Sleep-endocrine effects of mifepristone and megestrol acetate in healthy men

Klaus Wiedemann, Christoph J. Lauer, Margarete Hirschmann, Kristina Knaudt, and Florian Holsboer

Max Planck Institute of Psychiatry, Clinical Institute, 80804 Munich, Germany

    ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References

Administration of steroid hormones was demonstrated to modulate the sleep electroencephalogram (EEG) and sleep-associated hormonal secretion in specific ways. The present study was conducted to compare the effects of mifepristone (Mif), a mixed glucocorticoid (GR) and progesterone receptor (PR) antagonist, and megestrol acetate (Meg), a PR agonist. Nine healthy men were pretreated with either placebo or 200 mg Mif or 320 mg Meg, or a combination of both. Changes in plasma adrenocorticotropic hormone (ACTH), cortisol, and growth hormone concentrations were registered every 30 min; sleep EEG recordings were obtained continuously. Administration of Mif increased the morning plasma ACTH and cortisol surges, whereas Meg had the opposite effect. Growth hormone secretion was lowered by Mif pretreatment and enhanced by Meg. Simultaneous administration of both compounds led to largely compensated effects. The sleep EEG changes induced by Mif were a slight increase in the time awake and a delayed onset of slow-wave sleep. Meg led to a reduction of rapid-eye-movement sleep. Simultaneous administration of Mif and Meg showed a synergism in increasing time awake and shallow sleep: it therefore may be concluded that the sleep EEG effects are mediated by an interaction of GR and PR in unknown mechanisms.

adrenocorticotropic hormone; cortisol; glucocorticoids; growth hormone; progesterone; sleep electroencephalogram

    INTRODUCTION
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Abstract
Introduction
Methods
Results
Discussion
References

IN ADDITION to their well-established endocrine effects, steroids also modulate the sleep electroencephalogram (EEG). Steroids exert their effect through two different mechanisms: genomic actions through nuclear receptors and nongenomic actions through membraneous sites. The genomic actions are mediated by cytoplasmatic mineralocorticoid receptors (MR) and glucocorticoid receptors (GR), which after ligand binding may form either homodimers or heterodimers, all of which have different DNA binding properties and transactivating potencies (39). The effects of these steroid-activated receptors on sleep architecture in men were first discovered by Gillin et al. (16) and subsequently corroborated in other sleep-endocrine studies (5, 17). Besides MR and GR, additional binding sites of steroids located at gamma -aminobutyric acid (GABA)-gated ion channels have also been identified. These sites mediate a fast-onset modulation of chloride conduction by GABA (1, 31), which may also have effects on the sleep EEG (5, 37).

Up to now, discrimination of the systemic effects by this binary nuclear receptor system was difficult, since synthetic steroid receptor agonists proved not to be sufficiently specific. With the availability of mifepristone (RU-486; Mif), a GR antagonist, a more specific investigation of GR-mediated effects has become possible. For example, we recently demonstrated that administration of 400 mg Mif resulted in a considerably enhanced morning rise of plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations and a profound deterioration of nocturnal sleep pattern with frequent awakenings and a reduction of slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep (40).

Mif also binds at progesterone receptors (PR), which further complicates the allocation of steroid effects via GR to specific regulatory brain functions. Despite many data collected from animals and humans during the menstrual cycle and pregnancy, the involvement of PR in sleep EEG effects remains uncertain (10, 23, 26, 28, 29). Most recently, Driver and Shapiro (14) were unable to find any significant variation of sleep parameters during the menstrual cycle.

The aim of the present study was to compare the effects of the mixed GR/PR antagonist Mif and the progesterone derivative megestrol acetate (Meg) on hormonal secretion and sleep regulation. Meg has strong PR agonistic properties, but, in contrast to naturally occurring progesterone (8), it is not metabolized to derivatives that are able to bind at GABA receptors (11). Thus Meg has an advantage over progesterone for studies on PR-mediated effects on sleep.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Subjects. Nine healthy male volunteers, aged 25-32 yr and of normal body weight (63-80 kg), were investigated in our Sleep Research Unit. Each subject was given a thorough medical examination and evaluated by a semistructured interview. Individuals with drug abuse, a personal or family history of psychiatric disorders, or a recent stressful life event were excluded. Subjects who complained of symptoms suggestive of sleep apnea or sleep-associated movement disorders such as restless legs syndrome were not included. Furthermore, none of the participants had been subjected to sleep deprivation, alcohol during the 2 days preceding the polysomnography, excessive coffee intake (restricted to 150 ml in the morning), or nicotine intake (restricted to a maximum of 3 cigarettes on day before investigation). Subjects with shift work or time shifts during the 3 mo preceding the study period were also excluded. In addition, all subjects had been free of prescription and nonprescription drugs such as salicylates or antihistamines for at least 3 mo. Urinary drug screens (barbiturates, benzodiazepines, opiates, cannabinoids, phencyclidine, cocaine, amphetamines, and related compounds) were negative for each volunteer and at each occasion. Written informed consent was obtained from each subject; the protocol had been approved by the ethics committee on human experiments at the Max Planck Institute.

Substances. Mif [RU-486; 11beta -(4-dimethyl(amino)phenyl)-17beta -hydroxy-17alpha -(prop-1-ynyl)-estra-4,9-dien-3-one] was obtained from the manufacturer Roussel-UCLAF, Romainville, France. In different in vivo and in vitro models, it has been proved to antagonize the action of glucocorticoids and progestins (35). Meg (17alpha -acetoxy-6-methylpregna-4,6-diene-3,20-dione), which possesses a strong progesterone activity, is commercially available from Bristol-Myers Squibb, Munich, Germany.

Investigation procedure. All subjects were kept under video observation in a sound-shielded room in our Sleep Research Unit. They slept for 2 nights in a row on four occasions (trials 1-4), separated by at least 1 wk. The first night of each trial served for habituation to the experimental setting, including the attachment of the electrodes and cannulation of a forearm vein to avoid a needle effect on sleep EEG. In the four trials, the volunteers received in a prospective, randomized double-blind setting, placebo (Pla, at 1400, 1430, and 1900), 200 mg Mif (200 mg Mif at 1400 and Pla at 1430 and 1900, respectively), 320 mg Meg (Pla at 1400 and 160 mg Meg at 1430 and 1900, respectively), or a combination of 200 mg Mif and 320 mg Meg (Mif at 1400 and 160 mg Meg at 1430 and 1900, respectively). This time schedule was based on the pharmocokinetics of Mif and Meg. Mif has a half-life of >20 h and a time to maximal plasma concentrations of ~4-6 h. Meg has a half-life of ~12 h; therefore, the dosage was divided. During the night, approximate steady-state conditions could be expected. At 1800, all volunteers had an electrolyte- and calorie-balanced standard meal; at 1930, an intravenous cannula was placed into a forearm vein connected to through-the-wall tubing. A saline infusion (0.9% NaCl) at 70 ml/h was given to keep the line patent. Blood samples were drawn every 30 min via the through-the-wall tubing from 2200 to 0700 to avoid direct manipulations in the investigation room. EEG electrodes were fixed at 2200. The subjects were allowed to sleep between 2300 (lights off) and 0700 (lights on).

Sleep EEG analysis. Sleep polygraphs of the respective nights were recorded and visually scored according to standard procedures (25). Scoring was done by a trained technician unaware of the experimental design. The sleep EEG parameters routinely calculated have been described elsewhere (25). For inferential statistical analysis, the following two sets of sleep variables were taken into consideration: set A (variables measured during whole night), sleep period time, sleep efficiency, the latencies to sleep onset and SWS as well as the relative amounts of time awake, stage 2 sleep, SWS, and REM sleep; and set B (variables measured separately for 1st and 2nd halves of night), the relative amounts of time awake, SWS, and REM sleep.

Hormonal measurements. Plasma cortisol concentrations were analyzed using a commercially available radioimmunoassay kit with coated-tube technique (ICN Biomedicals, Carson, CA). The detection limit was 0.3 ng/ml plasma; intra- and interassay coefficients of variation for 20 and 40 ng/ml levels were below 7%. Immunoradiometric assays without extraction procedures were used (Nichols Institute, San Juan Capistrano, CA) for ACTH and growth hormone (GH) measurements. The detection limit for ACTH was 3.5 pg/ml in our hand, and the intra- and interassay coefficients of variation at 20 pg/ml plasma were below 8%. For GH, the minimal detectable amount was 0.2 ng/ml plasma; both coefficients of variation at 5 ng/ml plasma were below 8%.

Statistical methods. Hormonal concentrations at single time points were examined and compared between treatments on the exploratory level. For confirmatory analysis of hormones, areas under the curve (AUC) were calculated according to the trapezoid rule, and mean locations (ML) of their time series during the first and second halves of the night were considered. For variance homogeneity, AUC values were log transformed. Comparisons of AUC and ML variables between the various treatments and the first and second halves of the night were performed for each hormone separately by multivariate analysis of variance (MANOVA) with repeated-measures design. Because dependence between hormones could not be excluded, a simultaneous consideration of all hormones in a single MANOVA design, which had to be the regular procedure for analyzing various effects, was not possible here. The small sample sizes and the multitude of variables would have led to singularities, making any further analysis questionable. The same MANOVA design was applied to set B sleep EEG variables. Thereby treatment and time were both two within-subjects factors, the first with four levels (Pla, Mif, Meg, Mif/Meg) and the second with two levels (1st and 2nd halves of night). The MANOVA design for set A sleep EEG variables consisted of only one within-subjects factor (treatment). The aforementioned note for hormones is also valid for the sleep EEG variables. In the case of significant main or interaction factor effects, subsequent univariate F tests within MANOVA were used to identify those variables that contributed to the overall main effects. For variables showing significant treatment effects, tests with simple effects (contrasts) followed to identify the treatment levels with significant differences in those variables. An alpha  of 0.05 was accepted as the nominal level of significance. Apart from the global hypotheses concerning the main factor effects, all other effects were tested for significances at a reduced level (adjustment of alpha  according to Bonferroni procedure) for keeping the type I error <= 0.05. All results are expressed as means ± SE.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Hormones. As indicated in Fig. 1 and Table 1, administration of 200 mg Mif significantly enhanced the release of ACTH and cortisol in the morning hours. This is confirmed by the statistical analysis, in which, for the variables AUC and ML for both hormones ACTH and cortisol, significant treatment and time effects were found by MANOVA [Wilks multivariate tests of significance; treatment effect on ACTH and cortisol: minimal approx. F value with df(6,3) = 22.44, significance of F = 0.014; time effect on ACTH and cortisol: minimal approx. F value with df(2,7) = 94.21, significance of F < 0.0001]. These effects became overt especially when the first and second halves of the night were compared (2200-0300 and 0300-0700). Until 0300, no trial effects were obvious. After administration of Meg, the morning rise of ACTH and cortisol was largely suppressed, leading to significant differences between the treatments (tests with contrasts in MANOVA: P < 0.05 for the differences in ACTH and cortisol between Meg and all other treatments in 2nd half of night). The combination of Mif and Meg led to nearly balanced effects: after a significant delay of the morning rise by ~3 h the 0700 plasma concentrations of ACTH and cortisol were comparable to those of the Pla trial (Fig. 1). Especially the last hour of investigation (0600-0700) revealed highly significant differences of ACTH and cortisol secretion between the treatments (Table 1).


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Fig. 1.   Mean plasma hormonal concentrations of cortisol during 4 respective treatments as indicated. Mif, mifepristone; Meg, megestrol acetate. Dashed line indicates separation of 1st from 2nd half of night at 0300.

                              
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Table 1.   Effects of 200 mg Mif, 320 mg Meg, and 200 mg Mif + 320 mg Meg on hormone plasma concentrations in nine healthy volunteers

As shown in Fig. 2 and Table 1, the secretory activity of GH was also significantly affected by the factors time and treatment by time [Wilks multivariate test of significance; treatment effect on GH: approx. F(6,3) = 10.33, significance of F = 0.046; treatment by time effect on GH: approx. F(2,7) = 13.27, significance of F = 0.004]. GH concentrations after Mif were marginally lower than those of Pla during the first half of the night, whereas after Meg a considerable increase in the nocturnal release was seen (tests with contrasts in MANOVA: P < 0.05 for AUC and ML differences between Pla and Meg in 1st half of night). The effects of Mif and Meg on GH secretion were nearly counterbalanced by combined administration of Mif and Meg (Fig. 2).


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Fig. 2.   Mean plasma hormonal concentrations of growth hormone (hGH) during 4 respective treatments as indicated. Dashed line indicates separation of 1st from 2nd half of night at 0300.

Sleep EEG. Application of the repeated-measures MANOVA to sleep EEG parameters of the total night (set A) resulted in significant treatment effects [Wilks multivariate test of significance; treatment effect: minimal F value with df(3,6) = 5.19, significance of F = 0.042] to which the following parameters mainly contributed: time awake, which was significantly increased in the Mif-Meg condition compared with Pla and Meg; the amount of stage 2 sleep, which was increased after Meg administration compared with Pla and Mif-Meg; and the amount of REM sleep, which was decreased after administration of all active drugs compared with Pla (Fig. 3). The application of the repeated-measures MANOVA to the sleep EEG parameters of the first and second halves of the night (set B) yielded a significant treatment effect for only REM sleep [Wilks multivariate test of significance; approx. F(3,6) = 6.14, significance of F = 0.029], which is due to the significant difference between the Pla and Meg condition in the first half of the night (Table 2). As expected, comparisons between the first and second halves of the night revealed that SWS and REM sleep, but not time awake, showed significant differences [Wilks multivariate test of significance; minimal F value with df(1,8) for the test, involving time effect = 54.42, significance of F <=  0.0001]. They are significant in each of the treatment conditions (P < 0.05 for all tests with contrasts).


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Fig. 3.   Relative proportion of time awake, slow-wave sleep (SWS), and rapid-eye-movement (REM) sleep during whole night in relation to sleep period time (SPT). Pla, placebo. Mean ± SE values are given for 4 treatments as indicated.

                              
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Table 2.   Effects of 200 mg Mif, 320 mg Meg, and 200 mg Mif + 320 mg Meg on EEG sleep measures in nine healthy male subjects

During the Mif trial, both sleep-onset and SWS latencies were considerably prolonged (Table 2), and as a consequence, the amount of SWS during the first sleep cycle (values not considered in Table 2) was decreased (Pla: 38 ± 16%; Mif: 26 ± 13%; Meg: 34 ± 22%; Mif - Meg: 34 ± 21%). However, these differences were significant only at the nominal level.

    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

The major result of the present study is a dissociation between the effects of Mif and Meg on endocrine activity and sleep EEG. At the dosages used here, Mif and Meg exerted opposite effects on the secretion of ACTH, cortisol, and GH, but both steroids summated their negative effects on the quality of sleep.

As expected, Mif enhances hypothalamic-pituitary-adrenocortical (HPA) activity in the early morning hours via blockade of GR, which impairs the negative-feedback regulation (4). In addition, Mif suppresses the release of GH at the time around sleep onset. This finding agrees with previous reports (40) and is also explained by the GR antagonistic action of Mif, because GR agonists increase the number of GH-releasing hormone receptors (9) and stimulate the expression of the GH gene (35). These direct effects on somatotrophic cells are reported to be amplified by GR agonist-induced desensitization of somatostatin receptors (34). Meg suppresses ACTH and cortisol secretion, probably through GR agonistic effects (6, 12), since up to now the existence of PR on cortico- and somatotrophic cells has not been reported (41). In line with this interpretation is our finding that Meg has effects on plasma GH secretion that are comparable with those of dexamethasone (40). Also, a stimulation of estrogen receptors, which enhances the spontaneous secretion of GH and insulin-like growth factor I (3), is unlikely to be involved in this effect, since Meg exerts no effect at these receptors. When Mif and Meg are administered concomitantly, the secretory pattern of GH is indistinguishable from that under placebo. ACTH and cortisol surges in the morning hours are blunted after combined Mif and Meg treatment compared with Mif or Pla alone but not suppressed to the same extent observed during Meg alone. This observation suggests that Mif and Meg exert counteracting effects on the HPA activity, presumably via GR. Besides the incomplete suppression after combined Mif and Meg administration, the time course when the increase of the secretory activity occurs indicates a change in the feedback regulation.

Regarding sleep EEG, we observed that Mif increased the time awake, delayed the onset of sleep, and the onset of the first SWS period. The total amount of SWS during the first sleep cycle was decreased. These findings agree in general with those reported earlier by us (40) applying 400 mg of Mif, but they are less pronounced because of the lower dose used in the present study. Meg also decreased the amount of REM sleep; when coadministered with Mif, the amount of REM sleep further decreased and was significantly lower than under placebo conditions. Both Mif and Meg increased the time when the study subjects were awake. Thus Mif and Meg affected the sleep EEG similarly; i.e., there was a flattening of sleep and an increased amount of REM sleep. Whether these effects are mediated by either GR or PR alone or by combined receptor activation remains still unclear. Although the endocrine effects of Mif on nocturnal hormone secretion agree with its antiglucocorticoid action, the mechanims involved in its effects on sleep EEG remain open to speculation. Because GR agonists increase SWS (5, 16), we suggest that the reduction of SWS by Mif may be attributed to central GR antagonistic action (40). The reasons both Mif and Meg reduce REM sleep remain elusive. Both Mif and Meg bind to the PR (12, 32). According to systemic and molecular studies, PR-regulated processes are activated by Meg, whereas Mif acts in a largely inhibitory way (2, 12, 20, 32). Whether Mif and Meg share the same intrinsic activity in neuronal systems mediating REM sleep remains open. Fluctuations of endogenous progesterone levels in women during the menstrual cycle are reported to correlate with sleep EEG stages in some (26, 30, 36) but not all studies (10, 13). In this context also, decreasing estrogen levels could play an important role, since estrogens are reported to increase REM sleep (33). When the focus is on associations between progesterone levels and EEG sleep during pregnancy, a similar equivocal picture emerges despite considerably higher progesterone levels compared with those of the menstrual cycle (7, 18, 19). Recently, Driver and Shapiro (14) reported that REM sleep was decreased at ~23 compared with 12 wk of gestation. Those studies that found associations between sleep EEG stages and plasma progesterone concentrations agreed with the decreasing effect of progesterone on the amount of REM sleep. This is consistent with the view that Mif (17, 27) may also act beside Meg as partial agonist on PR-controlled REM sleep. In vitro experiments with rat pituitary tumor cells revealed that in the presence of GR the effects of combined Mif and Meg are neutralized, whereas in the absence of GR the effects of both drugs were found to be additive, presumably via an agonistic effect of Mif on the PR (24). However, as already mentioned, the antagonistic effects at GR also have to be taken into account.

For the molecular actions of Mif, two mechanisms have been suggested: Mif exerts its antiglucocorticoid activity both at the level of GR transformation and via alteration of a step subsequent to GR-DNA binding; and the PR antagonistic effect of Mif is thought to be related to a post-DNA binding step (2). PR occurs in two distinct forms, PRA and PRB (21), and the mRNAs of both receptor subtypes were found to be region specific (22). Although Mif is reported to exert its antiprogestin effects via PRA (38), it is unknown whether, and to what extent, Meg exerts its agonistic effects via both PRA and PRB or via one receptor only. Hence, several cellular mechanisms could possibly be involved in the diverging effects of Mif and Meg on hormonal and sleep EEG regulation: the affinity of both compounds to more than one steroid receptor, a tissue-specific receptor expression (22), differences in the accessibility of the genetic sequence (2), and mutual interaction of different receptor subtypes (39) could all be responsible for the observed effects.

In all, we found that both synthetic steroids Mif and Meg exert unidirectional effects on sleep EEG but opposing effects on sleep-associated hormone secretion. These findings underscore the impression that synthetic modifications of the steroid molecule can lead to drugs that produce specific effects on human sleep and associated endocrine activity.

    ACKNOWLEDGEMENTS

The authors thank Dr. Ullmann from Roussel-UCLAF, France, for the generous gift of RU-468, Dr. A. Yassouridis from the Max Planck Institute of Psychiatry for help with the statistical analysis of the data, and I. Hein for preparing the manuscript.

    FOOTNOTES

Address for reprint requests: K. Wiedemann, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.

Received 18 February 1997; accepted in final form 29 September 1997.

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Abstract
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Methods
Results
Discussion
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AJP Endocrinol Metab 274(1):E139-E145
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