Hormone Replacement for Premature Ovarian Insufficiency

Phase 3

Withdrawn

• Conditions: Primary Ovarian Insufficiency
• Interventions: Drug: Combined Oral Contraceptives; Drug: Hormone Replacement Therapy

• Registration Number: NCT02922348
• Lead Sponsor: University of Pennsylvania

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.

Study Timeline

• Study Start: 2016-03-01
• Study First Submitted: 2016-03-21
• Study First Submitted QC: 2016-09-29
• Study First Posted: 2016-10-04
• Primary Completion: 2018-12-01
• Study Completion: 2018-12-01
• Status Verified: 2019-07
• Last Update Submitted: 2019-07-03
• Last Update Posted: 2019-07-05

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: Female
• Target Recruitment: Not specified

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Combined Oral Contraceptives	Combined Oral Contraceptives	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)
Hormone Replacement Therapy	Hormone Replacement Therapy	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).

Primary Outcome Measures

Name	Time	Method
Recruitment	1 year	Patient willingness to participate and be randomized

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Penn Fertility Care; 🇺🇸 Philadelphia, Pennsylvania, United States