Rethinking first-line progestin use in endometriosis: a comparative therapeutic review and future-ready drug delivery perspective

Endometriosis is a chronic, relapsing inflammatory disease requiring sustained hormonal suppression, yet first-line management remains dominated by daily oral progestins designed for short-acting use. Although pharmacologically effective, long-term outcomes are frequently compromised by fluctuating exposure, tolerability-driven discontinuation, and poor persistence. This narrative comparative review examines first-line progestins across efficacy, safety, tolerability, and persistence, alongside long-acting platforms including intrauterine systems, vaginal rings, implants, injectables, and emerging depots. Relevant clinical, pharmacokinetic, adherence, formulation, and preclinical evidence was identified through iterative literature searches. By synthesizing clinical, pharmacokinetic, and adherence evidence within a unified translational framework, we identify formulation-driven gaps that may influence exposure stability and therapeutic durability. The analysis distinguishes delivery-modifiable constraints from biological limitations such as progesterone resistance and disease heterogeneity, and outlines priorities for next-generation formulation development. Aligning delivery architecture with disease chronicity may offer a pragmatic, scalable, and clinically impactful pathway to strengthen established progestin therapies while complementing molecular innovation. Interpretation is limited by heterogeneity in study populations, endpoints, and treatment durations, and by limited endometriosis-specific clinical evidence for several emerging delivery platforms.