Improving Sleep and Mood in the Peri-menopause

The Role of Sleep and Hormonal Interventions to Improve Climacteric Symptoms in the Peri-menopause

The perimenopause is known as a vulnerable period for some women, with noticeable somatic and psychological issues. Aside from climacteric symptoms, insomnia and depression are common. About half of women during the peri-menopausal period experience sleep problems like problems falling asleep, awakening during the night and being unable to return to sleep. This is often attributed to vasomotor symptoms, but this is not the only reason of poor sleep (Joffe et al., 2010). Also, the peri-menopausal period is a critical time for the occurrence of new onset and recurrent depressions (Cohen et al., 2006). It has been suggested that fluctuations in estradiol may increase the risk for depression by altering neuronal functions in the brain. But there are also indications that the risk for depression increases by indirect effects, such as the increase in insomnia. Poor sleep has increasingly been recognized as the key modifiable factor affecting mental issues like depression (Van Someren, 2021). While antidepressants and psychotherapies continue to be the treatments of choice for depression, and Cognitive Behavioral Therapy for sleep (CBTi) for insomnia, preclinical and clinical data support the benefits of estrogen-based therapies to improve mood, sleep and other menopause-related symptoms (Gordon et al. 2018). Transdermal estradiol patches, which provide a stable release of estradiol and lead to more stable blood levels, have been suggested to have a positive effect on sleep (Joffe et al., 2020) and depressive symptoms (Gordon et al., 2018) in randomized controlled trials. However, it is currently unclear if the relation between improvement in mood and estradiol patches is mediated by improvement in sleep problems, and if the effect of estradiol patches on sleep problems is more effective during peri-menopause than the current evidence-based sleep interventions of CBTi, preferably in combination with Circadian Rhythm Support (CRS). The aim of the study is to pinpoint the determinants of complaints about sleep and mood and how they respond to Menopausal Hormone Treatment (MHT) with and without the addition of a guided eHealth sleep intervention that combines CBTi + CRS.

Measurements will be conducted at baseline (T0), 2 months (T1) and 4 months (T3), with questionnaires, sleep measurements (EEG sleepband and actigraph) and skin conductance (to measure hot flushes). Participants will be recruited via www.slaapregister.nl and via OLVG outpatient clinic population of peri-menopausal women seeking help for climacteric complaints (like hot flushes, feeling bloated, increase in weight), including sleep problems. The participants are adults between 40-55 years old, with an Insomnia Severity Index score ≥10 and Climacteric Green Scale score ≥ 13.They have the self-considered capability to complete online questionnaires and diaries in Dutch.

The intervention will be MHT (estradiol transdermal patches 50 mcg (Systen), in combination with 200 mg progesterone (Utrogestan tablets for 2 weeks, adjusted to the menstrual cycle to prevent endometrium carcinoma according to the international MHT guidelines), with and without the addition of a guided eHealth sleep intervention that combines CBTi + CRS.

Study Overview

• Status: Not yet recruiting
• Conditions: Insomnia; Menopause
• Intervention / Treatment: Drug: Estrogens and Progestogens; Behavioral: Cognitive behavioral therapy for insomnia (CBTi), and circadian rhythm therapy

Detailed Description

The primary outcome measure is insomnia severity (Bastien et al., 2001). Secondary outcomes address five domains: depressive symptoms, symptoms of other mental health symptoms, climacteric symptoms, daytime functioning and well-being and other sleep measurements. The severity of mental health complaints characterizing different diagnostic dimensions, as well as well-being and daytime functioning including health behaviours and use of care, all assessed by online survey or clinical interview at T0, T1 (2 months) and T2 (4 months).

Climacteric symptoms are assessed with the Green Climacteric Scale at T0, T1, T2. Hot flashes are measured with ambulatory sternal skin conductance monitoring (Purplexus). The other sleep measures include other indicators of sleep and overnight alleviation of distress assessed from the Carney Consensus Sleep Diary, kept online for a week; rest-activity rhythm and activity-based sleep estimates obtained with an actigraph at 7 baseline nights (T0), 7 post-interventions nights (T1) and 7 follow-up nights (T2); objective sleep efficiency, REM sleep fragmentation and heartrate with an ambulatory headband EEG at 5 baseline nights (T0), 5 post-interventions nights (T1) and 5 follow-up nights (T2).

• Study Type: Interventional
• Enrollment (Estimated): 222
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anne-Sophie Koning, Dr.; Phone Number: +31 20 566 5500; Email: a.koning@nin.knaw.nl
• Study Contact Backup: Name: Francesca van Baarzel, MSc.; Phone Number: +31 20 566 5500; Email: f.van.baarzel@nin.knaw.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age between 40-55 years old
• Insomnia severity index score =>10
• Green Climacteric Score =>13
• Self-considered capability of completing online questionnaires and diaries in Dutch

Exclusion Criteria:

• CBTi treatment in past 3 months
• Bipolar disorder or psychotic disorder
• Contra-indication for Menopausal Hormonal Therapy
• Use of hormonal anti-conception

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hormones only; Participants will receive the standard care hormonal intervention.	Drug: Estrogens and Progestogens; Menopausal Hormone Therapy, formerly known as Hormone Replacement Therapy (HRT), is a medical treatment that involves the use of hormones to relieve the symptoms of menopause and to reduce the risk of certain long-term health conditions associated with menopause. Menopause is a natural biological process that occurs when a women's ovaries stop producing effects, and her estrogen and progesteron hormone levels subsequently decrease. MHT typically involves administration of a combination of sec steroids. In this study MHT consists of estradiol transdermal patches (50 mcg (Systen), which provide a stable release of estradiol and lead to more stable blood levels. This is combined with 200 mg progesterone (Utrogestan tablets for 2 weeks) adjusted to the menstrual cycle to prevent endometrium carcinoma according to the international MHT guidelines.; Other Names: Hormone replacement therapy
Experimental: Sleep intervention only; Participants will receive the sleep intervention, which includes cognitive behavioral therapy for insomnia, and circadian rhythm therapy.	Behavioral: Cognitive behavioral therapy for insomnia (CBTi), and circadian rhythm therapy; CBTi is a guided, internet-based cognitive behavioral therapy program for insomnia, containing information and exercises on sleep. It consists of five online sessions: Psycho-education on sleep, disordered sleep and sleep hygiene (i.e. general guidelines about health and environmental factors influencing sleep),; Sleep restriction (i.e. restrict time in bed to the average sleep time) and stimulus control training (i.e. reinforce association of bed with sleeping),; Rumination and relaxation techniques,; Cognitive restructuring (i.e. changing misconceptions about sleep),; Relapse prevention.
Experimental: Hormones and Sleep intervention; Participants will receive both the sleep intervention, which includes cognitive behavioral therapy for insomnia, and circadian rhythm therapy, and the standard care hormonal intervention.	Drug: Estrogens and Progestogens; Menopausal Hormone Therapy, formerly known as Hormone Replacement Therapy (HRT), is a medical treatment that involves the use of hormones to relieve the symptoms of menopause and to reduce the risk of certain long-term health conditions associated with menopause. Menopause is a natural biological process that occurs when a women's ovaries stop producing effects, and her estrogen and progesteron hormone levels subsequently decrease. MHT typically involves administration of a combination of sec steroids. In this study MHT consists of estradiol transdermal patches (50 mcg (Systen), which provide a stable release of estradiol and lead to more stable blood levels. This is combined with 200 mg progesterone (Utrogestan tablets for 2 weeks) adjusted to the menstrual cycle to prevent endometrium carcinoma according to the international MHT guidelines.; Other Names: Hormone replacement therapy; Behavioral: Cognitive behavioral therapy for insomnia (CBTi), and circadian rhythm therapy; CBTi is a guided, internet-based cognitive behavioral therapy program for insomnia, containing information and exercises on sleep. It consists of five online sessions: Psycho-education on sleep, disordered sleep and sleep hygiene (i.e. general guidelines about health and environmental factors influencing sleep),; Sleep restriction (i.e. restrict time in bed to the average sleep time) and stimulus control training (i.e. reinforce association of bed with sleeping),; Rumination and relaxation techniques,; Cognitive restructuring (i.e. changing misconceptions about sleep),; Relapse prevention.
No Intervention: No intervention; The control group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary outcome variable is the difference between the groups in the within-subject change in insomnia severity at T1 (2 months) and T2 (4 months) relative to T0 (baseline).	ISI (insomnia severity index)	month 2 vs. month 4

Collaborators and Investigators

• Sponsor: VU University of Amsterdam
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Netherlands Brain Foundation; Purplexus
• Investigators: Principal Investigator: Birit Broekman, Prof., OLVG and Amsterdam UMC, VU; Principal Investigator: Eus van Someren, Prof., Netherlands Institute for Neuroscience

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: March 5, 2024
• First Submitted That Met QC Criteria: March 5, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Estrogens
• Other Study ID Numbers: NL86165.100.24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No