The biology and clinical aspects of female infertility

Mitko Madjunkov, Svetlana Madjunkova, C. Librach, Clifford Librach
Systems biology in reproductive medicine · 2026 · vol. 72(1) , pp. 23–54 · doi:10.1080/19396368.2025.2593345 · PMID:41528185 · W7123691134
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This review details the biological and clinical factors contributing to female infertility, including HPO axis disruption, oocyte and uterine issues, genetic abnormalities, PCOS, endometriosis, and environmental influences, and discusses diagnostic and personalized treatment approaches.

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This review examines the multifactorial biological and clinical underpinnings of female infertility, covering disruptions in the hypothalamic-pituitary-ovarian axis, genetic abnormalities, and age-related oocyte decline. It highlights clinical causes such as polycystic ovary syndrome and endometriosis, which contribute to infertility through hormonal imbalance, inflammation, and impaired implantation, alongside environmental factors like obesity and stress. The authors emphasize that diagnosis requires a multidisciplinary approach involving hormonal profiling, imaging, and next-generation sequencing, while treatment is increasingly personalized using assisted reproductive technologies despite many cases remaining idiopathic. Relevance to endometriosis: listed as one clinical cause of infertility contributing to hormonal imbalance and impaired implantation, though the paper's main focus is a broad overview of female infertility.

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Abstract

Female infertility is a multifactorial condition with complex biological and clinical underpinnings. Biologically, female-related infertility may stem from disruptions in the hypothalamic-pituitary-ovarian (HPO) axis, impaired folliculogenesis, oocyte maturation defects, uterine abnormalities, endometrial dysfunction, and fallopian tube abnormalities. This review highlights key genetic mechanisms contributing to reproductive dysfunction and their relevance to diagnosis and treatment. Chromosomal abnormalities, including Turner syndrome and X-autosome translocations, also contribute to infertility and recurrent pregnancy loss (RPL). Age-related declines in oocyte quality and quantity-due to increased aneuploidy significantly impact fertility after the mid-30s. Clinical causes such as polycystic ovary syndrome (PCOS), luteal phase defects, and endometriosis contribute to infertility through hormonal imbalance, inflammation, and impaired implantation. Environmental and lifestyle factors-like endocrine-disrupting chemicals, obesity, smoking, and stress-further influence reproductive function. Evaluation requires a multidisciplinary approach combining hormonal profiling, imaging, and genetic diagnostics. Ovarian reserve assessment using anti-Müllerian hormone (AMH) and antral follicle count (AFC), hormonal evaluation along with ultrasound and hysterosalpingography, are central to clinical workups. Next-generation sequencing is enhancing the role of genetic screening in unexplained infertility and specific conditions like POI and endometriosis. Treatment options-ranging from ovulation induction to surgery and assisted reproductive technologies (ART)-are increasingly personalized based on underlying causes and patient profiles. Despite advances, many cases remain idiopathic, highlighting the need for deeper molecular research and refined phenotyping. This review emphasizes the importance of precision medicine and an evidence-based, patient-centered approach to improve fertility outcomes across a broad spectrum of infertility etiologies.
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Abstract Female infertility is a multifactorial condition with complex biological and clinical underpinnings. Biologically, female-related infertility may stem from disruptions in the hypothalamic-pituitary-ovarian (HPO) axis, impaired folliculogenesis, oocyte maturation defects, uterine abnormalities, endometrial dysfunction, and fallopian tube abnormalities. This review highlights key genetic mechanisms contributing to reproductive dysfunction and their relevance to diagnosis and treatment. Chromosomal abnormalities, including Turner syndrome and X-autosome translocations, also contribute to infertility and recurrent pregnancy loss (RPL). Age-related declines in oocyte quality and quantity—due to increased aneuploidy significantly impact fertility after the mid-30s. Clinical causes such as polycystic ovary syndrome (PCOS), luteal phase defects, and endometriosis contribute to infertility through hormonal imbalance, inflammation, and impaired implantation. Environmental and lifestyle factors—like endocrine-disrupting chemicals, obesity, smoking, and stress—further influence reproductive function. Evaluation requires a multidisciplinary approach combining hormonal profiling, imaging, and genetic diagnostics. Ovarian reserve assessment using anti-Müllerian hormone (AMH) and antral follicle count (AFC), hormonal evaluation along with ultrasound and hysterosalpingography, are central to clinical workups. Next-generation sequencing is enhancing the role of genetic screening in unexplained infertility and specific conditions like POI and endometriosis. Treatment options—ranging from ovulation induction to surgery and assisted reproductive technologies (ART)—are increasingly personalized based on underlying causes and patient profiles. Despite advances, many cases remain idiopathic, highlighting the need for deeper molecular research and refined phenotyping. This review emphasizes the importance of precision medicine and an evidence-based, patient-centered approach to improve fertility outcomes across a broad spectrum of infertility etiologies. Ethical approval This review did not require ethical approval. Disclosure statement No potential conflict of interest was reported by the author(s).

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Condition tags

endometriosisinfertility

MeSH descriptors

Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female Infertility, Female

Funding

funders
[{'doi': None, 'name': 'CReATe Fertility Research Programs, Toronto, ON, Canada', 'awards': []}]

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