Role of Estrogen Formulation and Route of Delivery on Skeletal Outcomes in Functional Hypothalmic Amenorrhea

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 issues, and difficulty remembering to change the patch once or twice a week vs. taking a pill daily. While combined oral contraceptive pills containing EE are not effective in improving bone outcomes, it is not clear whether oral 17β-E2 (a physiologic form of estrogen) could be as effective as transdermal 17β-E2 despite hepatic first pass metabolism. Importantly, oral and transdermal 17β-E2 are often used interchangeably in other hypogonadal states,14 despite some evidence that oral 17β-E2 suppresses IGF-1 and increases SHBG.15, 16 The investigators thus propose a randomized controlled trial (RCT) of 2 mg oral 17β-E2 (with cyclic progesterone) vs. 100 mcg transdermal 17β-E2 (with cyclic progesterone) vs. 30 mcg transdermal EE (with LNG) in young women 14-25 years old with FHA (who are in the process of accruing peak bone mass) to determine whether transdermal 17β-E2 is more effective than oral 17β-E2 or transdermal EE in improving bone outcomes, or whether one or both of the latter two modes of estrogen administration are equivalent to transdermal 17β-E2 in this context. Results from this study could markedly impact clinical management of young women with FHA and potentially allow for alternative forms of estrogen administration in those with FHA.

Aim 1: To characterize the impact of transdermal 17β-E2 (with cyclic progesterone) vs. oral 17β-E2 (with cyclic progesterone) and transdermal EE (with LNG) on bone geometry, structure, density and strength in young women 14-25 years old with functional hypothalamic amenorrhea. Investigators hypothesize that transdermal 17β-E2 will be superior to oral 17β-E2 and transdermal EE in achieving optimal improvement in:

Hypothesis 1A: Areal BMD at the spine, hip and femoral neck; spine trabecular bone score (DXA)