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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2706-2710
Copyright © 1998 by The Endocrine Society

Original Studies

Enhanced Slow Wave Sleep in Patients with Prolactinoma

Ralf-Michael Frieboes, Harald Murck, Günter Karl Stalla, Irina A. Antonijevic and Axel Steiger

Max Planck Institute of Psychiatry, Department of Psychiatry, Munich, Germany

Address all correspondence and requests for reprints to: Ralf-Michael Frieboes, Max Planck Institute of Psychiatry, Department of Psychiatry, Kraepelinstrasse 10, D-80804 Munich/Germany. E-mail: frieboes{at}mpipsykl.mpg.de


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Bidirectional interactions between nocturnal hormone secretion and sleep regulation are well established. In particular, a link between PRL and rapid eye movement (REM) sleep has been hypothesized. Short-term administration of PRL and even long-term hyperprolactinemia in animals increases REM sleep. Furthermore, sleep disorders are frequent symptoms in patients with endocrine diseases. We compared the sleep electroencephalogram of seven drug-free patients with prolactinoma (mean PRL levels 1450 ± 1810 ng/mL; range between 146 and 5106 ng/mL) with that of matched controls. The patients had secondary hypogonadism but no other endocrine abnormalities. They spent more time in slow wave sleep than the controls (79.4 ± 54.4 min in patients vs. 36.6 ± 23.5 min in controls, P < 0.05). REM sleep variables did not differ between the samples. Our data suggest that chronic excessive enhancement of PRL levels exerts influences on the sleep electroencephalogram in humans. Our result, which seems to be in contrast to the enhanced REM sleep under hyperprolactinemia in rats, leads to the hypothesis that both slow wave sleep and REM sleep can be stimulated by PRL. These findings are in accordance with reports of good sleep quality in patients with prolactinoma, which is in contrast to that of patients with other endocrine diseases.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A VAST literature indicates that there are bidirectional interactions between the nocturnal secretion of different hormones and the sleep electroencephalogram (EEG) (for reviews see Refs. 1, 2). This assumption is supported by studies in humans and animals of the interaction of the sleep EEG and sleep-associated hormone secretion under baseline conditions, after manipulation of sleep-wake behavior (e.g. sleep deprivation), and after administration of hormones. Another powerful approach is the study of sleep in patients with reduced or excessive release of hormones during aging, psychiatric disorders, and, in particular, endocrine diseases. Concerning the latter, sleep complaints are frequently reported among the pathological changes involving the hypothalamic-pituitary-adrenocortical (3, 4, 5), hypothalamic-pituitary-somatotrophic (6, 7), and hypothalamic-pituitary-thyroid (8, 9, 10) systems. For example, patients with acromegalia (6, 7), Cushing’s disease (3, 4), and hypothyroidism (8) show a reduction in non-rapid eye movement (REM) sleep, particularly in slow wave sleep (SWS). Interestingly, patients with prolactinoma subjectively sleep well. Until now, sleep-EEG recordings of patients with untreated pituitary PRL-secreting tumors have not been published. To examine changes in human sleep in chronical hyperprolactinemia, we investigated the sleep EEG in patients with prolactinoma and consecutive secondary hypogonadism but who had no further identified causes of possible sleep alterations.

Previous investigations—either under baseline conditions or after induced changes of PRL secretion levels—remain equivocal about an interaction of PRL secretion and the sleep EEG. In 1974, a relationship between PRL secretion and the non-REM-REM cycle in humans was reported, with PRL nadirs during REM periods and rising PRL levels during non-REM periods being described (11). Recently, by using EEG spectral analysis, a temporal relationship between {delta} waves and PRL secretion was found in young human subjects (12). Furthermore, systemic short-term administration of PRL stimulated REM sleep in intact animals (for review see Ref. 13), as well as in pontine cats after hypophysectomy (14), but antiserum to PRL decreased REM sleep in rats (15). In all these studies non-REM sleep, including SWS, remained unchanged (14, 15). Long-term hyperprolactinemia in rats that were grafted with a PRL-secreting tumor (SMtTW2) under the kidney capsule, resulted in an increase in nocturnal REM sleep duration, but a progressive decrease in REM sleep during the day; again SWS remained unchanged (16). In another experiment in adult rats bearing juvenile rat anterior pituitary grafts under the capsule of the kidney, a large increase in REM sleep and, in addition, enhanced duration of non-REM sleep with a trend to increased {delta} wave activity in spectral analysis has been described (17). In contrast to the latter study, in genetically hypoprolactinemic rats SWS enhancement and REM sleep suppression in sleep-waking registration has been reported (18). Taken together, these data support the hypothesis that there is an association between sleep parameters and PRL levels, either as a correlation between sleep-EEG parameters and nocturnal PRL secretion (11, 12), or as a direct promotion of sleep, particularly of REM sleep, by administration of PRL (13, 17).

On the other hand, the positive correlation between sleep cycles and plasma PRL concentrations was not confirmed by a study by van Cauter et al. (19). Instead, Wehr et al. (20) investigated circadian influences of sleep-wake and light-dark cycles on PRL secretion, and suggested that the nocturnal rise in PRL secretion is not sleep associated, but rather that it is rest dependent. In another study, the PRL secretory rate was enhanced during the whole sleep period independent of sleep quality, and experimentally impaired sleep did not influence PRL secretion in normal humans (21). Furthermore, in the recovery night following total sleep deprivation there was a distinct increase in PRL levels in young (22) and elderly subjects (23). In the latter study, Murck et al. (23) found that PRL secretion was by trend greater in older than in younger controls, whereas SWS was stimulated less in the elderly compared with young controls. The authors suggested that there might be a common mechanism for stimulation of PRL and sleep, but no causal relationship between the two factors. Because there are no studies examining long-term effects of increased PRL levels on sleep EEG in humans, the sleep-EEG investigation in patients with prolactinoma seemed to be a suitable instrument to study the relationship between excessively enhanced PRL levels and sleep in humans.


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

Seven outpatients, four women and three men, aged 24–48 yr (mean 32.1 ± 9.7 SD), were investigated in the sleep laboratory after informed consent had been obtained and after examination in the neuroendocrinological outpatient clinic of the Max Planck Institute of Psychiatry for evaluation of prolactinoma. At initial evaluation, the patients met the criteria for prolactinoma in hormone measurement and in magnetic resonance imaging of the sella region. PRL blood plasma levels were measured in the morning hours (between 0800 and 1000 h) and were between 146 and 5106 ng/mL (mean ± SD: 1450 ± 1810 ng/mL, normal range 1–25 ng/mL). Two patients had microprolactinoma (<10 mm) and five had macroprolactinoma (>10 mm): the demographic data are given in Table 1Go. Other possible etiologies of hyperprolactinemia beside a prolactinoma were ruled out. The patients had not been treated with drugs for at least 3 weeks before inclusion in the study and had never received dopamine-agonistic substances such as bromocriptine. Female patients using hormonal contraception were excluded from the study. All patients had a secondary hypogonadism accompanied by decreased testosterone/oestrogen and LH/FSH plasma levels, but they had no other endocrine abnormalities, in particular no alterations in insulin growth factor-I, TSH, free thyroid hormones, and cortisol. Their body mass index was within the normal range. Psychiatric diseases and especially symptoms of affective disorders were ruled out. The study control group consisted of sex- and age-matched (mean 32.7 ± 19.5 yr) healthy volunteers who were admitted to the trial after passing a rigid psychiatric, physical, and laboratory medical examination. In patients and controls, factors that could cause ambiguous results such as specific sleep disorders, shift work, or transmeridian flights in the last 3 months were all excluded.


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  		Table 1. Clinical data of patients

 
Materials and Methods

The sleep examination extended over two nights: The first night served as adaptation to the laboratory setting including fixation of EEG electrodes. Patients and probands were allowed to sleep between 2300 and 0700 h. During the second night the sleep EEG was recorded. In the room adjacent to the laboratory, the patients could be observed on a television screen, and polygraphic recordings (EEG, electrooculogram, electromyogram, and electrocardiogram) were monitored between 2300 and 0700 h. The patients were not allowed to sleep before lights off at 2300. Sleep-EEG recordings were scored manually using standard guidelines as previously described (24, 25). Beside the time spent in the different sleep stages (wakefulness, stages 1–4 sleep, and REM sleep), recorded with reference to sleep period time (lasting from sleep onset to final awakening), calculations of sleep parameters included total sleep time, sleep onset latency (time between lights off and the first occurrence of stage 2 sleep), REM latency (time span between sleep onset and first epoch containing REM sleep), and REM density (ratio of 3-sec mini-epochs per REM period, including at least one REM, to the total number of all 3-sec mini-epochs per REM period). For all investigated sleep variables, group values were expressed as mean ± SD. Variables of primary interest, differences between the controls’ and the patients’ stage 2 sleep, SWS, and REM sleep, were tested for significance with multivariate ANOVA (MANOVA), with {alpha} = 0.05 as a nominal level of significance. To test the influence of aging, which has an effect on sleep-EEG parameters per se (26), correlations between changes in sleep variables and age were calculated. Additionally, correlations between sleep-EEG variables and plasma PRL levels were computed. All correlations were calculated by Pearson’s correlation coefficients. To keep the type I error less or equal to 0.05 all posteriori tests about significance of the correlation coefficients were performed at a reduced level of significance (Bonferroni correction).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The sleep-EEG variables of the controls and patients with prolactinoma are given in Table 2Go. Figure 1Go shows representative hypnograms of a patient compared with those of the matched control. ANOVA revealed a significant group effect with an important contribution of the SWS parameter. Time spent in SWS was significantly enhanced in patients in comparison with controls. The other two parameters tested, the amounts of sleep stages 2 and REM, did not differ significantly, but there was a trend towards a decrease in REM sleep in the patients’ group. Furthermore, in the descriptive analysis there were some signs of an improvement of sleep, such as a shortened sleep onset latency and less time awake. The descriptive analysis showed that SWS was somewhat increased in the first half of the night, with the increase in the second half of the night being about 2- to 3-fold. The analysis of correlation coefficients showed a trend towards negative correlation between the sleep efficiency index and age (r = -0.70, P = 0.078), and a significant correlation between the amount of time awake in the second half of the night and age (r = 0.77, P < 0.05) in the controls. In the patients, there was a negative correlation between the amount of SWS and age (r = -0.79, P < 0.05). A positive correlation between PRL and sleep stage 1 in the patients (r = 0.92, P < 0.05) was the only correlation between the plasma PRL levels and sleep-EEG variables. In particular, there was no correlation between the plasma PRL levels and the amount of SWS (r = -0.17, P = 0.72).


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  		Table 2. Sleep-EEG variables in normal controls and prolactinoma patients

 


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  		Figure 1. Sleep pattern in one male 25-yr-old patient with prolactinoma, (A) and in one matched control (B). REM, rapid eye movement sleep; I–IV, Non-REM sleep stages 1 to 4.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We demonstrated for the first time that SWS is increased in patients with prolactinoma in comparison with controls, whereas REM sleep is not affected. Because SWS is elevated not only in the first half of the night, when physiologically the highest amount of SWS appears, but also in the second half of the night, where it is rare in normal subjects, our findings demonstrate a long-acting stimulation of SWS by chronic hyperprolactinemia in humans. This seems to be in contrast to the results of most previous animal research that has investigated the effects of PRL administration on the sleep EEG. After acute administration of PRL and chronic enhancement of plasma PRL in animals, REM sleep increased, whereas there were no significant changes of non-REM sleep in most of the studies (14, 15, 16, 27). Obál and coworkers (17), however, found a significant stimulation of non-REM sleep with a trend to {delta} wave activity enhancement in addition to the increase of REM sleep in rats with chronic hyperprolactinemia. On the other hand, in chronically hypoprolactinemic rats, SWS was also increased (18).

In general, sleep-EEG investigations in rats and humans have to be compared with caution, because in rats sleep is usually distributed over the day in fragmented episodes, whereas the sleep habits of patients and controls in our study only consisted of one continuous episode during the night. Nevertheless, on the assumption that there are comparable mechanisms of sleep regulation in all mammals including humans, the differences between our study results and previous research may be explained by dose-dependent influences of PRL on the sleep EEG and different durations of hyperprolactinemia.

Concerning dose dependency, PRL in human as well as in rat serum and cerebrospinal fluid (CSF) is directly correlated (28, 29), and a receptor-mediated mechanism for the transport of PRL from blood to CSF in epithelial cells of the choroid plexus has been shown (30). In rats, the CSF PRL is maintained within 2% of serum PRL levels in young female animals but within 31% in aged, constantly estrous animals (31). Therefore it can be suggested that in those investigations in rabbits and rats in which PRL was peripherally administered, central PRL concentrations were enhanced up to 2-fold according to the increase of PRL plasma levels (14, 27). For example, the mean plasma PRL concentrations in rats bearing anterior pituitary grafts were 9 ng/mL in the morning and 11 ng/mL in the evening in contrast to 2 and 6 ng/mL in the controls (17). In our study, the mean plasma PRL concentrations in the patients in the early morning were 1450 ng/mL (normal range up to 25 ng/mL), probably accompanied with a more than 20-fold CSF PRL increase. Within the limitations of the suggestion that animal and human data about sleep regulation are comparable, these differences could lead to a hypothesis of dose-dependent effects of central PRL concentrations. Sleep-promoting effects of central PRL in humans, as in animals, may be mediated by locus coeruleus (LC) neuronal activity. Rat LC neurons, in which PRL-like immunoreactivity has been found (32), and which are involved in sleep-wake cycle regulation, showed significantly different discharge rates for consecutive wake and sleep stages, in decreasing order: active waking, quiet waking, light sleep, SWS, REM sleep (33). These results lead to the hypothesis that in the LC, cellular activities during SWS and REM sleep are closely related. Therefore, we suggest that both of these sleep stages with hyperpolarized cell activity can, in general, be promoted by PRL. This suggestion supports the assumption that there is a direct association between central PRL levels and sleep-EEG parameters. In all of our patients the central PRL levels may have passed the level of SWS stimulation, and there was no additional correlation between plasma PRL levels and the amount of SWS within the group.

Beside the PRL CSF level, the duration of enhanced PRL concentrations before sleep-EEG investigation seems to play an important role. It is well known that there are differences between acute and chronic influences of hormones on the sleep EEG. Acutely administered cortisol, for example, enhances non-REM sleep and increases SWS in controls (34, 35, 36, 37), whereas patients with chronic hypercortisolism show a reduction of non-REM sleep (4, 5). Interestingly, the only investigation in rats, in which there are effects on the sleep EEG with significant increases of both REM and non-REM sleep, was that with 4–7 weeks of chronic hyperprolactinemia after anterior pituitary grafts implantation (17). Increased PRL concentrations may cause a rapid onset of REM sleep stimulation and a delayed onset of SWS effects. Therefore, after an increase of the PRL secretion with concomitant central PRL enhancement in humans, for example because of drug influences, a moderate PRL stimulation may lead to an increase in REM sleep, whereas under long-term excessive CSF PRL levels, SWS may be stimulated.

There are two major, opposite-regulating factors of PRL release (38) that have influences on sleep EEG themselves: vasoactive intestinal peptide (VIP) and dopamine (DA). Although excessive PRL levels may modulate their activity, it appears unlikely that VIP or DA, or both play an important role in the sleep-EEG changes in our study. After VIP administration in rats, increases of REM and non-REM sleep were observed, which were suggested to be mediated by PRL (39, 40). In young human control subjects, however, a prolongation of REM- and non-REM periods and an advanced occurrence of the cortisol nadir were found after repetitive administration of VIP (41). These changes are compatible with a phase-advance of sleep-endocrine activity. Because the PRL levels were only slightly, though significantly (about 1.5-fold) elevated in that study, it appears more likely that these effects reflect an action of VIP at the suprachiasmatic nucleus (41). Because no changes in the duration of non-REM and REM periods were detectable in our present study, a major impact of VIP appears unlikely. Concerning DA, there is good evidence that this substance specifically promotes REM sleep. Thus, L-dopa restores REM sleep in the reserpinized cat (42). Gammahydroxybutyrate induces REM sleep in male cats even after inhibition of serotonin synthesis by parachloro-phenylalanine, and it has been suggested that this effect is mediated by DA (43). The DA analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) also increases REM sleep and the mean duration of REM episodes in the rat, acting probably as an antagonist at postsynaptic receptors (44). In our study REM sleep remained unchanged, and therefore DA modulation appears not to be involved in the SWS stimulation under long-term hyperprolactinemia. It also seems unlikely that the secondary hypogonadism of the patients contributed to the sleep-EEG alterations. Administration of sexual steroids has effects on sleep regulation (45, 46), but the hypogonadism in our sample should result in a deterioration of sleep continuity and not in an improvement of deep sleep.

Interestingly, the changes in sleep are expressed more in the younger than in the older patients, as a negative correlation between age and SWS exists (26, 47, 48). Obviously, hyperprolactinemia stimulates SWS more potently in the younger patients than in the older ones, and thus the physiologically high amount of SWS in the young subjects is further enhanced under the pathological conditions. This finding has some similarities to the greater ability of GHRH and cortisol to stimulate non-REM sleep in young (36, 49) compared with older controls (34, 50). We suggest that the sleep-promoting efficacy of some hormones declines during aging independent of physiological concentrations of the substance in the elderly. Whereas GHRH secretion decreases during aging, other non-REM sleep-promoting hormones, namely cortisol and PRL concentrations (47, 51) remain unchanged or even increase.

Our results are in agreement with subjective reports of good sleep quality in patients with prolactinoma (38, 52). Whereas patients with other endocrine diseases often suffer from sleep complaints, patients with prolactinoma do not. Patients with acromegalia and Cushing’s disease and even patients with hypothyroidism often develop sleep disturbances with a reduction of non-REM sleep (4, 5, 6, 8). Whether patients with prolactinoma sleep objectively well has not been investigated until now. Within the limitations of the small study group, and hence a statistical analysis of only three variables (non-REM stage 2, SWS, and REM sleep) this investigation was able to show that patients with prolactinoma do not suffer from sleep impairments. Further studies using spectral analysis need to amplify the results in a longitudinal comparison of hyperprolactinemic patients before and under treatment. PRL, at least when greatly elevated, seems to improve and not to disturb sleep.


   Acknowledgments
 
We thank Annette Grasser, M.D. for recruiting patients.

Received February 9, 1998.

Revised April 27, 1998.

Accepted May 5, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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F. Obal Jr, F. Garcia-Garcia, B. Kacsoh, P. Taishi, S. Bohnet, N. D. Horseman, and J. M. Krueger
Rapid Eye Movement Sleep Is Reduced in Prolactin-Deficient Mice
J. Neurosci., November 2, 2005; 25(44): 10282 - 10289.
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 Am. J. Physiol. Endocrinol. Metab.Home page
J. C. Weikel, A. Wichniak, M. Ising, H. Brunner, E. Friess, K. Held, S. Mathias, D. A. Schmid, M. Uhr, and A. Steiger
Ghrelin promotes slow-wave sleep in humans
Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E407 - E415.
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