Menopause
Conditions
Brief summary
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
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: 1. 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. 2. 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.
Interventions
DRUGEstradiol , estriol , progesterone
DRUGestradiol, progesterone
DRUGestriol, progesterone
DRUGequine estrogens m-progesteroneacetate
Sponsors
Private Foundation through KU Endowment
University of Kansas
Jeanne Drisko, MD, CNS, FACN
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Cholesterol | Baseline and month 12 | 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. |
| Endometrial Measurement | Baseline and month 12 | 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. |
| Number of Participants Without Change in Baseline and Follow up Mammograms | baseline and month 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Without Change in Baseline and Follow up Bone Density | baseline and 12 months | 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. |
Countries
United States
Participant flow
Recruitment details
Double blind single site pilot clinical trial conducted at academic medical center. Participants randomized to one of 4 arms by computer assignment conducted at independent site not enrolling subjects.
Pre-assignment details
If participants were on hormone replacement at enrollment, needed to have 3 month washout period before randomization. Participants were required to be nonsmokers, have intact uterus, and be menopausal. Screening ultrasound of the uterus, bone density, screening metabolic panel, and baseline mammogram were required.
Participants by arm
| Arm | Count |
|---|---|
| Study Arm 1 Prempro, premarin .45mg, provera 1.5mg conjugated estrogens, medroxyprogesterone acetate
Prempro, premarin, provera conjugated estrogens, medroxyprogesterone acetate: Prempro, premarin .45mg, provera 1.5mg conjugated estrogens, medroxyprogesterone acetate | 6 |
| Study Arm 2 Estradiol .5mg, estriol 210mg, progesterone 100mg
Estradiol , estriol , progesterone: Estradiol .5mg, estriol 210mg, progesterone 100mg | 6 |
| Study Arm 3 estriol 2.5mg, progesterone 100mg
estriol, progesterone: estriol 2.5mg, progesterone 100mg | 5 |
| Study Arm 4 estradiol,progesterone
estradiol,progesterone: estradiol,progesterone | 4 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 2 | 0 |
| Overall Study | cancer unrelated to study discovered | 1 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Study Arm 1 | Study Arm 2 | Study Arm 3 | Study Arm 4 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 5 Participants | 4 Participants | 21 Participants |
| Region of Enrollment United States | 6 participants | 6 participants | 5 participants | 4 participants | 21 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 5 Participants | 4 Participants | 21 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 0 / 6 | 2 / 6 | 2 / 5 | 0 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 4 |
Outcome results
Primary
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.
Time frame: Baseline and month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Arm 1 | Change in Total Cholesterol | 221.5 mg/dL | Standard Deviation 12.5 |
| Study Arm 2 | Change in Total Cholesterol | 221.5 mg/dL | Standard Deviation 0 |
| Study Arm 3 | Change in Total Cholesterol | 223 mg/dL | Standard Deviation 26 |
| Study Arm 4 | Change in Total Cholesterol | 165.5 mg/dL | Standard Deviation 11 |
Primary
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.
Time frame: Baseline and month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Arm 1 | Endometrial Measurement | 13.0 mm | Standard Deviation 0 |
| Study Arm 2 | Endometrial Measurement | 10.0 mm | Standard Deviation 0 |
| Study Arm 3 | Endometrial Measurement | 2.5 mm | Standard Deviation 0.7 |
| Study Arm 4 | Endometrial Measurement | 3.1 mm | Standard Deviation 0.7 |
Primary
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.
Time frame: baseline and month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Arm 1 | Number of Participants Without Change in Baseline and Follow up Mammograms | 2 Participants |
| Study Arm 2 | Number of Participants Without Change in Baseline and Follow up Mammograms | 1 Participants |
| Study Arm 3 | Number of Participants Without Change in Baseline and Follow up Mammograms | 2 Participants |
| Study Arm 4 | Number of Participants Without Change in Baseline and Follow up Mammograms | 4 Participants |
Secondary
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.
Time frame: baseline and 12 months
Population: Only 7 participants completed both the baseline bone density and 12-month follow up bone density resulting in a discrepancy in evaluable numbers compared to other outcome measures.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Arm 1 | Number of Participants Without Change in Baseline and Follow up Bone Density | 1 Participants |
| Study Arm 2 | Number of Participants Without Change in Baseline and Follow up Bone Density | 1 Participants |
| Study Arm 3 | Number of Participants Without Change in Baseline and Follow up Bone Density | 2 Participants |
| Study Arm 4 | Number of Participants Without Change in Baseline and Follow up Bone Density | 3 Participants |