Processes, interventions and comparisons
The investigational treatment is micronized progesterone (Utrogestan®), in capsules of 100 mg. Progesterone is combined with and analyzed versus pre-defined doses of estradiol: In a 2 × 3 factorial design, the participants are randomized into six groups of 15 participants each, i.e. 90 in total (groups A-F). The intervention takes 12 months. Group A continues to receive the dose of estradiol at baseline and serves as the control group, group B receives the baseline dose of estradiol and micronized progesterone 200 mg every night at bedtime, group C receives the baseline dose of estradiol and micronized progesterone 400 mg every night at bedtime, group D receives twice the baseline dose of estradiol, group E receives the baseline dose of estradiol and micronized progesterone 200 mg every night at bedtime, group F receives twice the baseline dose of estradiol and micronized progesterone 400 mg every night at bedtime (Fig. 
Study set-up. (The established feminizing hormone therapy for transgender women after vaginoplasty or orchiectomy consists of estradiol, prescribed as tablets, patches, gel or spray. The baseline dose of estradiol (groups A, B, C) is defined as oral estradiol valerate (Progynova®), or estradiol hemihydrate tablets (generic, Estradiol Sandoz®, Estrofem®, Zumenon®), or transdermal estradiol patches (Systen®, Sandoz®), estradiol gel (Oestrogel®) or spray (Lenzetto®) resulting in serum estradiol concentrations of 200–400 pmol/L, which are the current local reference ranges. Twice the baseline dose of estradiol (groups D, E, F) is defined as doubling of the estradiol dose of the participant at study entry in order to achieve and maintain serum estradiol concentrations of 400–800 pmol/L. These higher concentrations can be considered safe as these are within the reference ranges stated in the international guideline for hormone treatment of gender dysphoria [Two doses of micronized progesterone are tested in order to investigate a potential dose-response effect. If a dose-response relation is established, this would support a biological effect of the treatment. The duration of the study will be approximately three years in total and will include 12 months of patient follow-up after the start of the intervention (Fig. 
Spirit figure of the trial