Dynamics of immune-endocrine crosstalk in human ovulation

Abstract

Ovulation is a highly coordinated physiological process initiated by the luteinizing hormone (LH) surge and accompanied by extensive transcriptional, biochemical, and structural remodeling of the preovulatory follicle. For decades, ovulation has been recognized as sharing features with localized inflammatory reactions, including leukocyte influx and accumulation, cytokine production, extracellular matrix (ECM) remodeling, and prostaglandin (PG) synthesis. Early human studies using follicular fluid analysis and granulosa cell culture demonstrated that multiple immune-associated mediators are present in the periovulatory follicle and can modulate steroidogenesis, PG production, and follicular remodeling, but these approaches were limited in their ability to define cellular sources. Recent advances in transcriptomic profiling, particularly single-cell RNA sequencing (scRNA-seq), have substantially refined this view by identifying heterogeneous leukocyte populations in human follicular aspirates, including distinct macrophage subsets, dendritic cells, natural killer cells, T and B lymphocytes, and neutrophils, each characterized by specific transcriptional profiles. These leukocytes express cytokines, chemokines, growth factors, angiogenic mediators, PG biosynthetic enzymes, and ECM-regulatory factors that overlap with mediators previously detected in periovulatory follicles or follicular fluid, thereby providing cellular context for earlier biochemical observations. This review integrates descriptive biochemical and functional studies with single-cell-based human data into a temporally resolved, cell-source-attributed model of immune-endocrine crosstalk during ovulation, clarifying which leukocyte populations produce which mediator, and when, and discuss how leukocyte-associated signals may contribute to ECM remodeling, cumulus expansion, granulosa cell differentiation, and luteinization. Although most mechanistic insights in humans derive from in vitro granulosa or granulosa-lutein cell models and association-based analyses of follicular fluid composition, the integration of descriptive biochemical studies with cell-specific transcriptomic profiling supports the concept that leukocytes are active participants in the human ovulatory process. Future research integrating time-resolved sampling, spatial transcriptomic mapping, and functional interrogation will be essential to define how immune-derived signals regulate in vivo human ovulatory process and their impacts on clinical reproductive outcomes.