Estrogen replacement therapy moderates the sleep disruption associated with nocturnal blood sampling.

STUDY OBJECTIVES: To determine whether chronic oral estrogen replacement therapy (ERT) (1) improves the sleep of older, non-symptomatic postmenopausal women; and (2) reduces the sleep disruption associated with a stressor (frequent remote nocturnal blood-sampling through an intravenous catheter). DESIGN: Descriptive, cross-sectional, secondary analysis of a larger study. SETTING: The General Clinical Research Center at the University of Washington Medical Center. PARTICIPANTS: Women aged 57-80 (mean age = 70) at least 5 years past menopause were recruited from the community. Hot flashes and significant sleep difficulties were exclusion criteria. The ERT group (n=37) consisted of women on chronic oral ERT for > or = 2 years. The NERT group (n=56) consisted of women not using estrogen (NERT) for > or = 2 years. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Following an adaptation night, polysomnographic measures were collected for 2 consecutive nights. A blood sample was collected every 20 minutes for the last 24 hours (including Night 2), through an intravenous catheter. The only group difference in sleep on the baseline (non-catheter) night was that NERT women had a shorter sleep latency. Sleep on the catheter night was characterized by increased wakefulness, longer sleep latency, and decreased REM sleep for both groups relative to the baseline. However, the impact of nocturnal blood sampling was much greater for NERT than for ERT women: they experienced significantly greater percent changes in more sleep-wake variables, particularly slow-wave sleep (SWS). CONCLUSIONS: In this cross-sectional study, the use of chronic oral ERT was associated with little effect on the sleep of older postmenopausal women not experiencing hot flashes, except in the presence of a challenge to sleep. ERT ameliorated the disruptive effect of nocturnal blood sampling on both objectively assessed and subjectively assessed sleep.

Treating age-related changes in somatotrophic hormones, sleep, and cognition.

Many of the body's systems that function to maintain optimal health and well-being decline with advancing age. Aerobic capacity, muscle mass, and strength all progressively decline. Significant sleep disturbances are associated with increases in morbidity and mortality. Cognition declines, impacting an older individual's ability to function independently. Interventions that could at least stabilize or possibly improve functional capacity, sleep quality, and cognitive function have the theoretical potential to prolong an older individual's ability to live independently, and interest in their possible utility is growing rapidly. One such intervention may be stimulation of the "somatotrophic" axis via growth hormone-releasing hormone (GHRH). Here we review the evidence for such somatotrophic interventions. We also report preliminary findings on the effects of chronic GHRH treatment on the somatotrophic hormones, body composition, functional status, sleep, and cognitive function of healthy older men and women from two major GHRH intervention studies, one recently completed and the other ongoing.

Thyroid hormones: positive relationships with cognition in healthy, euthyroid older men.

BACKGROUND: Although the association of clinical hypothyroidism with cognitive deficits is well known, the cognitive effects of thyroid hormones in euthyroid subjects are less studied and understood. The purpose of this study was to examine thyroid-cognition relationships in healthy, euthyroid older men. METHODS: We examined healthy men (N = 44, mean age = 72), excluding clinically hypothyroid/hyperthyroid or diabetic/hyperglycemic subjects and those with dementia, depression, CNS medications, or recent illness. Plasma samples obtained across a 24-hour period were pooled, then assayed for total thyroxine (TT4), total triiodothyronine (TT3), and T3 resin uptake. Free thyroxine index (FT4I) was calculated. A broad cognitive battery (including the Wechsler Adult Intelligence Scale-Revised [WAIS-R], the Dementia Rating Scale [DRS], and the Rivermead Behavioral Profile [PROFILE]) was administered to all subjects. RESULTS: Regression analyses controlling age and education showed TT4 and FT4I to have significant positive relationships with measures of overall cognition; TT4 accounted for 8% to 12% of the variance in omnibus cognitive measures such as WAIS Performance, WAIS Verbal score, and GLOBAL cognitive scores. CONCLUSIONS: Our findings suggest that within "normal" range of variation in plasma thyroid hormones, TT4 but not T3 positively associates with general cognition in healthy elderly men.

Reproductive hormones, aging, and sleep.

Insomnia, disturbed sleep, and fatigue are among the most frequent health complaints of perimenopausal women. Estrogen replacement therapy (ERT) usually improves sleep, most likely by alleviating vasomotor symptoms. However, sleep difficulties are not restricted to the perimenopausal period. Older postmenopausal women typically experience longer latencies to sleep onset, increased nocturnal waking, increased fragmentation of sleep, and less slow wave (deep) sleep. These sleep changes in older women may be partially related to the postmenopausal profile of sex steroid hormones. Estrogen has powerful effects on several biological factors that directly influence sleep, including body temperature regulation, circadian rhythms, and stress reactivity. The link between sleep disturbance in older women and these CNS effects of estrogen is largely speculative at present. This article reviews what is known, what remains to be addressed, and some clinical implications.

Growth hormone in postmenopausal women after long-term oral estrogen replacement therapy.

Studies of estrogen effects on growth hormone (GH) and its pulsatile release in postmenopausal women have typically utilized estrogen replacement therapy (ERT) of relatively short duration (days to weeks). The purpose of this study was to compare GH measures from healthy postmenopausal women who were on oral ERT for 3 years or more (n = 24; mean ERT duration = 16.1 years) with women not on ERT (NERT; n = 40). Blood samples were drawn remotely every 20 min for 24 h and then analyzed for mean 24-h GH, mean GH during sleep, and mean 24-h insulin-like growth factor-I (IGF-I). GH peak analyses were also performed. Mean 24-h GH and GH during sleep were significantly higher and IGF-I was significantly lower in ERT women compared with NERT women. In addition, use of long-term ERT was associated with more GH peaks relative to women not on ERT, but no change in GH peak amplitude or area. GH was not related to age in either group. GH was strongly and negatively correlated with measures of adiposity in NERT women but not in ERT women. In conclusion, long-term oral ERT is associated with increased circulating GH and decreased IGF-I levels, even after many years of treatment.

Successful 6-month endurance training does not alter insulin-like growth factor-I in healthy older men and women.

BACKGROUND: Lean body mass, strength, and endurance decline with advancing age, changes paralleled by declines in anabolic hormones, including growth hormone (GH) and insulin-like growth factor-I (IGF-I). Acute exercise has been shown to stimulate the GH/IGF-I axis, and long-term exercise increases GH. This study examined the effect of endurance training on IGF-I in healthy older men and women. METHODS: Thirty-one healthy older men (66.9 +/- 1.0 yrs, mean +/- SEM) and 21 healthy older women (67.1 +/- 1.7 yrs) were randomized to either 3d/wk, 6-month endurance (ET3) or stretching/flexibility (SF3) protocols. Another group of 15 healthy older men (69.0 +/- 1.3 yrs) participated in a more intensive 5d/wk, 6-month endurance protocol (ET5). Before and after training, subjects were weight stabilized and participated in maximal exercise tolerance testing, body composition assessment, and fasting blood sampling. RESULTS: ET3 training resulted in a significant increase (14%) in maximal aerobic power (VO2max), significant decreases in body weight (BW), fat mass (FM), and waist/hip ratio (WHR), and a significant increase in fat-free mass (FFM). No significant VO2max or body composition changes were observed in the SF3 group. For the ET5 group, a significant increase (22%) in VO2max and significant decrease in BW, FM, and WHR were observed. No significant changes in IGF-I were observed for any of the three groups. Pre- versus post-training IGF-I values were very stable (r = .86, p < .001) across subjects. CONCLUSIONS: Within-subject basal levels of IGF-I in healthy seniors were extremely stable between pre- and post-training assessments. Two endurance training protocols of magnitudes sufficient to significantly increase aerobic capacity and decrease measures of body adiposity did not significantly increase basal levels of IGF-I in healthy older men and women.

Objective sleep quality of healthy older men and women is differentially disrupted by nighttime periodic blood sampling via indwelling catheter.

Elucidation of sleep-endocrine relationships requires frequent blood sampling during sleep recording. Unfortunately, such sampling can itself affect sleep and indirectly, hormonal patterns. We examined the effect of catheterization and frequent nighttime blood sampling on the sleep of a large sample of healthy older men and women. A total of 113 healthy older [69.1 +/- 0.6 years, mean +/- standard error of the mean (SEM) adults (68 women and 45 men) were studied. Following an adaptation night sleep was recorded during an undisturbed night and a night of periodic blood sampling via i.v. catheter. Lights out and lights on were significantly delayed and advanced, respectively, on the catheterization night, resulting in a significantly shorter time in bed (TIB). Total sleep time and sleep efficiency were significantly reduced, and sleep latency, total wake time and the number of awakenings from sleep of > or = 1 minute were significantly increased. Rapid eye movement (REM) sleep percentage of TIB was significantly reduced. Stages 3/4 sleep [slow wave sleep (SWS)] percentage of TIB was significantly reduced, as was total delta energy during SWS. With the exception of total sleep time and sleep latency, all sleep-wake and delta variables were significantly correlated between nights. This was particularly the case for SWS and the delta energy variables. When examined separately by gender, both men and women showed significant catheter-based sleep disturbance. However, SWS and delta energy measures in men were unaffected by catheterization. The data clearly demonstrate that both the sleep maintenance and sleep architecture of healthy older men and women are significantly impacted by nighttime blood sampling procedures. Of the various measures examined here, SWS measures appear to be the least disrupted, particularly in men. These findings need to be taken into account in any study examining sleep-endocrine relationships utilizing older subjects.

Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men.

BACKGROUND: Sleep quality declines with age, with less time in deep or slow wave sleep (SWS) and reduced amplitude of the delta waves that characterize it. Age-related declines also occur in lean body mass, growth hormone (GH), and insulin-like growth factor 1 (IGF-1). These changes in sleep quality and anabolic status may be related, as administration of GH or growth hormone releasing hormone (GHRH) can enhance SWS and decrease awakenings in young men. Here we examine the relationship between plasma IGF levels and delta sleep quality in older men. METHODS: The sleep EEG of 30 healthy elderly men (64 +/- 6 yrs; range 50-75) was recorded on the second of 2 consecutive nights. Plasma samples were drawn within 3 weeks of EEG recording, and IGF levels were assayed by RIA after acid extraction. RESULTS: IGF explained 28% (semi-partial correlation coefficient r = .53; p = .003) of the variance in average delta energy per epoch of SWS, after age-related variance was removed. Higher IGF was associated with higher average delta energy. Similar results were obtained for total delta energy during SWS (r = .37, p = .04) 4nd time spent in SWS (r = .42, p = .02). Other measures of sleep quality (e.g., wakefulness, REM sleep) were not correlated with IGF. The IGF delta relationship was minimally influenced by moderator variables such as thyroxine (T3, T4), and/or body mass index (BMI). CONCLUSION: We conclude that age-adjusted IGF levels in healthy senior men co-vary significantly with SWS and the delta energy that characterizes it.

A note on the night-to-night stability of stages 3 + 4 sleep in healthy older adults: a comparison of visual and spectral evaluations of stages 3 + 4 sleep.

Night-to-night variability in the minutes of slow-wave sleep (SWS: combined minutes of stages 3 and 4 sleep) was examined for 50 healthy adults: 23 women (56-82 years old) and 27 men (54-74 years old). Visually rated SWS was more variable night to night than computer-evaluated SWS using power spectral techniques. The night-to-night correlation of the visually rated SWS was 0.61. The night-to-night correlation of the spectrally evaluated SWS was 0.91.

C STAGE, automated sleep scoring: development and comparison with human sleep scoring for healthy older men and women.

Using the sleep records of 200 men and women (age 55-85 years), we have developed a human-assisted computer scoring system, C STAGE. The system can have many applications, including quantitative electroencephalographic (EEG) analysis during specific stages of sleep. C STAGE classifies sleep/wake stages using power spectral analysis and other techniques applied to one channel of EEG data. Here we report comparability data between C STAGE- and human-rated sleep-stage scoring using Rechtschaffen and Kales criteria for 70 normal subjects (a subset of the 200). Because the method was developed using these subjects, we also report comparability data for an independent validation sample of 45 normal older men and women. For waking measures, sleep stages 3 and 4, and total sleep time, C STAGE yielded ratings comparable with the human rater (r = 0.73-0.91; p < 0.001). For sleep stages 1 and 2 and REM sleep, C STAGE correlated less well with human ratings (r = 0.59-0.81; p < 0.001). Overall, these correlations compare well with other currently available computer stage-scoring methods. Epoch-by-epoch comparisons in the validation sample revealed a mean proportion of agreement of 0.74 and a mean Kappa coefficient of 0.57, indicating the two methods provide reasonable agreement on an epoch-by-epoch basis. We conclude that C STAGE is a valid sleep/waking scoring system for healthy older adults.

Predicting long-term outcome in individuals at risk for Alzheimer's disease with the Dementia Rating Scale.

The Dementia Rating Scale, previously shown to be sensitive to dementia progression, was used to differentiate among normal control subjects, patients with Alzheimer's disease (AD), and those judged to be at risk for AD on the basis of subclinical memory impairment. The memory scale of the Dementia Rating Scale predicted with 93% accuracy which at-risk individuals would develop AD at 4- to 6-year follow-up.

Major unipolar depression and mild Alzheimer's disease: differentiation by quantitative tonic REM EEG.

In a previous report, tonic REM sleep epochs from the all-night sleep EEG were processed and analyzed to produce a diagnostic that discriminated mild Alzheimer's disease (AD) from cognitively unimpaired control subjects. Here, we examine the specificity of this diagnostic in distinguishing depression from AD. Twenty-four cognitively unimpaired seniors (aged 63 +/- 1.3) with major depressive disorder (unipolar) were monitored for all-night EEG in a manner identical to that used in our previous report. Tonic REM EEG epochs were preconditioned, spectrally analyzed and compared with known populations of control and AD EEG spectra. Instances when a given depressed subject's spectra fell within spectral zones unique to control or AD populations formed a diagnostic score (control, AD, neither of these). Diagnostic scores correctly identified 88% (21/24) of cognitively unimpaired seniors with major depressive disorder (unipolar). This can be compared with 89% (31/35) of mild AD subjects and 100% (43/43) of control subjects correctly identified in our previous report. This diagnostic also correctly classified as to eventual clinical AD/not AD outcome 8 subjects with both major depressive disorder and validated memory complaints. The diagnostic discrimination of AD is based on the fact that AD subjects have significantly less tonic REM EEG energy in the 13-30 Hz frequency range and more in the 1-10 Hz range than control or depressed subjects, as shown in conventional spectral analysis.

Quantitative analysis of the EEG during tonic REM sleep--methodology.

Frequency and amplitude characteristics of the clinical (waking) electroencephalogram (EEG) can be diagnostically useful in neuronal degenerative disorders such as Alzheimer's or other cortical dementias. However, interpretation of the clinical EEG may be limited by many factors, including movement and muscle artifacts and uncontrolled variations along the alert/drowsy continuum. Moreover, the clinical EEG involves subjective judgement by experts whose opinions often differ. In an effort to address these problems, we have developed a computer-automated technology that examines the digitized, all-night sleep EEG for frequency and amplitude characteristics of potential diagnostic relevance to Alzheimer's dementia. Robust time series analysis techniques and a modified power spectral analysis (Z-spectra) are used to suppress artifactual information and to automatically select samples of tonic REM sleep EEG. The spectra (amplitude vs. frequency relationship) of this specific EEG state is then assessed for diagnostically relevant information.

EEG markers of early Alzheimer's disease in computer selected tonic REM sleep.

All night sleep/wake EEGs were examined for diagnostic features sensitive to early Alzheimer's disease (AD) using computer automated techniques. Thirty-nine mild AD patients and 43 normal controls underwent 9 h of EEG recording in the sleep laboratory. All-night EEGs were screened for ideal, low artifact tonic REM sleep using autoregressive and power spectral techniques. The frequency spectra during tonic REM sleep revealed a significant shift towards slower wave forms in AD vs. control subjects. Beta (greater than 12 Hz) was reduced and theta and delta (2-8 Hz) increased in AD compared to control groups. This frequency shift was demonstrated by several analytic techniques, including binned spectral energies and unique zones in the frequency spectra. Discriminant analyses using optimal binned EEG variables correctly classified 74% of AD and 98% of control subjects, and unique zone scores correctly classified 92% of AD and 95% of control subjects, indicating that these sleep EEG changes are apparently predictive of AD status.

Entrained body temperature rhythms are similar in mild Alzheimer's disease, geriatric onset depression, and normal aging.

Sleep-wake rhythms are known to be altered in Alzheimer's disease (AD) and in unipolar depression. Other evidence suggests that the circadian rhythm in body temperature may be altered as well. Entrained circadian temperature rhythms were measured in healthy elderly men and women, as well as in men and women suffering from unipolar depression or mild AD, to examine this possibility. There were no differences in the temperature rhythm characteristics of subjects with depression or AD compared with healthy control subjects. However, gender differences were observed. Female control subjects showed a larger amplitude, higher peak temperature, and earlier acrophase relative to male control subjects. Also, the mesor of female AD subjects was higher than for male AD subjects. These results are discussed in the context of the widely varying subject populations used in other studies.

Healthy elderly women and men have different entrained circadian temperature rhythms.

Body core temperature was measured in healthy elderly men and women under entrained conditions. Female subjects showed a larger amplitude and a higher peak temperature than male subjects. In addition, acrophase was advanced for females by an average of 49 minutes. Variability in acrophase was greater for males than females. This pattern of gender differences varies considerably from the pattern others have observed in young subjects, suggesting that aging may affect the circadian timing system of males and females differently.

The early ontogeny of sodium appetite in spontaneously hypertensive vs. normotensive rats.

Rats of various strains differ widely in their appetite for sodium. For example, the Okamoto-Aoki spontaneously hypertensive rat (SHR) exhibits a much greater salt appetite than its normotensive control strains. Developmental observations of salt appetite in this strain have been collected only for rats at or above weanling age. In this experiment, the salt appetite of the SHR was compared with that of normotensive Sprague-Dawley and Wistar-Kyoto rats, at 3, 6 and 12 days after birth. The results show that the increased salt appetite of the SHR is a fundamental behavioral trait that appears very early in life. This observation is consistent with a defective central angiotensin system in SHR rats.

Elevated salt appetite and brain binding of angiotensin II in mineralocorticoid-treated rats.

Angiotensin II (Ang II) and aldosterone levels increase with sodium deficiency, promoting sodium conservation and arousing a salt appetite in rats. The mechanism(s), by which these two hormones interact to produce salt appetite is not known. The experiments reported here tested the possibility that increased mineralocorticoids change the number and/or affinity of Ang receptors in the brain. Rats were given a series of deoxycorticosterone acetate (DOCA) injections (500 micrograms/day, s.c., for 4 days) which are known to produce a salt appetite when given in conjunction with an intracerebroventricular injection of Ang. The binding of 125I-Ang II to membranes prepared from the septal-anteroventral third ventricular region was then examined. DOCA treatment resulted in a significant increase in the number of Ang binding sites (Bmax) with no change in binding affinity (Kd). The binding of 125I-Ang II was then investigated in membranes prepared from 12 other brain regions as well as the pituitary and adrenal gland, showing that the increase in binding capacity occurred in only a few specific brain regions. A third experiment verified that the DOCA treatment used here was sufficient to arouse a salt appetite when combined with a single intracerebroventricular injection of Ang II. The mechanism that underlies the production of salt appetite by aldosterone and Ang II may at least partially consist of mineralocorticoid-induced increases in the number of Ang receptors in discrete brain regions.

The ontogeny of salt preference in rats.

Many mammals eat salt irrespective of need. This behavior, called salt preference or appetite, is studied primarily in adults. Little is known about its ontogeny. In these experiments, 3-18-day-old rat pups were offered saline, quinine, or ammonium chloride solutions by infusion through an anterior oral catheter, and intake was measured. At 6-18 days, pups showed the inverted U-shaped preference-aversion curve for NaCl that is characteristic of adult rats. Thus, rats express a preference for salt at a very early age. However, the curves were broader than the typical adult curve and were shifted along the concentration gradient in an age-related fashion. Consumption of quinine and ammonium chloride showed similar age-related changes. These changes may reflect the postnatal timing of the development of the rat gustatory system.

Interference with central actions of angiotensin II suppresses sodium appetite.

We have proposed that sodium appetite is aroused by a synergy in the brain of angiotensin II and aldosterone. This hypothesis was tested with 1) chronic intracerebroventricular infusion of captopril, which blocks the conversion of angiotensin I to angiotensin II, or 2) intracerebroventricular injection of eight-substituted analogues of angiotensin II, which block its receptors. Both treatments resulted in a suppression of the sodium appetite induced by sodium deficiency. The suppression was specific for the deficiency-induced appetite, because spontaneous ingestive behaviors were not changed nor was sodium excretion. In addition, the rats continued to express a sodium appetite aroused by pharmacological doses of deoxycorticosterone acetate when they received the highest dose of chronic intracerebroventricular captopril. These results offer compelling evidence for the idea that angiotensin II action in the brain is necessary for expression of sodium appetite.