• Areal Bone Content [ Time Frame: Change from Baseline to Month 24 ]
  Areal bone content as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).
• Bone Micro-architectural Parameters [ Time Frame: Change from Baseline to Month 24 ]
  Bone micro-architectural parameters as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).
• Volumetric Bone Density [ Time Frame: Change from Baseline to Month 24 ]
  Volumetric bone density as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).
• Bone Strength Estimates [ Time Frame: Change from Baseline to Month 24 ]
  Bone strength estimates as measured by high resolution peripheral quantitative computed tomography (HR-pQCT).
• Vertebral Fracture Rates [ Time Frame: Change from Baseline to Month 24 ]
  Vertebral fracture rates as measured by lateral spine x-ray

Currently, no therapy exists to improve bone health in females with anorexia nervosa (AN) other than improving body mass. Transdermal estrogen is being investigated as to whether it has benefit to bone health parameters.

While numerous studies have sought to orally replace estrogen in adolescents and women with AN, the replacement therapy suppresses IGF-1, and as a result oral estrogen studies have demonstrated no bone health benefit in AN. However, transdermal physiologic estrogen, due to no first-pass metabolism in the liver, is not IGF-1 suppressive. IGF-1 is known to be hormone that directly affects bone formation and is considered to be osteoanabolic (helps increase bone mass).

• Experimental: Treatment

  Participants randomized to the treatment arm will be divided by maturational status:

  • Participants who have had their first period or have a bone age greater than or equal to 14 years will receive PrClimara® 25 (estradiol hemihydrate transdermal system - 25 mcg/day) as a weekly patch, for 24 months.

    o These participants will also receive progesterone (Provera 10 mg tablet) orally every 4 weeks, for 7 days during the second half of the planned menstrual cycle, in order to induce a menstrual period.

  • Participants who have not yet had their first period and have a bone age below 14 years will receive an increasing dose of estrogen. These participants will be initiated on graduated dose of transdermal 17-β estradiol patches:

    • 3.1 mcg/day (1/8 patch) for first six-months,
    • 6.2 mcg/day (1/4 patch) for second six-months,
    • 12.5 mcg/day (1/2 patch) for third six-months, and
    • 25 mcg/day (full patch) for final six-months.
  Intervention: Drug: Estradiol Hemihydrate Transdermal System
• No Intervention: No Treatment
  The participants in this group will not receive the estrogen patch nor the oral progesterone.

Inclusion Criteria:

• Female
• Age 12 - 19 years old

• Meet DSM-5 criteria for Anorexia Nervosa

  o Criteria includes: persistent restriction of energy intake leading to significantly low body weight; either an intense fear of gaining weight or persistent behavior that interferes with weight gain; and a disturbance in the way one's body weight or shape is experienced

• Amenorrhea for at least three months

  • Amenorrhea is a required inclusion criteria as participants with intact menstruation do not meet justification for estrogen replacement (as they are not estrogen deficient)
  • Participants will have been seen and assessed by anorexia clinic physician prior to enrollment to exclude and treat other causes of amenorrhea
• Agree to use a highly effective contraceptive method for the duration of study therapy.

Exclusion Criteria:

• Uncontrolled or chronic medical conditions that may influence bone health (i.e. hyperthyroidism, diabetes mellitus, or celiac disease)
• Use of supraphysiologic corticosteroids for greater than three months
• Pregnancy or attempting pregnancy
• Cigarette smoker
• Known history of a blood clotting disorder (i.e. Factor V Leiden, Protein C Deficiency, etc.)
• Known predisposition to estrogen-related cancers, such as breast or ovarian cancer (e.g. BRCA1)
• Hypersensitivity to this drug or to any ingredient in the formulation or component of the container
• Liver dysfunction or disease as long as liver function tests have failed to return to normal
• Known or suspected estrogen-dependent malignant neoplasia (e.g. endometrial cancer)
• Endometrial hyperplasia
• Known, suspected, or past history of breast cancer
• Undiagnosed abnormal genital bleeding
• Known or suspected pregnancy or lactation
• Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease)
• Active or past history of confirmed venous thromboembolism (such as deep vein thrombosis or pulmonary embolism) or active thrombophlebitis
• A high risk of venous or arterial thrombosis, including known thrombophilic disorders
• Partial or complete loss of vision due to ophthalmic vascular disease
• Presence or history of liver tumours (benign or malignant)
• Ongoing use of estrogen containing contraception (oral birth control pill, vaginal ring, patches, depo injections)