Work

The immunogenetic basis of ovarian apoptosis: from TNF-α polymorphisms and signaling pathways to glucocorticoid-mediated rescue

Year: 2026

Type: article

Abstract: The convergence of immunogenetics and reproductive endocrinology highlights Tumor Necrosis Factor-alpha (TNF-α) as a central mediator of ovarian physiology. This review explores how variations in the TNF gene promoter contribute to the contrasting clinical manifestations of Premature Ovarian Insufficiency (POI) and Polycystic Ovary Syndrome (PCOS). Specifically, we examine the TNF-α paradox: the phenomenon in which heightened inflammation drives rapid follicular depletion in POI, whereas the chronic inflammatory environment in PCOS is associated with extended ovarian reserve and delayed menopause.By synthesizing data across genetic epidemiology, molecular signaling, and pharmacology, we propose an integrated framework for ovarian immune regulation. Key promoter polymorphisms, particularly − 1031T/C (rs1799964) and − 308G/A (rs1800629), are highlighted as primary drivers of the local inflammatory baseline. The ultimate fate of a follicle is governed by the interplay between these genetic predispositions and the local ovarian microenvironment, specifically the dynamic between TNFR1/TNFR2 signaling and the inhibitory influence of anti-Müllerian Hormone (AMH).Furthermore, this paper delineates the intracellular mechanisms underlying TNF-driven anovulation, emphasizing ceramide-dependent apoptosis and the transcriptional silencing of the Steroidogenic Acute Regulatory (StAR) protein via JNK activation. Concluding with a comparative pharmacological analysis of glucocorticoids (including Dexamethasone, Betamethasone, Prednisolone, and Hydrocortisone), we outline a potential pathway for follicular rescue. This strategy hinges on targeted upregulation of DUSP1 (MKP-1) and SGK1, underscoring the potential for genotype-informed precision interventions to manage reproductive disorders.

Source: Journal of Ovarian Research

DOI: 10.1186/s13048-026-02112-y

Authors: Farzaneh Motafeghi, Parham Mortazavi, Nasrin Ghassemi Barghi