The human ovary produces male sex hormones (androgen) and female sex hormones (estrogen).
Currently, androgen is not included in hormone replacement therapy for women with premature
ovarian failure. Present hormone replacement therapy (HRT) was designed to treat women who
experience ovarian failure at menopause (around the age of 50). However, 1% of women will
experience premature failure of the ovaries before the age of 40. There have been no
studies conducted to determine proper hormone replacement therapies for these younger women.
Some research suggests that the usual menopausal hormone replacement therapy is not
adequate to protect young women with premature ovarian failure from developing osteoporosis.
Women with premature ovarian failure have abnormally low levels of androgens circulating in
their blood. This may contribute to the increase risk for osteoporosis.
This study will compare two treatment plans for women with premature ovarian failure.
Treatment plan one will be physiological estrogen hormone replacement. Treatment plan two
will be physiological estrogen hormone replacement plus androgen. The study will attempt to
determine which plan is more beneficial to women in relation to osteoporosis and heart
The hormones will be contained in patches and given by placing the patches against the
patient's skin. The patches were designed to deliver the same amount of hormone as would be
normally produced by the ovary in young women.
The success of the treatment will be measured by periodically checking the density of
patient's bone in the leg (femoral neck bone) . Researchers will take an initial (baseline)
measurement of bone density before beginning treatment and then once a year, for 3
additional years, during treatment. The study will also consider bone density of the spine,
bone turnover, heart disease risk factors, and psychological state.
Present menopausal hormone replacement therapy regimens were designed for women who
experience ovarian failure around age 50. At least 1% of women, however, experience
premature ovarian failure before the age of 40, but there have been no studies establishing
optimal hormone replacement therapy regimens for these younger women. Available evidence
suggests that the usual menopausal hormone replacement therapy is not adequate to protect
young women with premature ovarian failure from developing osteoporosis. Women with
premature ovarian failure have abnormally low circulating androgen levels, which may
contribute to their risk for osteoporosis. We plan to compare physiological estrogen
replacement with physiological estrogen plus androgen replacement in young women with
premature ovarian failure to determine which regimen is more beneficial for bone mineral
density and other metabolic parameters related to the risk for cardiovascular disease. This
study employs transdermal estradiol and testosterone "patches" designed to deliver the same
amount for each sex steroid normally produced by the ovary in young women in a physiological
manner. Women with premature ovarian failure will be randomized to receive either estradiol
plus placebo patches or estradiol plus testosterone patches. Both groups will receive
cyclic progestin treatment. A group of age-matched women with normal ovarian function will
serve as contemporaneous controls for bone density and other study measures. The primary
outcome parameter is femoral neck bone mineral density, to be assessed at baseline, and
after 1, 2, and 3 years of treatment. Other outcome parameters include lumbar spine bone
mineral density, markers of bone turnover, cardiovascular disease risk factors, and
- INCLUSION CRITERIA:
Patients with karyotypically normal spontaneous premature ovarian failure (as defined by
screening protocol 91-CH-0127, i.e. women who have at least 4 months of amenorrhea, two
FSH levels above 40 mIU/ml, at least one month apart, and a normal 46, XX karotype,
diagnosed with premature ovarian failure prior to the age of 40) who are between the age
of 18 and 42 years will be candidates.
Smokers (more than 2 cigarettes per day).
Alcohol users (more than 2 drinks of alcohol per day).
Body mass index (BMI, kg/m(2)) greater than or equal to 30 and less than or equal to 19.
Previous history of hip fracture or other active hip pathology.
Abnormalities of the hip precluding the assessment of bone mineral density.
Major dermatologic disorders, or a history of skin sensitivity to adhesive bandages, tape
or transdermal matrix patches.
Hirsutism score greater than 8.
Acne score greater than 1.
Baseline free testosterone (FT) levels above the normal range (greater than 6.3 pg/ml in
our current essay) and/or SHBG levels less than 36 nmol/L.
Any prior treatment in the past 6 months known to affect bone other than estrogen (i.e.,
calcitonin, biphosphonates, fluoride, anabolic steroids, testosterone, or herbal therapy
that contains androstenedione, and DHEA).
Current and/or past use of: diuretics, anticoagulants (heparin, Coumadin), glucocorticoid
drugs, gonadotropin-releasing hormone agonist or antagonist therapy, chemotherapy.
Medical history of:
Anorexia nervosa, hyperprolactinemia, insulin-dependent diabetes, Cushing's syndrome,
gastrectomy, osteogenesis imperfecta, mastocytosis, rheumatoid arthritis, long-term
parenteral nutrition, hemolytic anemia, hemochromatosis and thalassemia, ankylosing
spondylitis, multiple myeloma, Vitamin D deficiency, Paget's disease, primary
hyperparathyroidism, hyperthyroidism, hypothyroidism, any cancer or any other major
Contraindications to hormone replacement therapy:
Thromboembolic event associated with previous estrogen use History of endometrial cancer
History of breast cancer
Hypertriglyceridemia (fasting triglyceride levels greater than 500 mg/dL)
LDL greater than 190mg/dl
Patients taking "statins"
Serum Alkaline phosphatase greater than or equal to 2X the upper limit of normal
Serum GGT greather than or equal to 2X the upper limit of normal
Abnormal values on two or more hepatic panel tests
Undiagnosed Vaginal Bleeding
Known sensitivity to agents
Note: We will include patients with premature ovarian failure on antidepressant
medications, since today's most common antidepressant medication (Prozac) does not have a
major import on cognitive function. However, we will note whether they are on these
CONTROL SELECTION CRITERIA:
Healthy non-pregnant regularly menstruating women (cycles between 21 and 35 days),
non-smokers, non-alcohol users, under no medications, using non-hormonal contraceptive
methods (i.e. barrier methods of contraception, or sterilization) and with no intention to
conceive within the following 3 years.