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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 1134-1139
Copyright © 2001 by The Endocrine Society

Original Studies

Disruption of the Nocturnal Testosterone Rhythm by Sleep Fragmentation in Normal Men

Rafael Luboshitzky, Ziva Zabari, Zilla Shen-Orr, Paula Herer and Peretz Lavie

Endocrine Institute (R.L.), Haemek Medical Center, Endocrine Laboratory (Z.S.O.), Rambam Medical Center, Haifa 32000, Israel; and The Sleep Research Center (Z.Z., P.H., P.L.), Technion, Israel Institute of Technology, Haifa 32000, Israel

Address all correspondence and requests for reprints to: Prof. R. Luboshitzky, Endocrine Institute, Haemek Medical Center, Afula 18101, Israel.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Recently, we have demonstrated that in normal men the nocturnal testosterone rise antedated the first rapid eye movement (REM) sleep episode by about 90 min and was correlated with REM latency. To further elucidate whether the diurnal testosterone rhythm is a sleep-related phenomenon or controlled by the circadian clock, we determined serum testosterone levels in 10 men during the ultrashort 7/13 sleep-wake cycle paradigm. Using this schedule, subjects experienced partial sleep deprivation and fragmented sleep for a 24-h period. Serum testosterone levels were determined every 20 min between 1900–0700 h with simultaneous sleep recordings during the 7-min sleep attempts. The results were compared with those obtained in men during continuous sleep. Although mean levels and area under the curve of testosterone were similar in both groups, fragmented sleep resulted in a significant delay in testosterone rise (03:24 h ± 1:13 vs. 22:35 h ± 0:22). During fragmented sleep, nocturnal testosterone rise was observed only in subjects who showed REM episodes (4/10). Our findings indicate that the sleep-related rise in serum testosterone levels is linked with the appearance of first REM sleep. Fragmented sleep disrupted the testosterone rhythm with a considerable attenuation of the nocturnal rise only in subjects who did not show REM sleep.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE RELEASE of testosterone from the testis is episodic and occurs in response to a pulsatile gonadotropin stimulus (1, 2). In addition, an overall diurnal rhythm is seen for testosterone with a peak time around 0800 h and a trough around 2000 h (3, 4, 5). The causes of this testosterone rhythm are not known. Several studies have indicated that the nocturnal rhythm is related to REM–non-REM sleep cycles (6, 7, 8). Schiavi et al. (7) demonstrated that in healthy, aging men, there were positive associations between sleep efficiency, REM latency, number of REM episodes, and plasma testosterone levels. Low sleep efficiency indices and decreased number of REM episodes were associated with attenuated testosterone levels (7). Recently, we demonstrated that the nocturnal testosterone rise in normal young adult men studied during continuous sleep began on falling asleep and reached a plateau approximately 90 min later, at the approximate time of the first REM episode. The slope of testosterone curve during the initial sleep period was significantly correlated with REM latency, but not with other sleep stages. LH levels did not differ between waking, REM, and non-REM periods (9). These data suggest that either the rise in testosterone may be causally related to first REM episode, or alternatively, both the rise in testosterone and the first REM latency reflect a common underlying circadian rhythm.

The present study was undertaken to further delineate whether the nocturnal testosterone rhythm is sleep related or whether this rhythm is controlled by the circadian clock. We used the 7/13 ultrashort paradigm (10, 11, 12), whereas subjects were partially sleep deprived and had fragmented sleep. Melatonin onset and core body temperature were used as circadian markers (12).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Ten healthy men (aged 22–26 yr) volunteered to participate in the study. All were in good health, nonsmoking, within 10% of ideal body weight and received no medications. The study was approved by the Helsinki Committee of the Medical Center, Afula, Israel. All participants gave their informed consent before the onset of the study.

Study protocol

Subjects were admitted to the Sleep Research Center between 2200 and 2300 h. They slept between 0100 and 0600 h for habituation, with electrodes attached for sleep recordings. At 0600 h, an iv catheter was inserted into an antecubital vein, kept patent by a slow infusion of 0.9% NaCl. At 0700 h, subjects began a schedule of 7 min sleep, 13 min awake, for 24 h (7/13 ultrashort sleep paradigm) as previously described (10). In brief, every 20 min, subjects were instructed to be in bed in a dark room and attempt to fall asleep. Electrophysiological recordings were carried out during the 7 min sleep attempts (in a completely darkened room) to determine the sleep stages. At the end of the 7-min trials, whether asleep or awake, subjects were asked to leave the bedroom. Light intensity during the 13-min intervening wake period was <=50 lx. This cycle was repeated 72 times, until 0700 h the next day. A large number of studies using this paradigm have revealed that subjects adapted to the fragmented sleep without difficulties and that the pattern of sleep propensity obtained with this paradigm is very stable and reliable (10, 11, 13).

Blood samples (3 mL) were collected every 20 min in between sleep attempts, from 1900 h-0700 h. Liquid food (Ensure plus) providing complete balanced nutrition of 355cal/237 mL (Abbott Laboratories, Columbus, Ohio) was given every 3 h.

Results of sleep recordings and serum testosterone levels in this group (fragmented sleep) were compared with a group of six healthy men of similar age (aged 21–25 yr) during continuous sleep between 2200–0700 h as previously described (9). Throughout the study, core body temperature was recorded once per minute using Minilogger 2000 (Mini-Mitter) with the YSI, Inc. 400 disposable rectal probe.

Analysis of sleep stages

Electrodes were attached for the following electrophysiological recordings: two electroencephalograms (EEG levels C3-A2, C4-A1), two electrooculograms, and one electromyogram of the mentalis. Sleep stages were recorded in 30 sec epochs according to conventional criteria. Each of the 7-min trials was scored for sleep stages 1,2, 3/4, and REM according to previously described criteria (13). As reported before (14), the sleep propensity function obtained by the 7/13 paradigm is characterized by three features: an evening nadir in sleepiness (the forbidden zone for sleep), the sleep gate, and the nocturnal crest in sleepiness. The sleep gate, which represents an abrupt increase in sleep propensity from a low level during the forbidden zone to the nocturnal crest, was determined as described before (15). It was the trial during which subjects obtained at least 3.5 min of sleep of any stage followed by at least 5 of 6 trials meeting the same criterion. Latency to first REM episode in the 7/13 paradigm was calculated as the time between the sleep gate and the first appearance of at least 30 sec of REM sleep in any of the 7-min sleep attempts. Sleep data in the continuous sleep group were analyzed by conventional methods to determine sleep latency, sleep stages and REM latency. REM latency in this condition was the time from sleep onset to the first appearance of REM sleep.

Testosterone measurements

Blood was centrifuged, immediately separated, and stored at -20 C until assayed. Serum testosterone levels were determined by RIA (Diagnostic Products Corp., Los Angeles, CA). The intraassay coefficients of variations (CV) were 6.0% and 3.0% for low (2.2–4.0 nmol/L) and high (29.4–62.0 nmol/L) concentrations, respectively. The interassay CVs were 1.9% and 1.6%, respectively. The sensitivity of the assay was 0.15 nmol/L.

Melatonin measurements

Serum melatonin levels were determined every 20 min between 1900 and 0000 h by RIA (Bühlmann Laboratory, Albshwill, Switzerland). The assay sensitivity was 2.0 pmol/L. The intraassay CVs were 4.9% and 5.8% for low (4–12 pmol/L) and high (42–106 pmol/L) concentrations, respectively. The interassay CVs were 7.8% and 6.7%, respectively.

Statistical analysis

Mean serum testosterone levels, the integrated nocturnal testosterone values (area under the curve; AUC) from 1900 to 0700 h were determined in the two groups. The onset of the nocturnal melatonin rise was defined as the time when melatonin levels exceeded 10 pmol/L with subsequent samples until 0000 h being higher than this value. Prior samples revealed melatonin concentrations between 2.0–10.0 pmol/L.

The onset of the testosterone rise was defined as the time of the first occurrence of at least three consecutive samples exceeding the mean levels obtained between 1900 and 2100 h more than 1 SD.

Independent two-sample t tests were used to compare the mean testosterone levels and AUC, between the subjects who had REM sleep episodes and those who did not have REM in the 7/13 sleep group. Also, independent two-sample t tests were used to compare the same testosterone parameters of the fragmented sleep group with the continuous sleep group. The testosterone curves were modeled as three separate fractions: before testosterone rise, between testosterone rise and first REM, and after the first REM. The mean slope of the linear regression lines fitted to the middle fraction of the testosterone curves was correlated with REM latency. We also used t tests to determine whether each group had a nonzero slope and whether the two groups had statistically significant different slopes. Independent two-sample t tests were used to compare the mean sleep stages (percent) between the subjects during fragmented and continuous sleep.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All subjects completed the experimental paradigm. As expected, during fragmented sleep subjects had significantly less sleep and significantly different sleep stage distribution. As shown in Table 1Go, during fragmented sleep, subjects had significantly less REM sleep (4.9 min ± 5.7 vs. 67.4 ± 12.3; P < 0.0001) and more sleep stage 1 (26.1 min ± 8.9 vs. 7.2 ± 1.6; P < 0.0001) as compared with continuous sleep. All subjects showed a well-defined sleep gate that occurred on average at 2316 h. Sleep fragmentation by the 7/13 paradigm blunted the nocturnal rise in testosterone. The peak in testosterone rise for each of the ten men is shown in Table 2Go. Only four of the 10 subjects showed visible nocturnal increase in testosterone levels.


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  		Table 1. Nocturnal (2200–0700 h) sleep stages data during fragmented and continuous sleep in normal men (values are given as mean ± SD)

 

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  		Table 2. The onset of the nocturnal testosterone rise and first REM episode in Normal men during fragmented and continuous sleep

 
In spite of the blunted nocturnal rise in testosterone in the fragmented sleep condition, it was still related to the appearance of REM sleep in this paradigm. Five of the 10 subjects showed REM sleep in this paradigm, these occurred with latencies ranging from 2–5 h from the sleep gate. Figure 1Go (A and B) compares the nocturnal rise in testosterone under the continuous (n = 6) and fragmented (n = 10) sleep conditions. None of the five subjects without REM sleep showed any testosterone rise, whereas four of the five subjects who showed REM sleep showed a testosterone rise (Table 2Go). The only subject who had REM sleep and did not show testosterone rise, had higher testosterone levels from the start of the study (Fig. 2Go). During continuous sleep, all subjects had REM episodes and a nocturnal testosterone rise (Table 2Go).



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  		Figure 1. Nocturnal testosterone curves in normal men during fragmented (A) (n = 10) and continuous (B) sleep (n = 6). The mean time for the first REM episode during continuous sleep is indicated by an arrow. During continuous sleep (B) lights were off between 2200 and 0700 h.

 


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  		Figure 2. Nocturnal testosterone curve in an adult man during fragmented sleep. Note that he had five REM episodes (indicated by arrows), no testosterone rise and sustained elevated testosterone levels throughout the night.

 
The mean slope of testosterone rise of subjects in the 7/13 paradigm with REM (b = 0.15 ± 0.05), was significantly higher than those without REM (b = 0.01 ± 0.03) (P < 0.03), but was not different than that of the continuous sleep group (b = 0.16 ± 0.03).

To further investigate the possible presence of a circadian rhythm in testosterone secretion, we synchronized testosterone levels, according to the sleep gate in the 7/13 paradigm group, to sleep onset time in the continuous sleep condition and then, according to the nocturnal melatonin onset in each condition (Table 2Go). During continuous sleep, nocturnal rise in testosterone was evident when hormone levels were synchronized with either sleep onset time or with melatonin onset time (Fig. 3Go). During fragmented sleep, nocturnal testosterone rise was evident only in subjects with REM. The testosterone rise occurred when hormone levels were synchronized with either melatonin onset time (Fig. 4AGo) or with the sleep gate (Fig. 4BGo). To examine the differences between subjects with and without REM sleep, core body temperature (CBT) and melatonin data were averaged separately for the two groups (data not shown). Subjects with REM tended to have earlier peaks in CBT (18:20 ± 0:10) and melatonin onset (22:00 ± 0:41) than subjects without REM (19:40 h ± 0:14 and 22:52 h ± 0:41, respectively).



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  		Figure 3. The dual effect of sleep and the circadian clock on the nocturnal testosterone rhythm in adult men during continuous sleep. First, Testosterone levels were synchronized to melatonin onset time (0). Second, Testosterone levels were synchronized to sleep onset time (0).

 


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  		Figure 4. The dual effect of the circadian clock (A and B) and sleep (C and D) on the nocturnal testosterone rhythm in adult men during fragmented sleep. Data from subjects with REM episodes are given in A and C, whereas B and D contain data from subjects without REM sleep episodes. The figures on the abscissa in A–B refers to the time (in hours) before and after the nocturnal melatonin onset, and in C–B to the time (in hours) before and after the sleep gate.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we have demonstrated that the diurnal testosterone rhythm in normal men was disrupted during fragmented sleep. Whereas during continuous sleep testosterone rise antedated first REM episode by about 90 min, during fragmented sleep this rise was observed in only four of ten subjects, occurring 5 h later and coinciding with the time of the first REM. This delay in REM sleep is in close agreement with previous findings with the ultrashort paradigm (10). Despite the disruption in testosterone rhythmicity, mean hormone levels and AUC were similar during continuous and fragmented sleep.

Diurnal rhythm of testosterone already exists at 4–5 yr of age (16). In adult men, the diurnal testosterone rhythm revealed higher levels at night and minimal in the late evening. The amplitude of the rhythm being approximately 20% of the mean testosterone level (7, 17, 18).

The effect of advancing age on the chronobiology of testosterone and LH in healthy young and elderly men were investigated. Both young and elderly men had significant diurnal rhythms in serum testosterone although the rhythm in elderly men was attenuated compared with the young. Mean LH levels did not vary over the 24 h period in both young and elderly men (19). Blunted testosterone rhythm was also observed in young men with testicular failure (20).

Several factors may be expected to influence the diurnal rhythm of testosterone. Among these are LH, diurnal changes in Leydig cells response to LH, intrinsic levels of gonadal factors such as inhibin-ß, the circadian clock, sleep related processes or sleep associated variations in testicular blood flow. In healthy adult men, testosterone rhythm was positively correlated with serum inhibin-ß rhythm with higher values in the early morning hours and lower values in the evening (21).

Whereas in pubertal boys, sleep-related LH elevations are common (17, 22), only 15% of adult men have sleep-related LH elevations (22, 23, 24), and there is no clear circadian rhythm (17, 19). Therefore, it is likely that the robust diurnal testosterone rhythm is only partially controlled by LH. The hypothesis that the diurnal testosterone rhythm is driven by the circadian clock (7, 17) was not supported by our findings. Synchronizing testosterone levels to melatonin onset did not reveal any change in testosterone levels in the fragmented sleep condition. In contrast, the nocturnal rise in melatonin is independent of sleep and was shown to persist in the 7/13 paradigm in the present study and in a previous report (12).

Cooke et al. (25) have demonstrated that the major factors implicated in the testosterone rhythm amplitude were increasing saturation of the binding proteins following rise in testosterone production and the changes in protein concentration related to postural changes. The authors also suggested that the rise in cortisol concentration in the early morning by competing with testosterone for albumin binding sites, may be responsible for the diurnal testosterone rhythm.

It cannot be excluded that changes in posture also contributed to our results. On lying down there is a decrease in protein concentration that is considered to be due to a shift of fluid into the vascular compartment under decreased hydrostatic pressure. This may cause dilution of nondiffusable compounds present in serum (25). In our study during fragmented sleep, subjects were recumbent for the 7-min sleep attempts and then they left the bedroom for 13 min, at which time they were ambulatory. During continuous sleep, subjects were always recumbent from 2200–0700 h. Therefore, it is possible that changes in postures may have contributed to the loss of the night-time rise in testosterone levels. However, dependency of testosterone rise on REM sleep observed during the 7/13 paradigm as previously observed during continuous sleep is hardly explained by postural changes.

Our present results confirm that the rise in testosterone is related to the appearance of the first REM episode of the night. This is supported by the significant relationship between REM latency and the slope of the testosterone rise, the difference in the slopes of testosterone between subjects with and without REM episodes during fragmented sleep, and by the findings in one of the subjects who had several REM episodes without testosterone rise. This man had sustained elevated testosterone levels above the threshold of 13 nmol/L. This threshold was suggested as partially responsible for initiating nocturnal penile tumescence at about the time of the first REM sleep episode (26). Previous studies have shown that a single circadian oscillator controls REM sleep, core body temperature, and melatonin (27). Assuming that the same oscillator was controlling testosterone, we anticipated the persistence of the diurnal testosterone rhythm under fragmented sleep condition. However, the lack of circadian rhythm in testosterone under the 7/13 paradigm, even when synchronized to melatonin onset, precludes such an explanation. Thus, it is possible that the testosterone rhythm is dependent on a specific phase relationship between sleep and the underlying circadian oscillator, rather than on the circadian oscillator per se. Further studies should elaborate this possibility.


   Acknowledgments
 
We thank Mrs. Frances Nachmani for her secretarial assistance.

Received May 1, 2000.

Accepted November 8, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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