GREB1 as a Context-Dependent Molecular Switch in Endometrial Estrogen–Progesterone Crosstalk: From Physiological Receptivity to Endometriosis Pathogenesis—A Narrative Review

In this narrative review, we summarize current evidence regarding the endometrium undergoes cyclic remodeling driven by estrogen (E2) and progesterone (P4) signaling, with precise coordination essential for receptivity and pregnancy establishment. GREB1, initially identified as an estrogen-responsive co-activator in breast cancer, plays a pivotal, context-dependent role in endometrial biology. In normal physiology, GREB1 predominantly supports progesterone signaling: it is directly induced by progesterone receptor (PR) and functions as a critical co-activator that reinforces PR-dependent transcription, enabling stromal decidualization, implantation window formation, and receptivity. Genetic deletion or silencing of GREB1 selectively impairs progesterone-driven responses while largely sparing estrogen-mediated proliferation. In pathological conditions such as endometriosis, the regulatory balance shifts dramatically. Estrogen dominance and progesterone resistance redirect GREB1 toward an ERα-centered feedforward loop, amplifying proliferative, invasive, and angiogenic gene programs that promote lesion persistence and progression. This bidirectional feedforward mechanism with steroid receptors explains GREB1’s opposing roles in health and disease. The findings position GREB1 as a promising biomarker of tissue-level progesterone responsiveness in infertility and as a selective therapeutic target for estrogen-driven endometrial disorders, potentially allowing disruption of pathological amplification while preserving physiological function. As a narrative review, this article synthesizes current knowledge while highlighting areas requiring further systematic investigation.

GREB1, endometrium, progesterone receptor, estrogen receptor, feedforward loop, decidualization, endometrial receptivity, endometriosis, progesterone resistance, steroid hormone co-regulator, implantation failure, context-dependent regulation

At first glance, the endometrium appears to be a transient tissue—built, shed, and rebuilt in a matter of weeks. In reality, it operates as a highly disciplined system, one that must synchronize cellular proliferation, differentiation, immune tolerance, and vascular remodeling with remarkable precision.1 This orchestration depends largely on the shifting balance between estrogen (E2) and progesterone (P4). During the proliferative phase of the menstrual cycle, estrogen promotes expansion of epithelial and stromal compartments, effectively preparing the structural groundwork.2 As the cycle progresses, progesterone assumes control, driving stromal decidualization, opening the window of implantation, and sustaining the early stages of pregnancy.3 When this hormonal dialogue falters, the consequences are often clinically visible—unexplained infertility, recurrent implantation failure (RIF), thin endometrium, endometriosis, and endometrial hyperplasia or carcinoma frequently share this common denominator.4 For decades, research in this field has been guided by a relatively straightforward framework: estrogen signals through estrogen receptor α (ERα/ESR1), progesterone through the progesterone receptor (PR/PGR), and downstream transcriptional programs follow accordingly.5 ERα activates classic proliferation-associated genes such as c-MYC and CCND1, whereas PR governs decidualization markers including PRL, IGFBP1, and HOXA10.6 While this model has been indispensable, it has become increasingly clear that receptor-centric explanations alone are insufficient. Hormonal signals rarely act in isolation, and their biological impact depends heavily on intermediary factors that fine-tune signal strength, duration, and context. Among these intermediaries, steroid hormone receptor co-regulators have emerged as critical signal integrators. One such molecule, Growth Regulation by Estrogen in Breast Cancer 1 (GREB1), has attracted growing attention. Initially identified in estrogen receptor–positive breast cancer as a direct transcriptional target and potent co-activator of ERα, GREB1 was shown to recruit p300/CBP and p160 family members, enabling large-scale estrogen-responsive transcription. Subsequent work expanded its relevance beyond oncology, revealing a substantial role in endometrial biology.7 In the endometrium, GREB1 occupies an unexpectedly nuanced position. It responds not only to estrogen but also directly to progesterone signaling, and it proves indispensable for progesterone-driven decidualization of human endometrial stromal cells.6 Silencing or genetic deletion of GREB1 markedly disrupts progesterone responsiveness, yet leaves estrogen-induced epithelial proliferation largely intact. This asymmetry suggests that, under physiological conditions, GREB1 preferentially serves the progesterone axis rather than acting as a generic estrogen amplifier.8 Paradoxically, the situation appears reversed in pathological settings. In endometriosis, GREB1 expression is frequently elevated and closely associated with estrogen-dependent proliferation and invasiveness of ectopic lesions.9 The same molecule that supports endometrial receptivity in health seems to fuel disease progression when hormonal balance collapses. How can a single co-regulator exert such opposing effects?8 A pivotal study published in 2024 in Nature Communications offers a compelling hypothesis to explain this paradox. Based primarily on murine models and a limited cohort of human endometrial samples (n=9 proliferative vs n=9 secretory phase specimens), the authors propose that GREB1 participates in a shared feedforward loop with steroid hormone receptors, forming self-reinforcing circuits with either ERα or PR. Crucially, the direction of this loop is not fixed. In hormonally balanced, receptive endometrium, progesterone induces GREB1, which then acts as a PR co-activator, selectively amplifying progesterone-dependent transcription. In contrast, in estrogen-dominant, progesterone-resistant environments—such as endometriotic lesions—the progesterone–GREB1 circuit collapses, while an estrogen–GREB1–ERα loop becomes dominant, reinforcing proliferative signaling.8 This context-dependent switching behavior positions GREB1 as more than a passive co-factor; it functions as a molecular decision point within endometrial hormone signaling. In this review, we outline the fundamental biological properties of GREB1, examine its progesterone-oriented role in normal endometrial physiology, and explore its estrogen-driven pathogenic functions in disorders such as endometriosis.10 By integrating recent high-impact evidence, we aim to clarify how GREB1 operates as a context-sensitive switch in estrogen–progesterone crosstalk and to consider its potential as a biomarker and therapeutic target in infertility and endometrial disease.11 To construct this narrative review, a comprehensive literature search was conducted using databases including PubMed, Web of Science, and Scopus. Search terms included combinations of “GREB1”, “endometrium”, “estrogen receptor”, “progesterone receptor”, “decidualization”, and “endometriosis”. The review primarily synthesizes literature published over the last two decades, with a specific focus on high-impact molecular, transgenic, and clinical studies that elucidate the mechanistic roles of GREB1 in reproductive biology. Fundamental Biological Characteristics and Regulatory Patterns of GREB1 The GREB1 gene is located on human chromosome 2p25.1 and spans approximately 108 kb, comprising 33 exons.12 It encodes a large protein of roughly 1962 amino acids.13 Although a closely related homolog, GREB1L, exists, the two proteins differ substantially in expression patterns and functional roles, indicating limited redundancy.13 Structurally, GREB1 displays a complex domain organization. The most functionally critical region lies within the C-terminal portion of the protein, encompassing the so-called GREB1_2nd domain (approximately amino acids 1500–1800).14 This region adopts an α/β folding architecture and is highly conserved across species, strongly implying an essential role in protein–protein interactions and chromatin-associated functions. Frameshift or truncating mutations affecting this domain often result in loss of function, underscoring its biological importance. In addition, GREB1 contains multiple putative phosphorylation sites and a nuclear localization signal, consistent with its predominant activity as a nuclear transcriptional regulator.15 GREB1 was originally characterized as a classic estrogen-responsive gene. In estrogen receptor–positive cells, E2 stimulation rapidly induces ERα binding to estrogen response elements within GREB1 regulatory regions.6 Chromatin immunoprecipitation sequencing (ChIP-seq) studies reveal that ERα primarily occupies enhancer elements associated with GREB1, accompanied by enrichment of active histone marks such as H3K27ac and recruitment of transcriptional initiation complexes. GREB1 mRNA and protein levels typically rise within hours of estrogen exposure, often increasing by an order of magnitude.16 This regulatory pattern has been extensively validated in breast cancer cell lines and later confirmed in other estrogen-responsive tissues, including the endometrium. What became apparent only later is that GREB1 is not exclusive to estrogen signaling. In 2017, a seminal study demonstrated that progesterone also directly regulates GREB1 expression.6 Using an in vitro decidualization model of human endometrial stromal cells, investigators showed that progesterone treatment robustly increased GREB1 transcript and protein levels.8 Disrupting GREB1 expression blocked the induction of hallmark decidualization genes, establishing GREB1 as a functional component of the progesterone response.17 This finding was reinforced by subsequent PR ChIP-seq analyses, which identified bona fide progesterone response elements within the GREB1 promoter.16 In vivo, Greb1 knockout mice exhibit profound defects in progesterone-driven endometrial remodeling, while estrogen-induced epithelial proliferation remains largely preserved—an observation that strongly supports a preferential role for GREB1 in the progesterone pathway under physiological conditions.8 Beyond serving as a hormone-responsive gene, GREB1 actively participates in transcriptional regulation as a co-activator. Biochemical and proteomic studies show that GREB1 physically associates with ERα or PR, enhancing receptor occupancy at chromatin and facilitating recruitment of co-activator complexes, including p300/CBP and p160 family members (NCOA1/SRC-1, NCOA2/GRIP1, NCOA3/AIB1).18 Through these interactions, GREB1 promotes chromatin relaxation and RNA polymerase II engagement, thereby amplifying hormone-dependent transcription. Notably, the C-terminal domain is essential for this co-activation function; mutations within this region markedly diminish GREB1 activity.14 In the endometrial context, GREB1-associated transcriptional programs encompass a broad spectrum of biological processes, including cell-cycle regulation, apoptosis, and key signaling pathways such as WNT and LIF signaling. Estimates suggest that GREB1 contributes to the regulation of nearly half of hormone-responsive genes in certain cellular settings, highlighting its capacity to shape global transcriptional output rather than modulating isolated targets.6 Taken together, GREB1 occupies a unique position at the intersection of estrogen and progesterone signaling.16 It functions simultaneously as a direct transcriptional target and as a co-activator of both receptors, creating the structural basis for bidirectional and self-reinforcing regulatory loops. This dual identity confers exceptional flexibility, allowing GREB1 to selectively amplify estrogen or progesterone signals in response to the local hormonal milieu and cellular context. How this flexibility manifests in normal physiology and becomes distorted in disease forms the focus of the sections that follow19 (Figure 1). Role of GREB1 in Normal Endometrial Physiology—Predominantly Progesterone-Driven Across the menstrual cycle, the endometrium undergoes a sequence of tightly timed transformations that depend less on the presence of hormones than on their orderly succession.20 Estrogen expands the tissue, but progesterone defines its function. Within this framework, GREB1 emerges not as a general amplifier of steroid signaling, but as a molecule whose physiological relevance is strongly weighted toward the progesterone-dominated phase.21 Evidence for this bias first became apparent in cellular models of decidualization. In human endometrial stromal cells, progesterone exposure induces a rapid and sustained increase in GREB1 expression, closely paralleling the activation of classical decidual markers.6 When GREB1 expression is experimentally reduced, the decidual program falters: prolactin and IGFBP1 induction weakens, FOXO1 signaling becomes unstable, and stromal cells fail to complete the morphological transition from fibroblast-like precursors to polygonal decidual cells.22 These changes are not subtle. The extracellular matrix remains poorly remodeled, and the coordinated gene expression pattern that normally accompanies immune tolerance and vascular adaptation fails to materialize. In this setting, GREB1 behaves less like a peripheral modulator and more like a structural component of the progesterone response.23 Animal studies reinforce this interpretation. In wild-type mice, progesterone stimulation produces the expected constellation of uterine changes—stromal edema, angiogenic remodeling, and decidual transformation. In contrast, Greb1-deficient uteri respond weakly to progesterone, exhibiting reduced endometrial thickness, impaired stromal differentiation, and sharply diminished implantation rates. Notably, estrogen-driven epithelial proliferation remains largely intact in these animals. Ki67-positive epithelial cells expand normally under estrogen exposure, suggesting that GREB1 loss does not globally disrupt estrogen responsiveness in the uterus. This selective phenotype is difficult to reconcile with a model in which GREB1 functions primarily as an estrogen co-activator in normal endometrium.8 Transcriptomic profiling offers additional clarity. In the absence of GREB1, progesterone-responsive gene clusters—particularly those involved in receptivity and stromal–epithelial communication—are disproportionately affected.8 Genes such as WNT4, LIF, HOXA10, and BMP2 show marked downregulation, whereas many estrogen-regulated proliferative genes remain comparatively stable. The functional implications of this imbalance are intuitive: the tissue grows but fails to mature. Expansion occurs without the differentiation required for embryo acceptance.24 Furthermore, it is well established that ER and PR regulation of endometrial epithelial proliferation is not strictly cell-autonomous; rather, it is heavily dependent on paracrine signaling from the underlying stroma to the epithelia. While current evidence highlights GREB1’s role in direct transcriptional co-activation within stromal cells, its specific contribution to this vital stromal-epithelial crosstalk remains a critical knowledge gap. Understanding how GREB1-modulated stromal factors signal to the epithelial compartment is essential for a complete picture of its regulatory capacity, and future studies are needed to address this missing link. At the mechanistic level, this progesterone bias reflects the formation of a self-reinforcing regulatory circuit. Progesterone activates PR, predominantly the PR-B isoform, which directly induces GREB1 transcription.8 Newly synthesized GREB1 then associates with PR on chromatin, enhancing receptor occupancy and stabilizing the recruitment of co-activator complexes such as p300/CBP and NCOA family members. This interaction promotes local chromatin accessibility and amplifies transcription of progesterone-dependent genes. The result is a positive feedforward loop that selectively strengthens progesterone signaling during the secretory phase, ensuring that decidualization proceeds with sufficient intensity and coherence.6 What is equally important is what GREB1 does not do under physiological conditions. Although GREB1 is capable of interacting with ERα, its contribution to estrogen-driven transcription in normal endometrium appears limited.25 GREB1 expression in the epithelial compartment is relatively low during the proliferative phase, and genetic deletion of Greb1 does not significantly alter estrogen-induced expression of canonical targets such as CCND1 or c-MYC. This suggests that additional layers of regulation—possibly involving receptor isoform balance, cell-type–specific chromatin landscapes, or local paracrine cues—restrict GREB1’s engagement with the estrogen pathway in healthy tissue.26 Clinical observations mirror these experimental findings. In women with thin endometrium or recurrent implantation failure, GREB1 expression in the mid-secretory phase is frequently reduced. This decrease correlates with impaired progesterone responsiveness and diminished expression of decidual markers, even when circulating hormone levels appear adequate.8 In rare cases involving loss-of-function GREB1 variants, the defect becomes strikingly evident: progesterone supplementation fails to rescue endometrial receptivity, and repeated assisted reproductive attempts yield poor outcomes. These cases underscore a practical point—progesterone signaling cannot be evaluated solely by hormone levels or receptor presence. Its downstream amplification machinery matters, and GREB1 appears to be a key component of that machinery.8,27 Taken together, the evidence supports a model in which GREB1 acts as a progesterone-biased regulator in normal endometrial physiology. By reinforcing PR-dependent transcription while exerting minimal influence on estrogen-driven proliferation, GREB1 helps maintain the delicate balance between growth and differentiation that defines a receptive endometrium.8 This physiological role provides a critical reference point. Only against this backdrop does the pathological redirection of GREB1 toward estrogen dominance, discussed in the next section, become fully intelligible.28 Pathological Redirection of GREB1: Estrogen-Driven Amplification in Endometrial Disease Pathological endometrial conditions rarely arise from the appearance of entirely new signaling pathways.29 More often, they reflect the misappropriation of physiological mechanisms that normally operate under strict contextual control. The behavior of GREB1 in endometriosis exemplifies this principle. A co-regulator that supports progesterone-dependent differentiation in healthy endometrium becomes, under altered hormonal and inflammatory conditions, an amplifier of estrogen-driven pathology.30 Endometriosis is characterized by a distinctive local environment: estrogen levels are persistently elevated, progesterone responsiveness is blunted, and inflammatory signaling remains chronically active.31 Within this milieu, GREB1 expression is consistently increased in ectopic lesions compared with eutopic endometrium. For instance, immunohistochemical evaluations have demonstrated significantly stronger GREB1 nuclear staining in endometriotic epithelial cells compared to healthy secretory endometrium (eg, n=9 proliferative vs n=9 secretory phase specimens in recent profiling). Early histological and transcriptional studies already hinted at this association, showing strong GREB1 staining in lesion epithelium and a positive correlation with estrogen-regulated proliferative genes.32 More recent single-cell analyses have refined this picture, revealing that GREB1 upregulation is particularly pronounced in epithelial-like populations within lesions, rather than in stromal compartments that dominate normal progesterone responses.33 Functional studies confirm that this elevation is not incidental. Reducing GREB1 expression in cultured endometriotic cells significantly suppresses proliferation, decreases Ki67 positivity, and attenuates invasive behavior.34 In animal models, genetic or experimental disruption of Greb1 leads to a marked reduction in ectopic lesion volume, despite preservation of estrogen responsiveness in the native uterine endometrium. These findings suggest that GREB1 selectively fuels pathological growth without being universally required for estrogen signaling across all tissues.35 Mechanistically, the pathogenic role of GREB1 in endometriosis reflects a reorientation of its feedforward circuitry. In estrogen-dominant settings, ERα strongly induces GREB1 transcription.36 The resulting increase in GREB1 protein promotes direct interaction with ERα on chromatin, enhancing receptor stability, co-activator recruitment, and transcriptional output at estrogen response elements. This establishes a self-reinforcing loop: estrogen activates ERα, ERα induces GREB1, and GREB1, in turn, amplifies ERα-driven transcription. Genes governing cell-cycle progression, angiogenesis, and survival—such as c-MYC, CCND1, and VEGFA—become sustained outputs of this loop, driving lesion persistence and expansion.37 Concurrently, the progesterone-associated arm of GREB1 regulation collapses. Progesterone resistance, a hallmark of endometriosis, limits PR function at multiple levels, including reduced PR-B expression, impaired chromatin binding, and antagonism by inflammatory signaling pathways.38 As PR activity wanes, the progesterone–GREB1 feedforward loop loses traction, effectively freeing GREB1 to engage almost exclusively with ERα. This shift does not require new molecular functions; rather, it represents a redistribution of an existing co-regulatory capacity toward the dominant hormonal signal.39 Several factors appear to reinforce this redirection. Local estrogen production within lesions, driven by aberrant aromatase expression, sustains ERα activation even in the absence of systemic estrogen surges.40 Pro-inflammatory cytokines such as IL-1β and TNF-α further suppress progesterone signaling while enhancing estrogen receptor activity through NF-κB–dependent mechanisms. Epigenetic alterations, including changes in histone acetylation and chromatin accessibility at the GREB1 locus, may bias transcriptional responsiveness toward estrogen response elements.41 Together, these influences create a permissive landscape in which the estrogen–GREB1–ERα loop becomes the default regulatory state. Importantly, this estrogen-oriented role of GREB1 is not unique to endometriosis. Similar patterns have been observed in adenomyosis, where GREB1 expression correlates with the depth of myometrial invasion, and in estrogen receptor–positive endometrial carcinoma, where GREB1 functions as a co-activator that supports tumor proliferation and progression.42 These parallels suggest that GREB1 acts as a context-sensitive amplifier of estrogen signaling across multiple endometrial pathologies, rather than as a disease-specific anomaly.43 From a conceptual standpoint, the pathological behavior of GREB1 underscores a broader theme in endocrine regulation: co-regulators do not inherently encode “good” or “bad” outcomes.44 Their impact depends on the signaling environment in which they operate. In healthy endometrium, GREB1 stabilizes progesterone-driven differentiation and receptivity. In estrogen-dominant, progesterone-resistant tissue, the same molecular machinery is repurposed to sustain pathological growth. Recognizing this duality is essential for interpreting experimental data and for considering GREB1 as a potential clinical target.45 This pathological redirection also provides a mechanistic bridge between seemingly disparate features of endometriosis—estrogen dependence, progesterone resistance, chronic inflammation, and lesion persistence. Rather than invoking separate pathways for each feature, GREB1-centered feedforward amplification offers a unifying explanation. How this switch is regulated at the molecular level, and how it might be selectively disrupted without impairing physiological endometrial function, becomes the focus of the next section.46 The GREB1–Steroid Receptor Feedforward Loop: Molecular Logic and Context Dependence The dual behavior of GREB1 in physiological and pathological settings does not arise from fundamentally different molecular functions, but from the way a single regulatory circuit is engaged under different conditions.47 At the center of this behavior lies a feedforward loop linking GREB1 with steroid hormone receptors—primarily estrogen receptor α (ERα) and progesterone receptor (PR).8 This loop, elucidated in detail by recent chromatin- and proteomics-based studies, operates as a self-reinforcing system whose direction and output are dictated by the surrounding hormonal and cellular context. At a mechanistic level, the architecture of the loop is straightforward. Hormone binding activates the receptor, which then occupies its cognate response elements in target gene regulatory regions, including the GREB1 locus. Transcriptional induction of GREB1 follows.8 Newly synthesized GREB1 protein subsequently associates with the activated receptor on chromatin, stabilizing receptor binding and facilitating recruitment of co-activator complexes such as p300/CBP and members of the p160/NCOA family.48 This cooperation promotes histone acetylation, chromatin relaxation, and efficient RNA polymerase II loading, thereby amplifying transcription of receptor target genes. Because GREB1 enhances the activity of the same receptor that induces its expression, the system functions as a closed, positive feedforward loop.49 What makes this loop biologically distinctive is not its structure, but its flexibility. GREB1 can engage with either ERα or PR using the same C-terminal interaction domain, yet the consequences of these interactions diverge sharply depending on which receptor dominates the regulatory landscape. In receptive endometrium, progesterone signaling prevails.50 PR—particularly the PR-B isoform—binds progesterone response elements within the GREB1 promoter, driving GREB1 expression. GREB1 then preferentially associates with PR, reinforcing progesterone-dependent transcriptional programs essential for stromal decidualization, angiogenesis, and immune modulation. In this context, the feedforward loop selectively amplifies differentiation rather than proliferation.51 In estrogen-dominant pathological states, the same molecular machinery is repurposed. Elevated estrogen levels drive robust ERα activation, which strongly induces GREB1 transcription. GREB1, in turn, interacts with ERα on chromatin, increasing receptor residence time and transcriptional output at estrogen-responsive loci. The resulting loop sustains expression of genes governing cell-cycle progression, survival, and tissue invasion. Importantly, this shift does not require new protein interactions or mutations in GREB1 itself. Instead, it reflects a change in receptor availability, activity, and chromatin accessibility that biases GREB1 toward one signaling partner over the other.16 Progesterone resistance plays a decisive role in this redirection. In endometriosis and related disorders, PR expression—particularly PR-B—is reduced, and PR chromatin binding is impaired.52 Inflammatory signaling further suppresses PR activity while indirectly enhancing ERα-driven transcription. Under these conditions, the progesterone–GREB1 arm of the loop weakens, leaving GREB1 functionally unopposed in its engagement with ERα. The loop does not switch because GREB1 “chooses” estrogen; it switches because progesterone signaling no longer competes effectively for GREB1’s co-activator capacity.53 Epigenetic regulation adds another layer of control. Chromatin accessibility at the GREB1 locus and at downstream target genes differs markedly between normal endometrium and pathological lesions.54 Histone acetylation patterns, DNA methylation status, and enhancer usage can all influence whether estrogen or progesterone response elements are preferentially engaged.55 These epigenetic features, shaped by hormonal history and inflammatory cues, likely determine how readily GREB1 transcription responds to one receptor versus the other.56 In this sense, the feedforward loop is not merely hormone-sensitive but epigenetically primed.57 Cell-type specificity further refines loop output. In normal endometrium, GREB1 expression and function are most pronounced in stromal cells during the secretory phase, aligning with progesterone-driven differentiation.58 In endometriotic lesions, GREB1 activity is concentrated in epithelial-like populations, where estrogen signaling predominates.59 The same co-regulator thus participates in distinct transcriptional programs depending on cellular identity, reinforcing the idea that context, rather than intrinsic molecular preference, governs GREB1 function.60 Compared with other steroid receptor co-regulators, GREB1 occupies an unusual position. Many co-activators modulate receptor output without themselves being receptor targets. GREB1, by contrast, is both induced by and required for maximal receptor activity, enabling the formation of self-reinforcing loops.61 This dual role grants GREB1 exceptional leverage within hormonal networks, but also makes its dysregulation particularly consequential. Once engaged, the loop can sustain signaling even in the face of fluctuating hormone levels, lending stability to physiological processes—and persistence to pathological ones.62 Understanding the GREB1–steroid receptor feedforward loop reframes how estrogen–progesterone crosstalk is conceptualized in the endometrium. Rather than a simple balance between two opposing hormones, the system relies on context-dependent amplification nodes that determine which signal gains dominance. GREB1 represents one such node. Its ability to toggle between progesterone- and estrogen-centered loops provides a coherent explanation for its protective role in normal physiology and its pathogenic influence in disease.63,64 This mechanistic insight also raises an important translational question: can the loop be selectively disrupted to suppress pathological estrogen amplification without undermining progesterone-dependent endometrial function? Addressing that question moves the discussion from mechanism toward clinical application, which we consider next.64 While this bidirectional feedforward model provides a unifying and elegant molecular logic, it is important to acknowledge the limitations of the current evidence base. The framework currently relies predominantly on a single foundational study and lacks independent replication, with its translational evidence restricted to small human sample sizes. Therefore, this mechanism is best understood as a well-supported and highly promising hypothesis rather than an established scientific consensus, highlighting an urgent need for extensive validation in larger clinical cohorts. Clinical Implications: Biomarker Potential and Therapeutic Opportunities Translating molecular insight into clinical utility often depends on whether a mechanism clarifies real diagnostic uncertainty or opens a plausible therapeutic window. In this regard, GREB1 occupies a particularly promising position. Its role as a context-dependent amplifier of steroid hormone signaling links molecular regulation directly to two central clinical problems in reproductive medicine: impaired endometrial receptivity and estrogen-driven endometrial disease.65 From a diagnostic perspective, GREB1 offers information that conventional hormone measurements cannot capture.66 Serum estrogen and progesterone levels frequently appear normal in patients with recurrent implantation failure or thin endometrium, yet tissue responsiveness remains inadequate. GREB1 expression, by contrast, reflects the functional integrity of downstream progesterone signaling. In mid-secretory endometrium, reduced GREB1 levels consistently associate with blunted decidualization marker expression and impaired receptivity.67 This pattern suggests that GREB1 could serve as a molecular readout of progesterone sensitivity rather than hormone availability—a distinction of practical importance in assisted reproductive settings.68 Spatial expression patterns may be as informative as absolute levels. In healthy endometrium, GREB1 activity concentrates within stromal compartments during the window of implantation.69 In pathological states, including endometriosis, expression shifts toward epithelial populations and becomes uncoupled from the normal cycle-dependent rhythm. Incorporating GREB1 localization—via immunohistochemistry or immunofluorescence—alongside quantitative transcript analysis could therefore improve discrimination between physiological variation and clinically meaningful dysfunction.70 In principle, such assessments could be integrated into pre-ART endometrial evaluation, helping identify patients unlikely to benefit from progesterone escalation alone.71 Genetic data further strengthen the case for GREB1 as a biomarker. Common polymorphisms within the GREB1 locus repeatedly emerge in genome-wide association studies of endometriosis, suggesting that altered regulation of this gene contributes to disease susceptibility.72 At the other end of the spectrum, rare loss-of-function variants provide striking examples of impaired progesterone responsiveness despite intact receptor expression.73 Together, these findings argue that GREB1 status—genetic and epigenetic—captures a dimension of endometrial biology that is currently underrepresented in clinical practice.74 Therapeutically, the GREB1-centered feedforward loop offers a more nuanced target than global hormonal suppression. Current treatments for endometriosis often rely on reducing estrogen production or action systemically, an approach that carries substantial side effects and compromises fertility.75 By contrast, selectively disrupting the estrogen–GREB1–ERα amplification loop could, in theory, attenuate lesion growth while preserving broader endocrine function. Preclinical studies lend support to this concept: silencing GREB1 reduces estrogen-driven proliferation and invasiveness of endometriotic cells and diminishes lesion burden in animal models, without abolishing normal uterine estrogen responsiveness.76 Several intervention strategies can be envisioned. One approach would target GREB1 expression directly, using RNA interference or gene-silencing technologies.77 Another would focus on the protein–protein interface between GREB1 and ERα, aiming to uncouple co-activation without eliminating receptor signaling entirely.78 A third strategy might intervene downstream, disrupting GREB1-dependent transcriptional nodes that disproportionately contribute to pathological growth. Although none of these approaches has yet reached clinical testing, the mechanistic specificity of GREB1 makes them conceptually attractive, particularly for patients with hormone-resistant disease.79 Importantly, GREB1 targeting may also complement, rather than replace, existing therapies. In patients with partial progesterone resistance, dampening estrogen–GREB1 amplification could restore hormonal balance and enhance responsiveness to progesterone-based treatments. This combination strategy aligns with the emerging view that endometrial disorders reflect dysregulated signal integration rather than absolute hormone excess or deficiency.80 Beyond endometriosis, the implications extend to other estrogen-responsive conditions. In adenomyosis and estrogen receptor–positive endometrial carcinoma, GREB1 expression correlates with invasive behavior and proliferative capacity, raising the possibility that GREB1-directed interventions could have broader applicability. At the same time, caution is warranted.81 Given GREB1’s essential role in normal progesterone-driven decidualization, indiscriminate inhibition could compromise fertility.82 Any therapeutic approach must therefore discriminate between pathological estrogen amplification and physiological progesterone support—a challenge, but not an insurmountable one.83 In sum, GREB1 bridges mechanistic insight and clinical relevance with unusual clarity. As a biomarker, it captures functional hormone responsiveness at the tissue level. As a therapeutic target, it offers a route to modulate hormonal signaling with greater precision than traditional endocrine interventions.84 Whether these possibilities can be realized will depend on future studies that integrate molecular profiling, clinical phenotyping, and targeted intervention. What is already clear is that GREB1 shifts the conversation—from asking how much hormone is present, to asking how hormonal signals are interpreted and amplified within the endometrium.85

GREB1 has emerged as more than a downstream component of steroid hormone signaling. It functions as a regulatory node capable of reshaping how estrogen and progesterone signals are interpreted within the endometrium. Under physiological conditions, GREB1 aligns predominantly with progesterone action, reinforcing decidualization and supporting the establishment of a receptive uterine environment. In pathological settings marked by estrogen dominance and progesterone resistance, the same molecular machinery is redirected, enabling GREB1 to amplify estrogen-driven transcriptional programs that sustain aberrant proliferation and tissue invasion. This duality does not reflect contradictory functions, but rather a context-dependent reallocation of co-regulatory capacity. The identification of a GREB1-centered feedforward loop with steroid receptors provides a unifying framework for understanding several long-standing features of endometrial disorders. Progesterone resistance, impaired receptivity, estrogen dependence, and lesion persistence can be viewed not as isolated phenomena, but as interconnected outcomes of dysregulated signal amplification. By occupying the intersection of hormone responsiveness and transcriptional reinforcement, GREB1 helps explain how relatively modest shifts in hormonal or inflammatory context can produce disproportionately large biological effects. This conceptual shift carries practical implications. GREB1 challenges the prevailing emphasis on circulating hormone levels and receptor expression as primary determinants of endometrial function. Instead, it draws attention to the intracellular mechanisms that govern signal strength and direction. Assessing GREB1 expression, localization, and regulatory integrity offers a way to evaluate tissue-level hormone responsiveness more directly, with potential relevance for infertility assessment and disease stratification. At the same time, the feedforward architecture surrounding GREB1 presents an opportunity for therapeutic intervention that is more selective than global endocrine suppression. Looking ahead, several questions warrant focused investigation. How is GREB1 engagement with ERα or PR specified at the chromatin level in different cell types? Can epigenetic or inflammatory cues be manipulated to redirect GREB1 activity back toward a progesterone-supportive state? And critically, can interventions targeting GREB1 disrupt pathological estrogen amplification without compromising the progesterone-dependent processes essential for fertility? Addressing these questions will require integrated approaches that combine molecular profiling, functional modeling, and carefully designed clinical studies. Despite the compelling molecular logic of the GREB1-centered feedforward loop, it is crucial to recognize the limitations of the current evidence base. A substantial portion of the mechanistic data relies heavily on murine knockout models and in vitro cellular assays. Direct evidence from human tissues remains somewhat restricted to comparatively small descriptive cohorts, and the spatial dynamics of GREB1 have yet to be validated across large, diverse patient populations. Furthermore, while the translational potential of these findings is highly attractive, the application of GREB1 as a clinical biomarker or a therapeutic target is currently hypothesis-generating. Rigorous, large-scale clinical validation is required before these molecular insights can be confidently translated into standard diagnostic or therapeutic practice. More broadly, the story of GREB1 underscores an emerging principle in reproductive endocrinology: hormonal balance is governed not only by ligand availability and receptor presence, but by context-sensitive amplification mechanisms embedded within transcriptional networks. Recognizing and interrogating these mechanisms may prove essential for advancing precision medicine in endometrial disorders. In this sense, GREB1 serves both as a molecular switch and as a conceptual guide—pointing toward a more nuanced understanding of how steroid hormones shape reproductive health and disease (Figure 2). Data Sharing Statement This is a review article. No new datasets were generated or analyzed during the current study. All data discussed are derived from previously published peer-reviewed literature, which are cited in the reference list. Ethical Statement Ethical approval is not applicable for this study as it is a review article. Author Contributions Zhiqiang Wang and Jinwei Yang are co-first authors. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Funding This work was supported by: 1. Joint Scientific Research Foundation of Gansu Province (General Project), Grant No. 25JRRA1235 (to Bo Yan). Project title: Study on the Impact and Mechanism of GREB1 Gene Mutation on Endometrial Receptivity. 2. Key Research and Development Program of Gansu Province (Social Development Field), Grant No. 25YFFA056 (to Zhiqiang Wang). Project title: Genetic Factors in Oocyte Maturation Disorders and Embryonic Development Blockage. Disclosure The authors declare that they have no competing interests or financial relationships that could be construed as a potential conflict of interest.

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