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<p>Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, characterized by hyperandrogenism, polycystic ovarian morphology, and ovulatory dysfunction. Its pathogenesis involves a multifactorial interplay of genetic predisposition and fetal environmental influences, compounded by systemic metabolic disturbances such as hyperinsulinemia, insulin resistance, chronic inflammation, oxidative stress, and dyslipidemia. This review aims to integrate current knowledge on ovarian and endometrial cellular dysfunction in PCOS, with particular emphasis on the regulatory roles of autophagy, cellular senescence, and apoptosis. A comprehensive literature search was performed without temporal restrictions. In granulosa cells, activation of autophagy through the AMPK–mTOR and PI3K–AKT pathways has been reported, while androgen excess and insulin resistance contribute to impaired follicular development and reduced oocyte quality. By contrast, diminished autophagy in the endometrium is associated with functional impairment and decreased receptivity. Aberrant autophagy interacts with mitochondrial dysfunction, oxidative stress, chronic inflammation, and hyperandrogenism, forming a central pathogenic nexus that links defective decidualization with cellular senescence. In addition, epigenetic modifications may account for interindividual variability in insulin sensitivity and hormonal responsiveness, and have been implicated in the influence of fetal environmental factors and exposure to endocrine-disrupting chemicals. In conclusion, dysregulated metabolic and reproductive signaling, together with alterations in autophagy, cellular senescence, apoptosis, and epigenetic programming, critically contribute to ovarian and endometrial dysfunction in PCOS, ultimately impairing reproductive outcomes. By synthesizing these interconnected mechanisms, this review provides a comprehensive perspective on the pathophysiology of PCOS and highlights key directions for future investigation.</p>

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Molecular Mechanisms Underlying Reproductive Dysfunction in Polycystic Ovary Syndrome

  • 期刊论文

  • 发表日期：

    2026年4月20日

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  • Hiroshi Kobayashi,
  • Hiroshi Shigetomi,
  • Miki Nishio,
  • Mai Umetani,
  • Shogo Imanaka,
  • Hiratsugu Hashimoto

摘要

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, characterized by hyperandrogenism, polycystic ovarian morphology, and ovulatory dysfunction. Its pathogenesis involves a multifactorial interplay of genetic predisposition and fetal environmental influences, compounded by systemic metabolic disturbances such as hyperinsulinemia, insulin resistance, chronic inflammation, oxidative stress, and dyslipidemia. This review aims to integrate current knowledge on ovarian and endometrial cellular dysfunction in PCOS, with particular emphasis on the regulatory roles of autophagy, cellular senescence, and apoptosis. A comprehensive literature search was performed without temporal restrictions. In granulosa cells, activation of autophagy through the AMPK–mTOR and PI3K–AKT pathways has been reported, while androgen excess and insulin resistance contribute to impaired follicular development and reduced oocyte quality. By contrast, diminished autophagy in the endometrium is associated with functional impairment and decreased receptivity. Aberrant autophagy interacts with mitochondrial dysfunction, oxidative stress, chronic inflammation, and hyperandrogenism, forming a central pathogenic nexus that links defective decidualization with cellular senescence. In addition, epigenetic modifications may account for interindividual variability in insulin sensitivity and hormonal responsiveness, and have been implicated in the influence of fetal environmental factors and exposure to endocrine-disrupting chemicals. In conclusion, dysregulated metabolic and reproductive signaling, together with alterations in autophagy, cellular senescence, apoptosis, and epigenetic programming, critically contribute to ovarian and endometrial dysfunction in PCOS, ultimately impairing reproductive outcomes. By synthesizing these interconnected mechanisms, this review provides a comprehensive perspective on the pathophysiology of PCOS and highlights key directions for future investigation.