Phytoprogestins and Progesterone Receptor Modulation: A Systematic Review of Apigenin, Baicalein, Baicalin, Kaempferol, and Guggulsterone

Abstract

Plant-derived compounds with progesterone receptor (PR)-related activity (phytoprogestins) have been proposed as potential alternatives to endogenous progesterone; however, their pharmacological equivalence and clinical applicability remain uncertain. This systematic review aimed to evaluate how selected phytoprogestins, apigenin, baicalein and its glycoside baicalin, kaempferol, and guggulsterone, differ from natural progesterone in terms of receptor activity, safety profile, and pharmacokinetic characteristics, and to identify key translational barriers to their clinical development. A systematic search of ScienceDirect and PubMed up to May 2025 identified 374 and 63 records, respectively. Following screening and eligibility assessment in accordance with PRISMA guidelines, 22 studies were included for qualitative synthesis. Across direct PR-related assays and supporting preclinical models, the included studies demonstrated that phytoprogestins exhibit partial agonistic, antagonistic, or context-dependent PR modulation rather than full physiological activation and frequently interact with additional steroid or xenobiotic receptors. The included PR-related studies, considered alongside supporting pharmacokinetic and toxicological literature, indicated that flavonoid-based phytoprogestins have limited systemic exposure because of low oral bioavailability and extensive first-pass metabolism, while compound-specific endocrine, reproductive, and drug-interaction concerns remain. These findings indicate that phytoprogestins differ mechanistically and pharmacokinetically from endogenous progesterone and cannot be considered direct substitutes, and that further development would require formulation optimization and comprehensive endocrine safety evaluation.