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Summary

Recently a systematic review and meta-analysis was conducted at West China School of Medical, Sichuan University, China, aimed at investigating whether menopausal hormone therapy can improve sleep quality [1]. The authors included randomized controlled trials (RCTs) from multiple databases, abstracts, and other full-text sources. Fifteen studies were included (n=27,715). The meta-analysis showed that hormone therapy improved self-reported sleep quality, but did not improve polysomnograms (PSG), compared with the control group. Estrogen/progestogen combined therapy improved sleep, but estrogen-only therapy did not. Among estrogen regimens, 17β estradiol and conjugated equine estrogens improved sleep quality, especially the former, but estradiol valerate did not. Transdermal estrogen improved sleep better than oral administration. Comparing different progestogen types, micronized progesterone and medroxyprogesterone acetate showed improvement effects on sleep. The authors concluded that hormone therapy has a beneficial effect on sleep disturbance to some extent, and the formulations and routes of administration of hormonal agents influence the effect size.

Commentary

Clinically, approximately 40% to 56% of postmenopausal women self-report sleep disturbances. Sleep disorders are mainly manifested as three conditions: trouble falling asleep, multiple awakenings, and early awakening [2]. The Study of Women’s Health Across the National (SWAN) in US tracked sleep quality in 3,045 multi-ethnic women for 8 years [3]. Trouble falling asleep and multiple awakenings increased as women experienced from early menopause to menopause. But early awakening decreased after the menopause. Therefore, the manifestation of sleep disturbance may vary at different times during the menopausal transition.

PSG includes electroencephalogram analysis and a variety of biological indicators that help diagnose sleep disorders. In the present commented meta-analysis, menopausal hormone therapy had no effect during PSG monitoring. This might be due to the small number of RCTs included in the meta-analysis and the lack of multiple or long-term monitoring. However, in the Wisconsin Sleep Cohort Study, PSG monitoring showed an increase in slow wave sleep (SWS) in perimenopausal and postmenopausal women compared to premenopausal ones [4]. Sleep was monitored at baseline, 6 and 10 years, in a prospective study conducted at the Turku Sleep Research Center in Finland with follow-up to 10 years. Results at 6 years showed a decrease in total sleep time and sleep efficiency after controlling for body mass index, menopausal vasomotor symptoms and depressive symptoms, and was not associated with FSH-levels. Elevated FSH-levels are associated with an increased proportion of SWS, which may have the purpose of compensating for sleep-loss due to decreased sleep efficiency [5]. The latest study reported results of 10 years follow-up. Increased FSH was associated with prolonged sleep latency, whereas aging was associated with shortened sleep latency. It has been reported that the decline in sleep quality in middle-aged women is related to aging, not to the menopausal transition [6].

The present meta-analysis did not show any general benefit of estrogen-only therapy on sleep quality. However, it has to be considered that estrogen-only therapy is commonly performed in postmenopausal women after hysterectomy, and the incidence of sleep disorders in these postoperative women is significantly higher than that observed in natural postmenopausal women. Having much more health problems and social mental factors in surgical menopause women may be part of the reason [7]. In fact, most literature suggests that menopausal sleep disorders are associated with lower estrogen levels [8]. But the mechanism of estrogen improving sleep remains unclear. One explanation is that insomnia is linked to elevated cortisol levels at night. Corticotropin-releasing hormone (CRH), which regulates cortisol levels, is secreted by the hypothalamus. Menopausal unstable estrogen levels could influence sleep by interfering with the stability of hypothalamic regulation through estrogen receptors. Estrogen therapy can stabilize the hypothalamic-pituitary-ovarian axis and improve sleep quality during menopausal transition [9].

In terms of estrogen selection, this meta-analysis was unable to determine the benefit of estradiol valerate for sleep. Estradiol valerate is a prodrug of 17β-estradiol, which needs to be metabolized into estradiol and valerate for any further action. Regarding estrogenic activity, this indeed leads to an about 25% decrease in bioavailability of estradiol valerate compared with 17β-estradiol. However, in principle (as expected) other studies have also shown that the use of estradiol valerate can improve sleep quality [10]. Furthermore, the sample sizes in the estradiol valerate subgroups in all three RCTs included in the present meta-analysis were small (experimental group n= 22, 16, 33), and unclear bias in terms of selection, performance, detection and attribution may also influence the result. Therefore, the results of the meta-analysis should be considered prudently for clinical decision making.

Another result of the meta-analysis is that transdermal administration appears to be superior to oral estrogen therapy in improving sleep. Indeed, it has been reported that transdermal estrogen may reduce the time to sleep and the number of awakenings [11]. Different reasons for better sleep qualities using transdermal estradiol may be possible, like constant instead of fluctuating estradiol levels and differences direct or indirectly related to the avoidance of the first past liver effect by the transdermal delivery route like differences in estradiol metabolism, production of hepatic factors (e.g. SHBG) etc. However, in total there are only the few subjective reports of improvement in sleep evaluation, and objective evidence like research using sleep laboratories is insufficient. Therefore, further research is needed for confirmation.

There are many confounding factors in studies investigating sleep of menopausal women, such as patients’ past disease history, drug history, sleep habits, and menopausal discomfort symptoms such as hot flashes. This meta-analysis is a comprehensive review of the current literature under the guidance of a prospectively registered protocol, and detailed analysis of menopausal hormone therapy was performed as well. So the results and conclusions should have certain reference value for clinical decision making. However, the limitations outlined above should be considered because more original research data is needed like well-designed clinical studies with larger sample sizes and research on the underlying mechanisms of hormone therapy related to sleep.

Dr. Che Xu and Prof. Dr. Xiangyan Ruan
Department of Gynecological Endocrinology,
Menopause Clinic and Fertility Protection Centre,
Beijing Obstetrics and Gynecology Hospital,
Capital Medical University, China

References

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    https://pubmed.ncbi.nlm.nih.gov/35102100/
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    https://pubmed.ncbi.nlm.nih.gov/33326582/
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    https://pubmed.ncbi.nlm.nih.gov/20551846/
  8. Baker FC, de Zambotti M, Colrain IM, Bei B. Sleep problems during the menopausal transition: prevalence, impact, and management challenges. Nat Sci Sleep. 2018;10:73-95.
    https://pubmed.ncbi.nlm.nih.gov/29445307/
  9. Gordon JL, Girdler SS, Meltzer-Brody SE, et al. Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: a novel heuristic model. Am J Psychiatry. 2015;172(3):227-36.
    https://pubmed.ncbi.nlm.nih.gov/25585035/
  10. Zhang J, Shao S, Ye C, Jiang B. A Clinical Study of the Effect of Estradiol Valerate on Sleep Disorders, Negative Emotions, and Quality of Life in Perimenopausal Women. Evid Based Complement Alternat Med. 2021;2021:8037459.
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  11. Geiger PJ, Eisenlohr-Moul T, Gordon JL, Rubinow DR, Girdler SS. Effects of perimenopausal transdermal estradiol on self-reported sleep, independent of its effect on vasomotor symptom bother and depressive symptoms. Menopause. 2019;26(11):1318-1323.
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