Perimenopausal transdermal estradiol and sleep

Summary

This randomized double-blind placebo-controlled study by Geiger et al. assessed the effects of transdermal estrogens on sleep independent of its well known beneficial effects on vasomotor symptoms (VMS) and mood improvement. A group of 172 healthy perimenopausal and early postmenopausal women age 45-60 were randomized to 100 micrograms of transdermal estradiol with progesterone 200 mg for 12 days every 3 months for 12 months versus placebo. Standard questionnaires, including the 14 item St. Mary’s Sleep Questionnaire, the 20 item CES-D (the Center for Epidemiologic Studies-Depression Scale), and the Greene Climacteric subScale for VMS were administered at baseline and in the estrogen-only months. After controlling for baseline levels, transdermal estrogen reduced both minutes to fall asleep (-0.12 p=0.02), and number of awakenings (-0.11 p=0.02). Multivariate analyses found that reductions in VMS and mood improvement could not fully explain the improvement in sleep difficulties. The authors concluded that the efficacy of hormone therapy (HT) could not only be explained by improvements in vasomotor or depressive symptoms but through other biological mechanisms [1].

Commentary 

Sleep problems increase 2-3.5 times in women over the menopause transition [2]. These problems most commonly include nighttime awakenings [3], but also insomnia, obstructive sleep apnea, restless legs syndrome, and periodic limb movement disorder. Sleep difficulties have a large impact on a woman’s quality of life as well as her work productivity, memory, mood, and general health, including cardiovascular disease, diabetes, cognition, and deficits in immune functions. The etiology of new insomnia at menopause that occurs in up to 56% of perimenopausal women compared to 31% of older premenopausal women [3] has been debated. Possible explanations include estrogen fluctuations [4] resulting in night sweats or menopause- associated mood changes such as anxiety or depression, the menopause itself, ageing or co-morbid health, or pre-existing sleep problems. Options for treatments include treating the underlying responsible condition, sleep hygiene [5] cognitive behavioural therapy, exercise, [6] venlafaxine [7] and eszopiclone [8], and hormone therapies, including progesterone alone [9]. Nonhormonal therapies for vasomotor symptoms, such as SSRI’s, SNRI’s, and GABA agents have also been utilized for patients with sleep disturbances [10]. A recent meta-analysis of 7 RCT trials found that the improvement due to HT was mainly associated with the treatment of nighttime vasomotor symptoms with uncertain effects in women without VMS. However, there were many issues in this meta-analysis, including the definition and lack of standardization scales to evaluate sleep difficulties. In addition, the formulation of medications to treat hot flashes, the lack of baseline comparisons as well as the confounder of different progestins’ independent effect on sleep was noted [11]. The KEEPS (Kronos Early Estrogen Prevention Study) trial also compared oral (0.45 mg conjugated equine estrogen) versus transdermal (50 μgm estradiol) hormone on self-reported sleep in 727 women via the 9 item Pittsburgh (PSQI). Sleep satisfaction and latency improved with both types of HT but more in transdermal estrogen than oral. Changes in scores correlated with all domains except sleep latency and efficiency. This also suggested that HT affects other mechanisms associated with sleep beyond the treatment of hot flashes [12]. More research to investigate this mechanism is indicated. These studies suggest that a trial of hormone therapy may be an option for peri and early menopausal women with new sleep problems to alleviate these issues even in the absence of vasomotor symptoms.

 

 

Wendy Wolfman

Professor Department of Obstetrics and Gynaecology, University of Toronto

Director Menopause and POI Units Mt. Sinai Hospital, Toronto, Canada

 

References

 

  1. Geiger P, Eisenlohr-Moul T, Gordon J, Rubinow D, Girdler S. Effects of perimenopausal transdermal estradiol on self-reported sleep independent of its effect on vasomotor symptom bother and depressive symptoms. Menopause 2019 ;26:1318-1323.
    https://www.ncbi.nlm.nih.gov/pubmed/31688579

  2. Tom SE, Kuh D, Guralnik JM, Mishra G. Self-reported sleep difficulty during the menopausal transition: results from a prospective cohort study. Menopause 2010;17:1128-1135.
    https://www.ncbi.nlm.nih.gov/pubmed/20551846

  3. Kravitz HM, Ganz PA, Bromberger J, Powell LH, Sutton-Tyrrell K, Meyer PM. Sleep difficulty in women at midlife: a community survey of sleep and the menopausal transition. Menopause 2003;10:19-28.
    https://www.ncbi.nlm.nih.gov/pubmed/12544673

  4. Baker FC, Lampio L, Saaresranta T, Polo-Kantola P. Sleep and sleep disorders in the menopausal transition. Sleep Med Clin 2018;13:443-456.
    https://www.ncbi.nlm.nih.gov/pubmed/30098758

  5. Duman M, Timur Tashan S. The effect of sleep hygiene education and relaxation exercises on insomnia among postmenopausal women: A randomized clinical trial. Int J Nurs Pract 208;24(4);e12650.
    https://www.ncbi.nlm.nih.gov/pubmed/29569793

  6. Guthrie KA, Larson JC, Ensrud KE, Anderson GL, Carpenter JS, Freeman EW, Joffe H, LaCroix AZ, Manson JE, Morin CM, Newton KM, Otte J, Reed SD, McCurry SM. Effects of Pharmacologic and Nonpharmacologic Interventions on Insomnia Symptoms and Self-reported Sleep Quality in Women With Hot Flashes: A Pooled Analysis of Individual Participant Data From Four MsFLASH Trials. Sleep 2018:41(1).
    https://www.ncbi.nlm.nih.gov/pubmed/29165623

  7. Ensrud KE, Guthrie KA, Hohensee C, Caan B, Carpenter JS, Freeman EW, LaCroix AZ, Landis CA, Manson J, Newton KM, Otte J, Reed SD, Shifren JL, Sternfeld B, Woods NF, Joffe H. Effects of estradiol and venlafaxine on insomnia symptoms and sleep quality in women with hot flashes. Sleep 2015;38(1):97-108.
    https://www.ncbi.nlm.nih.gov/pubmed/25325454

  8. Soares CN, Joffee H, Rubens R, Caron J, Roth T, Cohen L. Eszoplicone in patients with insomnia during perimenopause and early postmenopause: a randomized controlled trial. Obstet Gynecol. 2006;108(6):1402-10.
    https://www.ncbi.nlm.nih.gov/pubmed/17138773

  9. Caufriez A, Leproult R, L’Hermite-Baleriaux M, Kerkhofs M, Copinschi G. Progesterone prevents sleep distubances and modulates GH, TSH, and melatonin secretion in postmenopausal women. J Clin Endocrinol Metab. 2011;96(4): E614-23.

  10. Attarian H, Hachul H, Guttuso T, Phillips B. Treatment of Chronic Insomnia Disorder in Menopause: Evaluation of Literature. Menopause 2015; 22: 674-84.
    https://www.ncbi.nlm.nih.gov/pubmed/25349958

  11. Cintron D, Lipford M, Larrea-Mantilla L, Spencer-Bonilla G, Lloyd R, Gionfriddo M, Gunjal S, Farrell A, Miller V, Murad M. Efficacy of menopausal hormone therapy on sleep quality: systematic review and meta-analysis. Endocrine 2017;55:702-711.
    https://www.ncbi.nlm.nih.gov/pubmed/27515805

  12. Cintron D, Lahr B, Bailey K, Santoro N, Lloyd R, Manson J, Neal-Perry G, Pal B, Taylor H, Wharton W, Naftolin F, Harman SM, Miller V. Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Menopause 2018; 25: 145-153.
    https://www.ncbi.nlm.nih.gov/pubmed/28832429

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