Bioidentical 'Natural' Hormone Evaluation in Early Menopause

Study Overview
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Brief Summary
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Prospective double blind pilot study comparing bioidentical 'natural' hormones to low-dose PremPro. Forty participants will be enrolled. The purpose of this study is to try to gather early information about safety when natural or bioidentical hormones are used during early menopause.

Detailed Description
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In spite of warnings regarding safety and adverse events widely publicized after the Women's Health Initiative (WHI), women continue to seek hormone replacement therapy for a variety of reasons. Increased cardiovascular events identified in WHI are an important concern for considering menopausal hormone replacement. There is the belief the 'natural' or bioidentical hormone replacement therapy could provide a safe alternative to widely used synthetic hormone replacement therapy. However, this has never been studied with any rigor and health care providers can not adequately advise patients seeking 'natural' bioidentical hormone therapy. This feasibility pilot study is designed as a prospective double blind study comparing 4 groups of women who are within 7 years of menopause. There will be 10 women in each of the 4 groups with a total of 40 women enrolled and these women will be treated for 12 months. The Long-Term Goal is to provide health care practitioners and consumers with evidence-based recommendations for the use of bioidentical hormone replacement. The Short-Term Goal of this pilot study is to determine if it is feasible to conduct a study in bioidentical hormones and obtain information that could lead to a larger more definitive study. We would like to provide safety information for bioidentical hormone use by evaluating surrogate markers for cardiovascular disease (lipid levels), with secondary evaluation of breast (mammogram) and uterus (endovaginal ultrasound), and to collect information about bone preservation. The information gained from this trial will provide information for a future trial to test the hypothesis that bioidentical hormone replacement therapy provides a safe alternative to standard hormone replacement therapy: To determine if bioidentical hormone replacement therapy is associated with improved lipid profiles (surrogate marker for cardiovascular disease) when compared to Prempro. This will be determined by evaluating lipid levels at baseline and during the 12-month treatment period. Secondary hypotheses will also be evaluated in the future to include: To determine if bioidentical hormone replacement therapy provides improved short-term risk profiles for uterine and breast health when compared to Prempro. This will be accomplished by requiring mammograms and endovaginal ultrasounds at baseline and the end of the 12-month treatment period. To determine if there is bone loss when using bioidentical hormone replacement when compared to Prempro. This aim will be evaluated by Dexa bone scan at baseline and at 12 months. Subjects will randomly be assigned to one of the four arms of the study for the 12 months of treatment. The standard of care arm will consist of 10 women receiving in a double blind fashion low-dose Prempro. There will be 3 treatment arms consisting of different combinations of E2 estradiol and/or E3 estriol, all combined with bioidentical progesterone. These 3 arms will each have 10 subjects randomized and the bioidentical hormone delivered in a double blind fashion. Since the gold standard for treatment is the conventional arm (Prempro), we will compare each bioidentical arms to the gold standard. This comparison will occur at the end of 12 months of treatment. In this pilot study, we also wish to collect preliminary data about the comparisons between the 3 bioidentical hormone arm and the conventional arm. This is necessary because there is currently anecdotal evidence that E3 alone without combination with E2 may constitute adequate therapy in spite of its low biological activity at the estrogen receptor. The use of high doses of E3 with or without E2 is in common use by complementary and alternative practitioners. It is expected in this small pilot study that bioidentical hormone will provide an adequate short-term safety profile for cardiovascular, breast and uterine health that will provide guidance for a larger trial that is longer in duration. It is also expected that bone density may be maintained by bioidentical hormone replacement when compared to Prempro. There may not be sufficient numbers to determine significance between the control arm and the treatment arms; however, we expect to collect useful information for future trials. It is assumed that equivalence will not likely be determined based on the sample size.

Official Title
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Prospective Double Blind Evaluation of Bioidentical Hormones

Conditions
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Menopause

Intervention / Treatment
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* Drug: Estradiol , estriol , progesterone
* Drug: estradiol, progesterone
* Drug: estriol, progesterone
* Drug: equine estrogens m-progesteroneacetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female Ambulatory Within 7 years post menopause Positive history of menopausal symptoms such as vasomotor symptoms or osteoporosis in a study subject unable to tolerate bisphosphonates FSH greater than 20 mIU/mL Intact uterus and at least one intact ovary Amenorrhea for 3 months or greater up to 7 years Normal pap smear results within 12 months Normal mammogram result within 12 months Agreeable to a 3 month washout period with no hormones prior to entering the trial Women who have no language barrier, are cooperative, and who can give informed consent before entering this study Exclusion Criteria: Unwilling to take hormone replacement for the 12 month period Evidence of clinically significant psychiatric disorder by history/examination that would prevent the patient from completing the study. Active deep venous thrombosis, pulmonary embolism, or a history of these conditions Active or recent arterial thromboembolic disease Undiagnosed vaginal bleeding Hypersensitivity to ingredients in Prempro Patients with known current bone disorders other than primary osteoporosis Patients with pathological fractures Patients with suspected or history of carcinoma of the breast or estrogen dependent neoplasms such as endometrial carcinoma. Patients who have ≥ 5mm endometrial thickness by endovaginal (transvaginal) ultrasound. Patients who have impaired renal function evidenced by serum creatinine greater than 2.5 mg/dL. Patients who have impaired hepatic function evidenced by transaminase (AST/ALT) ≥2.5X upper limit Patients with severe malabsorption syndromes. Patients who consume an excess of alcohol or abuse drugs (an excess of alcohol is defined as more than four of any one or combination of the following per day: 30 mL distilled spirits, 340 mL beer, or 120 mL wine). Treatment with therapeutic doses of any of the following medications more recently than 3 months: Estrogen Calcitonin Corticosteroids Progestins Progesterone Lithium Androgen Heparin Herbal menopause treatments SERMS Fluorides Phosphate binding antacids Bisphosphonates Vitamin D 50,000IU Anticonvulsants Patients who received any investigational drug within the proceeding month Tobacco use will not be allowed

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 equine estrogens m-progesteroneacetate<br>Menopausal women in first seven years of menopause randomized to arm 1 receive conjugated equine estrogens 0.45 mg combined with medroxyprogesteroneacetate 1.5 mg placed in a placebo capsule to disguise contents from participant and study team. Drug dosed daily for 1 year. Screening FSH and PAP. Baseline mammogram, bone density, pelvic ultrasound, EKG, blood work for cholesterol panel (surrogate marker for cardiovascular disease), BUN/Creatinine. Repeated at 12 months. Safety check at 6 months includes BUN/creatinine, EKG, cholesterol panel, estradiol, progesterone levels. | Drug: equine estrogens m-progesteroneacetate<br> <br> * Other names: Prempro;|
| Experimental: 2 estradiol estriol progesterone<br>Menopausal women in first seven years of menopause randomized to arm 2 estradiol .5mg, estriol 2.0mg, progesterone 100mg dosed orally / day placed in a placebo capsule to disguise contents from participant and study team. Drug dosed daily for 1 year. Screening FSH and PAP. Baseline mammogram, bone density, pelvic ultrasound, EKG, blood work for cholesterol panel (surrogate marker for cardiovascular disease), BUN/Creatinine. Repeated at 12 months. Safety check at 6 months includes BUN/creatinine, EKG, cholesterol panel, estradiol, progesterone levels. | Drug: Estradiol , estriol , progesterone<br> <br> * Other names: compounded bioidentical hormone;|
| Experimental: 4 estradiol progesterone<br>Menopausal women in first seven years of menopause randomized to arm 4 estradiol 0.5 mg, progesterone 100 mg dosed orally / day placed in a placebo capsule to disguise contents from participant and study team. Drug dosed daily for 1 year. Screening FSH and PAP. Baseline mammogram, bone density, pelvic ultrasound, EKG, blood work for cholesterol panel (surrogate marker for cardiovascular disease), BUN/Creatinine. Repeated at 12 months. Safety check at 6 months includes BUN/creatinine, EKG, cholesterol panel, estradiol, progesterone levels. | Drug: estradiol, progesterone<br> <br> * Other names: compunded bioidentical hormone;|
| Experimental: 3 estriol progesterone<br>Menopausal women in first seven years of menopause randomized to arm 3 estriol 2.5mg, progesterone 100mg dosed orally / day placed in a placebo capsule to disguise contents from participant and study team. Drug dosed daily for 1 year. Screening FSH and PAP. Baseline mammogram, bone density, pelvic ultrasound, EKG, blood work for cholesterol panel (surrogate marker for cardiovascular disease), BUN/Creatinine. Repeated at 12 months. Safety check at 6 months includes BUN/creatinine, EKG, cholesterol panel, estradiol, progesterone levels. | Drug: estriol, progesterone<br> <br> * Other names: compounded bioidentical hormone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Total Cholesterol | To determine if bioidentical hormone replacement therapy is associated with change in lipid profiles (surrogate marker for cardiovascular disease) when compared to Prempro and provide safety data to proceed to larger trial. This was determined by evaluating lipid levels at baseline and during the 12-month treatment period. Participants' values were averaged at baseline and again at 12 months; the average of the baseline value was subtracted from the average at completion. | Baseline and month 12 | 
| Endometrial Measurement | Baseline and 12 month follow up endovaginal ultrasound(completed at study site only) to evaluate endometrial stripe thickness for change on hormone therapy for all 4 arms. Endometrial thickness was measured in millimeters at baseline and again at 12 month completion. The average of the baseline value was subtracted from the average at completion for each group and reported in mm. Single participant in Arm 2: compared baseline to completion. | Baseline and month 12 | 
| Number of Participants Without Change in Baseline and Follow up Mammograms | Comparison at baseline and month 12 by descriptive analysis of breast mammograms. Assessing for changes in density and/or lesions for risk of breast stimulation from hormone replacement therapy. Mammogram readings for participants completing study in descriptive terms. Looking for significant change in breast tissue while on hormone therapy for 12 months. Those who had no change are counted below. | baseline and month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Without Change in Baseline and Follow up Bone Density | Comparison at baseline and month 12 by descriptive analysis of bone density. Assessing for changes in density related to hormone replacement therapy. Bone density readings for participants completing study in descriptive terms. Looking for significant change in bone density while on hormone therapy for 12 months. Those who had no change are counted below. | baseline and 12 months |