Effect of Menopausal Hormone Therapy on Sleep

A Phase IV, Multicentre, Prospective, Randomized Clinical Trial Investigating the Impact of Menopausal Hormone Therapy on Sleep in Peri- and Postmenopausal Women

The Effect of Menopausal Hormone Therapy on Sleep (menoSLEEP) study is investigating the effects of menopausal hormone therapy (MHT) on sleep problems in peri- and postmenopausal women with an indication for MHT. The aim of the study is to find out whether MHT improves subjective and objective sleep quality in these women. The primary objective is to measure sleep quality using several sleep-specific questionnaires and a sleep protocol.

The study is a multicentre, prospective, unblinded, randomised controlled trial involving 172 women. Participants will be divided into groups that will either receive MHT or act as a control group. All participants will complete seven questionnaires before and after MHT and keep a sleep diary. The duration of participation will vary between 8 and 16 weeks. The results should help to improve the treatment of menopausal sleep disorders and the quality of life of women affected.

Background and rationale

Having problems falling asleep and staying asleep (insomnia) can lead to impaired quality of life, cognitive impairment, increased risk of suicide, weight gain, cardiovascular disease and premature death. Sleep disturbances are reported by nearly one-third of the general population across all age groups. This number only increases with age, affecting nearly 50% of individuals older than 65 years. Women are more likely to experience difficulty initiating and maintaining sleep compared to men, which is dramatically increased during hormonal transitions such as pregnancy or menopause.

The sleep disorders that affect women in menopause are not only a result of increasing in age, but also of the new life situation as well as hormonal changes. In addition, the transition to menopause increases the risk of developing organic sleep disorders such as obstructive sleep apnea syndrome or restless legs syndrome.

Menopausal hormone replacement therapy (MHT) is the 1st-line treatment and most effective method for treating menopausal symptoms. Subjects with a combination of insomnia and hot flashes/night sweats (vasomotor symptoms; VMS) particularly benefit from MHT. However, women without VMS also report insomnia, and there are women with severe VMS whose sleep is not disturbed. Treatment of vasomotor symptoms can definitely reduce sleep disturbances caused by VMS in menopausal women, but has not been shown to eliminate all sleep problems.

In this context, the primary objective of the planned sudy is to investigate the exact effect of MHT on sleep patterns and problems in peri- and postmenopausal women with an indication for MHT.

Secondary objectives include investigating the subjective effects of MHT on sleep duration, difficulty sleeping through the night, time in bed, sleep latency, sleep efficiency, sleep regularity (Regularity Index), number of waking phases, subjective sleep quality, daytime sleepiness, early morning awakenings, number of nocturnal hot flashes, satisfaction with sleep behavior, impairments in daily life due to sleep problems and the influence of sleep problems on quality of life, depression and anxiety in peri- and postmenopausal women with an indication for MHT.

Overall, there is little data on the exact effects oft MHT in sleep disorders in peri- and post-menopausal women. The studies conducted so far have not used questionnaires as extensive as the one in the study that is proposed here. In particular in this study sleep is recorded via questionnaires and sleep logs over a longer period of time than has been the case in the majority of studies to date. This will help zero in on the true effects that MHT has on sleep. Therefore, the expected results of this study will have important implications for the field of menopause and sleep medicine. If MHT is shown to benefit peri- and postmenopausal women with sleep disorders the quality of life could be enhanced. For this reason, the investigators would like to investigate this topic by means of four comprehensive questionnaires and a sleep protocol among Swiss women.

Objectives

The primary objective is to test whether MHT has an impact on subjective sleep quality measured via the Insomnia Severity Index as well as the Sleep Health Score in peri- and postmenopausal women with an indication for MHT.

Secondary objectives are to test whether MHT has an impact on

• Sleep duration (Total sleep time, TST)
• Difficulty initiating sleep measured by the Latency to fall asleep (Sleep Latency, SL)
• Difficulty maintaining sleep measured via the Wake time after sleep onset (WASO)
• Time in bed (TIB)
• Sleep efficiency (SE)
• Sleep regularity (Regularity Index)
• Number of waking phases
• Daytime sleepiness
• Early morning awakenings
• Number of nocturnal hot flashes
• Satisfaction with sleep behavior
• Impairments in daily life due to sleep problems
• Symptoms of depression and anxiety measured via the PHQ2 and GAD2

Study design

Multicenter, prospective, non-blinded randomized controlled trial

Inclusion criteria

• Informed Consent as documented by signature
• Peri- and postmenopausal woman
• Indication for MHT (e.g. climacteric syndrome, osteoporosis, etc.)
• Age ≥ 18 years
• German Speaking

Exclusion criteria

• Obesity BMI ≥ 30 kg/m²

• Pregnancy or Lactation

• Status post Hysterectomy

• Systemic hormone therapy or hormonal contraception (estrogens, progestogens, androgens) during the study and within 12 weeks prior to study entry

• Prescribed medication for therapy of sleep problems 12 weeks prior to study entry (excluding phytotherapeutic agents and over the counter medication)

• Medication that could distort sleep (e.g. antidepressant, anticonvulsant and antipsychotic medications)

• Substance abuse (e.g. daily alcohol consumption, drugs in general)

• Contraindication for menopausal hormone therapy according to swissmedicinfo.ch

  • Neoplasia of the breast or other sexual organ
  • Benign or malignant liver tumors
  • Acute or chronic liver disease
  • Cholestatic jaundice
  • Porphyria
  • Arterial or venous thromboembolic events
  • Abnormal genital bleeding of unknown cause

• Known or suspected non-compliance due to inability to follow the procedures of the study (e.g. illiteracy, language problems, psychological disorders, dementia, etc.)

Measurements and procedures

The investigators(') plan to include 172 peri- and postmenopausal females with an indication for MHT (e.g. climacteric syndrome, osteoporosis, etc).

The participants are divided into four groups: a peri- and postmenopausal group as well as a control group for perimenopausal women and a control group for postmenopausal women.

All participants complete seven questionnaires and a 2-week sleep protocol once in the period of two weeks before MHT.

Subsequently, in participants in the peri- and postmenopausal group MHT is initiated. Four weeks after the establishment of MHT, the subjects are asked to complete the seven questionnaires and the sleep protocol again. Postmenopausal subjects complete the second sleep protocol for 2 weeks, perimenopausal subjects for 4 weeks (justification: MHT in the postmenopause is monophasic, while MHT in the perimenopause is biphasic and the combination of active substances in weeks 1 and 2 is different from that in weeks 3 and 4).

Participants in the peri- and post-menopausal control groups will start MHT treatment with a 6-week delay, and will also be asked to complete the seven questionnaires and a 2-week sleep protocol during the last 2 of these 6 weeks. The further course of the study on MHT is the same as described above for the peri- and postmenopausal groups.

Thus, the study duration for the individual participant is 8 weeks in the postmenopausal group, 10 weeks in the perimenopausal group, 14 weeks in the postmenopausal control group and 16 weeks in the perimenopausal control group.

The following examinations/ tests are carried out:

• The following parameters are obtained via peripheral venous blood sampling: FSH, LH, estradiol, progesterone, dehydroepiandrosterone sulfate, thyroid stimulating hormone, free triiodothyronine, free thyroxine, thyroid peroxidase antibody, prolactin, cortisol, glucose, insulin and blood lipids (cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides), HOMA-Index (Homeostatis Model Assessment), small blood count, holotranscobalamine, ferritin, creatinine, aspartate aminotransferase, alanine aminotransferase, sodium, potassium, magnesium, 25-hydroxy-vitamin-D3, C-reactive protein
• Subjects are asked to complete the following six questionnaires as well as a sleep protocol during the first two and in the last two to four weeks of the study, which will assess a wide variety of subjective and objective sleep, well-being and quality of life issues.
• Sleep health questionnaire
• ESS (Epworth Sleepiness Scale)
• ISI (Insomnia Severity Index)
• Sleep protocol
• Fatigue Severity Scale (FSS)
• Menopause Rating Scale II
• Single study question questionnaire pre-MHT
• Single study question questionnaire after waiting period
• Single study questionnaire post-MHT

Subjects come to a regular menopause consultation (covered by health insurance) due to various menopause-induced symptoms (such as hot flashes, night sweats, low or changing moods etc). In this initial regular consultation:

• A detailed medical history is taken.
• An appointment is made for the fasting morning blood test.
• The planned study is explained and an enquiry is made as to whether there is interest in participating.
• If there is interest in participating, then the participant information sheet, an informed consent form, 3 (peri- and postmenopausal group) / 4 (both control groups) stamped and addressed envelopes as well as two / tree times the seven study questionnaires and the sleep protocols are distributed to the test persons.Within the next 2 weeks, the subjects return for a routine fasting morning blood draw (covered by health insurance).

If the subjects are interested in the study, they will mail the consent form back to the investigators(') and complete the 7 questionnaires and the sleep protocol for two weeks. If the investigators(') receive a signed informed consent form the investigators(') will call the subjects to make sure there are no questions concerning the study.

After at least 2 weeks, following the regular menopause consultation, the subjects will be given an appointment to discuss the results of the regular blood draw. At this appointment a prescription for the menopausal hormone replacement therapy medication will be distributed to the peri- and postmenopausal group. The questionnaires and sleep protocol completed in the last two weeks will be submitted by the subject if they have not been returned by post in advance.

If the subjects were first assigned to one of the control groups then at this point they will have to wait another 6 weeks for the prescription for the menopausal hormone replacement therapy medication and will fill out the 7 questionnaires an the sleep protocol once again in the last 2 weeks of the 6-week waiting period. They will receive a phone call to ensure that they don't forget to fill out the questionnaires and sleep protocol anew. The completed questionnaires will be returned to the investigators(') with the stamped envelope. Now they will receive the prescription for the individual MHT that was discussed with them in the prior consultation.

Succeeding the four weeks of MHT use, all subjects (peri- and postmenopausal group as well as peri- and postmenopausal control group) again begin to complete the 7 study questionnaires and the sleep protocol for 2 / 4 weeks, depending on their MHT regime. They will receive a phone call to ensure that they don't forget to fill out the questionnaires and sleep protocol anew. The completed questionnaires will be returned to the investigators(') with the stamped envelope.

IMP: All swiss medic approved products for menopausal hormone therapy

Inclusion Criteria:

• Informed Consent as documented by signature
• Peri- and postmenopausal woman
• Indication for MHT (e.g. climacteric syndrome, osteoporosis, etc.)
• Age ≥ 18 years
• German Speaking

Exclusion Criteria:

• Obesity BMI ≥ 30 kg/m²

• Pregnancy or Lactation

• Status post Hysterectomy

• Systemic hormone therapy or hormonal contraception (estrogens, progestogens, androgens) during the study and within 12 weeks prior to study entry

• Prescribed medication for therapy of sleep problems 12 weeks prior to study entry (excluding phytotherapeutic agents and over the counter medication)

• Medication that could distort sleep (e.g. antidepressant, anticonvulsant and antipsychotic medications)

• Substance abuse (e.g. daily alcohol consumption, drugs in general)

• Contraindication for menopausal hormone therapy according to swissmedicinfo.ch

  • Neoplasia of the breast or other sexual organ
  • Benign or malignant liver tumors
  • Acute or chronic liver disease
  • Cholestatic jaundice
  • Porphyria
  • Arterial or venous thromboembolic events
  • Abnormal genital bleeding of unknown cause

• Known or suspected non-compliance due to inability to follow the procedures of the study (e.g. illiteracy, language problems, psychological disorders, dementia, etc.)