Influence of partial sleep deprivation on the secretion of thyrotropin, thyroid hormones, growth hormone, prolactin, luteinizing hormone, follicle stimulating hormone, and estradiol in healthy young women

153

Psychiatr_v Research. 48: I53- 178 Elsevier

Influence of Partial Sleep Deprivation on the Secretion of Thyrotropin, Thyroid Hormones, Growth Hormone, Prolactin, Luteinizing Hormone, Follicle Stimulating Hormone, and Estradiol in Healthy Young Women Andreas Baumgartner, Margot Dietzel, Angel Campos-Barros, Klaus-Jiirgen Ulrich Mannsmann Received

May 26, 1992; revised

version received

Bernd Saletu, Rainer Wolf, Grlf, Irene Kiirten, and

December

23, 1992; accepted

January

7, 1993.

Abstract. The influence of partial sleep deprivation during the second half of the night on the secretion of thyroid stimulating hormone (TSH), thyroxin (T,), free T, (ff,), triiodothyronine (T,), prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) was investigated in 10 healthy young women. Blood samples were drawn at hourly intervals over a 64-hour period (i.e., 3 consecutive days and nights). During night 2, all subjects were awakened at 1:30 a.m. During partial sleep deprivation, TSH concentrations increased significantly and remained elevated throughout the following day. Levels of T,, ff,, and T, were enhanced during the partial sleep deprivation hours only, and changes in these hormones seemed to be independent of TSH. PRL levels decreased, LH and E, concentrations increased, and GH and FSH secretion remained unchanged during partial sleep deprivation. This pattern of change of different endocrine axes during partial sleep deprivation resembles those seen after total sleep deprivation, suggesting that similar neurochemical changes are induced by both forms of antidepressant therapy. The late evening GH peak occurred almost exclusively before the onset of sleep. Partial sleep deprivation did not influence the chronobiological profiles of any of the hormones investigated. The chemical changes underlying these alterations are speculated to involve enhancement of central norepinephrine and dopamine activity with a concomitant increase in the activity of the sympathetic nervous system. Key Words. Thyroid stimulating hormone, thyroxin, triiodothyronine, Pflug and Tiille (1971) were the first to report the antidepressant night’s sleep deprivation. Numerous studies have since replicated

Andreas Baumgartner, M.D., and Angel Campos-Barros, Diplom-Biologe, Psychiatrische Klinik und Poliklinik, Freie Universtitat Berlin; Klaus-Jiirgen

gonadotropins.

effect of a total their finding (for

are on the staff of the

Graf, M.D., and Irene Ktirten (Laboratory Assistant) are on the staff of the Medizinische Klinik und Poliklinik (Hormone Research Laboratory) of the Klinikum Rudolf-Virchow (Charlottenburg), Freie Universitat Berlin; and Ulrich Mannsmann, Ph.D., is on the staff of the Institut fur Medizinische Statistik, Klinikum Steglitz, Freie Universtitat Berlin. Margot Dietzel, M.D., Bernd Saletu, M.D. (Professor of Psychiatry), and Rainer Wolf, M.D., are on the staff of the Psychiatrische Klinik of the University of Vienna, Austria. (Reprint requests to Dr. A. Baumgartner, Psychiatrische Klinik, Eschenallee 3, D-14050 Berlin, Germany.) 0165-1781/93/$06.00

@ I993 Elsevier Scientific

Publishers

Ireland

Ltd

154

reviews, see Gillin, 1983; Kuhs and Tiille, 1991). More recently, Schilgen et al. (1976) and Schilgen and Tiille (1980) also reported an antidepressant effect of sleep deprivation during the second half of the night that did not differ significantly from that seen after total sleep deprivation. The antidepressant properties of partial sleep deprivation have also been observed by Philipp (1978), Philipp and Werner (1979) and Baxter et al. (1986). However, improvement was only substantial if the patients were permitted to sleep during the first half of the night rather than the second (G&e and Tolle, 198 1). The mechanisms of action of both total and partial sleep deprivation are as yet unknown (Kuhs and Tblle, 1991). Because sleep deprivation induces profound changes in the secretory patterns of different endocrine axes in humans, the investigation of hormone secretion could provide some insight into the neurochemical alterations that occur during sleep deprivation. Endocrinologists were the first to report evidence that the endocrine profiles of many hormones-for example, thyroid stimulating hormone (TSH), cortisol, growth hormone (GH), and prolactin (PRL)-are altered during total sleep deprivation. For a brief review of the literature, see Table la. This and the observation that depressed patients show similar changes in endocrine secretory patterns to those seen in healthy subjects have led to a growing interest of psychiatry in total sleep deprivation (for a review, see Table 16). Specifically, an increase in the TSH levels of healthy subjects during total sleep deprivation has been reported by five studies, and in those of depressed patients in another six studies (Table 1). Almost all studies reported an earlier nocturnal increase in cortisol levels. The reports of a decrease in nocturnal GH secretion in normal subjects seem to be consistent. However, three of the four studies investigated only three to five healthy subjects. The results for PRL, which was found to decline during total sleep deprivation, were also obtained only in very small samples. With regard to thyroid hormones, increases in thyroxin (T4) and triiodothyronine (T,) levels have been found in two groups of normal subjects and four groups of psychiatric patients. To our knowledge, the effects of total sleep deprivation on luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) have been investigated in healthy adults only once (Akerstedt et al., 1980) and were, like our own preliminary results in depressed patients (Baumgartner et al., 19906) based on two blood samples or a small number of subjects. With respect to possible correlations between changes in hormone secretion and antidepressant response to sleep deprivation, we have reported a significant correlation between increases in TSH secretion and antidepressant effect in two of our studies (Baumgartneret al., 1990h; Baumgartner and Sucher, 1990). However, other studies failed to replicate this finding (Kasper et al., 1988; Sack et al., 1988; Kaschka et al., 1989; Baumgartner et al., 1990a, 1990~). Furthermore, responders to total sleep deprivation showed earlier nocturnal increases in cortisol levels than nonresponders (Baumgartner et al., 1990~). Antidepressant response and endocrine changes during sleep deprivation probably occur at different anatomical levels, with presumably different degrees of disturbance in the respective receptor systems. The possibility cannot therefore be excluded that the two phenomena have common underlying neurochemical mechanisms, despite the fact that no significant correlations have as yet been demonstrated. Studies on changes in biological

Table 1a. Neuroendocrine investigations during total or partial sleep deprivation: Studies in healthy subjects n Parker et al. (1976)

10

Parker et al. (1987)

4

Sack et al., (1988)

8

Brabant et al. (1990)

6

Palmblad et al. (1979)

10

Gillberg & Wkerstedt (1981)

12

Weitzman et al. (1983)

10

Parker et al. (1969)

5

Parker et al. (1979)

4

Minuto et al. (1981) Strassman

(1987)

et al. (1987)

T3

(Pulse frequency -,

t t

t t

ff4

ff3

amplitude

t

t

rT3

Cortisol

GH

5 12

LH

FSH

E2

T

t

(During partial sleep deprivation)

1 1 1

1 -

(At 8 a.m., basal and after DMI)

1

11 5

PRL

I)

t t

3

Kapen et al. (1974) et al. (1980)

T4

10

Sassin et al. (1973) Akerstedt

1 t t t t

6

Saletu et al. (1986)

Calil 8 Zwicker

TSH

I (Blood samples twice before and after a 48-hour sleep deprivation)

_

(In pubertal boys) _

1

Note. TSH = thyroid stimulating hormone. T, = thyroxin. Ts = triiodothyronine. R, = free T4. fig = free T3. GH = growth hormone. PRL = prolactin. LH = luteinizing hormone. FSH = follicle stimulating hormone. E, = estradiol. T = testosterone.

Table 1b. Neuroendocrine investigations during total or partial sleep deprivation: Studies in depressed subjects n Kasper et al. (1988) Sack et al. (1988) Kaschka

8

et al. (1990b)

14-50

T4

T3

fT4

fT3

rT3

Cortisol

GH

PRL

LH

FSH

E2

T

I

t

32

et al., (1989)

Baumgartner

TSH

(Rapid cycling bipolar patients only)

-

t t

f t

t t

1 -

1 t

t t

t -

t t

-

-

t

t

1

(Two blood samples only) Baumgartner et al. (199Oc)

14

Baumgartner et al. (1990a)

25

Yamaguchi et al. (1978)

20

Gerner et al. (1979)

t -

9

Gotze & Tolle (1987)

81

Baumgartner

15

& Sucher (1990)

t t

(4 hourly cortisol determinations

t

-

t

Note. TSH = thyroid stimulating hormone. T4 = thyroxln. Ts = trilodothyronlne FSH = folkle stlmulattng hormone. Ep = estradlol. T = testosterone.

-

in urine

t

fT, = free T,. ff,

(Paiial sleeide

t t t

pr ivion)

(n ’

6,

-

(In responders) (In responders) (Total sleep deprivation in bed)

= free T,. GH = growth hormone. PRL = prolactln. LH = luteinizing hormone.

157 parameters during partial sleep deprivation are particularly rare. We have found only two publications on this subject: (1) a brief report by Joffe et al. (1984) to the effect that nonsuppression in the dexamethasone suppression test and normal thyrotropin releasing hormone (TRH) response to TSH were associated with positive mood response to partial sleep deprivation; and (2) our own recent report of increases in TSH, T,, and free T, (fT,) levels in depressed patients after partial sleep deprivation (Baumgartner et al., 1990a). As yet, only one study has investigated the influence of partial sleep deprivation on hormone secretion (cortisol) in normal subjects: Saletu et al. (1986) reported an earlier nocturnal rise in cortisol during a night of sleep deprivation than during a night of sleep in healthy subjects. Before endocrine profiles and possible disturbances of these profiles can be examined during partial sleep deprivation in depressed patients, it is necessary to have a detailed understanding of the physiological events of endocrine secretion during partial sleep deprivation in healthy subjects. If only one hormone is investigated, the scope for interpretation of relationships between any changes in its secretory profile and underlying changes in neurochemical activity in the central nervous system (CNS) is limited, as each hormone is usually regulated by many different neurotransmitters. Simultaneous investigation of several endocrine axes subject to regulation by different central mechanisms might therefore provide greater insight into the neurochemical changes that occur during total sleep deprivation. Thus, on the basis of the results we obtained in depressed patients when we measured multiple hormonal axes during total sleep deprivation (elevated TSH, cortisol, and GH but decreased PRL concentrations), we hypothesized that total sleep deprivation induces enhanced noradrenergic and dopaminergic activity, which in turn both alleviates depressive symptoms and causes alterations in the secretion of the above-mentioned hormones (Baumgartner et al., 1990~). Finally, it has been postulated that depressed patients show a phase advance of a so-called “strong oscillator,” which drives the diurnal rhythms of cortisol, rapid eye movement (REM) sleep, and body temperature, in relation to a “weak oscillator,” which drives the sleep/wake cycle (Wehr and Wirz-Justice, 1981; Goodwin et al., 1982). Consequently, the effect of antidepressant drugs and sleep deprivation has been explained by a phase advance of the weak oscillator. For example, the earlier waking during partial sleep deprivation has been claimed to resynchronize both oscillators (Wehr and Wirz-Justice, 1981; Goodwin et al., 1982). In light of these hypotheses, it seemed interesting to investigate whether partial sleep deprivation influences the chronobiological rhythms of different hormones. For all these reasons, we decided to investigate the influence of partial sleep deprivation on the secretion of the nine different hormones in healthy subjects over a 68-hourperiod. The aims of the present studies are therefore: (1) to learn more about the effects of partial sleep deprivation on normal subjects, particularly on endocrine axes that have not yet been sufficiently investigated (e.g., the hypothalamicpituitary-gonadal [HPG] axis); (2) to measure hormones of different endocrine axes simultaneously to gain more insight into changes in CNS physiology during sleep deprivation; (3) to investigate whether endocrine changes following partial sleep deprivation differ from those observed after total sleep deprivation; and (4) to

158 determine whether hormone secretion

partial sleep deprivation in healthy subjects.

induces

chronobiological

alterations

in

Methods Subjects. The study was performed as a cooperative undertaking between the psychiatric departments of the University of Vienna and the Free University of Berlin. The investigation of the volunteers was carried out in Vienna, while the determinations of the hormone concentrations and the analysis of the data were done in Berlin. Ten healthy female volunteers (mean age: 24.2 years, range: 21-29 years; mean weight: 60.1 kg, range: 50-72 kg) were included in the study. All the women were in the early follicular phase of their menstrual cycles (days 3-5). They were not permitted to take any psychotropic medication, contraceptives, or any other drugs for 3 months before the study or during the study period. Women with a current or past history of psychiatric disease or substance abuse were not included in the study. The subjects spent a total of 5 days on a general psychiatric ward. The first 2 days served as a phase of adaptation to the study conditions and are referred to here as day -2 and day -I. During the last 3 days of the study (referred to as days l-3), blood samples were collected for hormone determinations. Over the 5 days of the observation period, meals were served at 7 a.m., 9 a.m., 12 p.m., and 5 p.m. No coffee or tea was allowed, and ail subjects were nonsmokers. They were permitted to walk around freely in the psychiatric department. No naps were taken during the day. The subjects were allowed to sleep between IO:30 p.m. and 6:30 a.m. During this period, all-night polygraphic recordings were carried out between IO:30 p.m. and 6:00 a.m. The electrodes were attached according to the international IO/ 20 system. In addition to the electroencephalographic channels C4-Al, 02-A] and 02-Cz, electrooculographic (EOG) channels and the submental electromyogram (EMG) were recorded on an eight-channel R-61 1 Beckman polygraph. Four channels (02-Cz, EMG, and 2 EOG) were also recorded on a Hewlett-Packard 3968 tape recorder. Thirty-second epochs were scored according to the criteria of Rechtschaffen and Kales (1968) as has recently been described in detail elsewhere (Dietzel, 1989). Partial sleep deprivation led to an enhancement of total sleep time (i.e., a decrease in hours spent awake and an increase in sleep efficiency and total sleep time). Less time was spent in stage I, whereas time in stage 2 and REM sleep increased. Finally, sleep latency was also reduced (Dietzel, 1989). After the first 2 days (day -2 and day -I), blood samples were drawn over a period of 3 days (days l-3). The samples were collected hourly through an intravenous catheter (at night, the catheter was passed through a hole in the wall and the blood was collected in the next room). The first blood sample was taken at 7 p.m. on day I, the last at 12 noon on day 3, (i.e., 65 samples were collected from each subject). All hormones were measured in duplicate with commercially available kits: TSH (IRMA kit, Henning, Berlin), T,. ff,, T, (RIA kits, Henning, Berlin). LH, FSH, E,, PRL, and GH were determined using the Maya clone kits from Serono. Details on the sensitivities of the kits used and the interassay coefficients of variation measured by our laboratory have been provided previously (Baumgartner et al., 1990h, 1990~). We attempted to analyze the data only with nonparametric methods, which we considered sufficient to demonstrate the effects of partial sleep deprivation on hormone secretion. We chose this procedure because our data did not fulfill the requirement of homogeneity of variance necessary for multivariate analysis of variance. Main effects on the hormone secretion at the individual measuring times during the 3 days were calculated by Friedman’s test. Individual comparisons (day I vs. day 2, day 2 vs. day 3, and day I vs. day 3) were performed using the Wilcoxon matched pairs signed rank test. To compare the results for the period of partial sleep deprivation with those for the respective periods on days 1 and 3, we used a method of comparing patterns of relationships. This “pattern test” is demonstrated by the following example for the hormone ff,. With the aim of showing that partial sleep deprivation stimulates secretion of ff,, we examined whether the following condition was met at the relevant measuring times: X: < X: and X: < X:, where i = 2,3,4,5 and 6 a.m. and e is

159 the secretion of ff, determined at Time i during Night k. If both relationships were obtained simultaneously at Time i, we rated this as 1; if they were not, we rated this as 0. By this means, we obtained a pattern of 5 digits for each patient (O-l). If partial sleep deprivation stimulates secretion of ff,, the typical pattern observed will consist mainly of “1”s. The object of this statistical procedure is to reject the hypothesis “partial sleep deprivation does not stimulate secretion of ff4,” thus confirming the alternative hypothesis “partial sleep deprivation stimulates secretion of ff,.” The corresponding statistical hypothesis was “the probability of observing a pattern with more than 2 zeroes is at least O.S.“The results for our 10 subjects were as follows: Pattern Frequency

00000 1

01110 1

01111 2

10111 2

11111 3

As an expression of the hypothesis “partial sleep deprivation does not stimulate the secretion of ff,,” the above observation has a probability < 0.05, which shows that partial sleep deprivation does stimulate secretion of ff,. The same technique was applied to the data for T, and T,. For PRL, we modified the null hypothesis and alternative hypothesis so as to show the fall in the secretion of PRL during partial sleep deprivation. The “pattern test” permits comparison of hormone secretion in different situations. It was also applied for comparison of daytime levels with nocturnal levels and to show the elevation of TSH concentrations throughout the day after partial sleep deprivation. For comparison of diurnal and nocturnal hormone secretion on days 1 and 3, two different phases were also compared with each other by means of the sign test. Hormone secretions determined between 11 p.m. and 6 a.m. (sleep) were compared with those found between 7 a.m. and 10 p.m. Significance was defined as ap value < 0.05.

Results TSH.

Fig.

significant

1 shows that partial rise in TSH concentrations

sleep deprivation had already induced a by 2 a.m. Friedman’s test showed main effects

Fig. 1. Mean thyroid stimulating hormone (TSH) concentrations in 10

between 2 and 5 a.m., between 9 a.m. and 1 p.m., and between 4 and 9 p.m. During and after sleep deprivation at all measuring times except 6,7, and 8 a.m., TSH levels were higher than the corresponding levels measured on days 1 and 3. The results of the pattern tests confirmed that TSH secretion during the period of partial sleep deprivation (2 to 6 a.m.) was higher than during the 2 control nights (p < 0.05). Fig. 1 shows that after partial sleep deprivation TSH levels between 9 a.m. and 1 p.m. and between 4 and 9 p.m. were higher than the corresponding levels on day 1. That is, after partial sleep deprivation TSH levels were elevated until the evening TSH surge began, this being smaller than the corresponding evening surge before partial sleep deprivation. No difference was found between the TSH secretion curves recorded on nights 1 and 3. On all 3 days, we found an increase in TSH levels after 7 p.m., which peaked before lights out and showed a marked decline in the first measurements carried out after the subjects retired to bed (11 p.m.). Partial sleep deprivation did not affect either the time of these rises and falls in evening TSH secretion or the sharp increases and subsequent falls in TSH secretion after waking. Thyroid Hormones. For T,, Friedman’s test showed significant main effects at 3,4, and 5 a.m (Fig. 2). Likewise the pattern test showed that T, levels were significantly higher between 2 and 6 a.m. on the night of partial sleep deprivation than on the other 2 nights. The Wilcoxon test revealed significant differences between T, levels measured at these times on the partial sleep deprivation night and each of the other 2 nights, respectively. We found the same main effects for free T, (ff,) in both Friedman’s and pattern tests; however, the individual comparisons were significant at 4 and 5 a.m. only (Fig. 2). During the daytime, neither T, nor ff, levels showed significant changes after sleep deprivation. However, both hormones exhibited a distinct diurnal profile: decreases were seen between 9 and 10 p.m. on all 3 days (i.e. before subjects went to bed and/or fell asleep). During nights 1 and 3, hormone levels remained low with a sharp increase between 5 and 7 a.m. (i.e., immediately before or after subjects awoke or arose). The sign test revealed significant differences between diurnal and nocturnal T, secretion on both days 1 and 3 (p = O.OOl), whereas for fT, the difference did not quite reach significance (p = 0.052). The same results were obtained with the pattern test. Partial sleep deprivation did not influence this rhythm, as the late evening declines and early morning increases occurred at the same time on both nights I and 3 (Fig. 2). Main effects for T, were found between 2 and 6 a.m. (pattern test) (Fig. 2). Although we found no main effects with Friedman’s test, comparison with the Wilcoxon text of the T, values for the day after partial sleep deprivation with the corresponding values measured on days 1 and 3 showed significantly higher T, levels after partial sleep deprivation than on day 1 at 11 a.m. and at 4, 5, and 6 p.m. The significance levels for the comparisons for the other measuring times after partial sleep deprivation (7 to 10 a.m., 12 to 3 p.m.) were all around 0.1. These data do not meet strict statistical criteria to demonstrate that partial sleep deprivation induced an elevation of T, levels that persisted after the day following partial sleep deprivation; however, the evidence is at least suggestive that this was indeed the case (see also Fig. 2).

161

Fig. 2. Mean thyroxin (T4), free T4, and triiodothronine (Ta) concentrations in 10 healthy young women

70

60

so

40

‘2 1 1

10

w

8

4

i

\ I

T3 Wmll

1.2

1

1.0

08

04

_________. IllllIIlll 13579111357

4 -l-

3 . p
===T

3

time

162 The T, concentrations followed the same diurnal pattern as described above for T, and ff,. Both the sign test and the pattern test revealed that T, secretion was significantly lower during nights 1 and 3 than during the respective days (p < 0.005). Again, the chronobiological rhythm of this hormone was found to remain unaffected by partial sleep deprivation. PRL. Friedman’s test showed main effects at 5,6, and 7 a.m. for PRL. Likewise, the pattern test showed the PRL levels between 2 and 6 a.m. to be significantly lower during partial sleep deprivation than on the 2 control nights. The Wilcoxon test revealed that there were also significant differences between the PRL levels at these measuring times during partial sleep deprivation and on each of the other 2 nights (Fig. 3). Interestingly, the nocturnal increase in PRL concentrations did not begin until after 10 p.m. on all 3 days (i.e., it was first evident in the first blood samples taken after “lights out”). Again, the early morning decline occurred after 6 p.m. on days 1 and 3 (i.e., in the first sample drawn after the subjects had awakened). Finally, the late afternoon peak occurred at 7 p.m. on both days 2 and 3, providing further evidence that partial sleep deprivation had no chronobiological effects on PRL secretion such as “phase advance” or “phase delay.” Fig. 3. Mean prolactin

(PRL) concentrations

in 10 healthy young women

GH. No effects of partial sleep deprivation on GH were observed at any measurement point (Fig. 4). The “nocturnal” rise in GH took place before the subjects had retired to bed or before the onset of sleep on all 3 evenings. GH fell sequentially on all 3 nights and remained unaffected by partial sleep deprivation on night 2. HPG Axis. Friedman’s test showed significant and for Ez at 3, 4, and 5 a.m., whereas FSH

main effects for LH at 3 and 4 a.m. secretion remained unchanged. The

163

Fig. 4. Mean growth hormone (GH) concentrations women GH

in 10 healthy young

pattern test also showed significantly higher LH and E, levels during the night of partial sleep deprivation. The Wilcoxon test showed that both the LH and the E, levels measured during partial sleep deprivation differed significantly from those obtained on the other 2 nights at all of the above-mentioned measurement points (Fig. 5). All three hormones showed a diurnal profile with concentrations decreasing as early as 6, 7, and 8 p.m., respectively (i.e., several hours before the subjects retired to bed). A rise in hormone levels occurred during the second half of the night, after 3, 4, and 5 a.m. (i.e., again before waking and rising, respectively). These nocturnal declines in hormone concentrations were similar to those described above for the thyroid hormones (Fig. 2) but they occurred about 3 hours earlier. The LH and FSH levels were significantly higher during the day than during the night (sign test, p = O.Ol), whereas the differences were not significant for E,. Partial sleep deprivation had no effect on the time at which the evening peak in LH levels occurred (6/7 p.m.).

Discussion Changes in Endocrine Secretion During Partial Sleep Deprivation. One purpose of our study was to use a “multihormone approach” to explore whether partial sleep deprivation affects the secretion of the hormones of the hypothalamicpituitary-thyroid (HPT) and HPG axes and also that of PRL and GH in normal subjects. Our results show that partial sleep deprivation was associated with an enhancement of levels of TSH, protein-bound and free thyroid hormones, LH, and E,; an inhibition of PRL secretion; and no change in GH and FSH secretion. The results for TSH, thyroid hormones, and PRL are consistent with corresponding data derived from total sleep deprivation studies (Table 1). To our knowledge, this is

164

Fig. 5. Mean concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) in 10 healthy young women

FSH

Wmll ld

-

&4

4.0 ;\

16 12ZIY_4-

Ez hhll J 7. 70UJ02 :/1 S54-

v

i‘l

50au42-

-I

__-

I1 -R

I135

____-___--. ,,,I

I,,,,, 7

01,13

6

7

P

165 the first study to investigate LH, FSH, and E, levels longitudinally during sleep deprivation and to find increases in LH and E, levels, so our data cannot be compared with the results of previous research. Our findings for cortisol were published in a previous article (Saletu et al., 1986). Cortisol showed an earlier increase during the partial sleep deprivation night than on nights 1 and 3. Our results show that endocrine changes induced by partial sleep deprivation resemble those seen after total sleep deprivation (TSD) (Table 1). The only exception was for GH secretion, which was found to be depressed during total sleep deprivation but was not affected during partial sleep deprivation. This difference obviously reflects the fact that the maximum secretion of GH occurs in the late evening or early part of the night and may therefore be affected by total sleep deprivation, whereas GH concentrations are near baseline in the second half of the night (Fig. 4) and are therefore not affected by partial sleep deprivation. To conclude, the results show that if subjects are awakened in the middle of the night (partial sleep deprivation), exactly the same changes in hormone secretion apparently occur as when they are kept awake the whole night (total sleep deprivation). The identical results were not necessarily to be expected, as there are differences between the two methods of carrying out sleep deprivation. While subjects undergoing total sleep deprivation have not slept for about 18 hours, those undergoing partial sleep deprivation have slept for 4 hours before being awakened at 1:30 a.m. This means that the duration of waking and/ or sleep before the onset of sleep deprivation is not relevant for the associated changes in hormone secretion. The important criterion seems to be that wakefulness is induced during regular sleep time. The results are consistent with our previous findings (Baumgartner et al., 1990~) and show that TSH and T, levels increase during partial sleep deprivation in depressed patients. In this study, we found no increases in T, levels, which most likely reflected the fact that we measured thyroid hormones at 8 a.m. only. Finally, the results for TSH are of particular interest. Some (but not all) studies have reported strong correlations between increases in TSH and the antidepressant effect of sleep deprivation. The antidepressant effect, however, is usually evident during the day following sleep deprivation and is subsequently abolished during the sleep period on the next night. In the present study, TSH was the only hormone that was also elevated throughout the day following partial sleep deprivation. Possible Neurochemical Mechanisms That May Underlie Changes in Endocrine Secretion During Partial Sleep Deprivation. One main purpose of our study was to investigate whether it is possible to draw any conclusions from the different changes in hormone concentrations during partial sleep deprivation about underlying alterations in neurotransmitter function. Considerations of this kind, although highly speculative, could be important because the neurochemical mechanisms that are involved in the pronounced antidepressant effect of sleep deprivation in depressed patients are completely unknown (Kuhs and Tolle, 1991). With respect to neuroendocrine investigations, it is obviously impossible to make any deductions about neurochemical changes on the basis of alterations in the secretion of only one hormone during sleep deprivation. However, investigations of changes in several hormones in different axes may shed more light on the changes in

166 CNS neurotransmitter function that occur during sleep deprivation. Specifically, we must find an explanation for increases in TSH, thyroid hormones, LH, and E,; earlier rises in cortisol; declines in PRL concentrations; and a concomitant lack of changes in GH and FSH. TSH has been found to exhibit a distinct diurnal profile, with rises in concentration during the evening and declines during the night (Weeke and Gundersen, 1978; Sowers et al., 1982; Parker et al., 1987; Brabant et al., 1991). The neurochemical mechanism underlying this rhythm has not yet been elucidated. However, most (but not all) research groups have found that decreases in dopaminergic inhibition are not a likely explanation (Scanlon et al., 1980; Sowers et al., 1982; Magee et al., 1986) and that the evening and/or nocturnal rises in TSH secretion are most probably due to enhanced TRH stimulation (Brabant et al., 1991). An involvement of noradrenergic receptors in the diurnal rhythm of TSH has as yet been investigated only once, and no effect of a,-adrenergic blockade on nocturnal TSH secretion was observed in a (5hydroxystudy in healthy women (Valcavi et al., 1987). The role of serotonin tryptamine, 5-HT) in TSH regulation is confusing (see Reichlin, 1986; Spira and Gordon, 1986). Jordan et al. (1979) reported that the diurnal peak of TSH in rats was serotonin-dependent. Thyroid hormone secretion was enhanced during partial sleep deprivation. The observed increases were in all likelihood not induced by enhanced TSH secretion alone, as TSH remained elevated until 9 p.m., whereas T, and (to a lesser degree) T, returned to normal as early as 5 and 6 a.m., respectively. Furthermore, the pronounced increases in T, levels (Fig. 2) are intriguing, as T, has a half-life of approximately 1 week and a doubling of the T, secretion rate over a 12-hour period would lead to only a 5% increase in the total extrathyroidal T, pool (Nicoloff, 1986). Moreover, clinical studies (Snyder and Utiger, 1973; Bremner et al., 1977) have found increases in TSH after TRH infusion which, while they were much more pronounced than those in our subjects during partial sleep deprivation, nevertheless induced much smaller rises in T, than those described above and no rises in T, at all. Finally, the increases in thyroid hormones after the rise in TSH occurred much later in these studies (2 to 3 hours) than in our own, where the increase in T, occurred concomitantly with the increase in TSH and the increase in T, occurred 1 hour later. Other substances that could be responsible for the rise in thyroid hormone levels include the catecholamines. The catecholamines stimulate thyroid hormone secretion directly by activating P-adrenergic receptors and inhibit it by activating a,adrenergic or cholinergic receptors (for a review, see Ahren, 1986). Although our cortisol data have already been published elsewhere (Saletu et al., 1986), investigation of the early rise in cortisol during partial sleep deprivation might provide useful insights in the search for a possible “common neurochemical mechanism” for endocrine changes during partial sleep deprivation. In brief, a stimulating influence of the a,-adrenergic receptor on CNS-induced cortisol secretion has repeatedly been reported in recent years (e.g., Al-Damluji et al., 1987; Raczkowska Naylor et al., 1988; Plotsky et al., 1989). However, this receptor seemed to have an effect on diurnal cortisol secretion only, while evening and nocturnal cortisol levels remained unaffected (Al-Damluji et al., 1987; Raczkowska Naylor et al., 1988). The hypothalamicpituitary-adrenal (HPA) axis is also influenced by 5-HT, probably by 5-HTl*

167 and/ or 5-HT2 receptors (e.g., Owens et al., 1990, 1991). Earlier articles (Krieger et al., 1968; Krieger and Rizzo, 1969; Chihara et al., 1976) and also one recent report (Banky et al., 1988) suggest an involvement of 5-HT and also acetylcholine in nocturnal rises of 17-hydroxycorticosteroid levels in the rat, cat, and human. GH is stimulated by a,-receptors, is probably inhibited by &-receptors, and is also stimulated by 5-HT and acetylcholine (for reviews, see Delitala et al., 1988; Dieguez et al., 1988). However, the 5-HT antagonist methysergide surprisingly enhanced GH secretion at night (Mendelson et al., 1975) and serotonergic lesions did not change nocturnal GH secretion patterns in rats (Banky et al., 1988), whereas the muscarinic antagonist scopolamine effectively blocked nocturnal GH peaks (Mendelson et al., 1978; McCracken et al., 1991) and the muscarinic agonist piperidine enhanced sleeprelated GH secretion but not daytime GH production (Mendelson et al., 1981). No influence of adrenergic antagonists (phentolamine and propranolol) on nocturnal GH secretion was reported in three and four healthy men, respectively (Lucke and Glick, 1970). This result is consistent with the finding that the a,-adrenergic receptor does not appear to stimulate GH secretion at night (Ghigo et al., 1990). As far as we know, PRL is the only one of these hormones that is not stimulated but inhibited by norepinephrine, probably through a /I-adrenergic mechanism (for a brief review, see Baumgartner et al., 1988). As regards the nocturnal surge of PRL, it has been reported that in the rat 5-HT contributes to the afternoon surge but not to the nocturnal increase (Banky et al., 1988; Mistry and Voogt, 1989). In humans, the nocturnal PRL rise may be suppressed by the nonspecific 5-HT antagonist methysergide (Mendelson et al., 1975). The HPG axis differs from all the hormones mentioned above insofar as in adults the data on changes in 24-hour secretory’patterns are contradictory. Whereas several older studies failed to show a diurnal rhythm for either LH or FSH in normal adult men (Krieger et al., 1972; Rubin et al., 1975), other authors described a decrease,in LH levels during sleep in adult women, but not in men (Kapen et al., 1975). These decreases were not influenced by the nonspecific 5-HT antagonist methysergide (Kapen et al., 1980). Rossmanith and Yen (1987) found decreases in LH pulse frequency and mean levels during sleep in women; these effects were suppressed by naloxone but not influenced by the dopamine antagonist metoclopramide. Elevated LH concentrations but reduced E, levels have been demonstrated during sleep in pubertal boys and girls (Boyar et al., 1972, 1976; Kapen et al., 1975). Finally, increased LH concentrations have also recently been reported in adult men during sleep (Fehm et al., 1991). In conclusion, the investigation of the influence of the sleep-wake cycle on the HPG axis produced varying results, probably because these variables are strongly affected by age and gender. Veldhuis et al. (1990) recently described changes in the amplitudes of the LH secretory burst but no changes in FSH secretory parameters over a 24-hour period. No significant changes in diurnal levels of total or free E, were reported in women in the midluteal phase of the menstrual cycle (Shang-Mian et al., 1990). As regards the neurochemical mechanisms that may underlie the changes in LH associated with partial sleep deprivation, the regulation of this hormone is extremely complex and is dependent on gender, phase of the menstrual cycle, and time of day (for a review, see Barraclough and Wise, 1982).

168 In conclusion, norepinephrine seems to stimulate LH secretion through the (x,adrenergic receptor under certain conditions (but not all), and serotonin has been reported to have both a stimulatory and an inhibitory effect. Of particular interest is the study by Rossmanith et al. (19883) which showed not only significant sleepassociated decreases in LH serum levels in women in the early follicular phase (i.e., in a sample comparable to our own), but also a lack of influence of the dopamine antagonist metoclopramide on LH pulsatile activity during the sleep/ wake period. that in rats, in addition to the hypothalamicAs regards E,, it is interesting pituitary-ovarian pathway of hormone regulation, there also seems to be direct neuronal control of ovarian steroid secretion by the sympathetic nervous system (Kawakami et al., 1981; Burden, 1985). For example, an increase in E, secretion has been induced in hypophysectomized and adrenalectomized rats by electric stimulation of hypothalamic areas (Kawakami et al., 1981). In this reaction, preceptors seemed to play a stimulatory role and a-receptors an inhibitory one (Ojeda and Aguado, 1985). The P-receptors in rat ovaries have been shown to be of the & subtype. How can the findings of this and other studies on hormone secretion during sleep deprivation be interpreted in the light of this very brief review of the neuroregulation of circadian hormone secretion? In our opinion, an enhancement of NE activity could result in an increase in TSH (via /3-adrenergic receptors?), cortisol, and LH levels (both a,-adrenergic receptors?) and possibly in a fall in PRL (P-receptors) concentrations. As nocturnal GH secretion is not sensitive to the a,-adrenergic receptor (see above), we would not expect an enhancement of GH secretion to accompany an increase in noradrenergic activity during sleep deprivation. As the sympathetic nervous system directly influences both thyroid hormone and E, secretion (see above)-probably through a facilitating & effect and an inhibiting a, effect-it might well be that the changes in thyroid hormone and E, levels associated with partial sleep deprivation are directly attributable to an enhancement of sympathetic tone during partial sleep deprivation. Our knowledge on the influence of sleep deprivation on neurotransmitter function in the CNS is limited to animal studies. A reduction in P-receptor binding after REM sleep deprivation has been reported in two studies (Mogilnicka et al., 1980; Radulovacki and Micovic, 1982) and total sleep deprivation reduced the circadian amplitude of the a- and /?-adrenergic receptors in rat frontal cortex (Wirz-Justice et al., 198 1). The down-regulation of the /?-adrenergic receptor could well result from an increase in noradrenergic activity. Elevations in 5-HT levels were found 2 to 6 hours after sleep deprivation in one study (Borbtly et al., 1980), but not in another (Wesemann and Weiner, 1982). Circadian 5-HT binding was significantly reduced after sleep deprivation (Wesemann et al., 1985). REM sleep deprivation induced supersensitivity of dopaminergic receptors (Tufik et al., 1978) and total sleep deprivation induced an increase in D,-receptor density in the limbic system but not in the striatum in rats (Demontis et al., 1990). A centrally mediated activation of the sympathetic nervous system during sleep deprivation is suggested, for example, by the finding that peripheral norepinephrine and epinephrine levels are elevated during sleep deprivation in normal subjects (Froberg et al., 1975; Mullen et al., 1981) and by

169 the facts that overall noradrenergic activity is higher during sleep deprivation than during sleep (see below) and that the central noradrenergic and peripheral sympathetic nervous systems are closely linked (Crawley et al., 1978, 1979). Our present data suggest that sleep deprivation influences the peripheral hormone secretion of the HPT and HPG (and probably also the HPA) axes through different pathways (the HP axes and the sympathetic adrenergic system). At present, it seems impossible to decide whether changes in peripheral thyroid hormone or E, levels during sleep deprivation are directly induced by an increase in the activity of sympathetic nerve fibers or by changes in circulating catecholamine levels. As regards a possible influence of 5-HT, enhanced secretory activity during sleep deprivation would result in stimulation of the HPA axis, PRL, and possibly LH and GH, whereas an influence on the HPT axis is uncertain. In the cholinergic system, a decrease in GH secretion would indicate a decrease in acetylcholine activity during sleep deprivation, which in turn would fail to explain the earlier rises in cortisol levels. An increase in dopaminergic tone would lead to a fall in TSH concentrations, which is the opposite of what we found during sleep deprivation. However, enhanced dopaminergic activity could also lead to the falls in PRL levels observed during partial sleep deprivation. If the increases in TSH secretion are due to TRH stimulation, then PRL should also be found to be elevated. In this case, a fairly strong inhibitor must have prevented those increases, and this is likely to have been dopamine. Furthermore, TRH stimulates TSH more strongly than PRL (Spencer et al., 1980). On the other hand, it seems likely that a stimulatory effect of TRH on TSH secretion would be much stronger than a possible TSH inhibiting action of dopamine, the final result being a net increase in TSH secretion. Overall, we believe that enhancements of noradrenergic activity (exerting an effect and Ez) and dopaminergic activity on TSH, cortisol, LH, thyroid hormones, (exerting an effect on PRL) best explain the endocrine changes described during partial sleep deprivation. An influence of 5-HT is possible, particularly in view of the early nocturnal increases in cortisol, whereas a major role of acetylcholine seems unlikely. We recently outlined elsewhere (Baumgartner et al., 1990~) how these considerations fit into current knowledge about the regulation of the sleep/ wake cycle. The noradrenergic activity of the locus ceruleus (LC) is high during waking and low during sleep in all three species investigated (rats, cats, and monkeys) (Foote et al., 1980; Aston-Jones and Bloom, 198 1). Therefore, as noradrenergic activity in the LC is essential for cortical arousal during waking hours, it might be reasonable to hypothesize that noradrenergic activity in the LC is higher during sleep deprivation than during a night of sleep. Enhanced noradrenergic function during sleep deprivation could thus lead to enhanced stimulation of adrenergic receptors. There is also some evidence that the dopaminergic system is vigilance-enhancing, but, in contrast to the noradrenergic system, it promotes motor activity rather than arousal (for a review, see Koella, 198%~). We therefore hypothesize that sleep deprivation intensifies dopaminergic activity, which would be a good explanation for the above hypothesis that enhanced dopaminergic activity is responsible for the declines in PRL levels. The role of 5-HT in the regulation of the sleep/wake cycle is still confusing (Jouvet, 1969; Koella, 19856; Trulson and Jacobs, 1979). Cholinergic

170 mechanisms also have a vigilance-enhancing action (Koella, 1985~). However, as cholinergic activity is also high during REM sleep, it is difficult to say whether “net cholinergic activity” during sleep deprivation is higher, lower, or the same as it is during a night of sleep. In conclusion, on the basis of our limited current knowledge of the neuroregulation of circadian endocrine rhythms and our probably more advanced knowledge of the regulation of the sleep/ wake cycle, we believe that the pattern of changes in hormone secretion described during both total and partial sleep deprivation in this and other studies may be explained (at least in part) by an enhancement of noradrenergic activity. These conclusions are in line with the hypothesis already formulated on the basis of the changes observed in endocrine axes during total sleep deprivation in depressed patients (Baumgartner et al., 1990~). Enhanced noradrenergic activity during sleep deprivation would then not only lead to the endocrine changes outlined above, but it could also contribute to the marked antidepressant effect of sleep deprivation, which is, in turn, consistent with current hypotheses on the role of norepinephrine in depressive disorder (e.g., Heninger and Charney, 1987). It must, of course, be emphasized that there are many serious limitations to our hypothesis. By far the worst problem is the uncertainty about the neuroendocrine regulation of most hormones in terms of receptor selectivity, differences between species, and anatomical level of action. The regulation of the diurnal secretion of different hormones is especially complex and so poorly understood that it is at best an oversimplification to say that adrenergic receptors stimulate TSH and cortisol secretion. Furthermore, it might well be that the changes that take place in hormone secretion are not related to one or more distinct neurotransmitters and their receptors but, for instance, can better be explained by an activation of certain mechanisms distal to the receptors, such as a certain second messenger or protein kinase or even an influence on gene expression. In light of the chronobiological hypotheses explored in this study, it is worthy of note that partial sleep deprivation did not affect the diurnal patterns of any of the hormones measured in this study. All distinct surges and declines, such as the afternoon surge of PRL and the evening increase in GH, occurred at exactly the same times on each of the 3 days of the investigation. We therefore found no evidence that partial sleep deprivation interferes with the chronobiological rhythms of endocrine systems in healthy subjects. As previously reported for our sample of depressed patients, we also found distinct diurnal profiles of T,, fT,, and T,, with a nocturnal decrease and early morning increases in the healthy subjects investigated in the present study. In brief, we concluded that the changes in total plasma volume or shifts in thyroid hormones from the vascular to the extravascular spaces that occur during the night and are dependent on either posture or the sleep/ wake cycle should be taken into account as causes of the diurnal variation (Baumgartner et al., 1990~). The evening peaks in GH occurred with a surprising regularity at 8 and 10 p.m., respectively (i.e., before the onset of sleep). This is additional evidence that nocturnal GH secretion is not always linked to slow wave sleep, as previously suggested

171

(Takahashi et al., 1968; Parker et secretion is related to sleep onset Jarrett et al., 1990) and there have sleep in a considerable number of Acknowledgments. This research (Grant No. Ba 932/4-l).

al., 1979). Other authors have suggested that GH rather than to slow wave sleep (Born et al., 1988; even been reports of GH surges before the onset of subjects (Steiger et al., 1987).

was supported

by the Deutsche

Forschungsgemeinschaft

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