Effects of hormone therapy with estrogen and/or progesterone on

International Journal of Gynecology and Obstetrics (2008) 103, 207–212
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Effects of hormone therapy with estrogen and/or
progesterone on sleep pattern in
postmenopausal women
Helena Hachul a,b,⁎, Lia R.A. Bittencourt b , Monica L. Andersen b ,
Mauro A. Haidar a , Edmund C. Baracat a , Sergio Tufik a
a
b
Department of Gynecology, Federal University of São Paulo (UNIFESP/EPM), São Paulo, Brazil
Department of Psychobiology, Federal University of São Paulo (UNIFESP/EPM), São Paulo, Brazil
Received 4 June 2008; received in revised form 11 July 2008; accepted 14 July 2008
KEYWORDS
Estrogen;
Hormone;
Menopause;
Periodic limb movements;
Polysomnography;
Progesterone;
Sleep
Abstract
Objective: To investigate the effects of estrogen and progesterone on sleep in postmenopausal
women. Method: The 33 participants were randomly assigned to an estrogen or placebo group
after undergoing clinical and hormonal assessments and a polysomnogram, and they underwent
the same tests again after 12 weeks. Then, while still taking estrogen or placebo, they all
received progesterone for another 12 weeks and underwent a final polysomnogram. Results:
Estrogen plus progesterone was more effective than estrogen alone in decreasing the prevalence
of periodic limb movement (PLM) (8.1% vs 2.8%), hot flashes (14.2% vs 0%), and bruxism (11.1% vs
0%) at night, or somnolence and attention difficulty during the day. The prevalences of breathing
irregularities, arousal from sleep, anxiety, and memory impairment were decreased in both
groups following progesterone treatment. Conclusion: While not significantly affecting sleep
quality, hormone therapy decreased the prevalence of arousal in both groups and that of PLM in
the group treated with estrogen plus progesterone.
© 2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
1. Introduction
⁎ Corresponding author. Rua Dr. Thirso Martins, 264 Suite 41,
Vila Mariana 04120-050, São Paulo, SP, Brazil. Tel.: +55 11 34739539;
fax: +55 11 34739539.
E-mail address: [email protected] (H. Hachul).
Sleep disturbances increase in frequency as women approach
and pass through menopause. These include insomnia [1],
poor sleep efficiency [2], difficulty in maintaining sleep [3],
breathing irregularity [4,5], and hot flashes. The close
relationship between sleep problems and decreased levels
of reproductive hormones in menopausal women has
suggested hormone therapy (HT) for their relief, with good
0020-7292/$ - see front matter © 2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijgo.2008.07.009
208
H. Hachul et al.
results, especially because hot flashes are reduced [6]. The
decreased production of progesterone after menopause has
also been associated with breathing irregularities during
sleep [7], likely the result of a decreased respiratory drive
[8], and micronized progesterone has been shown to induce a
better quality of sleep than medroxyprogesterone acetate
when associated with estrogens [9].
Few studies have objectively assessed sleep quality in
postmenopausal women undergoing HT. Yet, studies that
address the relationship between sleep quality and reproductive hormone levels in postmenopausal women are not
only important for understanding the neuroendocrinology of
this period of women's lives, but may also shed light on the
distinct role each hormone plays in the major changes
associated with menopause.
This single-center, prospective, placebo-controlled study
was designed to determine the effects of synthetic conjugated estrogens and medroxyprogesterone acetate on
subjective and objective sleep quality in postmenopausal
women. In addition, we assessed clinical and psychological
complaints as well as reproductive hormone levels before
and after treatment with estrogen, progesterone, or a
combination of the two.
2. Methods
2.1. Participants and study design
Of 65 postmenopausal women interviewed for this double-blind,
placebo-controlled study, 33 were invited to participate and gave
written informed consent. The inclusion criteria were postmenopausal status (at least 1 year of amenorrhea before enrollment
and a follicle-stimulating hormone (FSH) level N 30 mlU/mL); age
between 50 and 65 years; mean body mass index (BMI, calculated
as weight in kilograms divided by the square of height in meters)
less than 30; and no previous exposure to exogenous hormones.
None of the participants reported poor sleep quality as a
motivation to participate in the study. Exclusion criteria were
serious health problems; endometrial thickness greater than
5 mm on ultrasound or a positive result to a progesterone test;
atypical mammary hyperplasia; a reported history of endometrial or breast cancer; previous HT; and the use of antidepressants or sleep-inducing aids. The study was approved by the
institutional ethics committee (Approval No. 153/00).
The screening interview included taking the participant's
anthropometric measurements; determining both her baseline
score on the Kupperman index (KI, an instrument to score
menopausal symptoms [10]) and her reproductive hormone
levels; and giving her a complete gynecologic and hematologic
examination.
The study had an intersubject design by which each
participant underwent 2 treatments sequentially. Following a
night of adaptation, the women underwent hormone measure-
Figure 1
ment tests and a polysomnogram (testing 1 [T1]). They were
then randomly assigned to one of 2 groups, group 1 consisting of
14 participants who received 0.625 mg per day of conjugated
equine estrogens orally and group 2 of 19 participants who
received a placebo. The randomization was stratified to obtain
an approximately equal number of participants with the
following sleep difficulties as evidenced by the polysomnogram:
a sleep latency longer than 30 minutes; sleep stage 0 (resting but
awake) for more than 10% of the monitored period; final latency
longer than 10 minutes [11]; and a score higher than 5 on the
apnea-hypopnea index (AHI).
In the first phase of the study, treatment with estrogen or
placebo began on the first day of a 28-day cycle. After 12 weeks,
the women underwent a second physical examination and a
second round of tests that included the measurement of
reproductive hormone levels (data not shown) and a polysomnogram (testing 2 [T2]).
In the second phase, in addition to their previous treatment
(estrogen or placebo), all participants received 5 mg of
medroxyprogesterone acetate orally on the last 14 days of
each 28-day cycle. After 12 weeks, they returned for a medical
evaluation and a polysomnogram (testing 3 [T3]) (Fig. 1). The 5mg dosage was chosen because it provides maximum protection
against endometrial cancer and is known to control the
menstrual cycle during perimenopause. All participants took
the drug at dinner time to decrease the possibility of gastric
intolerance, and because its 18-hour half-life ensured an effect
through the night.
The women were followed up at monthly interviews, at which
time they received their medication for the next month. The
interview and testing procedures during these visits were
identical to those at the baseline visit. The reported adverse
effects were bleeding, mastalgia, and gastric intolerance; they
were mild, however, and did not cause participants to leave the
study.
Before the participants underwent a polysomnogram at
testings 1, 2, and 3, they answered a standardized questionnaire
covering all aspects of their sleep and designed to quantify
subjective sleep quality [12]. The severity of subjective
sleepiness before and during treatment was estimated using
the Epworth sleepiness scale (ESS), on which a score higher than
9 meant significant daytime sleepiness. Attention and/or
memory impairments and anxious and/or depressed states
were also documented. The KI score was used primarily for
risk-benefit evaluation.
2.2. Tests and analyses
Polysomnography was performed using a computerised polysomnograph (Sleep Analyzer Computer, version 9.3; Medilog
SAC, Oxford Instruments, Abingdon, England). Breathing was
assessed by monitoring movements of the chest wall and
abdomen using strain-gauge pneumographs, and nasal and
Flow chart of the study. Abbreviations: T1, testing 1; T2, testing 2; T3, testing 3.
Effects of hormone therapy with estrogen and/or progesterone on sleep pattern
Table 1
209
Baseline characteristics and hormonal concentrations for the 33 participants at study entry a
Variable
Group 1(n = 14)
Group 2(n = 19)
P value
Age, y
BMI
W/H ratio
Postmenopause, y
FSH, mlU/mL
LH, mlU/mL
Estradiol, pg/mL
Estrone, pg/mL
Progesterone, ng/mL
57.8
26.9
0.88
10.5
103.7
27.9
28.4
20.5
0.1
54.5
26.5
0.91
9.0
103.1
30.5
24.1
20.8
0.1
NS
NS
NS
NS
NS
NS
NS
NS
NS
(5.1)
(3.3)
(0.06)
(8.6)
(42.0)
(16.2)
(16.8)
(7.0)
(0.1)
(3.4)
(3.0)
(0.05)
(11.5)
(38.7)
(29.5)
(8.3)
(13.0)
(0.1)
Abbreviations: BMI, body mass index; FSH, follicle-stimulating hormone; LH, luteinizing hormone; NS, not significant; W/H, waist/hip ratio.
a
Values are expressed as mean (SD). Group 1 received estrogen for 12 weeks, then estrogen plus progesterone for another 12 weeks;
group 2 received placebo for 12 weeks, then placebo plus progesterone for another 12 weeks.
oral flows were assessed using thermistors. Arterial oxygen
saturation was measured using a pulse oximeter. Sleep latency
was measured as the interval between the time when the lights
were switched off and the first of 3 consecutive intervals, or
epochs, of stage 1 or any other stage of sleep (according to
standard criteria, 30-second scoring epochs on the electroencephalogram (EEG) were used to determine sleep stages [13]).
Apnea was defined as an airflow reduction of at least 80% and
hypopnea as an airflow reduction greater than 50%, or less if
associated with a 3% desaturation or arousal. Such events were
counted if they lasted more than 10 seconds. The score on the
apnea-hypopnea index (AHI) referred to the number of apnea or
hypopnea events per hour of sleep (a score b 5 being considered in
the normal range). Arousals were defined as abrupt shifts in
frequency lasting from 3 to 15 seconds on the EEG. Altered
respiratory events were classified according to the criteria
established by the American Association of Sleep Medicine [14].
Periodic limb movement (PLM) was assessed according to the
criteria of the American Sleep Disorders Association [15]. A PLM
was defined as activity bursts of the anterior tibialis muscle lasting
from 0.5 to 5 seconds and with amplitudes of at least 25% of the
burst recorded during calibration. A sequence of 4 or more PLM
events separated by 5 to 90 seconds is necessary for classification
as PLM. The score on the PLM index referred to the number of
PLM events per hour of sleep (a score b 5 being considered in the
normal range). The other sleep characteristics investigated were:
(A) sleep latency; (B) rapid eye movement (REM) sleep latency,
defined as the interval between sleep onset and the first epoch of
REM sleep; (C) early morning awakening, when participants woke
up before they intended and had difficulty going back to sleep;
(D) sleep efficiency, as percentage of the total recording time
spent sleeping; (E) percentage of the total recording time spent in
sleep stages 3 and 4 (defined as the presence of high-voltage, slowwave activity on the EEG during the recording period); (F)
percentage of the total recording time spent in REM sleep; (G)
number of arousals per hour; and (H) number of times sleep shifted
from one stage to another (or stage shift).
The participants' reproductive hormone levels are shown in
Table 1. Serum levels of progesterone, FSH, luteinizing hormone,
and estradiol were measured by competitive immunoassay
(Tosoh, Tokyo, Japan). The minimal detectable concentration
was 0.1 ng/mL for progesterone, 0.3 mIU/mL for FSH, 1.0 mIU/
mL for luteinizing hormone, and 15 pg/mL for estradiol. Estrone
was assayed by radioimmunoassay (Diagnostic Systems Laboratories, Webster, TX, USA).
Comparisons of qualitative variables between the 2 groups
were done using the v2 test, or the Fisher test when the
presumptions of the v2 test were not met. The v2 test was also
used to compare independent samples within the 2 groups.
Comparisons of quantitative variables, ie, of the values obtained
at each testing, were carried out using the nonparametric
Friedman K test for independent samples, which was followed
by multiple comparisons when needed. The results are
expressed as mean ± SD or as prevalence (for subjective
complaints). P b 0.05 was considered significant.
3. Results
All participants completed the study protocol. Baseline
characteristics and reproductive hormone values are shown
in Table 1. The 2 groups consisted of participants matched for
age, BMI, FSH level, ESS score, and sleep complaints, and
were not significantly different for anthropometric characteristics, years since menopause, clinical complaints, KI
score, or PSG results.
In both groups, the total KI score was markedly lower at
testings 2 and 3 than at testing 1 (Table 2). Although the score
was slightly higher at testing 3 than at testing 2 for group 1
(the estrogen, then estrogen plus progesterone group), the
difference in total KI score between testing 1 and testing 2 or
testing 3 was statistically greater for group 1 than for group 2
(the placebo, then placebo plus progesterone group).
The persons administering the tests and recording the
data were blind to the participants' complaints and treatment. Although an analysis of the polysomnograms did not
Table 2
Analysis of Kupperman index scores a
Group
Testing 1
(baseline)
Testing 2
(after 12 wk)
Testing 3(after
another 12 wk)
Group 1
Group 2
17.4 (8.6)
17.1 (9.5)
2.9 (2.7) b
7.3 (5.2) b, c
3.1 (2.9) b
6.7 (5.1) b, c
a
Values are expressed as mean (SD). Group 1 received estrogen
for 12 weeks, then estrogen plus progesterone for another
12 weeks; group 2 received placebo for 12 weeks, then placebo
plus progesterone for another 12 weeks.
b
P b 0.001 compared with the value at testing 1.
c
There was a statistical difference between the 2 groups.
210
Table 3
Subjective responses to a questionnaire regarding menopausal symptoms a
Complaint
Group 1
Hot flashes
Difficulty falling asleep
Frequent arousal
Restless legs
Bruxism
Snoring
Apnea
ESS score N 9
Anxiety
Memory impairment
Depression
Attention difficulties
Group 2
Pairwise comparisons between the 2 groups(P value)
Testing 1
(baseline)
Testing 2
(after 12 wk)
Testing 3(after
another 12 wk)
P value
Testing 1
(baseline)
Testing 2
(after 12 wk)
Testing 3(after
another 12 wk)
P value
Testing 1
(baseline)
Testing 2
(after 12 wk)
Testing 3(after
another 12 wk)
78.5
42.8
50.0
50.0
21.4
42.8
14.2
50.0
64.2
64.2
28.5
35.7
14.2 b, d
40.0
60.0
62.5
11.1
40.0 d
0 b, d
50.0 d
60.0
70.0
22.2
33.3 d
0 b, c, d
38.4
50.0
38.4 b
0 b, c, d
58.3
18.1 c
30.7 b, c
61.7 d
77.0 d
18.1
16.6 b, c, d
0.01
NS
NS
0.01
0.01
NS
0.01
NS
NS
NS
NS
0.01
68.4
52.6
52.6
42.1
10.5
73.6
26.3
31.5
52.6
63.1
31.5
42.1
57.8 d
37.5
62.5
50.0
18.7
71.4 d
25.0 d
26.6 d
68.7
75.0
37.5
50.0 d
42.1 d
47.0
41.1 c
58.8
13.3 d
58.8 b, c
7.7 b, c
35.2
47.0 c.d
53.0 c.d
23.5
41.1 d
NS
NS
0.01
NS
NS
0.05
0.01
NS
0.01
0.01
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
0.01
NS
NS
NS
NS
0.01
0.01
0.01
NS
NS
NS
0.03
0.01
NS
NS
NS
0.01
NS
NS
NS
0.04
0.01
NS
0.01
Abbreviations: ESS, Epworth sleepiness scale; NS, not significant.
a
Values are given as prevalence of the complaint. Group 1 received estrogen for 12 weeks, then estrogen plus progesterone for another 12 weeks; group 2 received placebo for 12 weeks, then placebo plus progesterone
for another 12 weeks.
b
Statistical difference with the value at testing 1.
c
Statistical difference with the value at testing 2.
d
Statistical difference between the 2 groups.
Table 4
Sleep characteristics obtained from polysomnograms a
Characteristic
Sleep latency, min
REM sleep latency, min
Early awake, min
Sleep efficiency, % of total time
Sleep stages 3 and 4, % of total time
REM, % of total time
Arousals, No. her hour
AHI score
SaO2min, %
PLM score
No. of sleep stage shifts
Group 1
Group 2
P value
Testing 1
(baseline)
Testing 2
(after 12 wk)
Testing 3(after
another 12 wk)
P value
Testing 1
(baseline)
Testing 2
(after 12 wk)
Testing 3(after
another 12 wk)
5.5 (21.6)
80.4 (36.6)
8.1 (10.8)
83.2 (7.6)
18.4 (8.9)
21.7 (4.0)
8.5 (4.6)
4.2 (3.9)
81.0 (6.2)
4.3 (4.6)
87.2 (23.3)
12.0
93.3
2.8
82.4
21.9
19.8
4.4
4.1
85.5
8.1
77.8
10.7
97.4
6.9
83.1
20.8
18.1
2.8
3.6
84.9
2.8
83.0
NS
NS
NS
NS
NS
NS
0.01
NS
NS
0.04
NS
14.9
97.7
4.7
83.2
19.3
20.3
16.9
6.5
83.4
6.2
91.3
12.1 (15.3)
97.7 (38.3)
6.4 (11.0)
84.8 (8.2)
21.2 (13.0)
18.6 (6.3)
7.3 (11.1) b
5.0 (5.8)
83.4 (6.6)
3.7 (6.0)
3.5 (30.0)
10.7
103.1
3.9
84.1
22.6
18.6
4.9
5.4
84.2
2.8
97.9
(1.9)
(33.1)
(3.8)
(8.1)
(7.8)
(5.7)
(4.3)
(4.1)
(6.7)
(10.8)
(23.1)
(7.2)
(59.3)
(11.6)
(6.9)
(7.9)
(3.0)
(2.5) b
(2.9)
(7.7)
(3.7) c
(15.1)
(14.9)
(43.8)
(8.2)
(7.7)
(5.6)
(5.5)
(15.1) d
(4.2)
(6.3)
(7.7)
(49.9)
(16.9)
(63.2)
(6.7)
(7.4)
(7.1)
(4.6)
(5.3) b
(6.3)
(5.2)
(3.9)
(4.4)
NS
NS
NS
NS
NS
NS
0.03
NS
NS
NS
NS
Pairwise comparisons
Groups 1 and 2 (P value)
T1
T2
T3
NS
NS
NS
NS
NS
NS
0.04
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
H. Hachul et al.
Abbreviations: AHI, apnea-hipopnea index; NS, not significant; PLM, periodic leg movement; SaO2 minimum arterial oxygen saturation per minute.
a
Values are given as prevalence of the complaint. Group 1 received estrogen for 12 weeks, then estrogen plus progesterone for another 12 weeks; group 2 received placebo for 12 weeks, then placebo plus progesterone
for another 12 weeks.
b
Statistical difference with the value at testing 1.
c
Statistical difference with the value at testing 2.
d
Statistical difference between the 2 groups.
Effects of hormone therapy with estrogen and/or progesterone on sleep pattern
reveal any statistically significant differences between the 2
groups for sleep latency during the study period, fewer sleep
complaints were reported in both groups after the progesterone treatment (Table 3). The main complaints were
frequent arousal, snoring, restless legs, excessive somnolence during the day, and, especially, difficulty in falling
asleep (of which 42.8% of the participants in group 1 and
52.6% in group 2 complained). In group 1, the prevalence of
hot flash and apnea complaints was decreased at testing 2
(after estrogen treatment) (P b 0.01), and the prevalence of
both somnolence and restless legs complaints was decreased
at testing 3 (after treatment with both estrogen and
progesterone). In group 2, compared with baseline values,
progesterone treatment reduced the prevalence of complaints of both hot flashes and bruxism (teeth clenching and
grinding) (P b 0.01) at testing 3. There were no significant
differences between baseline values and values at testing 2
or testing 3 for the other sleep characteristics studied, but a
smaller percentage of women reported snoring, apnea, or
arousal from sleep after taking progesterone. Comparisons
between the groups showed a significantly lower prevalence
of hot flashes, and snoring at testing 2, and apnea at testing 3
in group 1 than group 2 (P b 0.01).
Table 3 also reports the prevalence of complaints regarding mood, memory, and attention. There was a decrease in
the prevalence of complaints of attention difficulties at the
end of the study, but the decrease was greater in group 1
(P b 0.03) than in group 2 (P b 0.01). Moreover, treatment with
progesterone alone resulted in a lower percentage of women
complaining of anxiety or memory impairment (P b 0.01).
Although both groups had normal baseline sleep efficiency (Table 4), 12 of the 33 participants, 5 from group 1 and
7 from group 2, had a PLM score higher than 5. The only
statistically significant differences at the end of the study
were lower PLM scores in group 1 and fewer arousals in both
groups. The PLM score was decreased for 8 women after
estrogen plus progesterone treatment. At baseline, 14 of the
33 participants had an AHI score higher than 5, 4 in group 1
and 10 in group 2. The AHI score improved for 3 of the 4
participants in group 1 following treatment with estrogen
(P N 0.05) and in 8 of the remaining 11 following treatment
with progesterone (P b 0.06). After being treated with
progesterone, the women experienced fewer arousals during
sleep than at baseline (P b 0.03). No statistical differences in
other sleep characteristics were noted, whether across
treatments or between the groups.
4. Discussion
This study showed that HT-mediated improvement of subjectively reported sleep disturbances related to menopause can
be independent of objective effects on sleep characteristics.
Its main findings are that treatment with estrogen plus
progesterone was effective in reducing menopausal symptoms,
mostly suppressing hot flashes and bruxism events. Progesterone treatment alone resulted in fewer objective sleep arousals
per hour, fewer complaints of anxiety and memory impairment, and fewer complaints of snoring or apnea.
In light of the large number of women experiencing
menopausal symptoms, and the wide endocrinologic
research aiming at alleviating these symptoms, which are
211
known to include sleep-related respiratory disorders [16,17],
there is a surprising paucity of literature addressing sleep
difficulties in menopausal women.
Polysomnographic studies have found that menopausal
women with nocturnal hot flashes had lower sleep efficiency
than postmenopausal women without these symptoms [4],
and other studies have found strong relationships between
self-reported hot flashes and sleep complaints [20]. However, self-reports of sleep disturbance may reflect subjective
distress rather than objective sleep disruption. A 2003 study
by Young et al. [5] and a 2004 study by Freedman and Roehrs
[18] found, like ours, that sleep quality was not decreased in
these women, even those with menopausal symptoms. The
latter authors specifically reported that hot flashes did not
result in alterations of sleep architecture, sleepiness,
fatigue, or psychomotor performance in postmenopausal
women. They excluded more than one-third of the prospective subjects because they had sleep disorders unrelated to
menopause. By rigorously screening the study participants
they removed potential confounding factors.
In the present study, KI scores were improved in both
groups at testings 2 and 3. Hormone therapy may result in
physical and psychological improvement regardless of any
sleep improvement [19]; however, by improving menopausal
symptoms, it is a valuable predictive factor for a beneficial
effect on sleep [21]. In particular, the prevalence of
complaints regarding hot flashes was significantly reduced
by estrogen therapy, and estrogen plus progesterone led to a
complete cessation of complaints. This remarkable effect
may be related to improvement in subjective sleep quality.
The women in group 2 reported fewer arousals at night
although they saw no change in their diurnal somnolence.
We speculate that women affected with sleep problems
during menopause may be more likely to seek HT. Estrogen
seems to improve mood disturbances, although the subjective finding is not always supported by objective results
[22]. Young et al. [5] found no association between HT use
and better sleep quality whereas Sarti et al. [6] did. Since
estrogens seem to reduce the complaint of insomnia, we
wondered whether it was a placebo effect, and whether such
effect could last through the study. At any rate, we observed
a reduction in the number of apnea complaints after
12 weeks in the women taking estrogen.
The ventilatory effects of short-term medroxyprogesterone
acetate suggest that periodic administration might be sufficient to improve ventilation, and that periodic administration
may even be superior to continuous therapy [4]. Pickett et al.
[23] observed that postmenopausal women taking conjugated
estrogen plus medroxyprogesterone had fewer respiratory
disorders during sleep. In our study, complaints of apnea were
significantly reduced following treatment with progesterone.
Despite this subjective improvement of apnea, and a decrease
in snoring, no significant improvement in AHI score was noted,
however. The reduced prevalence of arousals at testing 3 could
be due to the well-documented hypnotic effect of progesterone. The effects of progesterone on sleep-related breathing
disorders [7] are still promising, although additional studies
should be conducted.
Objective sleep was not significantly improved after
estrogen and/or progesterone treatment, although there was
a trend toward improvement in objective sleep quality. We did
not detect any major alterations in polysomnographic
212
recordings in either group, although studies have found that
estrogen treatment led to significant relief of menopausal
symptoms [19]. This discrepancy may be due to differences in
study populations (eg, whether the women were perimenopausal or postmenopausal, had a natural or a surgically induced
menopause, or were younger or older) and methods (eg, different dosage, form, and duration of the hormonal treatment).
Our confidence in our findings is strengthened by our use
of a well-characterized, randomized, double-blind, placebocontrolled design. The screening interview included a
complete medical history, an evaluation of the women's
hormonal levels, and a detailed description of their
menopausal status. Furthermore, all participants underwent
3 polysomnograms. We were thus able to demonstrate the
distinct roles of estrogen, progesterone, and their combination on sleep and menopause-related symptoms.
Interestingly, although baseline PLM scores were within
normal ranges for both groups, the combined HT decreased
the number of complaints of restless legs and PLM events
with arousal. Few studies have reported the effects of
estrogen plus progesterone on PLM. Polo-Kantola et al. [24]
observed that estrogen improved subjective sleep quality
regardless of PLM or related arousal. Recently, we reported
that estrogen decreased PLM and increased REM sleep, in
addition to improving overall menopause symptomatology in
postmenopausal women with high PLM scores [25].
Despite the small number of participants and the possibility
of a type 2 error, the present results indicate that HTcombining
estrogen and progesterone improves subjective sleep in
postmenopausal women. Since sleep complaints are common
during menopause, future studies should include complete
investigations of both subjective and objective measures of
sleep prior to receiving HT. Additionally, it is important to
select study participants carefully for the actual assessment of
the effects of HTon sleep disturbances, and to dissociate these
effects from those normally produced by aging.
Acknowledgments
Wyeth supplied the estrogen, progesterone, and placebo for
this study but supplied no funds. The study was supported by
grants from Associação Fundo de Incentivo à Psicofarmacologia
(AFIP), Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq), and Fundação de Amparo à Pesquisa do
Estado de São Paulo (FAPESP). Sergio Tufik received Centro de
Excelência em Pesquisa, Inovação e Difusão (CEPID) grant 98/
14303-3 and Sergio Tufik, Monica L. Andersen, and Lia R. A.
Bittencourt received fellowships from CNPq.
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