Progesterone in recurrent pregnancy loss: from controversial efficacy to mechanism-based patient stratification

Progesterone supplementation has long been a controversial therapeutic intervention for recurrent pregnancy loss (RPL). Previous randomized controlled trials have yielded conflicting results, largely due to a "one-size-fits-all" approach that treats RPL as a homogeneous disease. From a pharmacological standpoint, this highlights the key challenge of patient heterogeneity in drug response. This review re-evaluates the role of progesterone by examining its different molecular mechanisms of action, including genomic and non-genomic signaling, immunomodulation (e.g., Treg cell induction, uterine natural killer cell regulation), and the modulation of endometrial receptivity. We then characterize the molecular heterogeneity of RPL, defining putative subtypes such as the "immune-dysregulated," "receptivity-defective," and "endocrine-insufficient" phenotypes. Crucially, we contend that the efficacy of progesterone is tightly linked to these specific pathological mechanisms. Finally, we propose a precision pharmacology framework that advocates for the use of mechanism-based biomarkers, such as endometrial transcriptomic signatures and immune cell profiles, to identify patient subgroups most likely to benefit from progesterone therapy. This paradigm shift from empirical supplementation to biomarker-guided prescription not only holds the potential to resolve long-standing controversies, but also paves the way for more effective, personalized pharmacotherapeutic strategies in RPL.