Hormone Replacement for Premature Ovarian Insufficiency (HOPE)

Optimal Hormone Replacement for Women With Premature Ovarian Insufficiency

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.

Study Overview

• Status: Withdrawn
• Conditions: Primary Ovarian Insufficiency
• Intervention / Treatment: Drug: Hormone Replacement Therapy; Drug: Combined Oral Contraceptives

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 Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Fertility Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Hormone Replacement Therapy; Hormone replacement therapy as indicated in Arm 1; Other Names: Prometrium; Provera; Estradiol; Micronized progestin; Medroxyprogesterone; Climera
Experimental: 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)	Drug: Combined Oral Contraceptives; Combined oral contraceptives as indicated in Arm 2; Other Names: Ethinyl estradiol; 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

Collaborators and Investigators

• Sponsor: University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: March 21, 2016
• First Submitted That Met QC Criteria: September 29, 2016
• First Posted (Estimate): October 4, 2016

Study Record Updates

• Last Update Posted (Actual): July 5, 2019
• Last Update Submitted That Met QC Criteria: July 3, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: premature ovarian failure; hormone replacement
• Additional Relevant MeSH Terms: Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Primary Ovarian Insufficiency; Menopause, Premature; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Estradiol; Contraceptive Agents; Ethinyl Estradiol; Contraceptives, Oral; Hormones; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate; Contraceptives, Oral, Combined; Progestins; Medroxyprogesterone; Norgestimate
• Other Study ID Numbers: 823553

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No