Abstract
Sleep disturbances are common among women during menopause. Hormone replacement therapy (HRT) using micronized progesterone (MP) may improve sleep, owing to its neurosteroid effects. Studies on the impact of oral MP on sleep quality in Japanese women are limited, given the recent introduction of MP in Japan. We conducted a single-arm, open-label study to examine the effects of HRT with estradiol (E2) and oral MP on sleep quality in 15 peri- and postmenopausal Japanese women who chose HRT to address their menopausal symptoms. The participants completed the Pittsburgh Sleep Quality Index (PSQI) and menopausal symptoms questionnaires at baseline, 1 month, and 3 months after HRT. The changes in PSQI scores were evaluated. Responders were defined as those with a ≥ 25% reduction in the PSQI global score at 1 month. The PSQI components and menopausal symptoms at baseline were compared between responders and non-responders. Initially, 86.7% of the participants were categorized as poor sleepers. The PSQI global score and sleep quality significantly improved at 1 and 3 months after HRT (baseline to 3rd month mean scores: from 7.8 to 6.1 to 6.5 and from 1.7 to 1.0 to 1.2, respectively). Responders (n = 5) exhibited poorer habitual sleep efficiency before treatment than the non-responders. However, menopausal symptoms did not differ significantly between the groups at baseline. The results indicate that HRT with E2 and MP is a promising treatment option for peri- and postmenopausal Japanese women experiencing sleep disturbances, especially those with poor sleep efficiency.
Keywords: Estrogen replacement therapy, Menopause, Progesterone, Sleep
INTRODUCTION
Sleep disturbances common during the menopausal transition in women and significantly affect their quality of life. Hormone replacement therapy (HRT) can simultaneously address menopausal symptoms and sleep disturbances.
The efficacy of HRT in treating sleep disturbances in perimenopausal women may depend on the type of hormone used, especially progestogen. Among the progestogens used for HRT, oral micronized progesterone (MP) is expected to alleviate sleep disturbances due to its structure being identical to endogenous progesterone, unlike synthetic progestins [1]. When administered orally, MP and its metabolites function as neurosteroids, potentially enhancing brain function [2]. A previous systematic review and meta-analysis revealed that self-reported sleep outcomes improved in several randomized controlled trials [3].
One report found that Japanese women experiencing hot flushes during menopause often suffer from more severe sleep issues than those without hot flushes [4], highlighting the potential of HRT in treating both symptoms. However, reports focusing on the effectiveness of HRT for sleep problems in Japanese menopausal women are scarce. While one report suggested the efficacy of HRT with oral estrogen and synthetic progestin in improving subjective sleep disturbance scores [5], the impact of HRT using MP on sleep disturbances has not yet been documented. Until 2021, only synthetic progestins were available for HRT in women with a uterus in Japan. Oral MP was introduced in Japan in November 2021, much later than in other countries. Considering that improving sleep disturbances in perimenopausal women through HRT could reduce the use of sleeping pills, it is crucial to verify the effects of HRT with MP on sleep quality in Japanese women.
In this study, we investigated changes in sleep quality after the initiation of HRT with estradiol (E2) and MP in Japanese women and examined the characteristics of patients whose sleep improved after the use of HRT with E2 and MP. These findings will inform future interventions aimed at enhancing sleep quality in Japanese perimenopausal women.
CASE REPORT
Participants
This single-arm, open-label study was conducted to evaluate changes in sleep problems after HRT with E2 and oral MP in peri- or post-menopausal women. The study participants were women who visited a gynecology clinic for the treatment of menopausal symptoms and decided to undergo HRT with E2 and oral MP between August 2023 and April 2024. E2 was administered either transdermally as estrogel, 17-beta-estradiol at 1.08 mg/day, or orally in the form of E2 tablets (1 mg/day). MP was administered in two regimens: cyclically at 200 mg/day for 14 days/cycle or continuously at 100 mg/day.
The inclusion criteria were women who were peri- or post-menopausal and had a uterus. Women who had contraindications for HRT and those who had undergone hysterectomy were excluded. Written informed consent was obtained from all participants prior to their participation.
The participants' characteristics were obtained from their medical records. All participants were given two questionnaires before the start of the HRT, 1 month after the start of the HRT, and 3 months after the start of the HRT. The questionnaires were the Pittsburgh Sleep Quality Index (PSQI) and the Menopausal Symptom Checklist for Japanese women.
The PSQI was used to assess the sleep quality. The PSQI comprises 19 items grouped into seven components. Each component was scored from 0 to 3, with higher scores indicating greater dysfunction. The summed score was reported as the global PSQI score, with a score greater than 5 typically indicating poor sleep quality. The PSQI is generally used worldwide. Moreover, the Japanese version of the PSQI has been validated [6].
The Menopausal Symptom Checklist for Japanese women was used to assess the participants' menopausal symptoms [7]. This checklist, developed by the Japan Society of Obstetrics and Gynecology in 2001, was used to analyze the characteristics of menopausal symptoms in Japanese women. It comprises 21 items, each scored on a three-point scale: severe, mild, and none [8]. In this study, “mild” or “severe” responses were classified as symptomatic.
Responses received between August 2023 and July 2024 were analyzed. The primary outcome was the change in the PSQI scores from pre-treatment to 1 and 3 months. Responders were defined as patients with a reduction in the global PSQI score of 25% or more in 1 month, whereas non-responders were defined as patients with a reduction in the global PSQI score of less than 25% in 1 month. The threshold criterion was derived from a previous study [9]. We compared the participants' backgrounds, PSQI scores, and menopausal symptoms before starting HRT between the responder and non-responder groups.
Statistical analysis
The sample size for the study was calculated using G*Power (ver. 3.1), targeting an effect size of 0.98, a significance level of 0.05, and a power of 0.95. Based on these parameters, it was determined that a total of 13 participants were needed.
Changes in the PSQI scores and comparisons of the quantitative variables between the responder and non-responder groups were performed using the Mann-Whitney U test. Chi-squared or Fisher's exact tests were used for categorical variables. The level of statistical significance was determined using a P value of less than 0.05. All data were analyzed using SPSS software (version 29.0, IBM Corp.).
Ethical considerations
This study was conducted in accordance with the principles of the Declaration of Helsinki. The ethics committee of the Tokyo Dental College Ichikawa General Hospital approved this study (approval no. I23-18, 2023). Written informed consent was obtained from all participants.
Of the 21 participants initially recruited for the study, 3 were excluded due to inadequate questionnaire responses, and 3 withdrew during the study period, resulting in a final sample size of 15 participants. The PSQI global scores of the participants at baseline ranged from 4 to 13, with a score of 7 at the center. Thirteen participants (86.7%) were poor sleepers because the cut-off point for their PSQI global scores was > 5 [10].
Table 1 presents the changes in the PSQI global score and each component for all participants before HRT and at 1 and 3 months. Following the administration of HRT, the PSQI global score and sleep quality significantly improved at both 1 and 3 months.
Table 1. Changes in the report regarding the PSQI score before HRT and 1 and 3 months after HRT.
| Before HRT | 1 month | 3 months | ||||||
|---|---|---|---|---|---|---|---|---|
| Mean | SD | Mean | SD | P value | Mean | SD | P value | |
| Global score | 7.8 | 2.5 | 6.1 | 2.1 | 0.013* | 6.5 | 2.3 | 0.021* |
| Sleep quality | 1.7 | 0.5 | 1.0 | 0.5 | 0.008* | 1.2 | 0.6 | 0.020* |
| Sleep latency | 1.1 | 1.1 | 1.0 | 0.8 | 0.527 | 0.8 | 0.7 | 0.194 |
| Sleep duration | 1.7 | 0.5 | 1.5 | 0.6 | 0.257 | 1.5 | 0.7 | 0.083 |
| Habitual sleep efficiency | 0.4 | 0.6 | 0.2 | 0.4 | 0.257 | 0.4 | 0.8 | 0.931 |
| Sleep disturbance | 1.1 | 0.6 | 0.9 | 0.4 | 0.180 | 0.8 | 0.4 | 0.180 |
| Use of sleeping medication | 0.6 | 1.2 | 0.7 | 1.3 | 0.655 | 0.7 | 1.3 | 1.000 |
| Daytime dysfunction | 1.3 | 0.6 | 0.9 | 0.5 | 0.059 | 1.2 | 0.7 | 0.480 |
PSQI: Pittsburgh Sleep Quality Index, HRT: hormone replacement therapy, SD: standard deviation.
*Statistical significance (P < 0.05) vs. before HRT.
The participants' characteristics are presented in Table 2. Of the 15 women enrolled in the study group, according to the reduction of the PSQI score in 1 month, five women were assigned to the responder group and ten to the non-responder group. None of the background characteristics differed significantly between the two groups. Regarding the PSQI score at baseline, only the habitual sleep efficiency was significantly worse in the responder group than in the non-responder group (P = 0.028).
Table 2. Participant characteristics and PSQI scores at baseline.
| Total (n = 15) | Responder (n = 5) | Non-responder (n =10) | P value | ||
|---|---|---|---|---|---|
| Age (y) | 49.3 ± 3.3 | 50.0 ± 3.0 | 48.9 ± 3.6 | 0.440 | |
| Menstruation status | |||||
| Perimenopausal | 11 | 1 | 0 | 0.337 | |
| Postmenopausal | 4 | 3 | 7 | ||
| History of bilateral oophorectomy | 0 | 1 | 3 | ||
| BMI (kg/m2) | 21.6 ± 4.3 | 20.1 ± 2.0 | 22.3 ± 5.1 | 0.594 | |
| Presence of partner | 0.242 | ||||
| Yes | 12 | 3 | 9 | ||
| No | 3 | 2 | 1 | ||
| Parity | 0.573 | ||||
| Yes | 8 | 3 | 5 | ||
| No | 7 | 2 | 5 | ||
| Occupation | 0.429 | ||||
| Housemaker | 2 | 0 | 2 | ||
| Worker | 13 | 5 | 8 | ||
| Concurrent medications | |||||
| Use of benzodiazepines | 2 | 1 | 1 | 0.675 | |
| Use of anti-depressants | 1 | 0 | 1 | 0.655 | |
| Use of sleep medication | 0 | 0 | 0 | ||
| Estrogen administration route | 0.667 | ||||
| Oral | 1 | 0 | 1 | ||
| Transdermal | 14 | 5 | 9 | ||
| Hormone therapy regimen | 0.264 | ||||
| Cyclic | 12 | 5 | 7 | ||
| Continuous | 3 | 0 | 3 | ||
| PSQI score at the initial visit | |||||
| Total score | 7.80 ± 2.48 | 9.00 ± 3.08 | 7.20 ± 2.04 | 0.310 | |
| Sleep quality | 1.67 ± 0.49 | 1.80 ± 0.44 | 1.60 ± 0.52 | 0.594 | |
| Sleep latency | 1.13 ± 1.13 | 1.60 ± 1.14 | 0.90 ± 1.10 | 0.310 | |
| Sleep duration | 1.67 ± 0.49 | 1.60 ± 0.55 | 1.70 ± 0.48 | 0.768 | |
| Habitual sleep efficiency | 0.40 ± 0.63 | 1.00 ± 0.70 | 0.10 ± 0.62 | 0.028* | |
| Sleep disturbance | 1.07 ± 0.59 | 0.80 ± 0.45 | 1.20 ± 0.63 | 0.310 | |
| Use of sleeping medication | 0.60 ± 1.24 | 0.60 ± 1.34 | 0.60 ± 1.26 | 1.000 | |
| Daytime dysfunction | 1.27 ± 0.59 | 1.60 ± 0.78 | 1.10 ± 0.32 | 0.371 | |
Data are presented as mean ± standard deviation or number.
PSQI: Pittsburgh Sleep Quality Index, BMI: body mass index.
*Statistically significant (P < 0.05) differences between the responder and non-responder groups.
We compared the differences in menopausal symptoms at baseline between the responder and non-responder groups. There were no significant differences in these symptoms, including vasomotor symptoms (VMS), between the groups (Table 3).
Table 3. Comparison of the menopausal symptoms between the responders and non-responders at baseline.
| Responder (n = 5) | Non-responder (n = 10) | P value | |||
|---|---|---|---|---|---|
| Yes | No | Yes | No | ||
| Hot flush | 3 | 2 | 6 | 4 | 0.706 |
| Sweating | 3 | 2 | 10 | 0 | 0.095 |
| Irritation | 3 | 2 | 8 | 2 | 0.407 |
| Anxiety | 3 | 2 | 6 | 4 | 0.706 |
| Worrying about trivial things | 4 | 1 | 7 | 3 | 0.593 |
| Feeling depressed | 2 | 3 | 6 | 4 | 0.427 |
| Tiredness | 5 | 0 | 8 | 2 | 0.429 |
| Tired eyes | 5 | 0 | 9 | 1 | 0.667 |
| Forgetfulness | 4 | 1 | 8 | 2 | 0.736 |
| Dizziness | 1 | 4 | 6 | 4 | 0.182 |
| Palpitations | 1 | 4 | 6 | 4 | 0.182 |
| Chest pain | 0 | 5 | 1 | 9 | 0.667 |
| Headaches | 4 | 1 | 7 | 3 | 0.593 |
| Stiff shoulders | 5 | 0 | 10 | 0 | N/A |
| Back pain | 3 | 2 | 8 | 2 | 0.407 |
| Joint pain | 2 | 2 | 4 | 6 | 0.594 |
| Sensitivity to cold | 5 | 0 | 5 | 5 | 0.084 |
| Numbness in the fingers | 2 | 3 | 0 | 10 | 0.095 |
| Sensitive to sound | 4 | 1 | 4 | 6 | 0.182 |
N/A: not applicable.
One missing value for Joint pain.
DISCUSSION
In this study, we aimed to investigate the impact of HRT with E2 and MP on sleep quality in Japanese menopausal women. We found that approximately 86.7% of participants initially had poor sleep quality. However, HRT with E2 and oral MP considerably improved their sleep quality. A study conducted in Japan reported that the prevalence of insomnia in peri- and post-menopausal women was approximately 50.8% [11]. The high percentage of poor sleepers in our study was higher than that reported in the previous study. This may be because all the women in our study opted for hormone therapy, indicating potentially more severe menopausal symptoms. Additional contributing factors could include differences in participants' menopausal status, the characteristics of the institutions involved, and the assessment methodologies used.
After the initiation of HRT with E2 and oral MP, the overall sleep and sleep quality scores improved in our study. A meta-analysis of two randomized controlled trials revealed that HRT with estrogen and MP may improve sleep quality [12]. In a study that compared the differential effects of two forms of HRT (using medroxyprogesterone acetate [MPA] or MP), the results suggested that MP may improve sleep quality more than MPA [13]. Both estrogen and progesterone are thought to be associated with sleep. Estrogen has the potential for direct and indirect effects on sleep, including the serotoninergic and dopaminergic systems [14]. Furthermore, a meta-analysis indicated that transdermal administration of E2 yields superior outcomes compared to oral administration. This advantage is ascribed to the transdermal route circumventing first-pass metabolism, which results in elevated serum E2 concentrations and enhanced bioavailability relative to that oral route [12]. Given that the predominant method of estrogen administration in our study was transdermal, this could contribute to the observed improvements in participants' sleep quality. In addition, allopregnanolone, a progesterone metabolite, induces GABAergic effects and helps promote sleep. Our results indicate the efficacy of HRT with E2 and MP for Japanese peri- and post-menopausal women.
Patients who showed a significant change in their PSQI global score had worse habitual sleep efficiency before treatment than those who did not in the present study. On the other hand, there were no differences in the background factors or menopausal symptoms between those whose sleep scores improved with HRT and those whose sleep scores did not. Several reports have shown that HRT improves sleep in women with VMS [15]. However, our results differ from existing results in that sleep improvement was not related to the presence or absence of VMS. Many patients often complain of middle-of-the-night awakening upon reaching peri-menopause. HRT with E2 and MP may improve such awakening in menopausal women, regardless of whether they have VMS.
This study had several limitations. First, the number of cases examined was small, making it difficult to generalize the results. Further comparative studies with other regimens and larger sample sizes are required to confirm the effect of HRT with E2 and MP on sleep quality in the Japanese population. Second, the Menopausal Symptom Checklist for Japanese women, which we used to assess the participants' menopausal symptoms, has not been validated. However, because there is no validated questionnaire to assess menopausal symptoms in Japan, we chose this checklist because it is considered the most appropriate. Future research should focus on developing a validated questionnaire to more accurately assess menopausal symptoms. Additionally, the efficacy of HRT with E2 and MP for addressing sleep problems should be re-evaluated in a large cohort of Japanese peri- and post-menopausal women. Despite these limitations, since no prospective studies have investigated the effects of HRT with E2 and MP on sleep in Japanese menopausal women, we decided to report the results of this study.
In conclusion, HRT with E2 and oral MP improved overall sleep and sleep quality in menopausal Japanese women. Particularly, those with previously poor habitual sleep efficiency experienced notable improvements in sleep quality after initiating HRT. These results suggest that HRT with E2 and MP may be a good treatment option for improving sleep problems in Japanese peri- and post-menopausal women, especially those with poor habitual sleep efficiency.
ACKNOWLEDGMENTS
We would like to thank all the staff at the Avance Ladies Clinic for their help in collecting data.
Footnotes
FUNDING: No funding to declare.
CONFLICT OF INTEREST: Mariko Ogawa received lecture fees from Otsuka Pharmaceutical Co., Bayer Yakuhin Ltd., Fuji Pharma Co. Ltd., and ASKA Pharmaceutical Co. Ltd. Kiyoshi Takamatsu received study funding from Astellas for another study and speaker fees from Otsuka Pharmaceutical Co. Ltd., Bayer Yakuhin Ltd., Tsumura & Co., and Fuji Pharma Co. Ltd. The other authors declare no conflicts of interest.
References
- 1.Sitruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P. Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications — a review. Contraception. 1987;36:373–402. doi: 10.1016/0010-7824(87)90088-6. [DOI] [PubMed] [Google Scholar]
- 2.Memi E, Pavli P, Papagianni M, Vrachnis N, Mastorakos G. Diagnostic and therapeutic use of oral micronized progesterone in endocrinology. Rev Endocr Metab Disord. 2024;25:751–772. doi: 10.1007/s11154-024-09882-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Nolan BJ, Liang B, Cheung AS. Efficacy of micronized progesterone for sleep: a systematic review and meta-analysis of randomized controlled trial data. J Clin Endocrinol Metab. 2021;106:942–951. doi: 10.1210/clinem/dgaa873. [DOI] [PubMed] [Google Scholar]
- 4.Tomida M, Otsuka R, Tange C, Nishita Y, Kimura T, Stoelzel M, et al. Vasomotor symptoms, sleep problems, and depressive symptoms in community-dwelling Japanese women. J Obstet Gynaecol Res. 2021;47:3677–3690. doi: 10.1111/jog.14937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Terauchi M, Obayashi S, Akiyoshi M, Kato K, Matsushima E, Kubota T. Effects of oral estrogen and hypnotics on Japanese peri-and postmenopausal women with sleep disturbance. J Obstet Gynaecol Res. 2011;37:741–749. doi: 10.1111/j.1447-0756.2010.01424.x. [DOI] [PubMed] [Google Scholar]
- 6.Doi Y, Minowa M, Uchiyama M, Okawa M, Kim K, Shibui K, et al. Psychometric assessment of subjective sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) in psychiatric disordered and control subjects. Psychiatry Res. 2000;97:165–172. doi: 10.1016/s0165-1781(00)00232-8. [DOI] [PubMed] [Google Scholar]
- 7.Aso T, Uchiyama S, Matsumura Y, Taguchi M, Nozaki M, Takamatsu K, et al. A natural S-equol supplement alleviates hot flushes and other menopausal symptoms in equol nonproducing postmenopausal Japanese women. J Womens Health (Larchmt) 2012;21:92–100. doi: 10.1089/jwh.2011.2753. [DOI] [PubMed] [Google Scholar]
- 8.Taga T, Ito K, Takamatsu K, Ogawa M, Funayama S, Inoue M. Menopausal symptoms are associated with oral sensory complaints in perimenopausal women: an observational study. BMC Womens Health. 2021;21:262. doi: 10.1186/s12905-021-01401-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zhu L, Pei Z, Dang G, Shi X, Su X, Lan X, et al. Predicting response to repetitive transcranial magnetic stimulation in patients with chronic insomnia disorder using electroencephalography: a pilot study. Brain Res Bull. 2024;206:110851. doi: 10.1016/j.brainresbull.2023.110851. [DOI] [PubMed] [Google Scholar]
- 10.Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193–213. doi: 10.1016/0165-1781(89)90047-4. [DOI] [PubMed] [Google Scholar]
- 11.Terauchi M, Obayashi S, Akiyoshi M, Kato K, Matsushima E, Kubota T. Insomnia in Japanese peri- and postmenopausal women. Climacteric. 2010;13:479–486. doi: 10.3109/13697130903353478. [DOI] [PubMed] [Google Scholar]
- 12.Pan Z, Wen S, Qiao X, Yang M, Shen X, Xu L. Different regimens of menopausal hormone therapy for improving sleep quality: a systematic review and meta-analysis. Menopause. 2022;29:627–635. doi: 10.1097/GME.0000000000001945. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Montplaisir J, Lorrain J, Denesle R, Petit D. Sleep in menopause: differential effects of two forms of hormone replacement therapy. Menopause. 2001;8:10–16. doi: 10.1097/00042192-200101000-00004. [DOI] [PubMed] [Google Scholar]
- 14.Haufe A, Baker FC, Leeners B. The role of ovarian hormones in the pathophysiology of perimenopausal sleep disturbances: a systematic review. Sleep Med Rev. 2022;66:101710. doi: 10.1016/j.smrv.2022.101710. [DOI] [PubMed] [Google Scholar]
- 15.Kagan R, Constantine G, Kaunitz AM, Bernick B, Mirkin S. Improvement in sleep outcomes with a 17β-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women. Menopause. 2018;26:622–628. doi: 10.1097/GME.0000000000001278. [DOI] [PMC free article] [PubMed] [Google Scholar]