Effects of Hormone Replacement Therapy on Inflammation and Stiffening of Artery Walls
Effects of Hormone Replacement Therapy on Inflammation and Stiffening of Artery Walls
This study will determine the effects of hormone replacement therapy (estrogen alone or
 estrogen and progesterone) on the walls of arteries in postmenopausal women. Inflammation and
 stiffness of artery walls are two risk factors for atherosclerosis-deposits of fatty
 substances (plaques) that can block the vessel, causing a heart attack or stroke. Estrogen
 raises the levels of certain substances in the blood that cause vessel inflammation and
 lowers the levels of others. This study will measure the net effects of estrogen on artery
 wall inflammation and stiffness.

 Postmenopausal women in good health may participate in this study. Volunteers will be
 screened for eligibility with a complete medical history, heart examination, and blood tests.
 Participants will be randomly assigned to receive either: 1) hormone therapy (estradiol 2 mg
 daily alone for women who have had a hysterectomy or estradiol plus micronized progesterone
 200 mg daily for women with an intact uterus); or 2) placebo (look-alike pills that contain
 no active drug). Women in both groups will take pills for 3 months, then no pills for 1
 month, and then will crossover to the alternate therapy for 3 months (i.e., those in the
 original placebo group will take hormones, and those in the hormone group will take placebo).
 At the end of each 3-month treatment period, participants will undergo the following
 procedures to assess blood vessel inflammation and stiffness:

 1. Blood tests - 60 cc (about 2 ounces) of blood will be drawn to measure levels of
 hormones, cholesterol, and substances in the blood that indicate inflammation of the
 vessels.

 2. Ultrasonography - an ultrasound probe will be applied gently on the neck to image the
 right and left carotid arteries (arteries in the neck that lead to the brain). During
 the procedure, the heart's electrical activity will also be monitored with an
 electrocardiogram and a blood pressure cuff will be wrapped around the arm to obtain
 blood pressure measurements every 5 minutes.

 3. Magnetic resonance imaging (MRI) - Images of the carotid arteries are taken while the
 volunteer lies on a table in a narrow cylinder containing a magnetic field. A padded
 sensor called an MRI coil is placed over the neck and earplugs are placed in the ears to
 muffle the loud noise of the machine during scanning. During the second half of the
 exam, gadolinium is injected through a catheter (thin, flexible tube) inserted into a
 vein. Gadolinium is a contrast agent that is used to brighten the scan images.

 Information from this study will increase knowledge about the effects of estrogen on vessel
 wall inflammation. As such, it may be used in the future to help guide decisions about
 chronic hormone replacement therapy in postmenopausal women.
Vascular inflammation plays an important role in the pathogenesis of atherosclerosis and may
 contribute to stiffening of arteries that increases the risk of myocardial infarction and
 stroke. Accordingly, therapies that reduce vascular inflammation may reduce cardiovascular
 risk. The effect of estrogen therapy on serum markers of inflammation in postmenopausal women
 is divergent: Estrogen increases the levels of C-reactive protein, interleukin-6, and matrix
 metalloproteinase-9 ( MMP-9), but decreases levels of the soluble cell adhesion molecules
 ICAM-1, VCAM-1 and E-selectin. MMP-9 is secreted by macrophages and cytokine-activated smooth
 muscle cells, with increased expression in the vicinity of atherosclerotic plaques. Although
 activation of MMP-9 by estrogen could be deleterious in women with coronary artery disease by
 digesting the fibrous caps of vulnerable plaques and provoking thrombosis (consistent with
 the Heart and Estrogen/progestin Replacement Study), activation of MMP-9 in healthy
 postmenopausal women may remove excess matrix proteins that contribute to arterial stiffness
 (reduced compliance), thus reducing cardiovascular risk (consistent with the Nurses' Health
 Study). Reduction of levels of cell adhesion molecules might protect against new plaque
 development in both groups of women. The purposes of this protocol are to determine the net
 effects of estrogen therapy on 1) vascular inflammation in postmenopausal women, using
 MRI/MRA imaging of the carotid arteries, and 2) arterial compliance, derived from carotid
 ultrasonography and blood pressure measurements.
Ability to comprehend or unwillingness to sign the consent form.

 No use of estrogen therapy within 2 months of this study.

 No history of breast cancer, uterine cancer, or estrogen-dependent tumor.

 No history of deep vein thrombosis or pulmonary embolus.

 No cigarette smokers (within 2 years).

 No diabetes mellitus (FBS greater than 120 mg/dL).

 Triglycerides less than 400 mg/dL.

 Blood pressure less than 160/90 without antihypertensive therapy.

 No history of coronary artery disease.

 No history of carotid artery disease or stroke.

 No history of pancreatitis.

 No history of claustrophobia.

 No history of involuntary motion disorder.

 Specific MRI exclusion criteria (i.e., no pacemaker, no cochlear implants, no AICD, no
 internal infusion pump, no metal implants or clips in field of view).

 No systemic inflammatory disorder (e.g., rheumatoid arthritis, periarteritis nodosa,
 systemic lupus erythromatosus, temporal arteritis).

 Must not have a need for chronic aspirin or NSAID therapy.