Hormone Replacement for Premature Ovarian Insufficiency

Study Overview
=================
Brief Summary
-----------------
The investigators intend to establish feasibility/acceptability of a pilot randomized trial comparing hormone replacement therapy (HRT) and combined oral contraceptives (COCs) in women with premature ovarian insufficiency to estimate differences in quality of life (QOL) and serum hormone assays and markers of bone turnover/cardiovascular risk. At baseline, QOL survey will be administered and serum testing performed. Patients then randomized to HRT or COCs. Repeat testing will be performed after 3 and 6 months.

Detailed Description
-----------------
Premature ovarian insufficiency (POI) is a term used to describe when a woman's ovaries stop working normally before the natural age of menopause. Early sequelae of POI include vasomotor symptoms, vaginal dryness, mood swings and insomnia due to estrogen deficiency. Long-term sequelae such as loss of bone mineral density and cardiovascular risk carry are considerable concerns. While exogenous estrogen replacement is recommended for the POI patient population, the optimal regimen for replacement is not clear. One approach to hormone replacement therapy (HRT) is to mimic physiologic ovarian function through full replacement doses of estrogen (either orally or transdermally) to reach the typical serum estradiol levels of a menstruating woman (approximately 104 pg/mL per day) with cyclic progestin therapy for endometrial protection. Another approach uses daily combined estrogen-progestin oral contraceptives (COCs), for ease of administration and increased social acceptability. To date, few studies have been performed comparing the two treatment methods in terms of quality of life measures (vasomotor symptoms, bleeding profile, sexual dysfunction, satisfaction with contraception), endocrine function, bone turnover or cardiovascular risk in POI patients. In this proposal, the investigators intend to establish feasibility and acceptability of a pilot randomized controlled trial comparing traditional HRT with COCs in women with POI and to evaluate differences in quality of life measures, hormone assays, bone turnover and cardiovascular risk between treatment arms. The investigators hypothesize that acceptability and feasibility of the pilot trial will be high and that differences will be detected for all measured variables between treatment arms. Demonstration of feasibility and acceptability of this pilot would allow for the pursuit of a larger trial and identification of a superior treatment regimen would have a meaningful impact on the short and long-term care of this patient population.

Official Title
-----------------
Optimal Hormone Replacement for Women With Premature Ovarian Insufficiency

Conditions
-----------------
Primary Ovarian Insufficiency

Intervention / Treatment
-----------------
* Drug: Hormone Replacement Therapy
* Drug: Combined Oral Contraceptives


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female patients, Between 14-45 years of age Post-menarchal Presence of uterus POI as defined by: change in menstrual function (oligomenorrhea and/or amenorrhea), elevated serum serum follicle stimulating hormone (FSH), low serum estradiol concentrations, or estrogen deficiency symptoms. Exclusion Criteria: Pregnancy or lactation within previous 3 months Use of hormonal contraception or replacement within previous 3 months Any contraindication to oral contraceptive pills or hormone replacement therapy per the current drug labels. These could include, but are not limited to: history of venous thromboembolism,estrogen-sensitive cancer history, regular cigarette smoking and history of or active liver disease, etc. Patients will be screened for pregnancy with a urine HCG test at time of screening

Ages Eligible for Study
-----------------
Minimum Age: 14 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hormone Replacement Therapy<br>Patient will be given hormones in the form of: transdermal estradiol patch (Climara) 100 mcg/24 hours weekly, progesterone (Prometrium) 200 mg per day for first 12 calendar days of each month (If patients insurance plan does not cover transdermal estradiol, they will be prescribed oral estradiol 2 mg daily. If patients insurance plan does not cover Prometrium, they will be prescribed medroxyprogesterone (Provera) 10 mg per day for first 12 calendar days of each month). | Drug: Hormone Replacement Therapy<br>* Hormone replacement therapy as indicated in Arm 1<br>* Other names: Provera;|
| Experimental: Combined Oral Contraceptives<br>Patients will be given hormones in the form of: monophasic combined oral contraceptive containing ethinyl estradiol 0.035 mg and norgestimate 0.25 mg, 1 tablet daily (21 days of active pills and 7 days of inactive pills) | Drug: Combined Oral Contraceptives<br>* Combined oral contraceptives as indicated in Arm 2<br>* Other names: Norgestimate;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment | Patient willingness to participate and be randomized | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vasomotor symptoms - Greene Climacteric Scale | Greene Climacteric Scale | 1 year | 
| Vasomotor symptoms - Menopausal Vasomotor Symptoms (MVS) survey | Menopausal Vasomotor Symptoms (MVS) survey | 1 year | 
| Bleeding profile - Bleeding questionnaire | Bleeding questionnaire | 1 year | 
| Bleeding profile - Menstrual diary | Menstrual diary | 1 year | 
| Sexual dysfunction - Female Sexual Function Index (FSFI) | Female Sexual Function Index (FSFI) | 1 year | 
| Satisfaction as Contraceptive Method | Birth Control Satisfaction Assessment | 1 year | 
| Hormone Assays - FSH (mIU/mL) | FSH (mIU/mL) | 1 year | 
| Hormone Assays - Estradiol (pg/mL) | Estradiol (pg/mL) | 1 year | 
| Hormone Assays - Sex-hormone binding globulin (nmol/L) | Sex-hormone binding globulin (nmol/L) | 1 year | 
| Hormone Assays - Total testosterone (ng/dL) | Total testosterone (ng/dL) | 1 year | 
| Hormone Assays - Free testosterone (ng/dL) | Free testosterone (ng/dL) | 1 year | 
| Hormone Assays - Anti-mullerian hormone (pmol/l) | Anti-mullerian hormone (pmol/l) | 1 year | 
| Hormone Assays - Dehydroepiandrosterone Sulfate (ng/mL) | Dehydroepiandrosterone Sulfate (ng/mL) | 1 year | 
| Hormone Assays - Thyroid stimulating hormone (U/mL) | Thyroid stimulating hormone (U/mL) | 1 year | 
| Bone Turnover Markers - Serum osteocalcin (ng/mL) | Serum osteocalcin (ng/mL) | 1 year | 
| Bone Turnover Markers - Serum N-telopeptide of type I collagen (nmol/L) | Serum N-telopeptide of type I collagen (nmol/L) | 1 year | 
| Cardiovascular Risk Markers - Total cholesterol | Total cholesterol (mg/dL) | 1 year | 
| Cardiovascular Risk Markers - Triglycerides (mg/dL) | Triglycerides (mg/dL) | 1 year | 
| Cardiovascular Risk Markers - Lipoprotein a (mg/dL) | Lipoprotein a (mg/dL) | 1 year | 
| Cardiovascular Risk Markers - Fasting glucose (mg/dL) | Fasting glucose (mg/dL) | 1 year | 
| Cardiovascular Risk Markers - Fasting insulin (pmol/L) | Fasting insulin (pmol/L) | 1 year | 
| Cardiovascular Risk Markers - Homeostatic model assessment (HOMA) insulin | Homeostatic model assessment (HOMA) insulin | 1 year | 
| Cardiovascular Risk Markers - Tissue-type plasminogen activator antigen (ng/mL) | Tissue-type plasminogen activator antigen (ng/mL) | 1 year | 
| Cardiovascular Risk Markers - Plasma plasminogen activator inhibitor 1 (ng/mL) | Plasma plasminogen activator inhibitor 1 (ng/mL) | 1 year | 
| Cardiovascular Risk Markers - Fibrinogen (mg/dL) | Fibrinogen (mg/dL) | 1 year | 
| Cardiovascular Risk Markers - Factor VII (%) | Factor VII (%) | 1 year | 
| Cardiovascular Risk Markers - C-reactive protein (mg/L) | C-reactive protein (mg/L) | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
premature ovarian failure, hormone replacement