CLIMACTERIC 2015;18:198–204
E ffects of estrogen therapy on postmenopausal sleep quality regardless of vasomotor symptoms: a randomized trial P. Tansupswatdikul, S. Chaikittisilpa, N. Jaimchariyatam*, K. Panyakhamlerd, U. Jaisamrarn and N. Taechakraichana Menopause Research Unit, Division of Reproductive Medicine, Department of Obstetrics-Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok; *Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Key words: POSTMENOPAUSE, INSOMNIA, SLEEP DISTURBANCE, ACTIGRAPHY, ACTIWATCH, ESTROGEN
ABSTRACT Objective To determine the effects of estrogen therapy on objective sleep quality in insomniac postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep. Study design Randomized, double-blinded, placebo-controlled trial, parallel design (ClinicalTrials.gov Identifier: NCT01501422). Methods Forty insomniac postmenopausal women with no severe vasomotor symptoms and/or recognized hot flushes during sleep were randomized into 2 months’ treatment with a 50-mg transdermal estradiol patch or placebo. Sleep quality was determined objectively with wrist actigraphy. Sleep efficiency, total sleep time, wake up after sleep onset and number of awakenings were compared before and after treatment. The Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) questionnaires were used for subjective sleep quality assessment before and after treatment. Results The study showed no significant difference in sleep efficiency improvement between women having estrogen alone or placebo (median 85.7% vs. 85.2%, respectively, p 0.71). Similarly, sleep quality scores assessed by ISI and ESS were not significantly different. Conclusion Estrogen therapy in insomniac postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep was not found to improve sleep efficiency during the study period.
INTRODUCTION Sleep complaints are increasing with age in both men and women. The changes in sleep patterns have been thought to reflect the normal developmental process which can be further compromised by sleep disturbances secondary to medical or psychiatric disorders1. Older women complain disproportionately about their sleep, particularly around the menopausal transition. One of our studies that has evaluated the prevalence of climacteric symptoms according to years after menopause found that the prevalence of insomnia was high during the perimenopause and the first few years after the final menstruation. This was in accordance with the prevalence of vasomotor symptoms in the studied population2. Whether sleep problems during the menopausal years are the result of sleep
interrupted by vasomotor symptoms or whether they are separate entities is still unclear. Sleep disturbance is commonly found in menopausal women but its burden has always been overlooked3. Forty-two percent of postmenopausal Asian women who visited the Menopause Clinic experienced sleep disturbance which was the main reason for seeking medical advice. If insomnia was not treated within a year, the women were ten-fold more likely to suffer from major depression and anxiety4. The characteristics of sleep disturbance in menopause included difficulty in sleep initiation, continuation and/or higher frequency of night awakenings and poor or tiring sleep5. The quality of sleep was worse in postmenopausal women compared to premenopausal women regarding prolonged sleep latency (SL) and increased proportion of rapid-eye-movement sleep affecting sleep continuation6.
Correspondence: S. Chaikittisilpa, Menopause Research Unit, Division of Reproductive Medicine, Department of Obstetrics-Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok; E-mail: [email protected] ORIGINAL ARTICLE © 2014 International Menopause Society DOI: 10.3109/13697137.2014.964670
Received 10-07-2014 Revised 05-09-2014 Accepted 08-09-2014
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Estrogen therapy and postmenopausal sleep quality Estrogen therapy is known to be beneficial in treating menopause-related symptoms and improving quality of life in postmenopausal women7. Steroid receptors have been discovered in several brain areas that are involved with sleep regulation and influence several neurotransmitters, i.e. cholinergic, serotonergic, dopaminergic and adrenergic neurotransmitters which play important roles in sleep regulation. Estrogen may be involved with restoration of various circadian hormones such as growth hormone, prolactin, cortisol and melatonin8. Moreover, estrogen also regulates g-aminobutyric acid (GABA) which plays a central role in sleep initiation and maintenance9. Nevertheless, the effects of estrogen on sleep quality are still inconclusive. Whether the claimed improvement in sleep pattern with estrogen therapy results from its treatment effects on severe vasomotor symptoms or recognized hot flushes which cause interrupted sleep is unclear. Hence, the aim of this study was to determine the effects of estrogen on sleep quality in insomniac postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep. In this study, we decided to use the 50-mg transdermal estradiol patch (Climara®) which has been shown to confer estradiol levels within the range of the follicular phase of the normal ovulatory cycle; the dose complies with the FDA recommendation for low-dose postmenopausal estrogen therapy10–12.
METHOD Study population The study was performed during July 2011–January 2012. Forty postmenopausal women, aged between 40 and 60 years old, were recruited from the Menopause Clinic, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Data for the inclusion and exclusion criteria were obtained in the clinic using a self-reported questionnaire, chart review and individual interview. The inclusion criteria included: (1) amenorrhea for at least 1 year naturally or post-bilateral oophorectomy; (2) insomnia diagnosed by ICSD-2 criteria (daytime impairment related to night-time sleep difficulty, complaint of difficulty in initiating sleep, or difficulty maintaining sleep or waking up too early, or sleep that is chronically nonrestorative or poor in quality and occurs despite adequate opportunity and circumstances for sleep); (3) good in writing and reading the Thai language; and (4) willing to give informed consent to participate. Women were excluded if they had severe vasomotor symptoms or recognized hot flushes during sleep, were known to have contraindications to estrogen such as a history of suspected or having estrogen-related cancers, thromboembolic diseases, acute liver or gall bladder diseases, cardiovascular diseases, cerebrovascular diseases, vasculitis, undiagnosed vaginal bleeding, allergic to estrogen/progestogen. We also excluded those with a history of chronic medical illness, primary sleep disorder, psychiatric disease such as depression, anxiety, schizophrenia including Alzheimer’s disease, history of alcohol or drug abuse, use of medication likely
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Tansupswatdikul et al. to influence sleep or vigilance within 1 month or use of postmenopausal hormone therapy within 6 months. The sample size was estimated based on a previous study13 that evaluated the effects of estrogen on objective sleep quality. With a level of statistical significance of 0.05% (a error 0.05, two-sided) and a power of study of 80% (b error 0.2), we obtained a sample size of 20 subjects per group after addition of 20% of calculated subjects. The study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand and all subjects provided their written informed consent before recruitment.
Study design The study was performed as a randomized, double-blinded, placebo-controlled trial in a parallel design with 1 : 1 allocation ratio (ClinicalTrials.gov Identifier: NCT01501422) (Figure 1). Each participant was interviewed in order to obtain information related to the sleeping behavior along with basic patient information. These included age, years since menopause, type of menopause, marital status, weight, height, body mass index (BMI), caffeine consumption, frequency of mild to moderate vasomotor symptoms, and sleep history. After being informed about the objective of the study, the experiment process, and the possible side-effects of the treatment, participants were allocated with block-of-four randomization into two groups. Participants received a 2-month treatment with either the 50-mg transdermal estradiol patch (Climara®) or a placebo patch (n 20/group). An independent pharmacist dispensed either the estrogen or the placebo patch according to the block-of-four randomization list. The estrogen and placebo patches were in packages and identical in appearance. They were pre-packed in envelopes and consecutively numbered for each woman according to the randomization schedule. Each woman was assigned an order number and received the patches in the corresponding pre-packed envelope. All participants, care providers, research assistants and those assessing the outcome were blinded to treatment allocation. All participants were interviewed about their baseline characteristics and asked to complete two selfadministered questionnaires. The first one was the assessment of severity of the insomnia problems indicated by the Insomnia Severity Index (ISI) and the second one was to evaluate daytime vigilance, as indicated by the Epworth Sleepiness Scale (ESS). Instruction to all participants was given on the Actiwatch (a wrist actigraphy method that uses an accelerometer to detect and log wrist movements to discriminate sleep from wake periods) and an Actiwatch was put on each participant’s non-dominant wrist all day for 7 days. The sleep diary was recorded during the period of wearing the Actiwatch. The participants revisited for the Actiwatch to be taken off after 7 days measurement and 7-day sleep data were retrieved from the actigraph. The sleep diary data were checked to ensure that the sleep diary was completely recorded. An 8-week period of either the 50-mg estradiol patch or the
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placebo patch was dispensed according to the block-of-four randomization. The participants were instructed to apply the patch to their lower abdomen according to standard instruction. The participants received a follow-up phone call after 4 weeks of patch application to assess treatment compliance and side-effects. At week 7, the Actiwatch instruction was re-explained to all participants and the same Actiwatch was put on their non-dominant wrist all day for 7 days. The sleep diary was again recorded during the period of wearing the Actiwatch as at the baseline visit. On the last visit at week 9, the Actiwatch was taken off and the 7-day data of the actigraph were retrieved for post-treatment data. The sleep diary data were checked to ensure that the sleep diary was completely recorded. The treatment compliance and sideeffects were assessed. Post-treatment evaluation with two self-administered questionnaires, the ESS and the ISI, was
done. Ten mg medroxyprogesterone acetate (MPA) were given for 14 days to non-hysterectomized participants who received estrogen at the end of the study for endometrial protection.
The Actiwatch device Actiwatch, the validated objective method of measuring sleep quality for insomnia, uses an accelerometer to detect and log wrist movement. This method is known as actigraphy and has been shown to be a useful means for discriminating sleep from wake activity. An objective recording is accomplished within a patient’s normal living environment for multiple, consecutive 24-h periods. The small size (similar to a wrist-watch) and rugged nature of the Actiwatch allow it to be comfortably worn during activities of daily living, including bathing,
Assessed for eligibility (n = 44) Enrollment Enrollment
Excluded (n = 4) 1 functional ovary left (n = 2) declined to participate (n = 2)
Randomized (n = 40)
Allocation Allocated to estrogen patch group
Allocated to placebo group
received estrogen patch (n = 20)
received placebo (n = 20)
did not receive estrogen patch (n = 0)
did not receive placebo (n = 0)
Follow-up Lost to follow up (n = 0)
Lost to follow up (n = 0)
Discontinued estrogen patch (n = 0)
Discontinued estrogen patch (n = 0)
Failed to retrieve post-treatment actigraph data (n = 1)
Failed to retrieve post-treatment actigraph data (n = 3)
Analyses Analyzed (n = 19)
Analyzed (n = 17)
Excluded from analysis (n = 0)
Excluded from analysis (n = 0)
Figure 1 Enrollment, intervention allocation, follow-up and data analysis
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Estrogen therapy and postmenopausal sleep quality swimming and even vigorous movement. Once activity data are retrieved using the Actiware® host software and a communication dock, they are displayed as an actograph, an insightful graphical display of sleep/wake patterns. This display allows for quick and easy interpretation and confirmation of the sleep schedule and is a useful tool to help sleep professionals accurately educate patients about their sleep patterns.
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Efficacy variables The primary efficacy variables were defined as sleep efficiency (SE; ratio of time spent asleep to the amount of time spent in bed). The secondary outcomes were other parameters retrieved from the actigraph: sleep latency (SL, time period measured from light out or bedtime to the beginning of sleep), wake after sleep onset (WASO, the sum of wake time from sleep onset to final awakening), the number of awakenings during sleep (NWAK), and total sleep time (TST, actual sleep time after lying in bed), and scores from the two sets of sleep questionnaires.
Statistical analyses Descriptive statistics (mean (standard deviation) or median (range) and percentage) were used to express demographic, baseline, and measurement outcome data. Comparisons of measurement outcomes (SE, SL, TST, WASO, NWAK, ISI score, ESS score) between the two groups after treatment were analyzed for statistical significance by ANCOVA if the data were normally distributed or the Mann–Whitney U-test if the data were not normally distributed. Comparisons of qualitative data were analyzed by the c2 test, and Fisher’s exact test was used to analyze the side-effects between the two groups. Data were analyzed by SPSS version 17.0. A p level of 0.05 was considered statistically significant.
RESULTS Study participants Forty postmenopausal women, aged between 40 and 60 years old, completed the study protocol. Only four post-treatment actigraphs could not be retrieved from the Actiwatch, three in the placebo group and one in the treatment group. Baseline characteristics showed no statistically significant differences for age, BMI, years since menopause, type of menopause, marital status, and caffeine consumption (Table 1). Most of the participants were naturally menopausal and their vasomotor symptoms did not occur more than ten times per month. The ISI showed the median score as moderate insomnia in both groups (Table 2).
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Tansupswatdikul et al. Table 1 Characteristics of participants in the group receiving estrogen and the group receiving placebo. Data are given as mean 1 standard deviation or n (%).There were no significant 2 differences between the two groups
Age (years) Body mass index (kg/m2) Marital status single couple Years since menopause Natural menopause Surgical menopause Caffeine consumption
Placebo group (n 20)
Estrogen group (n 20)
54.2 1 2 3.9 25.5 1 2 4.1
54.55 1 2 3.6 24.3 1 2 3.9
10 (50%) 10 (50%) 5.3 1 2 3.8 16 (80%) 4 (20%) 16 (80%)
7 (35%) 13 (65%) 5.7 1 2 4.3 15 (75%) 5 (25%) 10 (50%)
Efficacy Self-administered questionnaires Both the ISI score and the ESS score were not significantly different between the placebo and treatment groups at baseline. The ISI score that evaluated the severity of insomnia and the ESS score that evaluated daytime vigilance did not show a statistically significant difference between the two groups after 2 months of the study period (Table 2).
Sleep quality parameters from the actigraph All parameters of sleep quality retrieved from the actigraph after adjustment with the sleep diary were compared between the placebo and estrogen groups by the Mann–Whitney U-test. There was no improvement in sleep efficiency in both groups, as shown in Table 3. The data were re-analyzed with intention-to-treat (last observation carried forwards) (ITT LOCF) analysis (Table 4). Table 2 Sleep quality assessed by self-administered questionnaires. Data are given as median (1st quartile, 3rd quartile) Questionnaires Insomnia Severity Index24 Pretreatment Post-treatment Epworth Sleepiness Scale25 Pretreatment Post-treatment
Placebo group (n 20)
Estrogen group (n 20) p Value
16 (12.3, 18.8) 15 (10.3, 17.8) 13 (8.5, 14) 9.5 (8, 16.3)
0.50 0.35
8.5 (5.5, 12) 7.5 (5, 10)
0.61 0.90
6.5 (4.3, 12.8) 6 (4, 11)
I nsomnia Severity Index scores: 0–7, no clinically significant insomnia; 8–14, subthreshold insomnia; 15–21, clinical insomnia (moderate severity); 22–28, clinical insomnia (severe) Epworth Sleepiness Scale scores: 1–6, getting enough sleep; 7–8, score is average; 9, very sleepy and should seek medical advice
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Table 3 Parameters of objective sleep quality. Data are given as median (1st quartile, 3rd quartile)
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Sleep parameters
Placebo group (n 20)
Sleep efficiency (%) Pretreatment 85.2 (81.1, 88.1) Post-treatment 87.1 (84, 88.8) Total sleep time (h) Pretreatment 5.4 (4.4, 6.2) Post-treatment 5.4 (4.5, 6.3) Sleep latency (min) Pretreatment 12.9 (8.9, 22) Post-treatment 13.1 (8.3, 17.7) Number of awakenings (/night) Pretreatment 25.6 (20, 32.2) Post-treatment 25.8 (22.4, 35.2) Wake after sleep onset (min) Pretreatment 35.9 (23.6, 40.1) Post-treatment 27.2 (19.4, 40.7)
Table 5 Adverse effects of patches. Data are given as n (%) Placebo group (n 20)
Symptoms
Estrogen group (n 20)
p Value*
85.9 (80, 87.9) 85.7 (82.8, 89.3)
0.71 0.71
5.4 (5.2, 6.2) 5.4 (4.5, 6.3)
0.46 0.66
15.7 (8.6, 29.3) 13.2 (5.4, 21.4)
0.91 0.45
28.7 (22.7, 39.4) 26.0 (16.8, 35.7)
0.22 0.53
32 (21.6, 48.8) 29.9 (22.8, 43.2)
0.91 0.45
*, Mann–Whitney U-test, comparing pretreatment and post-treatment between groups Normative values of sleep parameters26: Sleep efficiency 86–87%; Total sleep time 6.5–6.6 h; Sleep latency 16–17 min; Wake after sleep onset 32–38 min
Safety The estrogen group experienced adverse effects of breast pain and vaginal discharge significantly more often than the placebo group, but skin rash was found significantly less often than in the placebo group. Other adverse effects were not different between the groups (Table 5).
DISCUSSION Sleep disturbance is multifactorial in etiology. This study aimed to evaluate the effects of estrogen on postmenopausal
Breast pain Vaginal discharge Skin rash Abdominal discomfort Bleeding per vagina
3 0 18 1 0
(15%) (0%) (90%) (5%) (0%)
Estrogen group (n 20) 10 8 8 1 1
(50%) (40%) (40%) (5%) (5%)
p Value 0.04 0.01 0.01 0.76 1.00
sleep quality, independent of other non-hormonal factors. Several studies have demonstrated improvement of subjective sleep quality with estrogen therapy using self-reported questionnaires9,13–16; however, there were some limitations to those studies. Estrogen is known to be the most effective treatment of VMS and night sweating, which cause interrupted sleep at night17. VMS was found to be highly associated with chronic insomnia9; as a consequence, the improvement of subjective sleep quality may be due to the relief of vasomotor symptoms17,18. To verify the genuine effects of estrogen on improvement of sleep quality, objective evaluation using accurate and reliable tools is needed. Polysomnography (PSG) has been considered to be a gold-standard measurement of objective sleep quality19, especially in respiratory-related disorders. Nevertheless, it has not been validated in insomniac patients because the tool needs many tag sites over the body which may, in themselves, disturb sleep initiation and continuation and is difficult to repeat. Patients need to be hospitalized and consequently the outcome may not represent the actual sleep pattern at home; this may result in either false improvement of sleep quality (reverse night effect) or false worse quality (first-night effect)20. Another validated tool which can be reliably used to assess sleep quality in insomniac patients is wrist actigraphy. This is a practical tool to assess sleep quality due to its repeatability, ease of use, ability to test at home, and is comfortable and convenient to wear as a sleeping wristwatch. Actigraphy was validated for assessment of sleep quality in insomniac
Table 4 Comparison of the sleep parameters retrieved from the actigraph Post-treatment (per protocol analysis) Placebo group (n 17) Sleep efficiency (%) Total sleep time (min) Sleep latency (min) Wake after sleep onset (min) Number of awakenings (/night)
85.2 5.4 13.1 27.2 25.8
(81.1, 88.1) (4.5, 6.3) (8.3, 17.7) (19.4, 40.7) (22.4, 35.2)
Estrogen group (n 19)
p Value*
85.7 (82.8, 89.3) 5.4 (4.5, 6.3) 13.2 (5.4, 21.4) 29.9 (22.8, 43.2) 26 (16.8, 35.7)
0.71 0.66 0.62 0.45 0.57
Post-treatment (ITT LOCF) Placebo group (n 20) 86.6 5.4 14.5 27.8 28.5
(83.2, 88.6) (4.4, 6.3) (8.7, 18.9) (17.8, 39.1) (23, 36.8)
Estrogen group (n 20) 85.6 5.4 13.6 32.2 25.6
(81.8, 89.1) (4.6, 6.3) (5.9, 20.3) (22.9, 42.6) (16.9, 34.3)
p Value** 0.89 0.64 0.43 0.21 0.53
*, Mann–Whitney U-test, comparing post-treatment data between groups LOCF, last observation carried forwards, comparing post-treatment data between groups Normative values of sleep parameters26: Sleep efficiency 86–87%; Total sleep time 6.5–6.6 h; Sleep latency 16–17 min; Wake after sleep onset 32–38 min
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Estrogen therapy and postmenopausal sleep quality patients in 2006 and was found to have high correlation with PSG21. Therefore, we decided to use actigraphy to evaluate the effects of estrogen on sleep quality in insomniac postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep. In the present study, we found no significant improvement in all objective sleep quality parameters. In previous studies using PSG measurement along with the questionnaires, estrogen was shown to improve sleep quality by reducing the frequency of awakening during sleep21,22 and increasing sleep efficiency23. These studies were conducted in a small number of participants, ranging from nine to 16 postmenopausal women in each study. The first study21 enrolled 16 hypogonadal women, aged 31–65 years, half of which were postmenopausal for 2–22 years and the other half having undergone oophorectomy, without data on years since menopause. The second study22 enrolled 11 naturally or surgically postmenopausal women with a mean age of 54.8 1 2 1.5 years with duration of menopause 6.7 1 1.2 years, with some women still continuing 2 hormone use until the study. The third study23 enrolled nine postmenopausal women who complained of frequent, severe hot flushes, aged 30–55 years, and were within 1–5 years of either surgical or natural menopause. Although it is difficult to compare the differences in menopausal stage or years since menopause in our study with the others, the contradiction in our study is probably elucidated by the fact that, first, we excluded participants who had severe vasomotor symptoms with a high probability of night awakening. The effects of estrogen on sleep may be due to the consequence of improving vasomotor symptoms rather than its direct effect on GABA-A or sleep regulation. Second, the use of PSG in the other studies could not exclude the first-night and reverse first-night effects, as mentioned earlier. The high occurrence of breast pain and increased vaginal discharge in the estrogen group could possibly unmask the double-blinded design. Skin rash was observed significantly more in the placebo group; this may result from the moisturizing effect of estrogen over the skin where the patch was attached, causing less irritation. The strengths of the present study were: (1) many tools were used for sleep quality assessment including the actigraph, the validated tool for assess insomnia, which was repeatable, mobile, with no need for admission, and the two selfadministered questionnaires to assess the severity and daytime sleepiness; (2) the transdermal route was chosen because of concern about patient compliance which may have interfered with the result. However, limitations of this study were the
Tansupswatdikul et al. small sample size and the lack of a record of confounders during the study. There were no serum estradiol measurements to assess subject’s adherence. The dose and the 2-month duration of estrogen use may not be enough to demonstrate the effects of estrogen on sleep quality. In addition, it may not be appropriate to generalize the results of this study to all stages of menopause or to different types of insomnia. This is a good pilot study to investigate the possible effects of estrogen on insomniac patients and whether the positive effects of estrogen on sleep are due to its indirect effect via relief of vasomotor symptoms or due to a direct effect on sleep regulation. Further study should be conducted in a larger sample size with better control of confounders.
CONCLUSION Estrogen therapy in insomniac, postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep did not show any significant improvement in sleep efficiency and other sleep parameters. The previous reports of estrogen therapy improving sleep quality were probably the consequences of the relief from vasomotor symptoms causing night awakening.
ACKNOWLEDGEMENTS We would like to give our sincere thanks to the Menopause Research Unit, Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University for the support of the present study. We really appreciate the kind assistance of Jirayos Chintanadilok, MD and Asst. Tayard Desudchit in procuring the actigraphy devices and Ms Somtawin Pojjanasopanakun, BSc as a research assistant. Conflict of interest The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding Ratchadapiseksompotch Endowment Fund, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Menopause research unit, Division of Reproductive Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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E ffects of estrogen therapy on postmenopausal sleep quality regardless of vasomotor symptoms: a randomized trial P. Tansupswatdikul, S. Chaikittisilpa, N. Jaimchariyatam*, K. Panyakhamlerd, U. Jaisamrarn and N. Taechakraichana Menopause Research Unit, Division of Reproductive Medicine, Department of Obstetrics-Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok; *Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Key words: POSTMENOPAUSE, INSOMNIA, SLEEP DISTURBANCE, ACTIGRAPHY, ACTIWATCH, ESTROGEN
ABSTRACT Objective To determine the effects of estrogen therapy on objective sleep quality in insomniac postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep. Study design Randomized, double-blinded, placebo-controlled trial, parallel design (ClinicalTrials.gov Identifier: NCT01501422). Methods Forty insomniac postmenopausal women with no severe vasomotor symptoms and/or recognized hot flushes during sleep were randomized into 2 months’ treatment with a 50-mg transdermal estradiol patch or placebo. Sleep quality was determined objectively with wrist actigraphy. Sleep efficiency, total sleep time, wake up after sleep onset and number of awakenings were compared before and after treatment. The Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) questionnaires were used for subjective sleep quality assessment before and after treatment. Results The study showed no significant difference in sleep efficiency improvement between women having estrogen alone or placebo (median 85.7% vs. 85.2%, respectively, p 0.71). Similarly, sleep quality scores assessed by ISI and ESS were not significantly different. Conclusion Estrogen therapy in insomniac postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep was not found to improve sleep efficiency during the study period.
INTRODUCTION Sleep complaints are increasing with age in both men and women. The changes in sleep patterns have been thought to reflect the normal developmental process which can be further compromised by sleep disturbances secondary to medical or psychiatric disorders1. Older women complain disproportionately about their sleep, particularly around the menopausal transition. One of our studies that has evaluated the prevalence of climacteric symptoms according to years after menopause found that the prevalence of insomnia was high during the perimenopause and the first few years after the final menstruation. This was in accordance with the prevalence of vasomotor symptoms in the studied population2. Whether sleep problems during the menopausal years are the result of sleep
interrupted by vasomotor symptoms or whether they are separate entities is still unclear. Sleep disturbance is commonly found in menopausal women but its burden has always been overlooked3. Forty-two percent of postmenopausal Asian women who visited the Menopause Clinic experienced sleep disturbance which was the main reason for seeking medical advice. If insomnia was not treated within a year, the women were ten-fold more likely to suffer from major depression and anxiety4. The characteristics of sleep disturbance in menopause included difficulty in sleep initiation, continuation and/or higher frequency of night awakenings and poor or tiring sleep5. The quality of sleep was worse in postmenopausal women compared to premenopausal women regarding prolonged sleep latency (SL) and increased proportion of rapid-eye-movement sleep affecting sleep continuation6.
Correspondence: S. Chaikittisilpa, Menopause Research Unit, Division of Reproductive Medicine, Department of Obstetrics-Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok; E-mail: [email protected] ORIGINAL ARTICLE © 2014 International Menopause Society DOI: 10.3109/13697137.2014.964670
Received 10-07-2014 Revised 05-09-2014 Accepted 08-09-2014
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Estrogen therapy and postmenopausal sleep quality Estrogen therapy is known to be beneficial in treating menopause-related symptoms and improving quality of life in postmenopausal women7. Steroid receptors have been discovered in several brain areas that are involved with sleep regulation and influence several neurotransmitters, i.e. cholinergic, serotonergic, dopaminergic and adrenergic neurotransmitters which play important roles in sleep regulation. Estrogen may be involved with restoration of various circadian hormones such as growth hormone, prolactin, cortisol and melatonin8. Moreover, estrogen also regulates g-aminobutyric acid (GABA) which plays a central role in sleep initiation and maintenance9. Nevertheless, the effects of estrogen on sleep quality are still inconclusive. Whether the claimed improvement in sleep pattern with estrogen therapy results from its treatment effects on severe vasomotor symptoms or recognized hot flushes which cause interrupted sleep is unclear. Hence, the aim of this study was to determine the effects of estrogen on sleep quality in insomniac postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep. In this study, we decided to use the 50-mg transdermal estradiol patch (Climara®) which has been shown to confer estradiol levels within the range of the follicular phase of the normal ovulatory cycle; the dose complies with the FDA recommendation for low-dose postmenopausal estrogen therapy10–12.
METHOD Study population The study was performed during July 2011–January 2012. Forty postmenopausal women, aged between 40 and 60 years old, were recruited from the Menopause Clinic, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Data for the inclusion and exclusion criteria were obtained in the clinic using a self-reported questionnaire, chart review and individual interview. The inclusion criteria included: (1) amenorrhea for at least 1 year naturally or post-bilateral oophorectomy; (2) insomnia diagnosed by ICSD-2 criteria (daytime impairment related to night-time sleep difficulty, complaint of difficulty in initiating sleep, or difficulty maintaining sleep or waking up too early, or sleep that is chronically nonrestorative or poor in quality and occurs despite adequate opportunity and circumstances for sleep); (3) good in writing and reading the Thai language; and (4) willing to give informed consent to participate. Women were excluded if they had severe vasomotor symptoms or recognized hot flushes during sleep, were known to have contraindications to estrogen such as a history of suspected or having estrogen-related cancers, thromboembolic diseases, acute liver or gall bladder diseases, cardiovascular diseases, cerebrovascular diseases, vasculitis, undiagnosed vaginal bleeding, allergic to estrogen/progestogen. We also excluded those with a history of chronic medical illness, primary sleep disorder, psychiatric disease such as depression, anxiety, schizophrenia including Alzheimer’s disease, history of alcohol or drug abuse, use of medication likely
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Tansupswatdikul et al. to influence sleep or vigilance within 1 month or use of postmenopausal hormone therapy within 6 months. The sample size was estimated based on a previous study13 that evaluated the effects of estrogen on objective sleep quality. With a level of statistical significance of 0.05% (a error 0.05, two-sided) and a power of study of 80% (b error 0.2), we obtained a sample size of 20 subjects per group after addition of 20% of calculated subjects. The study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand and all subjects provided their written informed consent before recruitment.
Study design The study was performed as a randomized, double-blinded, placebo-controlled trial in a parallel design with 1 : 1 allocation ratio (ClinicalTrials.gov Identifier: NCT01501422) (Figure 1). Each participant was interviewed in order to obtain information related to the sleeping behavior along with basic patient information. These included age, years since menopause, type of menopause, marital status, weight, height, body mass index (BMI), caffeine consumption, frequency of mild to moderate vasomotor symptoms, and sleep history. After being informed about the objective of the study, the experiment process, and the possible side-effects of the treatment, participants were allocated with block-of-four randomization into two groups. Participants received a 2-month treatment with either the 50-mg transdermal estradiol patch (Climara®) or a placebo patch (n 20/group). An independent pharmacist dispensed either the estrogen or the placebo patch according to the block-of-four randomization list. The estrogen and placebo patches were in packages and identical in appearance. They were pre-packed in envelopes and consecutively numbered for each woman according to the randomization schedule. Each woman was assigned an order number and received the patches in the corresponding pre-packed envelope. All participants, care providers, research assistants and those assessing the outcome were blinded to treatment allocation. All participants were interviewed about their baseline characteristics and asked to complete two selfadministered questionnaires. The first one was the assessment of severity of the insomnia problems indicated by the Insomnia Severity Index (ISI) and the second one was to evaluate daytime vigilance, as indicated by the Epworth Sleepiness Scale (ESS). Instruction to all participants was given on the Actiwatch (a wrist actigraphy method that uses an accelerometer to detect and log wrist movements to discriminate sleep from wake periods) and an Actiwatch was put on each participant’s non-dominant wrist all day for 7 days. The sleep diary was recorded during the period of wearing the Actiwatch. The participants revisited for the Actiwatch to be taken off after 7 days measurement and 7-day sleep data were retrieved from the actigraph. The sleep diary data were checked to ensure that the sleep diary was completely recorded. An 8-week period of either the 50-mg estradiol patch or the
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placebo patch was dispensed according to the block-of-four randomization. The participants were instructed to apply the patch to their lower abdomen according to standard instruction. The participants received a follow-up phone call after 4 weeks of patch application to assess treatment compliance and side-effects. At week 7, the Actiwatch instruction was re-explained to all participants and the same Actiwatch was put on their non-dominant wrist all day for 7 days. The sleep diary was again recorded during the period of wearing the Actiwatch as at the baseline visit. On the last visit at week 9, the Actiwatch was taken off and the 7-day data of the actigraph were retrieved for post-treatment data. The sleep diary data were checked to ensure that the sleep diary was completely recorded. The treatment compliance and sideeffects were assessed. Post-treatment evaluation with two self-administered questionnaires, the ESS and the ISI, was
done. Ten mg medroxyprogesterone acetate (MPA) were given for 14 days to non-hysterectomized participants who received estrogen at the end of the study for endometrial protection.
The Actiwatch device Actiwatch, the validated objective method of measuring sleep quality for insomnia, uses an accelerometer to detect and log wrist movement. This method is known as actigraphy and has been shown to be a useful means for discriminating sleep from wake activity. An objective recording is accomplished within a patient’s normal living environment for multiple, consecutive 24-h periods. The small size (similar to a wrist-watch) and rugged nature of the Actiwatch allow it to be comfortably worn during activities of daily living, including bathing,
Assessed for eligibility (n = 44) Enrollment Enrollment
Excluded (n = 4) 1 functional ovary left (n = 2) declined to participate (n = 2)
Randomized (n = 40)
Allocation Allocated to estrogen patch group
Allocated to placebo group
received estrogen patch (n = 20)
received placebo (n = 20)
did not receive estrogen patch (n = 0)
did not receive placebo (n = 0)
Follow-up Lost to follow up (n = 0)
Lost to follow up (n = 0)
Discontinued estrogen patch (n = 0)
Discontinued estrogen patch (n = 0)
Failed to retrieve post-treatment actigraph data (n = 1)
Failed to retrieve post-treatment actigraph data (n = 3)
Analyses Analyzed (n = 19)
Analyzed (n = 17)
Excluded from analysis (n = 0)
Excluded from analysis (n = 0)
Figure 1 Enrollment, intervention allocation, follow-up and data analysis
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Estrogen therapy and postmenopausal sleep quality swimming and even vigorous movement. Once activity data are retrieved using the Actiware® host software and a communication dock, they are displayed as an actograph, an insightful graphical display of sleep/wake patterns. This display allows for quick and easy interpretation and confirmation of the sleep schedule and is a useful tool to help sleep professionals accurately educate patients about their sleep patterns.
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Efficacy variables The primary efficacy variables were defined as sleep efficiency (SE; ratio of time spent asleep to the amount of time spent in bed). The secondary outcomes were other parameters retrieved from the actigraph: sleep latency (SL, time period measured from light out or bedtime to the beginning of sleep), wake after sleep onset (WASO, the sum of wake time from sleep onset to final awakening), the number of awakenings during sleep (NWAK), and total sleep time (TST, actual sleep time after lying in bed), and scores from the two sets of sleep questionnaires.
Statistical analyses Descriptive statistics (mean (standard deviation) or median (range) and percentage) were used to express demographic, baseline, and measurement outcome data. Comparisons of measurement outcomes (SE, SL, TST, WASO, NWAK, ISI score, ESS score) between the two groups after treatment were analyzed for statistical significance by ANCOVA if the data were normally distributed or the Mann–Whitney U-test if the data were not normally distributed. Comparisons of qualitative data were analyzed by the c2 test, and Fisher’s exact test was used to analyze the side-effects between the two groups. Data were analyzed by SPSS version 17.0. A p level of 0.05 was considered statistically significant.
RESULTS Study participants Forty postmenopausal women, aged between 40 and 60 years old, completed the study protocol. Only four post-treatment actigraphs could not be retrieved from the Actiwatch, three in the placebo group and one in the treatment group. Baseline characteristics showed no statistically significant differences for age, BMI, years since menopause, type of menopause, marital status, and caffeine consumption (Table 1). Most of the participants were naturally menopausal and their vasomotor symptoms did not occur more than ten times per month. The ISI showed the median score as moderate insomnia in both groups (Table 2).
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Tansupswatdikul et al. Table 1 Characteristics of participants in the group receiving estrogen and the group receiving placebo. Data are given as mean 1 standard deviation or n (%).There were no significant 2 differences between the two groups
Age (years) Body mass index (kg/m2) Marital status single couple Years since menopause Natural menopause Surgical menopause Caffeine consumption
Placebo group (n 20)
Estrogen group (n 20)
54.2 1 2 3.9 25.5 1 2 4.1
54.55 1 2 3.6 24.3 1 2 3.9
10 (50%) 10 (50%) 5.3 1 2 3.8 16 (80%) 4 (20%) 16 (80%)
7 (35%) 13 (65%) 5.7 1 2 4.3 15 (75%) 5 (25%) 10 (50%)
Efficacy Self-administered questionnaires Both the ISI score and the ESS score were not significantly different between the placebo and treatment groups at baseline. The ISI score that evaluated the severity of insomnia and the ESS score that evaluated daytime vigilance did not show a statistically significant difference between the two groups after 2 months of the study period (Table 2).
Sleep quality parameters from the actigraph All parameters of sleep quality retrieved from the actigraph after adjustment with the sleep diary were compared between the placebo and estrogen groups by the Mann–Whitney U-test. There was no improvement in sleep efficiency in both groups, as shown in Table 3. The data were re-analyzed with intention-to-treat (last observation carried forwards) (ITT LOCF) analysis (Table 4). Table 2 Sleep quality assessed by self-administered questionnaires. Data are given as median (1st quartile, 3rd quartile) Questionnaires Insomnia Severity Index24 Pretreatment Post-treatment Epworth Sleepiness Scale25 Pretreatment Post-treatment
Placebo group (n 20)
Estrogen group (n 20) p Value
16 (12.3, 18.8) 15 (10.3, 17.8) 13 (8.5, 14) 9.5 (8, 16.3)
0.50 0.35
8.5 (5.5, 12) 7.5 (5, 10)
0.61 0.90
6.5 (4.3, 12.8) 6 (4, 11)
I nsomnia Severity Index scores: 0–7, no clinically significant insomnia; 8–14, subthreshold insomnia; 15–21, clinical insomnia (moderate severity); 22–28, clinical insomnia (severe) Epworth Sleepiness Scale scores: 1–6, getting enough sleep; 7–8, score is average; 9, very sleepy and should seek medical advice
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Table 3 Parameters of objective sleep quality. Data are given as median (1st quartile, 3rd quartile)
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Sleep parameters
Placebo group (n 20)
Sleep efficiency (%) Pretreatment 85.2 (81.1, 88.1) Post-treatment 87.1 (84, 88.8) Total sleep time (h) Pretreatment 5.4 (4.4, 6.2) Post-treatment 5.4 (4.5, 6.3) Sleep latency (min) Pretreatment 12.9 (8.9, 22) Post-treatment 13.1 (8.3, 17.7) Number of awakenings (/night) Pretreatment 25.6 (20, 32.2) Post-treatment 25.8 (22.4, 35.2) Wake after sleep onset (min) Pretreatment 35.9 (23.6, 40.1) Post-treatment 27.2 (19.4, 40.7)
Table 5 Adverse effects of patches. Data are given as n (%) Placebo group (n 20)
Symptoms
Estrogen group (n 20)
p Value*
85.9 (80, 87.9) 85.7 (82.8, 89.3)
0.71 0.71
5.4 (5.2, 6.2) 5.4 (4.5, 6.3)
0.46 0.66
15.7 (8.6, 29.3) 13.2 (5.4, 21.4)
0.91 0.45
28.7 (22.7, 39.4) 26.0 (16.8, 35.7)
0.22 0.53
32 (21.6, 48.8) 29.9 (22.8, 43.2)
0.91 0.45
*, Mann–Whitney U-test, comparing pretreatment and post-treatment between groups Normative values of sleep parameters26: Sleep efficiency 86–87%; Total sleep time 6.5–6.6 h; Sleep latency 16–17 min; Wake after sleep onset 32–38 min
Safety The estrogen group experienced adverse effects of breast pain and vaginal discharge significantly more often than the placebo group, but skin rash was found significantly less often than in the placebo group. Other adverse effects were not different between the groups (Table 5).
DISCUSSION Sleep disturbance is multifactorial in etiology. This study aimed to evaluate the effects of estrogen on postmenopausal
Breast pain Vaginal discharge Skin rash Abdominal discomfort Bleeding per vagina
3 0 18 1 0
(15%) (0%) (90%) (5%) (0%)
Estrogen group (n 20) 10 8 8 1 1
(50%) (40%) (40%) (5%) (5%)
p Value 0.04 0.01 0.01 0.76 1.00
sleep quality, independent of other non-hormonal factors. Several studies have demonstrated improvement of subjective sleep quality with estrogen therapy using self-reported questionnaires9,13–16; however, there were some limitations to those studies. Estrogen is known to be the most effective treatment of VMS and night sweating, which cause interrupted sleep at night17. VMS was found to be highly associated with chronic insomnia9; as a consequence, the improvement of subjective sleep quality may be due to the relief of vasomotor symptoms17,18. To verify the genuine effects of estrogen on improvement of sleep quality, objective evaluation using accurate and reliable tools is needed. Polysomnography (PSG) has been considered to be a gold-standard measurement of objective sleep quality19, especially in respiratory-related disorders. Nevertheless, it has not been validated in insomniac patients because the tool needs many tag sites over the body which may, in themselves, disturb sleep initiation and continuation and is difficult to repeat. Patients need to be hospitalized and consequently the outcome may not represent the actual sleep pattern at home; this may result in either false improvement of sleep quality (reverse night effect) or false worse quality (first-night effect)20. Another validated tool which can be reliably used to assess sleep quality in insomniac patients is wrist actigraphy. This is a practical tool to assess sleep quality due to its repeatability, ease of use, ability to test at home, and is comfortable and convenient to wear as a sleeping wristwatch. Actigraphy was validated for assessment of sleep quality in insomniac
Table 4 Comparison of the sleep parameters retrieved from the actigraph Post-treatment (per protocol analysis) Placebo group (n 17) Sleep efficiency (%) Total sleep time (min) Sleep latency (min) Wake after sleep onset (min) Number of awakenings (/night)
85.2 5.4 13.1 27.2 25.8
(81.1, 88.1) (4.5, 6.3) (8.3, 17.7) (19.4, 40.7) (22.4, 35.2)
Estrogen group (n 19)
p Value*
85.7 (82.8, 89.3) 5.4 (4.5, 6.3) 13.2 (5.4, 21.4) 29.9 (22.8, 43.2) 26 (16.8, 35.7)
0.71 0.66 0.62 0.45 0.57
Post-treatment (ITT LOCF) Placebo group (n 20) 86.6 5.4 14.5 27.8 28.5
(83.2, 88.6) (4.4, 6.3) (8.7, 18.9) (17.8, 39.1) (23, 36.8)
Estrogen group (n 20) 85.6 5.4 13.6 32.2 25.6
(81.8, 89.1) (4.6, 6.3) (5.9, 20.3) (22.9, 42.6) (16.9, 34.3)
p Value** 0.89 0.64 0.43 0.21 0.53
*, Mann–Whitney U-test, comparing post-treatment data between groups LOCF, last observation carried forwards, comparing post-treatment data between groups Normative values of sleep parameters26: Sleep efficiency 86–87%; Total sleep time 6.5–6.6 h; Sleep latency 16–17 min; Wake after sleep onset 32–38 min
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Estrogen therapy and postmenopausal sleep quality patients in 2006 and was found to have high correlation with PSG21. Therefore, we decided to use actigraphy to evaluate the effects of estrogen on sleep quality in insomniac postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep. In the present study, we found no significant improvement in all objective sleep quality parameters. In previous studies using PSG measurement along with the questionnaires, estrogen was shown to improve sleep quality by reducing the frequency of awakening during sleep21,22 and increasing sleep efficiency23. These studies were conducted in a small number of participants, ranging from nine to 16 postmenopausal women in each study. The first study21 enrolled 16 hypogonadal women, aged 31–65 years, half of which were postmenopausal for 2–22 years and the other half having undergone oophorectomy, without data on years since menopause. The second study22 enrolled 11 naturally or surgically postmenopausal women with a mean age of 54.8 1 2 1.5 years with duration of menopause 6.7 1 1.2 years, with some women still continuing 2 hormone use until the study. The third study23 enrolled nine postmenopausal women who complained of frequent, severe hot flushes, aged 30–55 years, and were within 1–5 years of either surgical or natural menopause. Although it is difficult to compare the differences in menopausal stage or years since menopause in our study with the others, the contradiction in our study is probably elucidated by the fact that, first, we excluded participants who had severe vasomotor symptoms with a high probability of night awakening. The effects of estrogen on sleep may be due to the consequence of improving vasomotor symptoms rather than its direct effect on GABA-A or sleep regulation. Second, the use of PSG in the other studies could not exclude the first-night and reverse first-night effects, as mentioned earlier. The high occurrence of breast pain and increased vaginal discharge in the estrogen group could possibly unmask the double-blinded design. Skin rash was observed significantly more in the placebo group; this may result from the moisturizing effect of estrogen over the skin where the patch was attached, causing less irritation. The strengths of the present study were: (1) many tools were used for sleep quality assessment including the actigraph, the validated tool for assess insomnia, which was repeatable, mobile, with no need for admission, and the two selfadministered questionnaires to assess the severity and daytime sleepiness; (2) the transdermal route was chosen because of concern about patient compliance which may have interfered with the result. However, limitations of this study were the
Tansupswatdikul et al. small sample size and the lack of a record of confounders during the study. There were no serum estradiol measurements to assess subject’s adherence. The dose and the 2-month duration of estrogen use may not be enough to demonstrate the effects of estrogen on sleep quality. In addition, it may not be appropriate to generalize the results of this study to all stages of menopause or to different types of insomnia. This is a good pilot study to investigate the possible effects of estrogen on insomniac patients and whether the positive effects of estrogen on sleep are due to its indirect effect via relief of vasomotor symptoms or due to a direct effect on sleep regulation. Further study should be conducted in a larger sample size with better control of confounders.
CONCLUSION Estrogen therapy in insomniac, postmenopausal women without severe vasomotor symptoms and/or recognized hot flushes during sleep did not show any significant improvement in sleep efficiency and other sleep parameters. The previous reports of estrogen therapy improving sleep quality were probably the consequences of the relief from vasomotor symptoms causing night awakening.
ACKNOWLEDGEMENTS We would like to give our sincere thanks to the Menopause Research Unit, Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University for the support of the present study. We really appreciate the kind assistance of Jirayos Chintanadilok, MD and Asst. Tayard Desudchit in procuring the actigraphy devices and Ms Somtawin Pojjanasopanakun, BSc as a research assistant. Conflict of interest The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding Ratchadapiseksompotch Endowment Fund, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Menopause research unit, Division of Reproductive Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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