This is a randomized, double blind, placebo-controlled study of the effects of transdermal estradiol versus placebo on cognitive flexibility, reward processing, and eating disorder pathology in hypoestrogenemic female adolescents and young adults (ages 14-35 years) with an eating disorder characterized by extreme dietary restriction and/or excessive exercise. Subjects will be randomized 1:1 to 12 weeks of transdermal estradiol with cyclic progesterone or placebo patches and cyclic placebo pills. Study visits include a screening visit to determine eligibility and visits at baseline, 8 weeks, and 12 weeks. Study procedures comprise behavioral, neuroimaging, and endocrine assessments.

Inclusion criteria:

• Female
• 14-35 years
• Bone age ≥13.5 years (applicable only for participants <16 years)
• Clinically significant eating disorder characterized by restriction and/or excessive exercise and high drive for thinness
• Hypoestrogenemia: Oligo-amenorrhea defined as lack of menses for ≥3 months within a 6-month period of oligomenorrhea (cycle length ≥5 weeks) or absence of menses at >15 years if premenarchal or low estradiol levels evaluated by the study physician
• Low or normal weight defined by a body mass index that is <85th percentile for 14-18 year olds and a body mass index <25 kg/m2 for adults

Exclusion criteria:

• Suicidal ideation where outpatient treatment is determined unsafe by study clinician
• Other causes of oligo-amenorrhea, unless a study clinician determines that missed menstrual periods are more likely a consequence of restrictive eating
• Medications that contain estrogen ± progesterone within the past 3 months
• Levonorgestrel-releasing intrauterine device if subject is unable to provide two to three weekly blood samples for estradiol of if estradiol levels are determined to be too high by study doctor
• Neurological or psychiatric disorders that may impact neural circuitry of interest
• Lifetime history of seizure disorder or electroconvulsive therapy
• Pregnancy/breastfeeding
• Gastrointestinal tract surgery
• Contraindications to estrogen use
• Any other significant illness or condition that the investigator determines could interfere with study participation or safety or put the subject at any unnecessary risk