PCOS is one of the most common endocrine disorders affecting women of reproductive age, characterized by irregular ovulation, clinical or biochemical signs of elevated androgens, and the presence of polycystic ovarian morphology. A hallmark of the condition is an excess of small, arrested follicles that fail to reach developmental maturity, a phenomenon known as follicular arrest. Anti-Müllerian hormone, or AMH, is often elevated in PCOS patients because of the abundance of small growing follicles, and it has become a valuable biomarker for diagnosis and disease severity. Yet the cellular reasons why these follicles stall remain incompletely understood. Because granulosa cells supply the developing follicle with energy, growth factors, and vascular signals, they represent a logical place to look for the roots of this arrest.

To investigate, the team isolated granulosa cells from women undergoing in vitro fertilization at a single center, applying the Rotterdam criteria to diagnose PCOS. The final cohort consisted of a control group of twelve women whose serum AMH levels fell within the normal range of 2 to 5 nanograms per milliliter, and a PCOS group of eleven women who met the Rotterdam criteria and displayed elevated AMH above 5 nanograms per milliliter. To control for the possibility that differences might simply reflect follicle size rather than disease, the researchers further subdivided cells from both groups according to follicular diameter, comparing cells from large follicles exceeding 14 millimeters with those from small follicles under 14 millimeters. All cells were cultured under standardized laboratory conditions, allowing the team to compare morphology, proliferation, mitochondrial activity, and secretory function directly.

The results were consistent across several independent lines of measurement. Under the microscope, PCOS-derived granulosa cells displayed abnormal morphology and an enlarged cell size compared with cells from healthy controls. When their capacity to divide was assessed, the PCOS cells proliferated significantly more slowly. This impaired growth is particularly consequential because granulosa cell proliferation drives follicle expansion during development; cells that cannot multiply properly cannot support a follicle’s progression toward ovulation. The finding suggests that the follicular arrest characteristic of PCOS may begin within the somatic compartment of the follicle rather than being solely an oocyte problem.

Deeper analysis revealed where the cellular failure likely originates: the mitochondria. These organelles serve as the cell’s power plants, generating adenosine triphosphate, or ATP, the chemical currency that fuels virtually every energy-demanding process, including cell division, protein synthesis, and secretion. The researchers found that both mitochondrial function and intracellular ATP levels were significantly reduced in PCOS granulosa cells. This energy deficit provides a coherent explanation for the observed proliferation defect, as cells with insufficient ATP cannot sustain the biosynthetic workload required to replicate. Mitochondrial dysfunction in granulosa cells has been suspected in PCOS before, but linking it quantitatively to both proliferative failure and secretory impairment in the same cohort strengthens the case that it is a central defect rather than an incidental finding.

Perhaps the most novel component of the study concerns angiogenesis, the formation of new blood vessels, which is essential for follicle development. A growing follicle depends on a rich vascular network to receive oxygen, nutrients, and hormones from the bloodstream. Granulosa cells contribute to building this network indirectly through paracrine signaling, releasing factors that stimulate nearby endothelial cells to organize into vessel structures. To test this function, the team collected conditioned media, essentially the liquid culture environment in which the granulosa cells had been growing, and applied it to human umbilical vein endothelial cells in a tube formation assay, a standard laboratory test of angiogenic capacity. The conditioned media from PCOS granulosa cells significantly impaired the ability of endothelial cells to form tubes, demonstrating that the angiogenic support normally provided by these ovarian cells was diminished in the disease state.

The effect was not uniform across follicle sizes. Granulosa cells harvested from larger follicles showed a more pronounced impairment in angiogenic support than those from smaller follicles, an observation that could help explain why larger follicles in PCOS ovaries so often fail to progress to ovulation despite reaching substantial size. At the molecular level, the researchers examined the expression of angiogenesis-related cytokines and found that three key pro-angiogenic chemokines, CXCL6, IL8, and MCP1, were consistently downregulated in PCOS granulosa cells. Interestingly, vascular endothelial growth factor A, or VEGF-A, the most famous angiogenic factor, showed a less consistent pattern, suggesting that the angiogenic deficit in PCOS is not simply a matter of reduced VEGF but rather a broader disruption of the chemokine-mediated signaling network that coordinates blood vessel formation.

Taken together, the findings sketch a coherent mechanistic framework for how PCOS disrupts follicle development. Mitochondrial dysfunction reduces ATP availability, which in turn limits cellular proliferation and dampens the secretion of angiogenic chemokines. Reduced angiogenic signaling compromises the vascular supply to developing follicles, depriving both the granulosa cells and the oocyte of the metabolic support needed for maturation. The authors describe this as a functional interplay between metabolic dysfunction and disrupted chemokine-mediated angiogenic signaling, a chain of causation that connects the metabolic phenotype of PCOS to its reproductive consequences. Because the chemokines CXCL6, IL8, and MCP1 emerged as consistently downregulated factors, they represent plausible targets for interventions aimed at restoring follicular vascular support in affected women.

The study carries practical implications for fertility medicine. Many women with PCOS require assisted reproductive technology to conceive, and the quality of the follicular environment is a determinant of oocyte competence and embryo development. If the granulosa cell dysfunction identified here proves to be modifiable, strategies to improve mitochondrial function or replenish angiogenic chemokine signaling could theoretically enhance follicle quality in PCOS patients undergoing IVF. Such approaches remain speculative, and the study is a relatively small observational analysis conducted at a single center, so the findings will need replication in larger and more diverse cohorts before they translate into clinical protocols. The authors note that the work provides potential targets for improving reproductive outcomes rather than an immediate treatment.

Beyond its clinical relevance, the study contributes to a growing appreciation of the ovary as a metabolically demanding organ in which cellular energy status and developmental signaling are tightly intertwined. The follicle is often studied primarily through its hormonal and genetic regulation, but this research underscores that the physical infrastructure of follicle growth, from mitochondrial ATP production to the surrounding vasculature, may be equally decisive. For the millions of women living with PCOS worldwide, a condition that remains among the leading causes of anovulatory infertility, understanding that their follicles may be starved of both energy and vascular support offers a new dimension to the search for causes and cures. As research continues to map the molecular pathways linking mitochondrial health, chemokine signaling, and folliculogenesis, the granulosa cell may well emerge as a key gateway through which future therapies for PCOS are delivered.

The study was conducted under ethical oversight at Cathay General Hospital in Taipei, with approval from the hospital’s Ethics Committee and written informed consent obtained from all participants, in accordance with the Declaration of Helsinki. The work received financial support from the National Science and Technology Council of Taiwan and from Cathay General Hospital, and the authors declared no competing interests.

Readers should note that the article was published as an accepted manuscript in open access form, released early to provide faster access to peer-reviewed research. This version is citable and carries a permanent DOI, though it remains subject to editorial revisions before the final Version of Record replaces it. The research is categorized under topics including endocrine reproductive disorders, fertility, and gonadal disorders, reflecting its position at the intersection of reproductive endocrinology and cellular metabolism research.

Subject of Research: Mitochondrial dysfunction in granulosa cells is associated with impaired proliferation and angiogenic support in women with polycystic ovarian syndrome and elevated AMH

Article Title: Mitochondrial dysfunction in granulosa cells is associated with impaired proliferation and angiogenic support in women with polycystic ovarian syndrome and elevated AMH

Article References: Hong, K.-J., Lin, J.-J., & Lai, T.-H. (2026). Mitochondrial dysfunction in granulosa cells is associated with impaired proliferation and angiogenic support in women with polycystic ovarian syndrome and elevated AMH. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02264-x

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02264-x

Keywords: Mitochondrial, dysfunction, granulosa, cells, associated, impaired, proliferation, angiogenic, support, women, polycystic, ovarian

Polycystic ovary syndrome is characterized by a spectrum of clinical manifestations, including irregular menstrual cycles, anovulation, and hyperandrogenism. Despite its prevalence, the exact etiology of PCOS remains poorly understood, primarily due to the complex interplay of genetic, hormonal, and environmental factors. This study aims to elucidate one of the critical contributors to infertility in women suffering from PCOS—granulosa cell dysfunction.

Granulosa cells play a vital role in ovarian folliculogenesis, supporting oocyte maturation and ovulation. However, the phenomenon of pyroptosis, a form of programmed cell death associated with inflammation, poses significant concerns regarding the health of these cells. Zhang and colleagues have identified a potential link between the heightened levels of ER stress observed in oocytes and increased pyroptosis in granulosa cells, a finding that could reshape existing paradigms concerning ovarian function and fertility.

The study employed a mouse model to explore the biochemical and molecular underpinnings of this relationship. By inducing PCOS-like symptoms, the researchers were able to observe both the behavior of granulosa cells and the subsequent impact on oocytes. Their findings reveal that granulosa cell pyroptosis is significantly elevated in the presence of ER stress, suggesting a possible cascade of cellular events triggered by hormonal imbalances typical of PCOS.

One of the more striking outcomes of this research is the indication that managing ER stress in oocytes could mitigate the adverse effects of granulosa cell pyroptosis. By utilizing specific pharmacological agents known to alleviate ER stress, the study reports promising improvements in oocyte quality and viability. This transformative insight opens new avenues for targeted therapeutic interventions that could potentially enhance fertility outcomes in women diagnosed with PCOS.

The implications of this research extend beyond individual patient care; they also highlight a broader need for advanced diagnostic and treatment strategies that consider the complex biology of follicular development and oocyte health. As the medical community grapples with the increasing incidence of PCOS, understanding the cellular dynamics between granulosa cells and oocytes can inform clinical approaches to recovery and management.

Moreover, the role of inflammation in reproductive health cannot be understated. The study underscores the importance of an inflammatory milieu in the ovaries of women with PCOS, as the pyroptotic process in granulosa cells is associated with the release of pro-inflammatory cytokines. Such findings not only deepen the complexity of PCOS but also emphasize the necessity for anti-inflammatory strategies in ameliorating its effects.

Zhang et al.’s findings resonate with emerging trends in the field of reproductive biology, where the focus is shifting from traditional hormone-centric models of understanding reproductive disorders to a more comprehensive view that encompasses cellular health and microenvironmental conditions. This approach may ultimately lead to refined diagnostics and innovative therapeutic options tailored to individual patient histories.

In conclusion, the connection between granulosa cell pyroptosis and oocyte ER stress presents an exciting frontier in reproductive research. As we refine our understanding of these cellular interactions, it becomes increasingly clear that addressing cellular stressors could hold the key to improving fertility outcomes for women with PCOS. Researchers and clinicians alike are called to take these findings into consideration as we strive towards a future where managing reproductive health is informed by an intricate understanding of cell biology.

As this research paves the way for potential future clinical applications, it opens the floor for further studies aimed at validating these findings and exploring the broader implications they may have on reproductive health. The journey to unraveling PCOS continues, but through innovative research like this, we are one step closer to offering better solutions to those affected by this challenging condition.

Ultimately, the study by Zhang and colleagues serves as a crucial reminder of the intricate symphony that is human reproduction and the myriad factors influencing it. As new insights emerge, the scientific community is equipped with fresh perspectives that inspire hope and facilitate progress in overcoming the hurdles posed by conditions like polycystic ovary syndrome.

Subject of Research: The connection between granulosa cell pyroptosis and oocyte endoplasmic reticulum stress in a mouse model of polycystic ovary syndrome.

Article Title: Connection between granulosa cell pyroptosis and oocyte endoplasmic reticulum stress in a mouse model of polycystic ovary syndrome.

Article References: Zhang, Y., Xie, X. & Han, L. Connection between granulosa cell pyroptosis and oocyte endoplasmic reticulum stress in a mouse model of polycystic ovary syndrome. J Ovarian Res 18, 288 (2025). https://doi.org/10.1186/s13048-025-01841-w

Image Credits: AI Generated

DOI: https://doi.org/10.1186/s13048-025-01841-w

Keywords: Granulosa cells, pyroptosis, endoplasmic reticulum stress, polycystic ovary syndrome, fertility, inflammation, oocyte quality.