J Appl Physiol 92: 1684–1691, 2002.
First published December 7, 2001; 10.1152/japplphysiol.00919.2001.
Acetaminophen does not affect 24-h body temperature or
sleep in the luteal phase of the menstrual cycle
FIONA C. BAKER,1 HELEN S. DRIVER,1 JANICE PAIKER,1,2
GEOFFREY G. ROGERS,1 AND DUNCAN MITCHELL1
1
Wits Sleep Laboratory, Brain Function Research Unit, School of Physiology,
University of the Witwatersrand, and 2Department of Chemical Pathology,
South African Institute for Medical Research, Johannesburg 2193, South Africa
Received 4 September 2001; accepted in final form 28 November 2001
WOMEN WITH OVULATORY MENSTRUAL cycles show an increase in body temperature (of ⬃0.3–0.4°C) in the
luteal phase, compared with the preovulatory follicular
phase. The circadian rhythm of temperature also may
be altered with menstrual cycle phase: circadian am-
plitude may be blunted (8, 11, 25, 27, 35), although not
always (4), and phase may be delayed, with the minimum body temperature occurring later (8), in the luteal phase compared with the follicular phase. The
luteal phase elevation in body temperature is mediated
by progesterone. Body temperature rises rapidly in
response to progesterone administration in rabbits (34)
and in young men (38) and increases ⬃24 h after a
detectable increase in progesterone plasma concentration in women (24). The mechanism of thermogenic
action of progesterone is unknown, although it is
thought to be central rather than peripheral (7). The
rise in body temperature in the luteal phase and the
apparently normal thermoregulation around this elevated body temperature are reminiscent of the thermoregulatory changes associated with fever (26). Because
the change in thermoregulatory set point in fever is
mediated by cyclooxygenase (COX), prostaglandins or
other prostanoids might also underlie the thermoregulatory effects of progesterone in the menstrual cycle.
Indeed, blood prostaglandin concentrations are increased in the midluteal phase (15).
Thermoregulatory changes are not the only putative
progesterone-mediated changes in physiological rhythms
in the menstrual cycle. The menstrual cycle hormones
influence sleep (see Ref. 12 for review). Rapid eye
movement (REM) sleep has been reported to be reduced in the luteal phase, (2, 13), although not always
(4), and stage 2 non-REM sleep may increase (13), but
again not always (2, 28). These changes in sleep have
also been attributed to progesterone (13), and, as for
body temperature, could involve prostaglandins. Prostaglandins influence sleep: PGD2 promotes sleep,
whereas PGE2 induces wakefulness in animal models
(19). Few studies have investigated the involvement of
prostaglandins in sleep-wake regulation in healthy humans, and these studies rely on inhibiting COX activity. Findings are variable. COX inhibitors may suppress slow-wave sleep (SWS) and increase stage 2 sleep
(22), increase time spent awake and reduce sleep efficiency without affecting SWS (32), or have no effect on
Address for reprint requests and other correspondence: F. C.
Baker, School of Physiology, Univ. of the Witwatersrand Medical
School, 7 York Road, Parktown, 2193 Johannesburg, South Africa
(E-mail: [email protected]).
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
paracetamol; progesterone; rapid eye movement sleep; slowwave sleep
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Baker, Fiona C., Helen S. Driver, Janice Paiker,
Geoffrey G. Rogers, and Duncan Mitchell. Acetaminophen does not affect 24-h body temperature or sleep in the
luteal phase of the menstrual cycle. J Appl Physiol 92:
1684–1691, 2002. First published December 7, 2001; 10.1152/
japplphysiol.00919.2001.—Body temperature and sleep
change in association with increased progesterone in the
luteal phase of the menstrual cycle in young women. The
mechanism by which progesterone raises body temperature
is not known but may involve prostaglandins, inducing a
thermoregulatory adjustment similar to that of fever. Prostaglandins also are involved in sleep regulation and potentially could mediate changes in sleep during the menstrual
cycle. We investigated the possible role of central prostaglandins in mediating menstrual-associated 24-h temperature
and sleep changes by inhibiting prostaglandin synthesis with
a therapeutic dose of the centrally acting cyclooxygenase
inhibitor acetaminophen in the luteal and follicular phases of
the menstrual cycle in young women. Body temperature was
raised, and nocturnal amplitude was blunted, in the luteal
phase compared with the follicular phase. Acetaminophen
had no effect on the body temperature profile in either menstrual cycle phase. Prostaglandins, therefore, are unlikely to
mediate the upward shift of body temperature in the luteal
phase. Sleep changed during the menstrual cycle: on the
placebo night in the luteal phase the women had less rapid
eye movement sleep and more slow-wave sleep than in the
follicular phase. Acetaminophen did not alter sleep architecture or subjective sleep quality. Prostaglandin inhibition
with acetaminophen, therefore, had no effect on the increase
in body temperature or on sleep in the midluteal phase of the
menstrual cycle in young women, making it unlikely that
central prostaglandin synthesis underlies these luteal
events.
BODY TEMPERATURE AND SLEEP IN WOMEN TAKING ACETAMINOPHEN
METHODS
Subjects. Thirteen healthy young women without any
menstrual-associated complaints (21 ⫾ 3 yr) and 10 women
with primary dysmenorrhea (23 ⫾ 4 yr), with onset soon after
menarche, were recruited from a university student population and consented to participate in our study. Ethical clearance was obtained from the Committee for Research on
Human Subjects of the University of the Witwatersrand
(clearance no. M990203), which adheres to the principles of
the Declaration of Helsinki. All of the women completed
questionnaires and were interviewed to ensure that they had
regular sleep-wake schedules, were nonsmokers, and showed
no indication of sleep or medical disorders. All of the volunteers were of normal psychological status, as assessed with
the 30-item version of the General Health Questionnaire,
which correlates well with psychiatric interview (18). The
women were asked specifically about any mood changes that
J Appl Physiol • VOL
occurred during their menstrual cycles. None reported evidence of premenstrual syndrome (31). The dysmenorrheic
women were classified as having mild-to-moderate dysmenorrhea (1). The absence of any pathology was confirmed by a
gynecological examination.
Experimental procedure. For a month after entering the
study, the women completed a calendar of premenstrual
experiences (31), which confirmed that none suffered from
premenstrual syndrome. They measured their oral temperature every morning before getting out of bed using a digital
thermometer (Soar M.E., Nagoya, Japan) and used a commercially available self-test kit, which detects the presence of
luteinizing hormone (LH) in urine (ClearPlan One Step,
Unipath, Bedford, UK), to confirm ovulation. Only women
who had predictable and ovulatory menstrual cycles, as assessed by a biphasic temperature rhythm and the midcycle
presence of LH, were accepted for the recording phase of the
study. Twelve of the thirteen women without any menstrualrelated disorders and all ten dysmenorrheic women fulfilled
these criteria and participated in the study during the summer and autumn months.
All of the subjects were requested to maintain their customary weekday bedtime schedules, even on the weekend, for
at least 1 wk before a scheduled study night. On study nights,
the women maintained their habitual schedules but slept in
the controlled environment of our laboratory. Each woman
spent at least 5 nights in the laboratory: 1 adaptation night
and 2 recording nights in both the midfollicular phase (7–10
nights after the onset of menstrual flow) and the midluteal
phase (5–8 nights after the LH surge). The 2 recording nights
in each phase were separated by 1 night spent at home. The
adaptation night, held 1 or 2 nights before the first recording
night, allowed the subjects to familiarize themselves with the
environment and recording equipment. Seven of the control
women and seven of the dysmenorrheic women had their first
recording night in the follicular phase. Four of the women
returned to the sleep laboratory for a repeat recording, owing
to incomplete data collection or transient illness.
On study days, the subjects were allowed to pursue their
usual daytime activities, but they refrained from drinking
caffeinated or alcoholic beverages and did not participate in
any strenuous exercise for 8 h before the start of the sleep
recordings. Lights-out and lights-on times in the laboratory
were self-selected, based on the customary weekday bedtime
schedules for each individual. Lights were turned off between
2200 and 2330 and were turned on between 7 and 8 h later.
Medication. On each of the recording days, the women
were randomly given either acetaminophen (⫽ paracetamol,
650 mg/capsule, Tylenol Extended Relief Caplets, JanssenCilag Pharmaceuticals, Johannesburg, South Africa) or placebo (potato starch in an identical capsule), according to a
double-blind, crossover design within one menstrual cycle.
Each woman took a total of six capsules within each 24 h
recording period: two capsules between 5 and 8 h before
bedtime, two capsules at lights-out, and two capsules on
awakening. The total amount of acetaminophen taken over
24 h, therefore, was 3,900 mg, the maximum adult dose
registered for treatment of fever. The women were not taking
any medication other than that required for the study.
Data acquisition and analysis. Standard polysomnographic electroencephalographic (EEG), electrooculographic,
and electromyographic recordings were made on a digital
EEG (Medelec DG 20, Vickers Medical, Surrey, UK) at a
virtual recording speed of 15 mm/s and with a sampling rate
of 240 Hz. Low- (0.5 Hz) and high-frequency (30 Hz) filters
were applied to the EEG data before analysis. Twenty-second
epochs were scored according to modified standard criteria
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sleep, at least in young women in the follicular phase
and in young men (32).
COX inhibitors have been used to investigate the
interaction between progesterone and heat stress in
awake women, and results indicate that prostaglandins are not involved (7, 9). In both of these studies,
body temperature was only measured for a short daytime period, mostly in women who were taking synthetic steroids (7, 9). But synthetic steroid hormones,
such as those contained in oral contraceptives, influence body temperature and sleep differently from endogenous progesterone and estrogen (3). As far as we
are aware, no previous study has investigated the
involvement of prostaglandins in the upward shift of
body temperature over 24 h and sleep in the natural
luteal phase.
Members of the COX family are found in a variety of
tissues (14). However, if prostaglandins are involved in
mediating progesterone-induced effects on temperature and sleep in the luteal phase, then the candidate
prostaglandins are likely to be synthesized by COX in
the brain. A centrally mediated effect is proposed,
given the neurological basis of sleep and because the
thermogenic effects of progesterone are likely central
(7). Also, the change in set point during fever, of which
the luteal temperatures are reminiscent, occurs
through actions of prostaglandin in the brain (29). The
appropriate COX inhibitor to use in this case, therefore, is one that acts preferentially on brain COX, such
as acetaminophen. Acetaminophen exerts its antipyretic action in the central nervous system, probably by
inhibiting a specific isoform of COX, which may be a
variant of COX-2 or a unique isoform provisionally
named COX-3 (6, 45).
To investigate the possible involvement of prostaglandins in sleep and 24-h body temperature in general, as well as in luteal phenomena, we administered
acetaminophen in the follicular and luteal phases of
the menstrual cycle in the same women. We included
in our subject group women who suffered from primary
dysmenorrhea. Previously, we found that such women
had a higher nocturnal body temperature than women
without dysmenorrhea (2), which we postulated might
also be mediated by prostaglandins.
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J Appl Physiol • VOL
before statistical analysis through the arcsine square-root
transform.
A 5-ml blood sample was taken from the women between
0700 and 0800, after 1 of the recording nights in each phase.
The serum was frozen for later determination of estradiol,
progesterone, and prolactin, using automated chemiluminescent immunoassays (Bayer Diagnostics, Tarrytown, NY),
which were performed on one blood sample from each individual for each hormone assay. The mean within-assay variation was 7.2% in the estradiol assay, 6.6% in the progesterone assay, and 2.8% in the prolactin assay.
Statistical analysis. We evaluated sleep over the first 7 h of
the recording nights because it was the shortest period for
which all subjects were in bed. We excluded three of the
women without menstrual complaints and one of the dysmenorrheic women from analysis because they did not show
an increase in serum progesterone or body temperature in
the latter period of their cycles; therefore, we could not be
sure that they had ovulated. We also excluded one of the
women without complaints and one of the dysmenorrheic
women because their awake time was greater than 2 SD from
the mean on their acetaminophen and placebo nights, respectively, in the luteal phase.
We investigated differences in temperature and differences in subjective and objective sleep measures using a
two-way repeated-measures multivariate ANOVA (MANOVA)
at a 95% confidence interval, according to study group, menstrual phase, and drug. We failed to detect any significant
differences between the women without complaints and
those with dysmenorrhea in any of the variables assessed;
therefore, we subsequently grouped the women together and
performed a repeated-measures MANOVA, with factors of
menstrual phase and drug, for each variable. When appropriate, the Student Newman-Keuls (SNK) test was used to
identify the origins of any differences. We used paired t-tests
to compare hormone concentrations in the follicular and
luteal phases. Data from 16 women (age: 22 ⫾ 4 yr; mass:
60.1 ⫾ 8.4 kg; height 1.65 ⫾ 0.05 m; body mass index: 22.1 ⫾
2.8 kg/m2; menstrual cycle length: 28 ⫾ 2 days) were used in
the final sleep analysis. One of these women was excluded
from the temperature analysis because of frequent slippage
of the rectal probe. Sleep and temperature data for eight of
the women (all controls) on their placebo nights only have
previously been reported (3).
RESULTS
Hormones. The women had significantly higher
plasma progesterone concentrations [paired t-test:
t(15) ⫽ 12.4, P ⬍ 0.0001] in the luteal phase (35 ⫾ 11
nmol/l) than in the follicular phase (2 ⫾ 1 nmol/l).
Plasma estrogen concentrations were increased
[t(15) ⫽ 4.4, P ⫽ 0.0005] in the luteal phase (530 ⫾ 180
pmol/l) compared with the follicular phase (260 ⫾ 180
pmol/l). Prolactin concentrations were the same in the
luteal phase (19 ⫾ 8 ␮g/l) and the follicular phase (18 ⫾
10 ␮g/l). All hormone concentrations were within the
normal ranges for follicular and luteal phases (42).
Body temperature. Figure 1 shows the average
smoothed rectal temperature curves for 4 h before
lights-out and 20 h thereafter for the women taking
either placebo or acetaminophen in each menstrual
phase. Rectal temperature started dropping before
bedtime, associated with the declining phase of body
temperature and reduced activity of the women, and
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(37) by one scorer (F. C. Baker) blinded to the identity of the
subject or recording phase. Total time spent in bed refers to
the time from lights-out to lights-on. Total sleep time is
reported only for the first 7 h after lights-out, as the time
from sleep onset to waking (or to 7 h) minus in-bed wakefulness during that period. Sleep onset latency was taken as the
time from lights-out to the first minute of stage 2 sleep. The
time between sleep onset and the first indication of any REM
sleep was the REM sleep onset latency. The latency to SWS
was the time from sleep onset to the first of at least three
consecutive epochs of stage 3 sleep. Movement during sleep
refers to 20-s epochs scored as movement time, as defined by
Rechtschaffen and Kales (37).
Rectal temperatures were recorded every minute for at
least 60 h. Recordings started at least 4 h before lights-out on
the first day and included both recording nights, the night
spent at home, and the intervening day in each menstrual
phase. Temperature was recorded using indwelling rectal
thermistors connected to miniature temperature data loggers
(Stowaway XTI, Onset Computer, Pocasset, MA), custom
modified to have a narrow temperature range (34–46°C) and
high resolution (0.04°C). The thermistors were encased in a
polythene sheath and inserted into the rectum to a depth of
⬃100 mm. Subjects recorded the times when they removed
the probe for bathing or using the toilet, and the missing
temperatures were calculated by linear interpolation. Ambient dry-bulb temperature in the laboratory was recorded
every 30 min by a thermocouple array connected to a fixed
data logger (MC Systems, Cape Town, South Africa). Ambient temperature was maintained between 21 and 23°C
throughout the study. All thermistors and thermocouples
were calibrated by water immersion against a quartz thermometer (Quat 100, Heraeus, Hanau, Germany) to an accuracy of at least 0.1°C. The miniature data loggers maintain
accuracy even in the face of changing environmental temperatures (17).
Rectal temperature data were smoothed by a 15-min moving average of the 1-min recordings. We then calculated
mean 24-h and minimum temperatures. The time of the
minimum temperature for each individual was determined
from visual inspection of the smoothed temperature curves.
We also measured the extent of the nocturnal drop in body
temperature for each subject using the thermal response
index, an index used frequently by thermal physiologists. In
our case, the thermal response index was the time integral
(°C/h), over 410 min, of the change in rectal temperature
from the temperature recorded 10 min after lights-out (i.e.,
the area between the actual curve of rectal temperature vs.
time and a horizontal line drawn through the temperature
recorded 10 min after lights-out). We also calculated average
temperatures for designated nighttime (2100–0859) and daytime (0900–2059) 12-h periods, within each 24-h recording
period, for each subject. We then calculated mean differences
in temperature between the luteal and follicular phases for
each condition (placebo or acetaminophen) separately for day
and nighttime periods.
Before going to bed, the women completed a questionnaire
describing the events of that day and indicated their evening
anxiety on a 100-mm visual analog scale (VAS), anchored
from terribly agitated to utterly calm and peaceful. After
each recording night, the subjects assessed the preceding
night’s sleep quality on a 100-mm VAS with anchor points of
worst possible and best ever sleep. Morning vigilance was
rated on a similar VAS, anchored from feeling awfully sleepy
and lackluster to feeling marvelously alert and energetic.
The subjective VAS measurements (in mm) were normalized
BODY TEMPERATURE AND SLEEP IN WOMEN TAKING ACETAMINOPHEN
continued to drop sharply after lights-out, as the
women assumed a recumbent position and fell asleep.
Body temperature increased markedly after lights-on.
As expected, the women had significantly raised body
temperatures, with higher mean 24-h, lights-out, 7-h
in-bed, and minimum temperatures in the luteal phase
compared with the follicular phase (Table 1). The difference in luteal-follicular phase body temperatures
during the 12-h nighttime period (placebo: 0.40 ⫾
0.1°C, acetaminophen: 0.35 ⫾ 0.1°C) was larger
(MANOVA phase effect: F1,14 ⫽ 16, P ⫽ 0.001) than
during the 12-h daytime period (placebo: 0.25 ⫾ 0.2 °C,
acetaminophen: 0.26 ⫾ 0.2°C), indicating that the nocturnal decline in body temperature during the luteal
phase was dampened. Also, the in-bed thermal response index was smaller, implying less of a drop in
body temperature, in the luteal phase than in the
follicular phase (Table 1). The time at which the minimum body temperature occurred was not significantly
affected by menstrual cycle phase (Table 1). Acetaminophen had no effect on any of the body temperature
variables measured in each menstrual phase (Table 1).
The apparent difference in minimum body temperatures between the placebo and acetaminophen conditions (Fig. 1) is an artifact of plotting a mean temperature curve for several individuals, regardless of the
timing of their minimum temperatures.
Subjective assessments. Before going to bed, subjective assessments of anxiety were the same (phase:
F1,15 ⫽ 0.1, P ⬎ 0.5; drug: F1,15 ⫽ 0.3, P ⬎ 0.4) for the
placebo (71 ⫾ 27 mm) and acetaminophen (73 ⫾ 27
mm) conditions in the follicular phase as they were in
the luteal phase (placebo: 73 ⫾ 21 mm; acetaminophen:
67 ⫾ 24 mm). The women also reported a similar sleep
quality (drug: F1,15 ⫽ 0.6, P ⬎ 0.6) for the placebo (64 ⫾
22 mm) and acetaminophen (71 ⫾ 22 mm) nights in the
follicular phase, which did not differ (phase: F1,15 ⫽
0.4, P ⬎ 0.7) from that in the luteal phase (placebo:
71 ⫾ 19 mm; acetaminophen: 68 ⫾ 24 mm). Finally, the
women reported relatively high morning vigilance levels (63 ⫾ 21 mm) when taking placebo and when taking
acetaminophen (68 ⫾ 18 mm) in the follicular phase
and similar levels (phase: F1,15 ⫽ 0.01, P ⬎ 0.9; drug:
F1,15 ⫽ 1.1, P ⬎ 0.3) in the luteal phase (placebo: 64 ⫾
18 mm; acetaminophen: 66 ⫾ 20 mm).
Sleep composition. Table 2 shows selected sleep variables for the first 7 h after lights-out. The range of
times over which the women elected to go to bed and
woke up differed by ⬍90 min, and the group means by
⬍10 min between phases of the experiment. The
women had significantly less REM sleep in the luteal
phase than in the follicular phase, regardless of
whether they were taking acetaminophen or placebo
(Table 2). On the placebo night in the luteal phase,
SWS time was longer, and combined time spent awake,
moving, and in stage 1 sleep was shorter, than on the
placebo night in the follicular phase (Table 2).
Sleep in the follicular phase was unaffected by acetaminophen (Table 2). In the luteal phase, latency to
stage 3 sleep was significantly longer, but only by 2
min, when the women took acetaminophen compared
with placebo (Table 2). Time spent in the various sleep
stages in the luteal phase was not significantly affected
Table 1. Rectal temperature variables and statistical comparisons of 15 young women when they took either
acetaminophen or placebo in the midfollicular and midluteal phases of their menstrual cycle.
Follicular Phase
Variable
Luteal Phase
Placebo
Acetaminophen
Placebo
Acetaminophen
Statistical Comparison, MANOVA
Lights-out temperature, °C
37.0 ⫾ 0.2
37.0 ⫾ 0.2
37.4 ⫾ 0.3*
37.3 ⫾ 0.2*
Minimum temperature, °C
36.4 ⫾ 0.2
36.4 ⫾ 0.2
36.9 ⫾ 0.1*
36.9 ⫾ 0.1*
Mean 7-h in-bed temperature, °C
36.6 ⫾ 0.1
36.7 ⫾ 0.2
37.1 ⫾ 0.1*
37.0 ⫾ 0.1*
Mean 24-h temperature, °C
37.1 ⫾ 0.1
37.1 ⫾ 0.1
37.4 ⫾ 0.1*
37.4 ⫾ 0.1*
In-bed thermal response index, °C/h
⫺1.6 ⫾ 1.5
⫺1.7 ⫾ 1.2
⫺1.3 ⫾ 1.6*
⫺0.9 ⫾ 1.3*
01:13 ⫾
116 min
01:47 ⫾
129 min
02:33 ⫾
139 min
01:17 ⫾
115 min
Phase F1,14 ⫽ 69.6, P ⬍ 0.001
Drug: F1,14 ⫽ 0.4, ns
Phase: F1,14 ⫽ 216.2, P ⬍ 0.001
Drug: F1,14 ⫽ 0.04, ns
Phase: F1,14 ⫽ 144.8, P ⬍ 0.001
Drug: F1,14 ⫽ 0.01, ns
Phase: F1,14 ⫽ 123.6, P ⬍ 0.001
Drug: F1,14 ⫽ 1.4, ns
Phase: F1,14 ⫽ 4.8, P ⫽ 0.05
Drug: F1,14 ⫽ 0.2, ns
Phase: F1,14 ⫽ 0.6, ns
Drug: F1,14 ⫽ 0.9, ns
Time of minimum temperature
Values are means ⫾ SD. Temperature data from 1 woman was excluded from analysis because of frequent slippage of the rectal probe.
MANOVA, multivariate ANOVA; ns, not significant. * Significantly different from follicular phase.
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Fig. 1. Mean (⫾ SE) rectal temperatures for 4 h before lights-out and
20 h thereafter in 15 young women in the midfollicular and midluteal
phases of their menstrual cycles when they were taking either
antipyretic doses of acetaminophen or placebo. Vertical lines indicate
average time in bed.
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BODY TEMPERATURE AND SLEEP IN WOMEN TAKING ACETAMINOPHEN
Table 2. Selected sleep variables during the first 7 h of sleep after lights-out and statistical comparisons
for 16 young women when they took either acetaminophen or placebo in the midfollicular
and midluteal phases of their menstrual cycles.
Follicular Phase
Luteal Phase
Placebo
Acetaminophen
Placebo
Acetaminophen
Time of lights-out
22:53 ⫾
21 min
06:22 ⫾
20 min
394 ⫾ 8
22:59 ⫾
19 min
06:21 ⫾
25 min
397 ⫾ 7
22:58 ⫾
24 min
06:30 ⫾
22 min
397 ⫾ 10
22:55 ⫾
28 min
06:31 ⫾
26 min
398 ⫾ 9
Sleep onset latency, min
13 ⫾ 7
12 ⫾ 6
12 ⫾ 8
11 ⫾ 6
Latency to stage 3 sleep, min
10 ⫾ 3
10 ⫾ 3
8⫾2
10 ⫾ 4*
Latency to REM sleep, min
62 ⫾ 14
65 ⫾ 17
62 ⫾ 11
61 ⫾ 15
Stage 2 sleep, %
41 ⫾ 3
39 ⫾ 4
40 ⫾ 5
43 ⫾ 3‡§
Slow-wave sleep, %
24 ⫾ 3
26 ⫾ 5
28 ⫾ 5‡
24 ⫾ 4
REM sleep, %
22 ⫾ 2
23 ⫾ 2
20 ⫾ 3†
21 ⫾ 3†
Awake, movement,
and stage 1 sleep, %
11 ⫾ 2
9⫾2
9 ⫾ 3‡
9⫾3
Time of lights-on
Total sleep time, min
Statistical Comparison,
MANOVA
Phase: F1,15 ⫽ 0.3, ns
Drug: F1,15 ⫽ 0.9, ns
Phase: F1,15 ⫽ 4.4, ns
Drug: F1,15 ⫽ 0.05, ns
Phase: F1,15 ⫽ 1.9, ns
Drug: F1,15 ⫽ 2.1, ns
Phase: F1,15 ⫽ 1.6, ns
Drug: F1,15 ⫽ 0.6, ns
Phase: F1,15 ⫽ 1.4, ns
Drug: F1,15⫽5.1, P ⫽ 0.04
Phase: F1,15 ⫽ 0.3, ns
Drug: F1,15 ⫽ 0.3, ns
Phase: F1,15 ⫽ 5.8, P ⫽ 0.03
Drug: F1,15 ⫽ 0.2, ns
Phase-drug: F1,15 ⫽ 8.5, P ⫽ 0.01
Phase: F1,15 ⫽ 0.5, ns
Drug: F1,15 ⫽ 0.6, ns
Phase-drug: F1,15 ⫽ 8.9, P ⫽ 0.009
Phase: F1,15 ⫽ 7.6, P ⫽ 0.01
Drug: F1,15 ⫽ 2.4, ns
Phase: F1,15 ⫽ 5.0, P ⫽ 0.04
Drug: F1,15 ⫽ 1.0, ns
Phase-drug: F1,15 ⫽ 4.5, P ⫽ 0.05
Values are means ⫾ SD. REM, rapid eye movement. * Significantly different from placebo; † significantly different from follicular phase;
‡ significantly different from follicular phase (placebo); Student Newman-Keuls, P ⬍ 0.05; § significantly different from follicular phase
(acetaminophen), Student Newman-Keuls, P ⫽ 0.007
by acetaminophen, although the women tended to have
less SWS and more stage 2 sleep than on the placebo
night (SNK; P ⬍ 0.1). The women also spent a longer
time in stage 2 sleep in the luteal phase when they
were taking acetaminophen than they did during both
the placebo (SNK; P ⫽ 0.05) and acetaminophen (SNK;
P ⫽ 0.007) conditions in the follicular phase (Table 2).
DISCUSSION
We investigated the possible involvement of prostaglandins in raising body temperature in the luteal
phase of the menstrual cycle by administering to young
women the COX inhibitor acetaminophen, at a dose
that is antipyretic during fever. A menstrual phase
effect on body temperature over 24 h was evident, with
a significantly blunted nocturnal drop in body temperature in the luteal phase, compared with the follicular
phase. Acetaminophen had no effect on the postovulatory increase in body temperature over 24 h, regardless
of whether the women had taken placebo or acetaminophen. Acetaminophen also did not affect body temperature in the follicular phase.
Menstrual cycle phase influenced sleep architecture
but to a limited extent. During their nights on placebo
in the luteal phase, the women had less REM sleep,
more SWS, and slightly less time spent awake, moving,
and in stage 1 sleep, than in the follicular phase.
Acetaminophen did not significantly alter sleep architecture or subjective assessments of sleep quality in
either the follicular or luteal phase. Because prostaglandin inhibition with acetaminophen did not affect
J Appl Physiol • VOL
body temperature or sleep, it is unlikely that the postovulation effects on these physiological processes depend on increased brain prostaglandin synthesis. We
also confirm that a substantial increase in body temperature does not induce substantial changes in visually scored sleep architecture.
Blocking the synthetic pathway of a substance with a
drug is a classic way of investigating the normal function of that substance in physiological systems, such as
thermoregulation and sleep. We used the maximum,
therapeutic dose of acetaminophen. Acetaminophen is
a potent inhibitor of prostaglandin synthesis in selective tissues, most notably the brain (6). A quarter of the
dose of acetaminophen given in our study causes significant, rapid antipyretic activity (36), and a single
dose of acetaminophen (320 mg) effectively decreases
body temperature by ⬃60% in febrile children (10).
Although we did not measure prostaglandin concentrations, it is unlikely, therefore, that the lack of an
observed effect on body temperature and sleep was due
to an inadequate dose of acetaminophen. We also ensured that acetaminophen would be active throughout
the sleep period. Acetaminophen was ingested just
before lights-out, and biologically effective plasma levels are reached within 30 min (36). Also, we administered acetaminophen in an extended-release form that
is released slowly over 8 h: the half-life of extendedrelease acetaminophen is 4.0 h, compared with 2.6 h
for regular-release acetaminophen (44).
Initially, data from women with primary dysmenorrhea and those with normal menstrual cycles were
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BODY TEMPERATURE AND SLEEP IN WOMEN TAKING ACETAMINOPHEN
J Appl Physiol • VOL
COX. The study protocol of Murphy et al. (33) differed
from ours in that body temperature was measured at
the tympanic membrane, once every 15 min, while the
subjects were seated and kept awake for the 4-h nighttime recording period. The amplitude of the nocturnal
decline in body temperature is reduced in sleep-deprived subjects (5) and may have been influenced further because the subjects were seated rather than
recumbent. We measured temperature continuously in
the rectum, which better reflects core body temperature than does the tympanic membrane (16), and our
subjects were allowed to sleep normally.
Acetaminophen failed to influence not only body temperature but also sleep architecture. It is unlikely,
therefore, that any changes in sleep architecture in the
luteal phase result from central COX activity. Our
finding, that a therapeutic dose of acetaminophen did
not greatly alter sleep in the young women in our
study, supports that of Murphy et al. (32) in young
women in the follicular phase and in young men. COX
inhibitors that have both a peripheral and a central
action, however, do alter sleep; aspirin and ibuprofen
increase wakefulness and disrupt sleep (32). It remains
to be investigated whether a COX inhibitor with peripheral activity influences menstrual-associated
changes in sleep.
Drug dosage regimen may affect the extent of the
influence on sleep of COX inhibitors. Horne et al. (22)
found that aspirin, given over 3 days, decreased SWS
and increased stage 2 sleep, without affecting time
spent awake. These changes in sleep found by Horne et
al. are reminiscent of the small changes in our women
in the luteal phase after acetaminophen administration.
The small decrease in REM sleep that we found in
the luteal phase compared with the follicular phase is
similar to our previous findings (2) and to the trend
reported by Driver et al. (13). Progesterone may mediate the decrease in REM sleep in the luteal phase:
young men showed a significant reduction in REM
sleep after synthetic progesterone administration (46).
The decrease in REM sleep also could be a consequence
of the raised body temperature in the luteal phase.
Because thermoregulatory responses are disrupted
during REM sleep (see Ref. 20 for review), REM sleep
may be inhibited in the presence of elevated body
temperatures. We have not previously found an increase in SWS in the luteal phase compared with the
follicular phase (2, 4, 13), as we did in this study, but
others have done so (21, 41). Progesterone and its
metabolites enhance the effects of GABA (40) and may
enhance SWS. Schulz et al. (39) found an increase in
amplitude in the delta frequency range of the EEG in
young men after administration of pregnanolone, a
neuroactive metabolite of progesterone. Moldofsky et
al. (30), however, found a decrease in SWS in the luteal
phase compared with the follicular phase that correlated with plasma progesterone concentrations. Different study protocols, small sample sizes, and different
sampling times during the menstrual cycle may mask
small SWS effects in the luteal phase. It is clear, too,
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analyzed in two groups because we previously found
that dysmenorrheic women had higher nocturnal body
temperatures and slightly less REM sleep than did
asymptomatic women (2). In our present study, however, we found no significant differences in body temperature or sleep between the two groups of women.
Our sample size of only eight women with dysmenorrhea (or seven for temperature analysis) in this study
may have been too small to replicate the small differences found previously. Although we did not find differences in sleep and temperature between women
with and without dysmenorrhea, this does not confound our conclusion concerning brain prostaglandin
synthesis.
Consistent with the findings of others (8, 11, 25, 27,
35), body temperature was raised over 24 h and exhibited a smaller drop during the night in the luteal phase
compared with the follicular phase. In an earlier study,
our laboratory did not find a significant difference in
the nocturnal temperature drop in the luteal phase
compared with the follicular phase in eight young
women (4). Variation that exists among individuals in
body temperature profiles and the menstrual cycle may
necessitate larger sample sizes being investigated to
find an effect. Both the increased 24-h temperature
and the nocturnal blunting in the luteal phase are
conventionally attributed to increased progesterone
concentrations. Body temperature during fever is also
shifted upward and apparently regulated around the
elevated level (26). Thus we postulated that the thermal events of the luteal phase may depend on COX
activity in the brain, as fever does (29). However, our
results do not support this assumption. Our findings
support those of others who have shown that the body
temperature-raising effect of progesterone is unlikely
to involve prostaglandins (7, 9). Additionally, we have
shown that the nocturnal blunting of body temperature
in the luteal phase also is unlikely to be mediated by
prostaglandins. Progesterone may act through a pathway independent of prostaglandins to induce an upward shift in the thermoregulatory set point in the
luteal phase. Prostaglandin-independent pathways
that induce fever have been identified, involving factors such as corticotropin-releasing factor, endothelin-1, interleukin-8, or the carbon monoxide-heme
pathway (43). Alternatively, progesterone may act directly on thermoregulatory neurons in the preoptic
anterior hypothalamus. Indeed, progesterone rapidly
increases the firing rate of cold-sensitive neurons and
decreases the firing rate of warm-sensitive neurons
(34), with a consequent rise in body temperature.
In the absence of progesterone, in women in the
follicular phase and in men, a therapeutic dose of
either aspirin or ibuprofen has been reported to attenuate the circadian decline in body temperature (33).
The authors attributed this effect to the inhibition of
COX in the pineal gland with a consequent suppression
of melatonin secretion and its hypothermic effect (33).
We did not find any change in the circadian profile of
body temperature in the follicular phase after acetaminophen treatment, which ought to inhibit pineal
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BODY TEMPERATURE AND SLEEP IN WOMEN TAKING ACETAMINOPHEN
that the endogenous increase in body temperature in
the luteal phase does not have the same consequences
as experimentally increasing body temperature before
bedtime, which consistently induces an increase in
SWS (23).
In conclusion, we found that a therapeutic dose of
acetaminophen had no effect on the increase in body
temperature and little effect on the changes in sleep
architecture in the luteal phase of young women, making it unlikely that central COX activity underlies the
luteal events. If the events are caused by the increased
concentration of progesterone during the luteal phase,
then progesterone may act directly on the brain or via
mediators other than centrally synthesized prostaglandins.
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