Title: Hormone therapy for premature ovarian insufficiency: randomised trial and long-term evaluation
Funder: Department of Health and Social Care

Abstract: BACKGROUND:_x000D_ When menopause occurs in women under the age of 40, it is termed Premature Ovarian Insufficiency (POI). This affects at least 1 in every 100 women. The cause is often unknown, but may be due to genetic conditions such as Turner's syndrome, immune disorders, treatments for cancer, or surgery involving the ovaries. The main symptom is absent or very irregular periods. Many women get other menopause symptoms, such as hot flushes and sweats, loss of libido, painful intercourse, mood changes and fatigue. The ability to get pregnant naturally is greatly reduced. The impact of symptoms and infertility is distressing._x000D_ In the long-term, women with POI are at higher risk of bone thinning (osteoporosis), fractures, heart disease and memory problems compared with women who experience menopause at the typical age, around 51 years. Treatments involve taking hormones, either in the form of hormone replacement therapy or the combined oral contraceptive pill. Both have advantages and disadvantages, and healthcare professionals are uncertain which is the best for relief of symptoms and also for long-term risks of POI._x000D_ We conducted a survey of doctors and found about two-thirds of gynaecologists offer hormone replacement therapy, as the first treatment choice. All agree more information is needed to help women decide which treatment is best overall._x000D_ _x000D_ RESEARCH PLAN:_x000D_ We plan to undertake a research study in 480 women with POI. Participants will be assessed by gynaecologists, asked to complete questionnaires about their symptoms and have a bone density scan. They will be randomly allocated to take either hormone replacement therapy (as a tablet, patch or gel), or the contraceptive pill. Neither the women nor their doctors will be able to choose, but the women will know what treatment they are taking. This is called an ‘open randomised controlled study and is the most reliable way of determining the value of two treatments. We will ask women about their symptoms after 3, 6 and 12 months and then annually to 5 years, using paper or online questionnaires. We will also ask about the impact POI has on their sexual activity and their working life. Women will be asked to have repeat bone scans at 1, 2, 5 and 10 years. Women being treated at 3 London hospitals will also be invited to provide blood samples to look at bone and heart health in more detail._x000D_ Information about long-term consequences of POI, such as fractures, will be collected via information routinely recorded by the NHS._x000D_ _x000D_ PATIENT/ PUBLIC INVOLVEMENT_x000D_ We have worked closely with the POI patient group the Daisy Network, and the Turner’s Syndrome Society UK in developing this study. They distributed a survey to women, which indicated strong support for the study. They convinced us of the need to be flexible about types of hormone replacement therapy and the pill regimens offered in the study. The survey helped us prioritise the outcomes we will measure, to make sure they are those most important to women. We will convene a group of women to advise us on the patient information, design of the questionnaires and sustaining long-term engagement with participants._x000D_ _x000D_ DISSEMINATION_x000D_ The results of the study will be published in leading journals, presented at medical conferences and will feed into the next edition of the NICE guidelines. Information to help women decide about treatment for POI will be prepared for the patient groups and websites such as NHS Choices.

Lay abstract: RESEARCH QUESTION_x000D_ What is the most effective hormone treatment for women with premature ovarian insufficiency [POI] in the short and long term?_x000D_ _x000D_ BACKGROUND_x000D_ POI is a clinical syndrome defined by the loss of ovarian activity before the age of 40 years. Long-term hormone treatment, at least to the age of natural menopause, is recommended to reduce menopausal symptoms and reduce the risk of adverse long-term outcomes. Treatment can be either the combined oral contraceptive pill [COCP] or hormone replacement therapy [HRT]._x000D_ _x000D_ METHODS_x000D_ DESIGN Randomised, open, parallel, superiority trial with internal pilot_x000D_ SETTING UK gynaecology clinics, both specialist and general_x000D_ STUDY POPULATION Women with a diagnosis of POI (as per NICE guidance) regardless of cause_x000D_ _x000D_ HEALTH TECHNOLOGIES BEING ASSESSED:_x000D_ COCP: 30µg ethinylestradiol, with any progestogen, as an extended regimen._x000D_ HRT: continuous estradiol, either oral or transdermal, dose no less than 2mg orally or 50mcg patch or 2 pumps gel, transdermally. For women with a uterus, progesterone or progestogen, either oral, intrauterine or transdermal, continuous or cyclical. _x000D_ _x000D_ PRIMARY OUTCOME Bone mineral density [BMD] at 2 years from a standard lumbar spine DEXA scan_x000D_ SECONDARY OUTCOMES_x000D_ Short to medium term:_x000D_ 1. Individual domains and total score of MENQOL-Intervention questionnaire, at 3, 6 and 12 months then annually_x000D_ 2. BMD in hip at 2 years, and hip and lumbar spine at 1 and 5 years_x000D_ 3. Bone metabolism markers: a subset from 3 clinics, at 3 and 12 months_x000D_ 4. Cardiovascular markers: Weight at 3 and 12 months then annually, blood pressure at 3, 6, 12 months and then annually. Fasting lipids, glucose and insulin will be collected in a subset, at 3, 12 months and then annually_x000D_ 5. Sexual function at 3, 6, 12 months then annually_x000D_ 6. Work productivity at 3, 6, 12 months then annually_x000D_ 7. Pregnancy and outcome_x000D_ 8. Satisfaction with treatment_x000D_ 9. Change or cessation of treatment_x000D_ 10. Adverse events_x000D_ Long-term outcomes:_x000D_ 1. Individual domains and total score of MENQOL-I at 10 years_x000D_ 2. BMD in hip and lumbar spine at 10 years_x000D_ 3. BP and weight at 10 years_x000D_ 4. Pregnancy and outcome_x000D_ 5. Change or cessation of treatment_x000D_ 6. Bone fractures (any location)_x000D_ 7. Cardiovascular disease, cancer, cognitive/ neurological conditions, osteoporosis_x000D_ 8. Mortality_x000D_ SAMPLE SIZE_x000D_ Assuming a SD of 0.15 for lumbar spine BMD, 382 patients will be required to detect a between–group difference of 0.05g/cm2 (a small effect size of 0.333) with a 90% power, 5% 2-sided significance level and 1:1 allocation. Allowing for up to 20% loss to follow-up, will recruit 480 patients._x000D_ _x000D_ TIMELINES_x000D_ The research will have 4 stages:_x000D_ Years 1-6 Randomised trial (6 months set-up, 36 months recruitment, 2 year follow-up, report on primary outcome and biomarkers)_x000D_ Years 6-9 Randomised trial (medium-term data)_x000D_ Years 9-14 Cohort study (long-term data)_x000D_ Years 14-24 Routine data (very long-term data)_x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION_x000D_ The trial will ensure that young women receive the optimum initial therapy for relief of symptoms, quality of life and sexual function, and protection against long-term adverse consequences of oestrogen deficiency._x000D_ Results will be disseminated via the NIHR library, scientific papers, and conference presentations, and communicated to guideline development groups and commissioners. The Daisy Network and Turner’s Syndrome Support Society UK will lead on patient involvement.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH