Role of Estrogen on Skeletal Outcomes in FHA

The purpose of this study is to assess whether the natural form of estrogen (17-beta estradiol) given as a patch so that it is absorbed through your skin, is better at improving bone strength over 1 year than natural estrogen (17-beta estradiol) taken by mouth, or a synthetic form oestrogen (ethinyl estradiol) given as a patch that also provides birth control. Participants will: 1. Take estrogen for 1 year either (i) in its natural form as a patch twice a week (and progesterone by mouth for 12 days of each month), or (ii) in its natural form as a pill daily (and progesterone by mouth for 12 days of each month), or (iii) in a synthetic form as a birth control patch weekly for 3 weeks with 1 week off the patch. You will not be able to choose which form of estrogen you will receive as this will be assigned to you based on a pre-existing randomization sequence (like the flip of a coin) 2. Take provided calcium and vitamin D supplements 3. Attend 4 study visits over 12 months with two at the beginning and then every 6 months that include: * History and Physical Exams * Lab Work * Imaging studies * Questionnaires * Dietary recalls

Low bone mass is a major co-morbid complication of functional hypothalamic amenorrhea (FHA) in adolescents and young adult women, including those with anorexia nervosa (AN) and exercise-induced amenorrhea (EIA), and the prevalence of fractures is markedly higher than in normal-weight controls (43% in EIA, 38% in AN vs. 22% in controls).1 Adolescence and young adulthood are a critical time for bone accrual. Peak bone mass, a major determinant of bone mineral density (BMD) and fracture risk in adult life, is established between 20-25 years of age in women. Insults to bone accrual during the adolescent and young adult years could result in permanent bone mass deficits, leading to increases in fracture risk. Despite weight regain and menses recovery in some individuals, BMD remains lower than in normal-weight peers, likely because weight recovery is often partial, relapses are common, and not all hormonal alterations contributing to low BMD in FHA completely normalize.2, 3 Thus, additional intervention is necessary to optimize skeletal health. While many factors contribute to impaired skeletal health in FHA, a key contributor is the associated hypogonadism. Estrogen has anti-resorptive effects on bone through increases in osteoprotegerin and decreases in RANKL and inflammatory cytokines, and bone anabolic effects through inhibition of sclerostin. Yet, estrogen administration as the oral combined estrogen-progestin contraceptive pill is not effective in improving skeletal health4-6 because of hepatic first pass effects resulting in reduction in IGF-1 (a key bone trophic hormone, particularly during adolescence), and increases in SHBG (binding protein of the sex steroids), with a reduction in bioavailable estrogen.6, 7 In contrast, Investigators have demonstrated that transdermal physiologic 17β-estradiol replacement (17β-E2) (with cyclic progestin), which bypasses hepatic first pass metabolism and does not decrease IGF-1 or increase SHBG, increases bone accrual in adolescents and young adults with AN8 and EIA,6 resulting in its incorporation into Endocrine Society Guidelines for FHA management9. However, transdermal 17β-E2 (with cyclic progesterone) does not have contraceptive efficacy and is not suitable for sexually active young women, unless administered with another mode of contraception (e.g. a progestin releasing IUD), and not always desirable to young women, leading to reduced uptake. The transdermal contraceptive patch containing a non-physiologic form of estrogen (ethinyl estradiol, EE) with a progestin (levonorgestrel, LNG) offers a systemic route of estrogen administration with avoidance of hepatic first pass metabolism. However, it is not known whether this patch is effective in improving skeletal health in FHA. Limited available data suggest otherwise,10 possibly because of an increase in SHBG with EE, despite transdermal administration.11-13 Further, many women prefer an oral pill because of skin irritation with the patch, cosmetic iss trial.show_full_description

Inclusion Criteria: * Females, age 14-30 years, skeletally mature with bone age ≥ 14 years (only 2% of growth left) * Women of reproductive age: use of an effective non-hormonal contraceptive method or a progestin releasing intrauterine device (no systemic skeletal effects) for study duration if sexually active. Note: Women who receive a progestin implant for contraception after study enrollment will be allowed to continue and will not be excluded from study. * Biochemical criteria: negative βHCG (pregnancy test), TSH within 2x the upper limit of normal, prolactin \<10 ng/mL above upper limit of normal, potassium between 3.0-5.0, ALT ≤3 times upper limit of normal, LDL ≤190 mg/dl. * Patients with known hypothyroidism will be included if appropriately treated with levothyroxine and have a TSH within 2x the upper limit of normal for at least a month preceding the baseline study visit. * Menstrual criteria: \< 3 menses in the preceding 6 months. Exclusion Criteria: * Disease other than FHA known to affect bone, including untreated thyroid dysfunction, Cushing's disease, renal failure, diabetes mellitus 1. Primary thyroid dysfunction will be defined as a TSH level more than 2X the upper limit of normal per given reference range with unknown thyroid antibody status, or an abnormal TSH if known positive antibodies. 2. Patients with hypothyroidism will be excluded if not appropriately treated with levothyroxine and if they do not have a TSH level within 2X the upper limit of normal for at least a month preceding the baseline study visit, given possible effects on the reproductive axis and bone. * Use of other medications known to affect bone metabolism within 3 months of the study (other than calcium and vitamin D supplementation) * Substance use disorder; current smoker (\>10 cigarettes per day) * Pregnant, planning to become pregnant within 12 months of the end of treatment and/or breastfeeding * Hypertension or use of anti-hypertensive medications * Other conditions causing oligo-amenorrhea such as PCOS, premature ovarian insufficiency * Known sensitivity or absolute contraindication to any component of study medications (high risk thromboembolic disease, breast cancer or other estrogen- or progestin-sensitive cancer, liver tumors, acute viral hepatitis, decompensated cirrhosis, undiagnosed abnormal uterine bleeding * BMI ≥ 25 kg/m2 (efficacy of the contraceptive patch being used in the study is lower at higher BMIs)