Emerging Molecular Targets for Bioactive Molecules in Contraception and Gynecological Disorders: Pharmacological and Translational Perspective

Abstract

Contraception and gynecological disorders are major areas of unmet therapeutic need in reproductive medicine. Although hormonal contraceptives and conventional pharmacological treatments have improved reproductive health significantly, due to adverse effects, contraindications, adherence, recurrence and effects on fertility, it has been necessary to search for more targeted molecular treatments. Recent research in reproductive biology has identified molecular targets in gamete interaction, sperm motility, steroidogenesis, ovulation, endometrial receptivity, inflammation, angiogenesis, cellular proliferation, apoptosis and metabolic regulation. In contraception, sperm-specific proteins and ion channels such as epididymal protease inhibitor (EPPIN), calcium channel of sperm (CatSper), soluble adenylyl cyclase, sperm-specific sodium/hydrogen exchanger and retinoic acid receptor alpha are emerging as promising targets for non-hormonal approaches.

These pathways will allow for new bioactive molecules to be developed which have higher specificity and less systemic toxicity.  At the female gamete level, zona pellucida protein 2 (ZP2) is one of the new targets for preventing sperm-oocyte interactions. In gynecology, estrogen and progesterone receptors, cyclooxygenase-2/prostaglandin pathways, NF-κB, PI3K/AKT, AMPK, TGF-β/SMAD, Wnt/β-catenin, VEGF and oxidative stress pathways are emerging as pharmacologically relevant targets. Natural bioactive molecules such as curcumin, resveratrol, quercetin, epigallocatechin gallate, berberine, ginsenosides, flavonoids and various others can interact with many of these pathways simultaneously. Most of the evidence is still preclinical and there are still challenges in terms of bioavailability, target selectivity, pharmacokinetics, reproductive safety, standardization and clinical validation. This review discusses emerging molecular targets for bioactive molecules in contraception and major gynecological disorders and is focused on molecular mechanisms, pharmacological opportunities and translational challenges. Multi-omics, molecular docking, artificial intelligence, targeted drug delivery and biomarker-based clinical development may enable the transition of promising bioactive molecules from experimental observations to clinically useful reproductive therapeutics.