Transdermal Estrogen in Older Premenopausal Women With Anorexia Nervosa

Anorexia nervosa (AN) is a prevalent psychiatric disorder affecting up to 1% of college-aged
women in the US and an increasing number of women over 30 years of age. Among the many
medical co-morbidities associated with AN, the most common is significant bone loss, which
can persist despite weight recovery. Nearly 50% of women with AN have osteopenia with an
additional 30% meeting WHO criteria for osteoporosis. Importantly, this severe bone loss is
associated with an increased fracture risk. Nearly 30% of women with AN report a history of a
fracture and a prospective study demonstrated a 7-fold increased risk of fracture in women
with AN compared to age-matched controls. Because AN is a chronic disease that can persist
despite psychiatric and nutritional counseling, the bone loss and increased fracture risk can
persist and lead to lifelong morbidity. Therefore, finding a treatment for bone loss
associated with AN is of critical importance.

This 6 month open-label study will investigate in women (ages 25 to 50 years old) with AN
whether treatment with transdermal estrogen replacement will increase bone mineral density
(BMD), improve parameters of bone microarchitecture as assessed by high-resolution peripheral
quantitative computed tomography (HR-pQCT), and improve bone strength as estimated by
microfinite element analysis.

Inclusion Criteria:

- Female; ages 25-50 years

- Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) psychiatric
criteria for AN, including <85% of ideal body weight as defined by the 1983
Metropolitan Life Insurance Height and Weight Tables, and amenorrhea

- T-score of < -1.5 at spine or hip

- Treatment team or treatment professional in place for clinical treatment/monitoring
during the study

Exclusion Criteria:

- Diseases known to affect bone metabolism, including untreated thyroid dysfunction,
vitamin D deficiency, Cushing's syndrome, diabetes mellitus or renal insufficiency

- Personal history of venous or arterial clot

- History of stroke or myocardial infarction

- History of migraine headaches

- History of hypercoagulable disorder

- Personal history or history of a first-degree relative with breast cancer

- History of hereditary angioedema

- Any medication known to affect bone metabolism, including systemic glucocorticoids
within three months of the baseline visit, depot medroxyprogesterone within 6 months
of the baseline visit, oral bisphosphonates within one year of the baseline visit or
intravenous (IV) bisphosphonates within three years of the baseline visit

- Bone fracture within the prior 12 months

- Serum potassium < 3.0 meq/L or serum alanine aminotransferase (ALT) > 3 times the
upper limit of normal

- Fasting serum triglyceride level > 150 mg/dL

- Pregnant or breastfeeding

- Active substance abuse