The Immuno-Endocrine Feedback Loop for Endometrial Decidualization in Endometriosis

The intricate dialogue between endocrine signaling and immune-inflammatory homeostasis at the maternal-fetal interface remains one of the most complex frontiers in reproductive biology. In the recent review titled “Hormonal imbalance-mediated immune inflammation in endometrial decidualization disorder,” Yu et al., provide a masterly synthesis of how the disruption of this dialogue underpins the pathophysiology of endometriosis-associated infertility [1]. By moving beyond a reductionist view of hormonal deficiency, the authors delineate a self-perpetuating cycle where estrogen dominance and progesterone resistance act as both the drivers and the consequence of a chronic inflammatory state.

At the molecular core of this disorder lies a profound breakdown in homeostatic feedback loops. The authors highlight the critical role of the Estrogen-Prostaglandin E2 (PGE2) axis, where the local hyperestrogenism stimulates COX-2 expression, leading to elevated PGE2 levels [2]. This, in turn, acts as a potent stimulus for aromatase activity, further escalating local estrogen production. This feedforward mechanism is not merely an endocrine aberration; it is a primary driver of immune reprogramming. Through the activation of the NF-κB signaling pathway, this environment facilitates the transcriptional silencing of the progesterone receptor B (PR-B) isoform, effectively rendering the endometrium “blind” to the pro-gestational signals required for decidual transformation [3].

The immunological consequences of this hormonal landscape are equally significant. Yu et al., describe a shift in the endometrial microenvironment from receptive tolerance to inflammatory activation. The review synthesize evidence on how the failure of progesterone signaling—compounded by estrogen excess—shifts the maternal-fetal interface toward a pro-inflammatory state. This is characterized by the dominance of M1 macrophages over M2, a Th1-biased helper T-cell response, and the accumulation of cytotoxic uterine Natural Killer cells. These shifts collectively disrupted the immune tolerance required for successful decidualization, providing a clear explanation for why standard assisted reproductive technologies often come out with lower success rates in patients with severe endometriosis [4].

From a clinical perspective, this synthesis offers a compelling rationale for multi- modal therapeutic strategies. The authors identify promising strategies such as the use of Dienogest —not merely as a hormonal suppressant, but as a dual-action agent that restores the PR-B/PR-α ratio while inhibiting aromatase-mediated inflammation [5]. Furthermore, the discussion of emerging technologies, specifically single-cell RNA sequencing and endometrial organoids, signals a transition toward precision medicine. These tools allow for the mapping of individual immune and hormonal signatures, potentially dictating personalized fertility treatments in the future [6].

In summary, Yu et al., have successfully framed endometriosis-associated infertility as a systemic failure of the immuno-endocrine dialogue. By integrating the disparate threads of endocrinology, immunology, and molecular biology into a unified narrative, this work provides a vital framework for understanding the “endometrial factor.” This review stands as an essential resource for researchers and clinicians seeking to translate complex molecular interactions into improved reproductive outcomes.

1. Yu J, Qin R, Huang P, Hang F, Guo Y, et al. (2025) Hormonal imbalance-mediated immune inflammation in endometrial decidualization disorder.
2. Ota H, Igarashi S, Sasaki M, Tanaka T (2001) Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis. Hum Reprod 16: 561-566.
3. Zhao W, Wang Y, Liu J, Yang Q, Zhang S, et al. (2023) Progesterone Activates the Histone Lactylation-Hif1α-glycolysis Feedback Loop to Promote Decidualization. Endocrinology 165: bqad169.
4. Önalan G, Tohma YA, Zeynelo?lu HB (2018) Effect of etanercept on the success of assisted reproductive technology in patients with endometrioma. Gynecol Obstet Invest 83: 358-364.
5. Wang C, Zhao M, Zhang WQ, Huang MY, Zhu C, et al. (2020) Comparative analysis of mouse decidualization models at the molecular level. Genes (Basel) 11: 935.
6. Liu S, Li X, Gu Z, Wu J, Jia S, et al. (2025) Single-cell and spatial transcriptomic profiling revealed niche interactions sustaining growth of endometriotic lesions. Cell Genom 5: 100737.