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Open research questions in Reproductive Biology and Fertility

61 unresolved questions extracted from the limitations and future-work sections of 759 Reproductive Biology and Fertility papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Whether significant differences in pregnancy outcomes exist between autologous oocytes and fresh or frozen donor oocytes, when controlling for embryonic euploidy via PGT-A, remains unknown.

    LIVE BIRTH OUTCOMES IN PGT-A TESTED CYCLES: AUTOLOGOUS VERSUS DONOR OOCYTE IVF WITH FRESH AND FROZEN OOCYTES · 2026 · DOI

  • Future studies with larger sample sizes, optimized ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT ARTICLE IN PRESS gonadotropin doses, and evaluation of downstream fertilization and embryo development outcomes are warranted to define the role of gonadotropin supplementation in rescue IVM.

    Effect of gonadotropin supplementation on oocyte maturation and mean oocyte diameter in rescue IVM: a prospective sibling-oocyte study · 2026 · DOI

  • Across these studies, the predictive accuracy for nuclear maturation did not exceed 90%, suggesting that COC morphology alone is insufficient for reliable classification.

    Inverted microscopy as a high performance tool for pre denudation evaluation of oocyte nuclear maturity · 2026 · DOI

  • Confirm- ing patient identity with the transferring doctor also fosters communication between the embryologist and the reproduc- tive endocrinologist and minimizes the risk of an error [11], a step which was lacking in one of the reports, where the specimen information had not been matched to the patient file.

    Embryo mix-up due to erroneous identification in the context of medically assisted reproduction · 2026 · DOI

  • Insulin-like growth factor 1 (IGF-1) has been reported to regulate oocyte maturation through multiple intracellular signaling pathways; however, its molecular effects on maturation-associated genes in Kacang goat oocytes remain poorly characterized.

    Insulin-like growth factor 1 supplementation during in vitro maturation upregulates HRas, Cdc25, and IRS-2 expression in Kacang goat oocytes · 2026 · DOI

  • Background: Literature on the role of thermal discomfort (heat- and cold-stress) on in-vitro fertilization (IVF) outcomes are scarce and inconclusive.

    Thermal Discomfort and In-vitro Fertilization Treatment Outcomes · 2026 · DOI

  • However, the optimal timing of FET after fresh cycle cancellation remains unclear, with conflicting evidence as to whether shorter or longer intervals are associated with better pregnancy outcomes.

    Impact of interval after fresh cycle cancellation on first frozen embryo transfer outcomes · 2026 · DOI

  • Whether HyperSperm treatment reduces oxida- tive stress in sperm remains to be determined, although this seems unlikely given that the control samples did not exhibit clear signs of oxidative damage, such as impaired motility or reduced viability. While the underlying mechanisms remain unclear, these obser- vations warrant further investigation. We acknowledge some limitations of the current study: The participants’ cohort was limited in number.

    A multicenter, prospective sibling oocyte study revealed that HyperSperm™ improves the number and quality of embryos in patients undergoing in vitro fertilization · 2026 · DOI

  • In vitro maturation systems using GDF-9 have been tested in various species (canine, ovine, bovine, porcine) but standardized protocols and comparative efficacy across species remain unclear.

    GDF-9 Affects the Development and Maturation of Oocytes · 2026 · DOI

  • A substantial body of research evidence suggests that inflammation plays an integral role in the development of premature ovarian failure. Whether it is an imbalance of proinflammatory cytokines, aberrant activation of inflammatory signaling pathways, or immune cell-mediated autoimmune ovarian destruction, premature follicular apoptosis and depletion can lead to POI (7, 53). Inflammation may be both a common downstream pathway for different etiologies of POI (e.g. chemotherapeutic injury, autoimmunity, genetic mutations, etc.) and a self-amplifying factor that exacerbates and maintains ovarian decline. Consequently, considering POI as an inflammation-driven disease provides us with a new perspective for integrating various etiological factors. Within this framework, the success of various types of anti-inflammatory interventions in POI models is encouraging. These include glucocorticoids, which are used to suppress autoimmune inflammation; small molecules, which are used to block the release of inflammatory mediators; stem cell t h e r a p i e s, w h i c h a r e u s e d t o r e m o d e l t h e i m m u n e microenvironment; and multi-targeted modulation of natural products from traditional Chinese medicine. The efficacy of these strategies in reducing the inflammatory load of the ovary is evidenced by the restoration of ovarian function. In the future, the introduction of anti-inflammatory concepts in POI treatment is expected to open up new pathways. Yet, there is still a lot that remain to be investigated. Firstly, the POI patient population is highly heterogeneous. It is unknown whether the inflammation is comparable across subtypes. For example, there is a clear lack of large studies to address what proportion of patients with idiopathic POI have significant inflammatory abnormalities. In the future, for patients with ‘inflammation-dominant’ POIs, screening biomarker such as cytokine profiles, inflammation-related immune cell subtypes, gene expression, etc. will be indispensable. Secondly, inflammation is a wide category, and in particular for POI, we need to further refine what inflammatory pathways/factors are ‘cause’ and what are the ‘effect’. For example, we often see upregulation of IL-6 in POI cases; however, it remains unclear if this is a primary event leading to follicular cell death or more of a secondary change? These mechanistic questions can be resolved with access to patient tissues and models, but using histological techniques (single-cell RNA sequencing, proteomics, metabolomics, etc.) will allow us to distinguish between primary and secondary changes. Then, there is a local and systemic relationship that must be highlighted. In these patients, we often see changes in systemic inflammatory markers such as NLR ratio, C-reactive protein, etc., and the inflammatory milieu systemically can be playing a role by endocrine or immune pathways on the ovary; conversely, the hypoestrogenic state induced by ovarian failure can feed back to worsen systemic inflammation. Noting this local vs. systemic causality is critical to developing a holistic treatment strategy. On the clinical translation front, well-designed clinical trials are needed to evaluate the efficacy and safety of various antiinflammatory therapies in patients with POI.

    Mechanisms of inflammation in premature ovarian insufficiency and advances in therapeutic studies · 2026 · DOI

  • Small molecule therapies targeting inflammatory pathways The development of small molecule drugs targeting specific inflammatory signaling cascades represents a significant emerging frontier in POI therapy. Extensive evidence highlights the pathogenic role of the NF-kB and NLRP3 inflammasome pathways in POI, driving considerable interest in their respective inhibitors. Among NF-kB inhibitors, experimental agents like BAY 11-7082 (an IkB phosphorylation inhibitor) have demonstrated efficacy in reducing granulosa cell inflammation and apoptosis in vitro (118, 119). Clinically utilized immunosuppressants, such as azathioprine and leflunomide, may also attenuate ovarian inflammation through NF- KB blockade. Notably, naturally occurring small molecules with established safety profiles, such as Coenzyme Q10 (CoQ10), offer a highly translatable approach to targeting this cascade. By actively neutralizing reactive oxygen species (ROS) within the ovarian microenvironment, CoQ10 effectively blocks the ROS-mediated activation of NF-kB, thereby protecting granulosa cells from autoimmune and toxicological damage and preserving the remaining follicle pool (120, 121). Importantly, this mechanistic rationale has been successfully translated into clinical practice. Recent large-scale meta-analyses and randomized controlled trials confirm that CoQ10 supplementation in women with diminished ovarian reserve (DOR) or impending POI significantly improves follicular developmental competence, mitigates oxidative stress, and enhances overall clinical pregnancy outcomes (122, 123). Of the NLRP3 inflammasome inhibitors, MCC950 is a highly selective inhibitor of NLRP3 inflammasome, which has been validated to be effective in a variety of models of inflammatory diseases (124, 125). The utilization of MCC950 in ovarian ageing models has been reported to diminish IL-1b levels in the ovary and preserve a greater number of follicles (36, 49). While direct evidence in POI models remains limited, other small molecules like NMN and AKG operate through similar mechanisms to inhibit NLRP3- mediated pyroptosis (79, 80). Beyond classical signaling inhibitors, rebalancing the systemic inflammatory state using recombinant anti-inflammatory cytokines (e.g. IL-10 or interleukin 37, IL-37) holds therapeutic promise (126, 127). Furthermore, given the recent study suggesting a causal association between reduced plasma vascular endothelial growth factor (VEGF) and POI pathogenesis (71), exogenous VEGF supplementation or FLT1 receptor agonism may concurrently promote local neo angiogenesis and modulate immune responses (128). Finally, repurposing rheumatological biologics-such as antiinfliximab) and anti-IL-6 receptor antibodies (e.g. TNF-a (e.g. tocilizumab) monoclonal antibodies-to sequester specific proinflammatory cytokines represents a compelling avenue for future research (129, 130).

    Mechanisms of inflammation in premature ovarian insufficiency and advances in therapeutic studies · 2026 · DOI

  • Background: Despite the data published to date, prognostic factors and the clinical impact of ICSI cycles with smooth endoplasmatic reticulum aggregates (SERa) positive oocytes remain unclear.

    Live birth rate per transfer is not impacted by the proportion of smooth endoplasmatic reticulum aggregates oocytes · 2023 · DOI

  • Also, future studies are needed to identify biological markers to indicate the presence of residual follicles in POI to predict IVA treatment outcome.

    Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency · 2015 · DOI

  • This is the first report of cloning and analysing the porcine CDH1 cDNA that provides critical information for further research of its functions in pig embryo development.

    cDNA cloning of porcine CDH1 and its expression profile in porcine early parthenotes · 2012

  • Within this cohort, women with a BMI transcending 35 kg/m(2) were scarce (n = 2), because extremely overweight women are mostly advised to lose weight before starting ART.

    BMI-related metabolic composition of the follicular fluid of women undergoing assisted reproductive treatment and the consequences for oocyte and embryo quality · 2012 · DOI

  • The influence of delayed ICSI on embryological and clinical outcomes remains controversial, with inconsistent findings among previous studies.

    Day 1 versus Day 2 Intracytoplasmic Sperm Injection: Comparison of Fertilization and Embryo Development Outcomes in IVF Patients · 2026 · DOI

  • The effect of ICSI timing on blastocyst development could not be determined because of the absence of blastocyst data in the Day 2 group.

    Day 1 versus Day 2 Intracytoplasmic Sperm Injection: Comparison of Fertilization and Embryo Development Outcomes in IVF Patients · 2026 · DOI

  • Although first results are intriguing, existing evidence is limited due to small sample sizes, a lack of standardized techniques, and insufficient long-term safety data.

    Regenerative approaches in ovarian rejuvenation: hope for fertility restoration · 2026 · DOI

  • Cumulus cells have well-established roles early in ovulation but the key molecules that drive their behavior in later stages, leading to follicle rupture, remain underexplored.

    Proprotein convertase activity regulates cumulus-oocyte-complex matrix integrity and cumulus cell migration during ovulation via a GDF9-dependent mechanism · 2026 · DOI

  • We found substantial variation in how studies defined and reported participants’ groups as well as in their sequencing technologies and data analysis methods, with a lack of standardized reporting of background clinical information, data analysis methods, and pipeline details.

    Mapping ovarian cellular and molecular landscape across the lifespan of women: a scoping review · 2026 · DOI

  • The addition of antioxidants to cryopreservation media has been proposed to mitigate oxidative damage, although published results remain inconsistent across species, cryopreservation protocols, and antioxidant types and doses.

    Antioxidant supplementation in mammalian ovarian tissue cryopreservation: a scoping review of experimental models, protocols, and reported outcomes · 2026 · DOI

  • Despite their significance, the developmental origins, differentiation processes, and functional dynamics of theca cells remain incompletely defined, particularly in humans.

    Developmental and functional landscape of theca cells in ovarian biology · 2026 · DOI

  • ARTICLE SUMMARYThe fusome plays a key role in cyst formation in the Drosophila ovarian germline, yet regulation of fusome growth and distribution between germ cells after mitosis remains understudied.

    A β-importin promotes fusome growth and distribution in Drosophila ovarian germ cells · 2026 · DOI

  • Although many structural components of the fusome have been characterized, little is known about the genetic factors that control fusome growth and distribution between germ cells.

    A β-importin promotes fusome growth and distribution in Drosophila ovarian germ cells · 2026 · DOI

  • Despite the importance of this developmental window for establishment of pregnancy, the degree of biological variation among embryos and animals during this stage remains poorly characterized.

    Pronounced inter-gilt variability in the secretory activity of day 11 porcine embryos · 2026 · DOI

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61 open questions have been extracted from the limitations and future-work passages of 759 Reproductive Biology and Fertility 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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