Use of the Synthetic Hormone CDB-2914 in Treating Symptoms of Menopause
Use of the Synthetic Hormone CDB-2914 in Treating Symptoms of Menopause
This study will examine the safety and effectiveness of a synthetic hormone, CDB-2914, for
 treating symptoms of menopause. It will compare the effects of estrogen and CDB-2914 with
 those of estrogen and progesterone in postmenopausal women. The study will also evaluate
 whether CDB-2914 affects adrenal gland function. CDB-2914 is chemically similar to cortisol,
 a hormone that is produced by the adrenal glands and regulates the body's response to
 stresses, such as infection or injury.

 Healthy women volunteers between the ages of 45 and 70 who have not had a menstrual period
 for over a year, are not currently taking hormone replacement therapy, do not smoke and have
 not had a hysterectomy may be eligible for this study. Candidates will provide a medical
 history and have a physical examination, including a breast and pelvic exam. They will also
 provide a blood sample, have a mammogram and pap smear, and be instructed in dietary sources
 and/or supplements required to be sure they consume at least 1,000 mg. of calcium each day.

 Participants will be randomly assigned to take: a) estrogen plus CDB-2914, b) estrogen plus
 progesterone, or c) estrogen plus a placebo (look-alike tablet with no active ingredient)
 daily by mouth for 6 weeks. During the study period, they will keep a record of any symptoms,
 vaginal bleeding, and other medicines they take. They will return to the NIH Clinical Center
 weekly for blood tests and to fill out a questionnaire on mood, appetite, sleep patterns,
 menopausal symptoms, and other quality of life issues. At the 6-week visit, participants
 will:

 -  Bring a 24-hour urine collection

 -  Have a vaginal ultrasound to evaluate the effects of the medication on the thickness of
 the endometrium (lining of the uterus)

 -  Bring all bottles of study medication for a pill count

 -  Discuss any unusual or troubling symptoms with the study nurse or physician

 A final visit will be scheduled 1 to 3 weeks after the 6-week visit, when participants will
 turn in their calendar of daily symptoms and return unused progesterone pills.
Doctors recommend hormone replacement therapy to postmenopausal women as treatment for
 symptoms of estrogen-deficiency. However, many women do not take hormone replacement therapy
 because of side effects. In women with an intact uterus, estrogen must be given with
 progesterone to prevent overgrowth of the lining of the uterus. Side effects from
 progesterone may cause women to discontinue hormone replacement therapy.

 Compounds that are similar to naturally occurring hormones have been synthesized and studied
 for their ability to block or simulate the action of sex steroids such as estrogen and
 progesterone. The development of this class of compounds, called selective hormone receptor
 modulators, may provide new treatments that are targeted to specific organs or tissues. One
 example is the selective estrogen receptor modulator raloxifene, which blocks estrogen action
 at the uterus, and acts like estrogen at the bone. Raloxifene has been approved for use in
 post-menopausal women as a form of hormone replacement therapy and a treatment for
 osteoporosis. It provides many of estrogen's benefits without stimulating the uterine lining
 and thus may be taken without a progestin.

 This study evaluates the selective progesterone receptor modulator CDB-2914, a man-made
 hormone. Other progesterone receptor modulators have been shown to block estrogen's
 stimulating effect on the uterus in monkeys. If CDB-2914 has this effect in menopausal women,
 it may provide a new approach to hormone replacement therapy. In women studied at the NIH,
 single doses of CDB-2914 slowed uterine development or induced menses, depending on when it
 was given during the menstrual cycle. Like raloxifene, CDB-2914 has the potential for use in
 hormone replacement therapy, but to date the effects of its chronic administration have not
 been studied. This study aims to evaluate the safety and the physiologic and endocrine
 effects of chronic oral administration of CDB-2914 in postmenopausal women. All study
 subjects will receive daily oral estrogen and either CDB-2914, progesterone or a placebo to
 evaluate whether CDB-2914 blocks or enhances the usual effects of hormone replacement therapy
 on the uterine lining, lipid levels, clotting factors, bone turnover, hot flashes and quality
 of life. Weekly blood measurements, quality of life questionnaires, pre- and post-treatment
 ultrasound examinations of the uterus and a single biopsy of the uterine lining will be
 performed on all study subjects to assess these endpoints.
Participants must be female gender.

 Participants age must be 45-70 years inclusive.

 Participants FSH must be greater than 20 mlU/mL assay (this is a two-site immunofluorescent
 assay, Abbott Labs, post-menopausal range greater than 20).

 Participants must have12 month or greater history of amenorrhea.

 No current use of any sex steroid hormone replacement therapy (including selective estrogen
 receptor modulators) including transdermal, injectable, vaginal and oral preparations and
 willingness to abstain from such use during the study.

 Participants BMI 19-30.

 Participants must have a normal mammogram and pap smear at study entry.

 Participants must be able and willing to maintain a minimum daily intake of 1000 mg calcium
 from dietary sources and/or supplements for the duration of the study.

 Participants must have a normal pro-time and PTT at screening visit.

 Participants must be able to read and speak English fluently so as to allow accurate
 self-administration of medication, recording of symptoms and unassisted completion of
 weekly questionnaire.

 Participants must be in good health. Chronic medication use, except for glucocorticoid use
 or sex hormone replacement therapy, may be acceptable at the discretion of the principal
 investigator. Interval use of over-the-counter counter drugs, other than aspirin or NSAIDs,
 is acceptable but must be recorded.

 Particippants hemoglobin must be greater than 10 g/dL.

 Participants must be willing and able to self-administer daily medication, to complete
 self-administered questionnaires, to record daily symptoms and to return to the Clinical
 Center for weekly follow-up appointments for a minimum of 8 continuous weeks.

 Participants with a history of diabetes mellitus type I or II are not eligible.

 Participants with a history of malignancy within the past 5 years are not eligible.

 Participants must not have a current use (within 90 days of study entry) of drugs that
 affect bone turnover and mineral metabolism such as bisphophonates, parathyroid hormone,
 hydrochlorothiazide and calcitonin.

 Participants with triglyceride level of 500 mg/ml or greater at initial visit are not
 eligible.

 Participants must not use cholesterol-lowering medication currently or within 6 weeks of
 study entry.

 Participants with tobacco use currently or within 90 days of study entry are not eligible.

 Participants with a history of diseases that alter mineral metabolism such as
 hyperparathyroidism, chronic renal insufficiency and hemodialysis are not eligible.

 Participants requiring ongoing anti-inflammatory medication (e.g., aspirin, NSAIDs) whether
 prescribed or over the counter are not eligible.

 Participants with current use of anticoagulants (e.g. Warfarin, heparin), anti-platelet
 drugs or history of bleeding disorder are not eligible.

 Participants must not use OTC herbal or alternative treatments for hot flashes or other
 menopausal symptoms, such as DHEA, soy protein supplements, or other phytoestrogens within
 two months of study entry, and unwillingness to abstain from these products during the
 study.

 Participants must not use drugs that affect the frequency of intensity of hot flashes such
 as clonidine or SSRI's within 2 months of study entry.

 Participants must not have ischemic heart disease (e.g. angina, myocardial infarction or
 congestive heart failure).

 Participants must not have significant abnormalities in the history, physical or laboratory
 examination.

 Participants must not a history of venous thromboembolic events including deep vein
 thrombosis (DVT), pulmonary embolism, retinal vein thrombosis.

 Participants must not a history of stroke, complicated migraine, documented transient
 ischemic attack or uncontrolled hypertension.

 Participants must not absence of the uterus (hysterectomy).