the interrelation between psychiatric and thyroid disorders has been extensively studied in the past decades [ 1 , 2 ] and is currently in the focus of modern brain imaging techniques . in hypothyroid patients ,
thyroid hormone treatment reduced depressive symptoms and somatic complaints and restored the metabolic activity in brain areas that are integral to the regulation of mood and cognition . in patients with primary mood disorders , treatment with thyroid hormones normalised hypoperfusion of specific brain regions associated with depression .
clinical data have evidenced good efficacy of supraphysiological dosages of thyroid hormones in the treatment of unipolar and bipolar mood disorders .
high doses of up to 600  g per day of l - t4 were surprisingly well tolerated even over treatment periods of up to 51 months [ 5 , 6 ] , as indicated by cardiovascular monitoring , special questionnaires , and measurements of bone mineral density [ 6 , 8 ] .   disrupted sleep is considered both a prominent symptom of mood disorders and a typical sign of thyrotoxicosis . in the context of supraphysiological application of thyroid hormones in depressed patients , presumably leading to hyperthyroxinemia , investigation of sleep is consequently of particular interest .
we , therefore , felt it was worth investigating the effects of supraphysiological doses of l - t4 on sleep architecture by means of polysomnography . although it is well established that various hormones ( e.g. , growth hormone releasing hormone , corticotropin releasing hormone , and prolactin ) modulate sleep - wake activity , little is known about the effects and underlying mechanisms of changes in thyroid status on sleep .
hypothyroidism , a clinical syndrome characterized by a deficient thyroidal production of thyroid hormone , has been observed to be accompanied by increased numbers of awakenings and a reduced amount of   slow wave sleep ( sws ) in humans and rats .
patients with hypothyroidism may sleep for long periods during the day and , in severe cases , may lapse into stupor and even coma . on the contrary insomnia
is listed among the neuropsychiatric manifestations of thyrotoxicosis , the clinical syndrome of hypermetabolism that results from sustained increased serum concentrations of thyroid hormones .
three studies of patients with clinical or subclinical hyperthyroidism reported sleep problems as a frequent complaint and sleep quality being subjectively rated as bad [ 1416 ] .
with respect to sleep architecture , the results of some studies are in agreement , while others contradict each other : passouant and coworkers   observed an increased sleep latency , a reduced total sleep time , an increased rem density and rem duration as well as a reduction in slow wave sleep in eight patients with clinical hyperthyroidism .
observed a reduced sleep efficiency , low delta sleep , short rem latency , and a high rem density in one case of thyrotoxicosis .
in contrast to this finding , dunleavy et al .   reported a higher percentage of sws during the hyperthyroid state as compared to the sleep structure , once the thyroid hormone levels had returned to normal in a study of four subjects .
kales and coworkers   studied six patients with clinically determined hypothyroidism and found normal rem parameters , sleep latencies , and sleep duration , but an increase in sleep stage 2 ( s2 ) , and a reduction of sws .
the only finding that could be replicated was reduced sws in nine patients with hypothyroidism ruiz - primo et al .
however , it should be emphasized that all but one of these studies date back to a time when a commonly accepted and reliable system of sleep scoring was not yet available and thyroid dysfunction was diagnosed clinically . only in the study by kronfol et al .   were serum thyroid hormone levels determined .
thus , knowledge as to which disorders can cause sleep disturbances and which diseases can present initially as a sleep disorder , are helpful in managing the patients and in reducing the costs of diagnostic procedures and treatment by improving the diagnostic rationale .
the present study was part of a project that investigated differences in response to supraphysiological doses of levothyroxine between healthy individuals and patients with refractory depression . in this study , we investigated the effects of high , supraphysiological doses of levothyroxine on sleep and other physiological parameters ( electrocardiogram , heart rate , body temperature , and respiration rate ) in healthy individuals . by inducing an experimental hyperthyroid state in healthy individuals
, we also expected to get a clear picture of the effects of hyperthyroidism on sleep .
this study was part of a series of trials to investigate the effects , tolerability , and safety of treatment with supraphysiological doses of l - t4 in patients with refractory mood disorders and in healthy controls [ 7 , 10 , 26 ] .
thirteen healthy volunteers ( 6 female , 7 male ; age range : 2350 years , mean  sd : 36.2  8.8 years ) participated . inclusion or exclusion from the study was determined by a semistructured medical and psychiatric interview including a physical examination , an electrocardiogram ( ecg ) , measurements of blood pressure , heart rate and body weight , a laboratory workup including red and white blood cell count , blood chemistry , basal tsh , serum thyroid hormones ( total thyroxine [ t4 ] , free t4 [ ft4 ] , total triiodothyronine [ t3 ] , and free t3 [ ft3 ] ) , and thyroid autoantibodies ( thyroid peroxidase antibody , thyroglobulin antibody ) .
the inclusion criteria were 18 to 50 years of age , euthyroid status , absence of any signs of medical illness , euthymic mood ( as indicated by a score < 8 on the hamilton rating scale for depression ) .
the exclusion criteria were : past or current thyroid , medical or psychiatric disorder ; substance abuse or dependency , pregnancy or lactation ; and use of any medication or hormones , apart from oral contraception ( for details , see bauer et al .
, the initial dose of 50  g / d of l - t4 was administered as a single morning dose 1530 minutes prior to breakfast .
the dosage was increased by 50  g / d every three to seven days to achieve a dose of 500  g / d by day 42 , maintaining that dose for another two weeks .
the dosage of l - t4 was not further increased if the subject experienced intolerable symptoms or wished to discontinue the study . in the latter case ,
if the subject agreed , the highest possible l - t4 dosage was continued for a maximum of 14 days , and discontinued after carrying out the final examinations . if this was not possible , the final examinations were done immediately , hormone intake was discontinued immediately , and the sleep recording was performed the same night .
this was the case for three subjects . for the remaining ten subjects , at the end of the 14 days period on the maximum dosage of l - t4
one whole night 's sleep was recorded in the sleep laboratory , following the same protocol as mentioned below .
subjects documented their medication intake , heart rate , and possible side effects every morning . at weekly visits , the thyroid symptom list , a 24-item clinician - administered instrument to rate signs and symptoms of thyrotoxicosis , was completed for each subject .
safety evaluations regarding the laboratory and cardiovascular workup were performed weekly until the end of treatment . for safety reasons ,
compliance with medication was monitored by weekly measurement of tsh ( thyroid stimulating hormone ; usually suppressed at a l - t4 dose of > 200  g / d ) . before initiation of t4 administration ,
two subsequent nights of sleep were recorded polysomnographically , including the registration of the following leads : vertical and horizontal electrooculogram ( eog ) , electroencephalogram ( eeg ) with 5 leads ( c3-a2 , c4-a1 , c3-c4 , oz - a1 , and oz - a2 ) , mental electromyogram ( memg ) , and emg of both anterior tibial muscles ( temg ) ( pl - eeg , walter graphtec gmbh , bad oldesloe , germany ) . furthermore , nasal air flow , thorax movements , snoring , electrocardiogram ( ecg ) , and rectal body temperature ( w+w - recorder series 310 ; ysi thermistorsonden , serie 400 ) were recorded .
sleep recordings were analysed visually according to the rules of rechtschaffen and kales . to determine
the heart rate and respiration rate during sleep , the night was divided in three thirds . for each of the sleep stages
s2 , sws , and rem , ten artefact - free 30-second - epochs were identified in each third of the night . within these selected epoques ,
the first pre - medication night was an adaptation night and , therefore , not used for analysis .   to assess the effect of l - t4 on hormones of the hypothalamic - pituitary - thyroid ( hpt ) axis ( t3 , ft3 , t4 , ft4 , and tsh ) , physiological parameters ( core body temperature , heart and respiration rate ) and a number of sleep parameters were taken into account . these were time in bed ( tib ) , sleep period time ( spt ) , total sleep time ( tst ) , sleep efficiency ( sei : tst / tib  100 ) , number of changes of sleep stages ( css ) , body movement index ( bmi ; number of larger body movements during tst ) , eye movement index ( em ; number of rapid eye movements during rem = rem densitiy ) , latencies to sleep stage 1 ( l s1 ; time from lights off until the first occurrence of sleep stage 1 ) , to sleep stage 2 ( l s2 ; time from lights off until the first occurrence of sleep stage 2 ) , to slow wave sleep ( l sws ; time from lights off until the first occurrence of slow wave sleep ) , to rapid eye movement sleep ( l rem ; time from falling alseep until the first occurrence of sleep stage rem ) , the amount of wakefulness ( w ) , the duration of the sleep stages s1 , s2 sws , and rem , and movement time ( mt ) .
the individual differences between baseline levels and those under treatment were assessed by wilcoxon 's matched pairs signed ranks test .
although there was no reason to reject the hypothesis that the -values were normally distributed as tested by shapiro - wilk test , the nonparametric wilcoxon 's matched pairs signed ranks test was chosen instead of the t - test for paired observations , since the sample size is small .
during administration of l - t4 ( mean  sd : 476  41  g / d ) , serum total thyroid hormone levels ( t3 and t4 ) and free hormone levels ( ft3 and ft4 ) increased significantly ( all p < .01 ) . before administration of l - t4 ,
as expected from an intact negative feedback control of the hpt axis , the basal tsh values decreased significantly ( p < .05 ) during l - t4 administration ( table 1 ) .
tsh was fully suppressed in all individuals including subjects that had to discontinue l - t4 intake early , as well as those that reached the highest dosage .
therefore , the data of all 13 subjects included in the study was able be used for analysis of the sleep data .  
the results presented in table 2 demonstrate a statistically significant increase in heart rate and respiration rate during l - t4 intake .
the data also show that this increase persists during the sleep stages s2 , sws , and rem .
furthermore , the data indicate that the known tendency of a slightly higher heart rate and respiration rate in rem sleep is preserved during l - t4 intake
.   data on nocturnal core body temperature were available for 11 subjects only , because two subjects did not tolerate the rectal measuring device .
the mean values of body temperature tended to be slightly higher during l - t4 intake ; however , the differences were not statistically significant ( table 3 ) .
the standard deviation calculated on the basis of measurements read every 15 minutes , which was used as an indicator of variability , did also not show a clear trend .  
an intraindividual test ( wilcoxon 's matched pairs sing ranks test ) on homogeneity of the body temperature distributions revealed that , except for one female subject , the differences were statistically significant ( p < .05 ) . for seven of the ten subjects with statistically significant differences , body temperature measured prior to medication was lower than during l - t4 treatment .
the three subjects with a higher body temperature prior to l - t4 treatment were women .
a representative example of the time course of core body temperature differences in males recorded before and during l - t4 intake is shown in figure 1 . in females
, opposite trends were observed in different subjects ; some showed a decrease in core body temperature during treatment , others an increase ( see figures 2(a ) and 2(b ) ) .   in seven out of the eleven subjects in whom
core body temperature could be sampled , the nadir of body temperature was advanced during l - t4 intake by 15 minutes to 270 minutes .
it was most pronounced in three of these subjects with an advance of 75 , 150 , and 270 minutes , respectively . in one
no shift was found in two subjects , while due to a dislocation of the measuring device during sleep , the nadir could not be determined in one further subject .  
the medians of the individual differences between the pre - t4 treatment night and the night during l - t4 intake were close to zero for the entire group in the global sleep parameters tib and spt although there were marked differences in individual subjects , partly showing an increase partly a decrease .
tst tended to be shorter during l - t4 intake , the median of the individual differences was 38 minutes .
the sei tended to be slightly reduced during l - t4 intake . since two individuals showed a pronounced increase in their sei with medication while nine subjects showed the expected decrease , the differences on average were statistically not significant .
neither the sleep stage latencies nor their duration expressed as percentages revealed any systematic changes .
only two parameters showed a tendency in their variation , namely , bm and rem densitiy .
to our knowledge , this is the first study to investigate the effects of supraphysiological doses of l - t4 on sleep by means of polysomnography . all subjects developed hyperthyroxinemia as indicated by significantly elevated serum free thyroxine levels , heart rate , and respiration rate , and by suppression of basal tsh during treatment with l - t4 .
these results were expected from treatment with supraphysiological doses of l - t4 and are in line with those given in the pertinent literature .
it is also well established that increased serum levels of thyroid hormones may lead to an accelerated heart and respiration rate [ 2729 ] .  
the main finding of this study is that 8 weeks of treatment with supraphysiological doses of l - t4 do not profoundly influence the sleep structure .
this result was unexpected for two reasons : ( 1 ) patients with clinical hyperthyroidism frequently complain about sleep disturbances   and ( 2 ) previous studies have suggested a substantial role of the hpt system in sleep endocrine activity , and as evidenced in experimentally induced hypothyroid conditions in rats [ 32 , 33 ] .
however , there are studies demonstrating no alterations in sleep characteristics in subjects with overt hyperthyroidism   and thyroxine - injected ( euthyreot ) rats [ 32 , 35 ] .
furthermore , thyrotropin - releasing hormone ( trh ) exerts only weak effects on the sleep patterns of healthy male volunteers .
thus , it appears that normal thyroid hormones are necessary for sleep but that a further increase in thyroid hormone levels does not produce significant changes in the sleep architecture underlining the good tolerability of supraphysiological doses of l - t4 in the treatment of mood disorders .
however , we would like to emphasize that this may be different in patients with clinical hyperthyroidism who may well suffer from sleep disruption which is caused by higher and longer - lasting thyroid hormone levels than those which are produced in an eight - week experimental study .   in the male subjects , a slight increase in core body temperature
however , marked interindividual differences were present . in women , body temperature changes had opposite directions in different individuals .
this might be due at least in part to the influences of the menstrual cycle , which was not controlled for .
thyroid hormones increase thermogenesis as a result of the stimulation of numerous metabolic pathways involved in the development and delivery of energy to the tissues . as a result ,
high fever ( > 40c ) is a cardinal manifestation of severe forms of thyrotoxicosis .
the advancement of the nadir of body temperature that was observed in most of the subjects might be due to the suppression of tsh .
thus , it may be speculated that low / suppressed tsh levels could be responsible for inducing a phase advance state . with respect to treatment efficacy in depressed patients with l - t4 ,
it is of great interest that in the present study the effect of l - t4 was most pronounced on rem sleep . although rem latency , which is delayed by a number of antidepressive drugs ( e.g. , tri- and tetracyclic drugs , mao inhibitors ) , did not change markedly , rem density increased
this could be another indicator for the suggested stimulation of the cholinergic system , which is involved in mood regulation , by l - t4 . because of the marked effects of the hyperthyroxinemic state that was induced in this study , neither the subjects nor the physicians could effectively be blinded .
further work to establish the effect of thyroid dysfunction on sleep has to be done .
 disrupted sleep is prevalent in both mood and thyroid disorders . given the emerging use of thyroid hormones in the treatment of mood disorders , we investigated the effects of supraphysiological doses of levothyroxine ( l - t4 ) on sleep . in an open - label design , 13 healthy subjects received up to 500  g / day for an eight - week period . 
 a baseline night was polysomnographically recorded ( psg ) followed by psg under the maximum tolerated dose of l - t4 . all subjects developed hyperthyroxinemia . 
 the heart rate and respiration rate increased significantly with treatment ; a significant increase in body temperature was observed in men but not in women . 
 surprisingly , treatment with supraphysiological doses of l - t4 did not cause significant effects on sleep architecture . 
 however , the increase in body movements and rem density was close to reaching statistical significance . here , we report on the sleep data , thyroid hormone levels , and physiological parameters during sleep . 
 we conclude that experimentally induced hyperthyroidism does not profoundly change the sleep structure in healthy individuals underlining the good tolerability of treatment with supraphysiological doses of l - t4 in patients with mood disorders . 
1. Introduction
2. Methods
3. Results
4. Discussion