Assessment of Endometrial Thickness Among Adolescent and Young Adult Patients on Estrogen Replacement Therapy Using Continuous Oral Micronized Progesterone Versus the Etonogestrel Implant: a Prospective Pilot Study

Study Design and Research Methods This study is a prospective, observational pilot study to assess the acceptability of study procedures and describe initial trends in our outcomes of interest, including endometrial stripe thickness among patients on estrogen replacement therapy after six months of either continuous oral micronized progesterone or etonogestrel implant. Participants will self-select into one of two study arms: (1) oral micronized progesterone (Prometrium), 100mg daily; or (2) etonogestrel implant (Nexplanon).

Recruitment and Enrollment Providers will identify eligible patients at routine appointments in the Children's Hospital Colorado Pediatric and Adolescent Gynecology Clinics, Endocrine Clinic, Oncofertility Clinic, and Multidisciplinary Turner Syndrome Clinic. Providers will briefly discuss the study to assess patient interest and, if the patient expresses interest, patients will be approached by a member of the study team for potential study enrollment. A member of the study team will provide an in-depth explanation of the study, answer any questions, and review the informed consent form.

If a patient decides to participate in the study, they or their legal guardian will provide a digital signature on the eConsent form (and eAssent form for participants aged 12-17). If participants would like a copy of the eConsent form, a signed copy will be emailed to the address they provide. The original consent will be stored in the secure, password protected REDCap database.

Feasibility and Timeline We will be enrolling from the following Children's Hospital Colorado-affiliated clinics: Pediatric and Adolescent Gynecology Clinic, Endocrine Clinic, Oncofertility Clinic, and Multidisciplinary Turner's Clinic. Each of these clinics routinely treats pediatric and adolescent patients requiring hormone replacement therapy. We anticipate meeting enrollment goals within one year. In a review of ICD codes for primary ovarian failure, 313 patients presented to CHCO from October 1, 2022 to October 1, 2023. Of these patients, 87 were under the age of 25 and received prescriptions for estradiol. We anticipate a 15% enrollment rate (3-4 patients per month) which translates to an 11-to-12-month enrollment period. We also anticipate that recruitment in the oral progesterone arm will be significantly higher compared to the etonogestrel implant group (~7:1) based on clinical experience. Thus, we anticipate that recruitment may take longer in this group but will not have an enrollment timing estimate until enrollment begins. The recruitment timing of this pilot study will help inform the timeline and feasibility of a full study in the future.

Due to lack of existing literature, we do not know the optimal time to assess changes in endometrial thickness after hormone initiation in this exact study population. ACOG clinical consensus for endometrial hyperplasia is to perform histologic re-assessment of the endometrium 3-6 months after initiating progestin therapy for treatment.27 The initial clinical trials for the etonogestrel implant reference counseling patients that their bleeding pattern after 3-6 months of use will persist due to hormonal influence on the endometrium.24 Additionally, the only available study on the effect of desogstrel (the precursor hormone to etonogestrel) on endometrial protection and menstruation normalization among reproductive aged women was a 6 month randomized control trial. 25 Thus, by extrapolating this available data we will plan on a 6 month study timeline to allow enough time for endometrial changes to occur before performing a repeat ultrasound.