Estrogen Therapy as Prevention in the Progression of Aneurysm (EPPA) Trial

This is a prospective, randomized, placebo-control trial to test the effect of estradiol in
the prevention of progression of cerebral aneurysms. To evaluate the effect, each subject
will be treated with either oral estradiol or placebo for 6 months. Subjects will be randomly
assigned to 1 of 2 groups as follows:

Double Blind Treatment Group Open-Label Regimen A1 1 mg Estradiol daily for 180 days B1
Placebo for 180 days

Each group will be given oral Progesterone (3300 mg) for 10 days at the end of 90 days
regardless of menstrual pattern. Subjects will be asked to keep a menstrual calendar
throughout the trial. Serum markers will be drawn at baseline and every 90 days with the
results blinded until the end of the trial. Magnetic resonance angiography (MRA) studies of
the brain will be performed at month 6.

Inclusion Criteria:

- Generally healthy women, 40-52 years of age.

- At least one documented saccular intracranial cerebral aneurysm detected via catheter
angiography, magnetic resonance angiography or computed tomography angiography.

- Clinical diagnosis of perimenopause, defined as regular or irregular menses with or
without vasomotor symptoms.

Exclusion Criteria:

- Known or suspected estrogen-dependent neoplasia.

- Endometrial proliferation, hyperplasia, or malignancy at screening.

- Known hypersensitivity to estrogens, progestins.

- History of myocardial infarction, ischemic heart disease, lipid disorder, or
congestive heart failure.

- Known or suspected pregnancy, or recent breast feeding (within 6 months).