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Reproductive Genetics and Epigenetics: Insights into Infertility Failures and Treatment Pathways

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (25 February 2026) | Viewed by 12871

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Dr. Hossam H. Shawki

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Guest Editor

Department of Comparative and Experimental Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
Interests: laboratory animal science; reproductive genetics; reproductive development

Special Issue Information

Dear Colleagues,

Infertility affects millions of individuals and couples worldwide, with genetic and epigenetic factors playing critical roles in reproductive failures and treatment outcomes. This Special Issue focuses on cutting-edge research and reviews exploring the genetic and epigenetic mechanisms underlying infertility, providing a deeper understanding of how these factors influence reproductive health and the success of assisted reproductive technologies (ART). It underscores the roles of genetic and epigenetic factors in processes such as gametogenesis, fertilization, pregnancy, embryonic development, etc.

We welcome submissions on topics including genetic mutations, epigenetic modifications, inherited reproductive disorders, advances in ART, and epigenetic markers as diagnostic or therapeutic tools in fertility treatments. To bridge the gap between fundamental discoveries and clinical applications in reproductive medicine, this issue invites researchers to contribute original research, reviews, and case studies that explore the genetic and epigenetic underpinnings of infertility.

Dr. Hossam H. Shawki
Guest Editor

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Keywords

infertility
epigenetics
polymorphism
gametogenesis
fertilization
embryo development
reproductive organs
congenital malformations

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Published Papers (5 papers)

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Research

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21 pages, 3052 KB

Open AccessArticle

Epigenetic Landscape of Female Infertility: An Integrated Bioinformatics Perspective on DNA Methylation, MicroRNAs, and Gene Regulatory Networks Across PCOS, Endometriosis, and Diminished Ovarian Reserve

by Maroua Jalouli, Md Ataur Rahman, Saber Nahdi and Abdel Halim Harrath

Int. J. Mol. Sci. 2026, 27(4), 1785; https://doi.org/10.3390/ijms27041785 - 12 Feb 2026

Viewed by 1196

Abstract

Female infertility diseases such as polycystic ovary syndrome (PCOS), endometriosis, diminished ovarian reserve (DOR), and recurrent implantation failure (RIF) have different clinical phenotypes. However, they might be epigenetically convergent, and thus the therapeutic targets may be potential. This study utilized transcriptome data, microRNA (miRNA), and DNA methylation data from the granulosa cells of four Gene Expression Omnibus (GEO) datasets, GSE138518, GSE105765, GSE232306, and GSE92324, to conduct integrated bioinformatics analysis. We focused on differentially expressed genes (DEGs), constructed a miRNA–mRNA network, performed ROC curve analysis, and conducted function enrichment and drug repurposing studies. Our findings identified eight dysregulated genes (H19, SULT1A4, HCK, SPI1, CARD16, NFE2, LST1, and KRT8) common to PCOS, DOR, and RIF, which may serve to distinguish PCOS specifically. Moreover, these DEGs are associated with pathways such as innate immune activation, inflammatory responses, the NOD-like receptor signaling pathway, and Fc gamma R-mediated phagocytosis. Notably, MiRNAs differentially expressed in endometriosis (specifically hsa-miR-202-5p and hsa-miR-141-3p) were found to directly target this gene set, highlighting the role of epigenetic regulation across infertility diseases. Additionally, our drug repurposing analysis identified several FDA-approved drugs, including Abacavir and Peginterferon Alfa-2b, suggesting that the HCK gene may be a viable target for drug development to address female infertility. Furthermore, we identified 192 genes that correlated with DNA methylation and expression levels in PCOS. Thus, this study underscores the epigenetic convergence of different female infertility diseases and highlights potential biomarkers and therapeutic options that could enhance treatment in reproductive medicine. Full article

(This article belongs to the Special Issue Reproductive Genetics and Epigenetics: Insights into Infertility Failures and Treatment Pathways)

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17 pages, 386 KB

Open AccessArticle

Growth Hormone Therapy in Recurrent Implantation Failure: Stratification by FSH Receptor Polymorphism (Asn680Ser) Reveals Genotype-Specific Benefits

by Mihai Surcel, Georgiana Nemeti, Iulian Gabriel Goidescu, Romeo Micu, Cristina Zlatescu-Marton, Ariana Anamaria Cordos, Gabriela Caracostea, Ioana Cristina Rotar, Daniel Muresan and Dan Boitor-Borza

Int. J. Mol. Sci. 2025, 26(15), 7367; https://doi.org/10.3390/ijms26157367 - 30 Jul 2025

Cited by 1 | Viewed by 1418

Abstract

Recurrent implantation failure (RIF) remains a challenging clinical problem. Growth hormone (GH) co-treatment has been explored as an adjunct in poor responders and RIF patients, with inconsistent evidence of benefit. This prospective cohort study assessed the impact of GH supplementation in 91 RIF patients undergoing in vitro fertilization, stratified by FSHR (follicular stimulating hormone receptor) genotype Asn680Ser with or without GH supplementation. Patients were stratified by FSHR genotype into homozygous Ser/Ser versus Ser/Asn or Asn/Asn groups. Overall, GH co-treatment conferred modest benefits in the unselected RIF cohort, limited to a higher cumulative live birth rate compared to controls and elevated leukemia inhibitory factor (LIF) levels (p < 0.05 both). When stratified by FSHR genotype, the Ser/Ser subgroup exhibited markedly better outcomes with GH. These patients showed a higher (0.5 vs. 0.33, p = 0.003), produced more embryos (2.88 vs. 1.53, p = 0.02), and had a markedly improved cumulative live birth rate—50% with GH versus 13% without—highlighting a clinically meaningful benefit of GH in the Ser/Ser subgroup. No significant benefit was observed in Asn allele carriers. These findings suggest that FSHR genotyping may help optimize treatment selection in RIF patients by identifying those most likely to benefit from GH supplementation. Full article

(This article belongs to the Special Issue Reproductive Genetics and Epigenetics: Insights into Infertility Failures and Treatment Pathways)

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24 pages, 13153 KB

Open AccessArticle

Mating Increases CHST10 Activity in Rat Oviductal Mucosa to Induce the Synthesis of HNK-1 Glycoproteins: Possible Role in Sperm–Oviduct Interactions

by Francisca Fábrega-Guerén, Juan C. Andrade, Marlene Zúñiga-Cóndor, Patricio Morales, Benito Gómez-Silva and Lidia M. Zúñiga

Int. J. Mol. Sci. 2025, 26(7), 3309; https://doi.org/10.3390/ijms26073309 - 2 Apr 2025

Cited by 1 | Viewed by 1349

Abstract

Previously, we reported that mating induces an early transcriptional response in the oviductal mucosa of rats. The functional category ‘cell-to-cell signaling and interaction’ was overrepresented in this gene list. Therefore, in the present study, we describe the role of one of these genes, carbohydrate sulfotransferase 10 (Chst10), in the oviductal mucosa. CHST10 participates in the synthesis of the carbohydrate moiety human natural killer-1 (HNK-1), which mediates cell-to-cell interactions. When using one-dimensional Western blot and sulfotransferase analyses, we found that mating increased the protein level and activity of CHST10 in the oviductal mucosa at 3 h after stimulation. A two-dimensional Western blot analysis and mass spectrometry were used to identify the novel HNK-1 glycoproteins aldehyde dehydrogenase 9 family, member A1 (ALDH9A1), fructose bisphosphate aldolase A (ALDOA), and four and a half LIM domains protein 1 (FHL1) in the oviductal mucosa, and we found that mating induces the synthesis of their acidic variants. Interestingly, in the utero-tubal junction (UTJ), acrosome-reacted sperm apparently were interacting with regions in which ALDH9A1 and HNK-1 signals overlap. Furthermore, vaginocervical stimulation applied to unmated rats increased the mRNA level of Chst10 in the oviductal mucosa. In conclusion, mating increases the activity of CHST10 in the oviductal mucosa, which in turn induces the synthesis of acidic variants of ALDH9A1 and FHL1 via HNK-1 glycosylation. ALDH9A1, HNK-1-ALDH9A1, and/or other HNK-1 glycoproteins could participate in the negative selection of sperm in the UTJ, since we detected acrosome-reacted sperm apparently interacting with regions where these proteins are located. Finally, the sensorial component of mating could regulate early events (e.g., sperm transport and selection) occurring in the oviductal mucosa after mating. Full article

(This article belongs to the Special Issue Reproductive Genetics and Epigenetics: Insights into Infertility Failures and Treatment Pathways)

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Review

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19 pages, 2524 KB

Open AccessReview

Divergent Roles of HIF-1α and HIF-2α in Embryonic Development and Early Pregnancy

by Hossam H. Shawki, Asmaa Y. Ammar, Mohamed Mansour and Fatma M. Minisy

Int. J. Mol. Sci. 2026, 27(3), 1593; https://doi.org/10.3390/ijms27031593 - 6 Feb 2026

Cited by 2 | Viewed by 926

Abstract

Physiological hypoxia is a defining feature of early pregnancy, coordinating menstrual repair, implantation, decidualization, placental development, and fetoplacental adaptation. Hypoxia-inducible factors, HIF-1α and HIF-2α, act as master regulators of these processes by sensing oxygen tension and orchestrating cellular responses in metabolism, angiogenesis, immune regulation, and tissue remodeling. Although structurally related, HIF-1α and HIF-2α exhibit distinct spatial and temporal functions across reproductive stages. Embryonic HIF-1α is primarily involved in early embryonic development, whereas embryonic HIF-2α is required for later developmental stages. Furthermore, maternal HIF-1α acts early in pregnancy, coordinating metabolic adaptation, endometrial regeneration, decidualization, angiogenic expansion, placental organization, and maternal immune tolerance. In contrast, maternal HIF-2α regulates epithelial breakdown, trophoblast invasion, implantation mechanics, and vesicle-mediated trafficking. Mouse genetics demonstrate that disruption of either isoform leads to non-redundant defects in reproductive success, from failed implantation to placental insufficiency and fetal lethality. Pathological hypoxia or aberrant HIF signaling drives pregnancy disorders including preeclampsia, fetal growth restriction, recurrent pregnancy loss, and heavy menstrual bleeding. Defining the distinct roles of HIF-1α and HIF-2α supports the development of therapies targeting hypoxia-responsive pathways in infertility and obstetric disease. Full article

(This article belongs to the Special Issue Reproductive Genetics and Epigenetics: Insights into Infertility Failures and Treatment Pathways)

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21 pages, 1928 KB

Open AccessReview

Role of AMP-Activated Protein Kinase (AMPK) in Female Reproduction: A Review

by Nurul Ain Kamar Bashah, Adila A. Hamid, Siti Hajar Adam, Farah Hanan Fathihah Jaffar, Izzat Zulhilmi Abd Rahman and Mohd Helmy Mokhtar

Int. J. Mol. Sci. 2025, 26(14), 6833; https://doi.org/10.3390/ijms26146833 - 16 Jul 2025

Cited by 14 | Viewed by 4242

Abstract

The adenosine monophosphate (AMP)-activated protein kinase (AMPK) signalling pathway regulates cell metabolism, inflammation and the immune response. This signalling pathway is essential for maintaining reproductive homeostasis and influencing steroidogenesis, implantation, and embryonic development. The central sensor, AMPK, regulates cell function in response to metabolic stress. The dysregulation of AMPK signalling has been implicated in several female reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis, infertility, and reproductive ageing. This review provides an overview of the role of AMPK in reproductive function and disorders, as well as potential therapeutic targets to restore balance in this signalling pathway. It discusses AMPK signalling in folliculogenesis, oocyte maturation, pregnancy maintenance, pre-eclampsia (PE) pathogenesis, PCOS, preterm birth, endometriosis, dysmenorrhoea and other disorders related to female reproduction. A deeper understanding of AMPK signalling in these contexts could provide new insights for the development of therapeutic interventions for reproductive health. Full article

(This article belongs to the Special Issue Reproductive Genetics and Epigenetics: Insights into Infertility Failures and Treatment Pathways)

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