Role of estrogen formulation and route of delivery on skeletal outcomes in functional hypothalamic amenorrhea

/ABSTRACT Low bone mass and fractures are a major complication of functional hypothalamic amenorrhea (FHA) in adolescents and young adult women, including those with anorexia nervosa (AN) and exercise-induced amenorrhea (EIA). Despite weight regain and menses recovery, bone mineral density (BMD) remains lower than in normal-weight controls, likely because weight recovery is often partial, relapses are common, and not all hormonal alterations contributing to low BMD completely normalize. Thus, additional intervention is necessary to optimize skeletal health. A key contributor to impaired bone health is hypoestrogenism. Yet, estrogen administration as the combined oral contraceptive (COC) pill (containing ethinyl estradiol (EE) and a progestin) is not effective in improving skeletal health because of hepatic first pass effects resulting in a reduction in IGF-1 (a key bone trophic hormone, particularly during the adolescent years of peak bone accrual), and an increase in SHBG (with a reduction in bioavailable estrogen). In contrast, transdermal physiologic 17β-estradiol (17β-E2) (with cyclic progesterone), which bypasses hepatic first pass metabolism and does not decrease IGF-1 or increase SHBG, increases bone accrual in both AN and EIA. However, transdermal 17β-E2 with cyclic progesterone does not have contraceptive efficacy, leading to reduced uptake. The transdermal contraceptive patch containing a non-physiologic form of estrogen (EE) with a progestin (levonorgestrel, LNG) offers a systemic route of estrogen administration with avoidance of hepatic first pass metabolism. However, limited available data suggest an increase in SHBG with EE, despite transdermal administration. 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 COC 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, despite evidence that oral 17β-E2 suppresses IGF-1 and increases SHBG. We propose a randomized controlled trial of 2 mg oral 17β-E2 (with cyclic progesterone) vs. 100 mcg transdermal 17β-E2 (with cyclic progesterone) vs. 30 mcg transdermal EE (with levonorgestrel) in young women 14-25 years old with FHA 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. We hypothesize that transdermal 17β-E2 will be superior to oral 17β-E2 and transdermal EE in achieving optimal improvement in bone geometry, structure, density and strength (Aim 1), because of reductions in IGF-1 with oral 17β-E2 and increases in SHBG with oral 17β-E2 and transdermal EE (Aim 2). Results could be paradigm shifting in the clinical management of young women with FHA and potentially allow for alternative forms of estrogen administration in those with FHA. Project Number: 1R01HD119174-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Madhusmita Misra | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $692,843 | Activity Code: R01 | Study Section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11917401