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Open research questions in Reproductive System and Pregnancy

46 unresolved questions extracted from the limitations and future-work sections of 325 Reproductive System and Pregnancy papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Although the importance of nucleoside/nucleobase transporters during pregnancy has been studied in some species, their expression and the role of ADE at the maternal–conceptus interface have not been evaluated in pigs.

    Expression and Regulation of Nucleoside/Nucleobase Transporters and the Role of Adenine at the Maternal-Conceptus Interface in Pigs · 2026 · DOI

  • Advancing the field of endometrial receptivity requires a shift from morphology-based assessment toward molecularly defined, phenotype-oriented diagnostic frameworks. Future research should focus on identifying and validating standardized, clinically applicable molecular signatures capable of distinguishing functional from non-functional endometrium, independent of endometrial thickness. High-resolution single-cell approaches transcriptomics, spatial proteomics, and metabolomic profiling are expected to refine mechanistic subtyping and reveal actionable therapeutic targets. In parallel, well- designed prospective and multicenter clinical trials are needed to evaluate pathway-specific interventions, including regenerative, immune-targeted, and metabolic strategies, within clearly defined biological phenotypes.

    ENDOMETRIAL RECEPTIVITY: MOLECULAR MECHANISMS, THIN ENDOMETRIUM SUBTYPES, AND MECHANISM-BASED THERAPEUTIC APPROACHES · 2026 · DOI

  • Sacubitril/Valsartan (Sac/Val), an angiotensin receptor–neprilysin inhibitor, exhibits anti-inflammatory and anti-fibrotic properties; however, its effects on IUA and reproductive outcomes have not been previously studied.

    Sacubitril/Valsartan: Breaking barriers in uterine adhesion and boosting pregnancy outcomes by suppressing inflammation and fibrosis · 2026 · DOI

  • factors, The physiological integrity of endometrial function constitutes a fundamental cornerstone of female reproductive health. Multiple including cellular senescence, chronic pathological inflammation, iatrogenic injury, endometriosis, and microbiome dysbiosis, can impair endometrial receptivity through shared molecular pathways, ultimately leading to recurrent implantation failure and adverse pregnancy outcomes. This review has summarized these molecular mechanisms and provided an evidence-informed overview of current therapeutic strategies based on published literature. Among available interventions, intrauterine PRP infusion appears promising based on published network meta-analyses, suggesting potential efficacy in thin endometrium and RIF. However, the overall evidence remains limited by protocol heterogeneity, indirect comparisons, and lack of long-term safety data. G-CSF, PBMCs, and growth hormone show therapeutic potential but further validation. Stem cell-based therapies remain experimental and have been used only in research settings. require Future research may focus on several areas: (i) personalized strategies based on molecular subtyping; (ii) clinical translation and safety evaluation of stem cell and exosome-based therapies; and (iii) deeper understanding of endometrial regeneration mechanisms. Such efforts could help establish a foundation for and precision management of ultimately and pregnancy outcomes.

    Endometrial dysfunction in embryo implantation: from molecular mechanisms to clinical management · 2026 · DOI

  • formulations, treatment duration, and patient populations across the included RCTs. Most studies were not powered to detect differences in live birth rates. For the general IVF population, the specific route of estrogen administration appears to have limited impact on ultimate pregnancy success. Extended estrogen exposure has been used empirically for patients with thin endometrium, but robust evidence for this strategy is lacking (80). 6.1.2 Growth hormone (GH) associated with GH promotes endometrial proliferation and angiogenesis by upregulating insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) expression (81). Network meta-analyses have demonstrated that intramuscular injection of increased is recombinant human GH endometrial thickness, ranking favorably among six commonly used interventions for thin endometrium (82); it has also been associated with improved clinical pregnancy rates compared to controls (OR = 1.73, 95% CI 1.02–2.94) (83). However, a recent that GH RCT administration in comparable endometrial (9.30 mm vs. 9.18 mm, thickness P > 0.05) and clinical pregnancy rates (78% vs. 76%, P > 0.05) found the cycle resulted in donor oocyte recipient cycles from day 2–12 of compared to controls, suggesting that the benefit of GH may be limited to specific populations, such as those with refractory thin endometrium, rather than unselected patients (84). intervention The evidence for GH is characterized by marked populationdependent heterogeneity. Positive findings come primarily from studies enrolling patients with thin endometrium or prior implantation failure, whereas a recent well-controlled trial in healthy donor oocyte recipients found no benefit. This discrepancy suggests that GH has been studied primarily as a in selected patients with endometrial rescue dysfunction, whereas routine use in all ART cycles is not supported by current evidence. Limitations include small sample sizes in most positive studies, variability in dosing regimens (daily vs. every-other-day, starting day of cycle), and lack of long-term safety data. Studies reporting positive outcomes have focused on patients with refractory thin endometrium or prior implantation failure; a negative trial in healthy donor oocyte to recipients suggests unselected populations.

    Endometrial dysfunction in embryo implantation: from molecular mechanisms to clinical management · 2026 · DOI

  • Drug repurposing strategies Based on transcriptome-drug feature matching, alreadyapproved drugs such as genistein, pioglitazone, and alprostadil are predicted to improve endometrial function, although clinical validation is pending (39). 6.6.2 Induced pluripotent stem cells (iPSCs) Differentiation into oocyte-like cells has been achieved in animal models, but remains at the preclinical stage (105, 106). 6.6.3 Personalized treatment selection Individualization of endometrial preparation based on patient characteristics has been proposed as a strategy to optimize reproductive outcomes (107). Precision therapy based on dysbiotic, inflammatory, or mixed endometrial dysfunction) represents a future direction, although rapid point-of-care testing tools are currently lacking (42).

    Endometrial dysfunction in embryo implantation: from molecular mechanisms to clinical management · 2026 · DOI

  • In this study, we implemented an AI-driven, unsupervised topic discovery framework to systematically synthesize and reinterpret two decades of research on bioengineered models of the female reproductive system. Unlike conventional narrative reviews, which rely on manual article selection and predefined thematic categories, our approach enables data-driven comparison across thousands of publications by extracting latent semantic structures directly from biomedical text. To improve clarity and methodological transparency, the analytical workflow was explicitly structured into sequential steps, including corpus preprocessing, contextual embedding generation using BioBERT, and topic extraction using BERTopic with density-based clustering. This stepwise framework ensures reproducibility and facilitates interpretation of how thematic structures are derived from the underlying text data. By integrating BioBERT-based contextual embeddings with density-based clustering, we reconstructed the research landscape of the endometrium, placenta, ovary, fallopian tube, and cervix in a reproducible and scalable manner. Advances in AI technologies are transforming the research framework of the female reproductive system and are emerging as powerful tools in this field. Using this AI-driven framework, research trends and highly emphasized keywords within each reproductive organ category can be rapidly and systematically identified. By organizing large-scale literature into semantically coherent topic clusters, the framework allows efficient comparison of dominant research themes and frequently discussed biological and engineering concepts across organ domains. Beyond literature summarization, the cluster-based topic analysis provides a quantitative basis for gap analysis across reproductive organs and technological platforms. High-density topic clusters were predominantly associated with endometrial and placental models, reflecting sustained methodological development in organoids, barrier systems, and vascularized microphysiological platforms. In contrast, comparatively sparse or fragmented topic representations were observed for biologically critical yet technically challenging areas such as fallopian tube modeling and ovarian aging. These gaps are consistent with prior reports highlighting persistent limitations in cell sourcing, long-term culture stability, and hormone-responsive modeling for these organs. Importantly, the ability of AI-based topic modeling to reveal such imbalances enables underexplored yet Lee et al. Nano Convergence (2026) 13:24 clinically relevant domains to be identified in an unbiased manner, thereby informing future research prioritization.

    AI-driven text mining of the female reproductive system: enabling multiscale biomedical modeling and personalized medicine · 2026 · DOI

  • The proposed optimal timing of progesterone administration (immediately after egg release) to maximize PIBF-mediated protection during fetal-placental endometrial invasion has not been validated clinically; randomized trials comparing immediate post-ovulation progesterone supplementation with standard luteal-phase dosing in PIBF-responsive versus non-responsive populations are needed.

    The Role of Membrane Progesterone Receptor Associated Proteins in Gynecological and Reproductive Disorders, and Cancers: An Editor’s Historical Perspective · 2026 · DOI

  • The hypothesis that PIBF splice variants produced by embryonic, mesenchymal, and trophoblast cells provide immunoprotection against cellular immune attack during fetal-placental invasion at day 6 post-ovulation requires direct evidence through targeted generation and functional validation of these specific splice variants and their effects on cytotoxic T-lymphocyte activity.

    The Role of Membrane Progesterone Receptor Associated Proteins in Gynecological and Reproductive Disorders, and Cancers: An Editor’s Historical Perspective · 2026 · DOI

  • While synthetic progestins (medroxyprogesterone acetate, norethindrone, dydrogesterone, 17-hydroxy progesterone) failed to increase serum PIBF levels, the structural or functional basis for why these compounds do not activate mPR-mediated PIBF production despite inducing similar endometrial histologic changes as natural progesterone remains unexplained.

    The Role of Membrane Progesterone Receptor Associated Proteins in Gynecological and Reproductive Disorders, and Cancers: An Editor’s Historical Perspective · 2026 · DOI

  • The differential susceptibility of mPRs on gamma/delta T cells versus rapidly proliferating cancer cells to mifepristone-mediated PIBF suppression in the presence of progesterone has been identified but not mechanistically characterized; direct comparison of mPR signaling pathways and ligand-binding kinetics between these cell types is needed.

    The Role of Membrane Progesterone Receptor Associated Proteins in Gynecological and Reproductive Disorders, and Cancers: An Editor’s Historical Perspective · 2026 · DOI

  • The discrepancy between high PIBF secretion by breast cancer cells in culture versus absent elevated serum PIBF levels in women with breast cancer (nPR-positive and nPR-negative) requires investigation of the mechanisms controlling PIBF transit from the cancer microenvironment to systemic circulation, and whether local PIBF accumulation in tumors versus serum PIBF have distinct immunological functions.

    The Role of Membrane Progesterone Receptor Associated Proteins in Gynecological and Reproductive Disorders, and Cancers: An Editor’s Historical Perspective · 2026 · DOI

  • No prominent signaling pathways were identified between the IOFN and IOFC groups, the IOFC and IOFP groups, and the IOFN and IOFP groups, limiting understanding of pathway-level changes in inner ovarian fluid metabolites.

    Metabolic profiling of a polycystic ovary syndrome-like organoid model reveals the critical role of glutamine in local endometrial dysregulation related to implantation failure · 2026 · DOI

  • Not evaluated linically significant endometrial threshold level of progesterone on the day of ovulation trigger and insufficiently studied the possible mechanisms of the effect of a premature increase of progesterone on the outcomes of IVF.

    Clinical view of the ineffectiveness of IVF problem with endometrial receptivity · 2017 · DOI

  • WIDER IMPLICATIONS OF THE FINDINGS: Caution when using HRT for FET is warranted since the rate of early pregnancy loss is alarmingly high in some reports.

    Frozen embryo transfer: a review on the optimal endometrial preparation and timing · 2017 · DOI

  • Two evolutionary issues, however, are insufficiently appreciated in these analyses: the selection pressure infections pose to the human female reproductive system, and the variety of different—and possibly conflicting—immunological functions in the healthy human female reproductive and genital tract.

    Menstrual Function, Menstrual Suppression, and the Immunology of the Human Female Reproductive Tract · 2010 · DOI

  • Although immune cells are known to play a central role in maintaining FRT equilibrium, the underlying mechanisms remain incompletely understood.

    Granzyme A Regulates Uterine Immune-Endocrine Homeostasis in the Female Reproductive Tract 2302876 · 2026 · DOI

  • Mechanistic work has predominantly been confined to individual signaling pathways examined in isolation, and convergence of hormonal, immune, and epigenetic systems on the receptive state remains insufficiently characterized.

    Multidimensional regulatory architecture of endometrial receptivity and its translational implications for implantation failure · 2026 · DOI

  • Dietary fiber, composed of diverse polysaccharides, has been shown to enhance Tregs populations and improve implantation outcomes, yet the specific components responsible remain unclear.

    Dietary Fiber Polysaccharide Components Supplementation Modulate Uterine Immune Microenvironment to Support Embryo Implantation via <scp>SCFAs</scp> ‐Driven Tregs Differentiation · 2026 · DOI

  • 1778706 including endometrial pattern However, several limitations of this study should be acknowl- edged.

    The multiple positive effects of Honghua Ruyi Pills combined with estradiol valerate and dydrogesterone tablets on postoperative recovery in women after artificial abortion · 2026 · DOI

  • Although professional organizations currently recognize male gender as a possible risk factor, specific recommendations on the diagnostic and therapeutic field are still lacking, and the condition necessitates a high level of suspicion and case-by-case management.

    Recurrent miscarriage and male factor infertility: diagnostic and therapeutic implications. A narrative review. · 2023 · DOI

  • In spite of a variety of methods such as adhesiolysis, inserting intrauterine devices, and administering high doses of estrogen, treatments remain insufficient.

    The efficacy of Ankaferd Blood Stopper<sup>®</sup> in an experimental Asherman syndrome model created in rats · 2019 · DOI

  • Alternative miscarriage management procedures need to be investigated; procedures that have lower risks for an adverse reproductive function and allow for shorter time intervals between treatments.

    Six-month recovery needed after dilation and curettage (D and C) for reproductive outcomes in frozen embryo transfer · 2018 · DOI

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46 open questions have been extracted from the limitations and future-work passages of 325 Reproductive System and Pregnancy papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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