Open research questions in Estrogen and related hormone effects

What the literature leaves open

• Physiological concentration of estradiol is insufficient to suppress THIK-1, suggesting that estradiol-mediated inhibition is of limited significance.

  Inhibitory effect of 17β-estradiol on the THIK-1 channel · 2026 · DOI

• A central challenge in the therapeutic exploitation of GILZ is its profound context dependence. The biological effects of GILZ vary with cellular identity, activation state, and tissue microenvironment, making uniform outcomes across immune and non-immune com- partments unlikely (118). Although L-GILZ has established physio- logical functions in vivo, evidence supporting endogenous expression and specialized biological roles for several other reported GILZ isoforms remains limited. Consequently, systemic GILZ modulation may produce unpredictable or unintended effects in tissues beyond the intended target. Successful translation of GILZ-based therapies will require precise cell- and tissue-specific targeting that accounts for

  Glucocorticoid-induced leucine zipper as a context-dependent central integrator of innate and adaptive immune homeostasis · 2026 · DOI

• Examples include the difference in bioavailability and expression of key enzymes involved in estrogen production, conversion, transport, and signaling, which include but are not limited to aromatase, HSD17b1, SHBG, TNF-a, IL-6 and ERa.

  Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan · 2025 · DOI

• Although some research progress discovery has been made regarding ER-a in targeted therapy of breast cancer, anti-ER- a therapy in EC still needs to be further explored in depth.

  Progress of estrogen receptor and spliceosome in endometrial carcinoma · 2025 · DOI

• have been reported Immune cells are not merely passive targets of steroid hormones through their receptors but also possess the potential to convert and metabolize these hormones on their own (Rubinow, 2018). Human convert alveolar macrophages androstenedione to testosterone and other through specific enzymatic catalytic activities (Milewich et al., 1983). Moreover, human monocyte-derived macrophages can convert dehydroepiandrosterone (DHEA) to testosterone, estradiol, and other steroids in the presence of LPS (Schmidt et al., 2000). These findings offer and microenvironment-dependency of steroid hormone conversion in macrophages. into the heterogeneity to steroids insights and cholesterol al., 2017), Furthermore, it has been shown that immune cells have the capacity for de novo steroidogenesis starting from cholesterol. For instance, the expression of StAR has been detected in macrophages (Ma et al., 2007; Taylor et al., 2010), suggesting at least the ability to to import produce into mitochondria testicular macrophages steroidogenic substrates. Primary rat have been reported to produce corticosterone in vitro (Wang et this production is derived from de novo steroidogenesis or from the conversion of other steroids. Furthermore, it has been reported that testicular macrophages produce progesterone de novo, which is promoted by cAMP and inhibited by M1 polarization inducers (Yamauchi et al., 2022). These discoveries suggest the potential involvement of macrophages in local feedback loops with Leydig thus influencing and contributing to the regulation of cells, testosterone production. remains unclear whether although it The existence of steroidogenesis and steroid signaling within immune cells presents new possibilities for understanding how immune cells communicate and shape the physiology of immune responses, as well as how they become dysregulated in disease states. The impact of nuclear receptor signaling pathways, such as those mediated by steroid hormone receptors, is profound. Given that the GR alone can regulate up to 20% of genes, these pathways hold the potential to revolutionize our understanding of immune regulation (Galon et al., 2002; Weikum et al., 2017). Technological liquid advancements, single-cell chromatography/tandem resolution omics, transcriptomics, multimodal techniques, steroid our enhancing are production and gene expression networks related to steroid understanding improvements spectrometry, and spatial particularly mass in of FIGURE 2 Hormone signaling in the testis. Cartoon depicting an adult mouse testis, showing localization of hormone receptors in different cell types and known (solid lines) and putative (dashed lines) interactions between cell types. P4, progesterone; G, glucocorticoid. Figure created with BioRender.com. in immune cells. Chromosome conformation responsiveness capture assays can analyze changes in genome interactions, contributing to the elucidation of mechanisms by which nuclear receptors bind to chromatin and regulate gene expression (Chakraborty et al., 2021). These developments are poised to deepen our understanding of immune regulation and contribute to the development of new therapeutic strategies.

  Steroid hormone signaling: multifaceted support of testicular function · 2024 · DOI

• This study identified a significant gap in understanding the safety consequences of small molecule interactions with various NRs; it also provided the nonclinical and clini- cal safety effects associated to functional interactions with 44 of 48 human-expressed NRs through the systematic analysis of various sources.

  Safety Implications of Modulating Nuclear Receptors: A Comprehensive Analysis from Non-Clinical and Clinical Perspectives · 2024 · DOI

• Similarly, hormone receptor localization in testicular cells warrants further study. Still, the complexity of their interactions and the mechanisms underlying their effects on male reproductive health remain incompletely understood (Figure 2).

  Steroid hormone signaling: multifaceted support of testicular function · 2024 · DOI

• A limitation of this study is the use of an immunodeficient nude mouse model, which does not fully replicate the tumor immune microenvironment.

  Metabolic activation of LDHA by ERRα represses inflammasome-dependent pyroptosis and promotes ovarian cancer chemoresistance · 2026 · DOI

• ERα is regulated through interactions with various coactivators; however, the precise mechanisms of these interactions are not yet fully understood.

  HSD17B7 Counters Bone Loss in Estrogen Deficiency via Estrogen Receptor Stabilization and Mediates the Effect of Raloxifene · 2026 · DOI

• The RNA-binding protein DEAD-box helicase 3 X-linked (DDX3X) has been implicated in the translational regulation of androgen receptor (AR) mRNA; however, the underlying binding mechanisms are not well defined.

  Molecular insights into DDX3X–androgen receptor mRNA regulation via non-canonical G-quadruplex in castration-resistant prostate cancer · 2026 · DOI

• Background/Objectives: Tamoxifen, a selective estrogen receptor modulator widely used as an adjunct in the treatment of breast cancer, has known effects on bone metabolism, although its impact on osseointegration and cellular responses during early bone healing remains unclear.

  Behavior of Osteoblastic Lineage Cells When in the Presence of Tamoxifen: In Vitro and In Vivo Studies on Osseointegration · 2025 · DOI

• New biomarkers are thus suggested and should be further explored to tailor the best treatment to each patient.

  Interaction between redox regulation, immune activation, and response to treatment in HER2+ breast cancer · 2025 · DOI

• Nevertheless, the influence of ROS on treatment efficacy and prognosis in patients with HER2+ BC remains to be elucidated.

  Interaction between redox regulation, immune activation, and response to treatment in HER2+ breast cancer · 2025 · DOI

• BACKGROUND: Data on the effectiveness of ovarian function suppression (OFS) in premenopausal patients with hormone receptor (HR)-positive, HER2-positive breast cancer are sparse.

  Ovarian Function Suppression in HR-Positive, HER2-Positive Breast Cancer: An Exploratory Analysis of the HERA Trial · 2025 · DOI

• 1 (female-derived) cell lines are widely used in immunology research and are considered preferred models for studying signaling pathways, yet their responses to gonadal hormones remain poorly understood.

  Cell line-specific estrogen responses uncover functional sex differences in murine macrophages · 2025 · DOI

• Among these factors, the immune phenomena likely to respond to an immunomodulatory intervention are difficult to diagnose,The definition of diagnostic criteria for “rejection” is not consensual, with a dozen cases published in literature, and variable treatments whose effectiveness beyond 1 year has not been evaluated (steroids, rituximab).

  12-7: LONG-TERM EFFECT OF BASILIXIMAB IN ISLET DYSFUNCTION · 2025 · DOI

• Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood.

  The prognostic value of MEK pathway–associated estrogen receptor signaling activity for female cancers · 2024 · DOI

• Estrogens can affect the immune inflammatory response through estrogen receptor alpha (ERα), but the specific role of estrogen member receptor G-protein coupled receptor 1 (GPER1) in this process remains unclear.

  G-Protein Coupled Receptor 1 Is Involved in Tetrachlorobisphenol A-Induced Inflammatory Response in Jurkat Cells · 2024 · DOI

• Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation.

  Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor–Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination · 2024 · DOI

• Despite extensive research, the genes/proteins and pathways responsible for the physiological effects of estrogen remain elusive.

  Proteomic Analysis Reveals Major Proteins and Pathways That Mediate the Effect of 17-β-Estradiol in Cell Division and Apoptosis in Breast Cancer MCF7 Cells · 2024 · DOI

• This case illustrates the utility of in-office ultrasonography combined with dynamic examination for the often underrecognized pathology associated with aromatase inhibitor-associated musculoskeletal syndrome in breast cancer survivors.

  Aromatase Inhibitor-Associated Distal Radioulnar Joint Instability and Tear of the Extensor Digiti Minimi · 2024 · DOI

• Radioulnar joint subluxation with extensor tendon tear has not been previously reported in patients with aromatase inhibitor-associated musculoskeletal syndrome.

  Aromatase Inhibitor-Associated Distal Radioulnar Joint Instability and Tear of the Extensor Digiti Minimi · 2024 · DOI

• cancer-associated processes and therapy resistance, the fusion partner plays an equally important role by adding structural flexibility and potential new interaction sites, although their functional contribution remains to be explored.

  ESR1 fusion proteins in breast cancer: distinguishing oncogenic drivers from passenger events · 2026 · DOI

• We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations.

  ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer · 2021 · DOI

• these steroids remains unclear, but the presence of progestin (4) and glucocorticoid (6) receptors suggests their involvement.

  Binding of the anti-progestin ru-486 to rat ovary steroid receptors · 1983 · DOI

Most-cited papers in Estrogen and related hormone effects

• The Steroid and Thyroid Hormone Receptor Superfamily · Science · 1988 · 5,497 citations
• Molecular basis of agonism and antagonism in the oestrogen receptor · Nature · 1997 · 2,796 citations
• The Protective Effects of Estrogen on the Cardiovascular System · New England Journal of Medicine · 1999 · 2,389 citations
• Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women · JAMA · 2003 · 1,473 citations
• The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. · Environmental Health Perspectives · 1995 · 754 citations
• Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. · Environmental Health Perspectives · 2003 · 742 citations
• The estrogenic activity of phthalate esters in vitro. · Environmental Health Perspectives · 1997 · 682 citations
• The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogen-sensitive cells. · Environmental Health Perspectives · 1994 · 440 citations
• Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. · Environmental Health Perspectives · 2002 · 406 citations
• ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer · Breast Cancer Research · 2021 · 383 citations

Most recent work

• GLP-1 Receptor Agonists Plus Progestins and Endometrial Cancer Risk in Nonmalignant Uterine Diseases · JAMA Network Open · 2026
• Steroidal Compounds at the Crossroads of Inflammation and Cancer: Implications for Drug Discovery and Therapy · Biomedicines · 2026
• Switching to camizestrant at ESR1 mutation emergence before disease progression during first-line treatment of hormone receptor-positive advanced breast cancer (SERENA-6): extended analysis of a double-blind, placebo-controlled, randomised, phase 3 trial · The Lancet Oncology · 2026
• Approved Steroidal Drugs (2000–2025): A Medicinal Chemistry Perspective · Journal of Medicinal Chemistry · 2026
• Evaluating progesterone receptor agonist megestrol plus letrozole for women with early-stage estrogen-receptor-positive breast cancer: the window-of-opportunity, randomized, phase 2b, PIONEER trial · Nature Cancer · 2026
• Rethinking synthesis and function of neuro-estrogen and neuro-androgen in the hippocampus: some methodological problems and possible solutions · bioRxiv · 2026
• SYNTAX Reads the Motif and Domain Grammar of the Androgen Receptor Proximal Interactome · bioRxiv · 2026
• A Spatiotemporal Atlas of Extranuclear Androgen Receptor Proximal Interaction Networks · bioRxiv · 2026
• Pharmacodynamics of Camizestrant Treatment in Postmenopausal Women With Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Primary Breast Cancer: Results From the Randomized, Presurgical SERENA-3 Study · Journal of Clinical Oncology · 2026
• Signaling Under Stress: Targeting the Glucocorticoid Receptor in Cancer · Cancer Research · 2026

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