Methodological considerations in the ADAPT-1 ovarian stimulation study

Methodological considerations in the ADAPT-1 ovarian stimulation studyDear Editors, We read with interest the article by Bernabeu et al. (2025) describing the ADAPT-1 trial comparing recombinant human folliclestimulating hormone (r-hFSH) delta with alfa.While the authors should be commended for adding clinical data on ovarian stimulation, several pharmacological and methodological issues temper the interpretation of its results.We outline considerations that are critical for readers. Lack of bioequivalence and unreliable IU-to-µg conversionAlthough follitropin delta and alfa share the same FSH DNA and amino acid sequence, their glycosylation profiles differ substantially: follitropin delta contains both α2,3-and α2,6-linked sialic acids and more tri-/tetra-antennary structures, whereas follitropin alfa has only α2,3-linked sialic acids (Håkan and Grundemar, 2014).These glycosylation differences are not minor; they alter pharmacokinetics and receptor interactions, leading to higher exposure (AUC) and reduced clearance for follitropin delta in preclinical models (Arce et al., 2014;Monica et al., 2023), and are expected to influence both bioassay readouts and clinical efficacy in humans.Precisely because the rat Steelman-Pohley bioassay underestimates follitropin delta activity in humans, the follitropin delta SmPC (Summary of Product Characteristics) mandates dosing in micrograms and explicitly states that this mass-based dose cannot be extrapolated to other gonadotropins (SmPC, 2021).Despite this, the ADAPT-1 trial assumed a conversion factor of 15 µg � 225 IU as a working approximation.However, this empiric factor is not scientifically justified as a general equivalence metric, does not establish bioequivalence between follitropin delta and alfa, and cannot be validly used across different dosing regimens or patient populations (Bernabeu et al., 2025).