ABSTRACT Heavy menstrual bleeding (HMB) is common among adolescents and young adults with a heritable bleeding disorder (BD) and negatively impacts health-related quality of life and physical and mental health status. Effective treatment options are available that decrease bleeding and improve quality of life, but were not studied in those with BD, so we do not know if there is similar effectiveness in this condition. We also do not know the impact of treatment on diagnostic testing for BD or on improvement of iron deficiency. Given these gaps in knowledge, the primary objective of the Heavy Menstrual Bleeding Progestin Treatment in Bleeding Disorders Study is to conduct a multicenter prospective pragmatic trial, enrolling adolescents and young adults with HMB cared for at collaborating multi-disciplinary menstrual clinic sites nationally who are choosing to initiate hormonal menstrual suppression with a progestin treatment option (N=300). In Aim 1, we will compare outcomes related to (a) bleeding management, (b) quality of life, and (c) repletion of iron storage levels after six months of treatment with either 52 mg levonorgestrel-releasing intrauterine system (LNG-IUD) or oral norethindrone acetate 5 mg daily (NETA) in those with a diagnosed heritable BD. The primary outcome will be treatment success with a Pictorial Blood Loss Assessment Chart (PBAC) score <50 points by six months. Secondary objectives to assess bleeding management will include change in PBAC from baseline to 6 months, and self-reported treatment success. Quality of life outcomes will include change in validated scales (aMBQ, PROMIS-25, PROMIS-29) to assess health-related quality of life which are specific to adolescents and young adults in the setting of HMB. We will compare the change in ferritin levels at six months from baseline to determine the relative amount of benefit obtained from either treatment option. In Aim 2, we will compare outcomes after LNG-IUD in those with and without a BD, assessing rates of expulsion and method continuation between the two groups in addition to the outcomes assessed for Aim 1. In Aim 3, we will improve our understanding of the impact of HMB and iron deficiency on von Willebrand disease (VWD) diagnostic studies by comparing change in von Willebrand factor levels before and after successful treatment in those with HMB without a previous diagnosis of VWD, aiding our understanding of diagnostic parameters. Despite significant safety records, concerns about the use of hormonal medications in youth grow among U.S. families and providers. We must measure the therapeutic impact of treatment – not just on bleeding, but also on quality of life and health. This study will demonstrate the relative benefits of menstrual suppression treatment options for adolescents and young adults with HMB and heritable BDs, will provide population-specific estimates for expected benefit that can be used in treatment counseling, and will highlight the impact of treat...