Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure

Study Overview
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Brief Summary
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The aim of the study is to determine whether physiological sex steroid replacement improves parameters of skeletal, cardiovascular and reproductive health of women treated with current sex steroid replacement regimens.

Detailed Description
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Premature ovarian failure, defined as the onset of the menopause before the age of 40 years, is a relatively common problem that affects 1% of women. There are a variety of aetiologies underlying premature ovarian failure including Turner syndrome and those with idiopathic onset, however with the increasing success of intensive treatment for childhood cancer, there are increasing numbers of young survivors, with a variety of late effects of treatment, including premature ovarian failure. Evidence is required for the optimal management of young women with premature ovarian failure, either as a result of childhood cancer treatment or for other reasons. These women are currently offered combined sex steroid replacement in the convenient form of the oral contraceptive pill, or hormone replacement therapy, designed for older women after the menopause. These preparations are not designed to achieve physiological replacement of oestrogen or progesterone, either in dosage or in biochemical structure - many preparations using synthetic derivatives. These younger women who have differing metabolic and psychological requirements are looking to a future of 30 or more years of replacement. The optimal mode of SSR is not known for young women with premature ovarian failure, however there is concern that current regimens may be inadequate for optimal skeletal and cardiovascular health. Current preliminary data demonstrates that use of physiological sex steroid replacement improves uterine parameters. Evidence is required to determine whether optimising sex steroid replacement can also significantly improve parameters of skeletal and cardiovascular health. Young women with ovarian failure face several decades of hormone replacement, so small improvements in management may make large differences to later morbidity and mortality. The aim of the study is to determine whether physiological sex steroid replacement improves parameters of skeletal, cardiovascular and reproductive health of women treated with current sex steroid replacement regimens.

Official Title
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Comparison of Standard and Physiologic Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure and the Assessment of Skeletal, Cardiovascular and Reproductive Parameters

Conditions
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Premature Ovarian Failure

Intervention / Treatment
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* Drug: Ethinylestradiol / Norethisterone
* Drug: Estradiol / Progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premature Ovarian Failure Exclusion Criteria: Intercurrent illness
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Treatment with standard sex steroid replacement regimen | Drug: Ethinylestradiol / Norethisterone<br>* Oral ethinylestradiol 30mcg and norethisterone 1.5mg daily for weeks 1-3, followed by 7 pill free days<br>* Other names: Loestrin 30, Galen Ltd, UK;|
| Experimental: 2<br>Treatment with physiologic sex steroid regimen | Drug: Estradiol / Progesterone<br>* Transdermal estradiol 100mcg daily for week 1, then 150mcg daily for weeks 2-4; and vaginal progesterone pessaries 200mg twice daily for weeks 3-4<br>* Other names: Cyclogest, Activis UK Ltd;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 24 hour ambulatory blood pressure |  | Before each washout period, then at 0, 3, 6 and 12 months of each treatment | 
| Bone mineral density measurements (DEXA) |  | Baseline, 14 and 24 months | 
| Uterine ultrasound scan to assess uterine volume, endometrial thickness, and uterine artery blood flow |  | Before each washout period, then at 0, 3, 6 and 12 months of each treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central arterial blood pressure and arterial stiffness measured using peripheral arterial tonometry |  | Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase | 
| Biochemical evidence of activity on the renin-angiotensin system, including plasma renin activity, angiotensin II, aldosterone, creatinine, urea and electrolyte concentrations. |  | Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase | 
| Serum markers of collagen turnover and bone matrix formation |  | Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase | 
| Hormonal assays for gonadotrophins, FSH, LH and sex steroids estrogen and progesterone |  | Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Premature ovarian failure, Sex hormone replacement, HRT, Blood pressure, Bone mineral density, Bone metabolism, Uterine function