamine deficit.     

Catecholamine and cortisol levels during sleep in women with irritable bowel syndrome

Abstract  Evidence suggests that patients with irritable bowel syndrome (IBS) are hyper-responsive to environmental, physical and visceral stimuli. IBS patients also frequently report poor sleep quality. This study compared serum cortisol and plasma catecholamine levels during sleep between women with IBS ( n  = 30) and healthy controls ( n  = 31), and among subgroups within the IBS sample based on predominant stool patterns, IBS-diarrhoea ( n  = 14), IBS-constipation ( n  = 7) and IBS-alternators ( n  = 9). Cortisol was measured from serial blood samples drawn every 20 min, and catecholamines every hour, in a sleep laboratory from 8  pm until awakening. Because of the varied sleep schedules of the individual participants, each subject's hormone series time base was referenced with respect to their onset of Stage 2 sleep. Overall, there were no significant differences in cortisol or catecholamine patterns between women with IBS and controls, nor were there any group by time interactions. However, women with constipation-predominant IBS demonstrated significantly increased noradrenaline, adrenaline and cortisol levels throughout the sleep interval, and women with diarrhoea-predominant IBS were significantly lower on noradrenaline and cortisol. These results suggest that differences in neuroendocrine levels during sleep among IBS predominant bowel pattern subgroups may be greater than differences between IBS women and controls. Neuroendocrine profiles during sleep may contribute to our understanding of symptom expression in IBS.     

Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans

Ghrelin is an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor. It is hypothesised to play a key role in energy balance stimulating food intake and body weight. Besides GH-releasing hormone (GHRH) and somatostatin, it is thought to be a regulating factor of GH release. Ghrelin also appears to be involved in sleep regulation. We showed recently that ghrelin promotes slow-wave sleep and the nocturnal release of GH, cortisol and prolactin in humans. Similarly, promotion of non-rapid-eye-movement (NREM) sleep was reported in mice after systemic ghrelin. If ghrelin is a factor that induces and/or maintains sleep, it should be enhanced after a period of sleep deprivation (SD). To clarify this issue, nocturnal ghrelin, GH, ACTH and cortisol plasma concentrations were determined and simultaneously sleep electroencephalogram (EEG) was recorded (2300-0700 h) during sleep before and after 1 night of total SD in 8 healthy subjects. Compared to baseline, ghrelin levels increased earlier by a non-significant trend, already before the beginning of recovery sleep. Further a non-significant trend occurred, suggesting higher ghrelin secretion in the first half of the night. The ghrelin maximum was found significantly earlier after SD than at baseline. GH secretion during the first half of the night and total night after SD were elevated. ACTH and cortisol were also elevated, which was most pronounced during the second half of the night. No effects of SD on the time of the maximum were found for GH, ACTH and cortisol. The increase in ACTH after SD is a novel finding. Whereas the effects of SD on ghrelin levels were relatively weak, our findings are in line with the hypothesis that ghrelin is a sleep-promoting factor in humans. Ghrelin may be involved in sleep promotion after SD.     

Impact of sleep deprivation and subsequent recovery sleep on cortisol in unmedicated depressed patients

OBJECTIVE: One night of sleep deprivation induces a transient improvement in about 60% of depressed patients. Since depression is associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis, the authors measured cortisol secretion before, during, and after therapeutic sleep deprivation for 1 night. METHOD: Fifteen unmedicated depressed inpatients participated in a combined polysomnographic and endocrine study. Blood was sampled at 30-minute intervals during 3 consecutive nights before, during, and after sleep deprivation. Saliva samples were collected at 30-minute intervals during the daytime before and after the sleep deprivation night. RESULTS: During the night of sleep deprivation, cortisol levels were significantly higher than at baseline. During the daytime, cortisol levels during the first half of the day were higher than at baseline in the patients who responded to sleep deprivation but not in the nonresponders. During recovery sleep, cortisol secretion returned to baseline values. CONCLUSIONS: This study demonstrated a significant stimulatory effect of 1 night of sleep deprivation on the HPA axis in unmedicated depressed patients. The results suggest that the short-term effects of antidepressant treatments on the HPA axis may differ from their long-term effects. A higher cortisol level after sleep deprivation might transiently improve negative feedback to the hypothalamus or interact with other neurotransmitter systems, thus mediating or contributing to the clinical response. The fast return to baseline values coincides with the short clinical effect.     

Clinical and biological correlates of sleep deprivation in depression

Sleep deprivation is reported to have therapeutic effectiveness in depressive illness. Furthermore, the response to sleep deprivation has important research implications. Recent conceptual advances, resulting in increased understanding of the role of abnormal biological rhythms and neurotransmitter function of the pathophysiology of affective disorder, highlight the future role of sleep deprivation in the research and treatment of these disorders.