Toward Personalized Endometriosis Models: Organoids

Patient-Derived Organoids Capture Subtype-Specific Biology in Endometriosis

Key Points

Highlights: 

• Patient-derived organoids successfully model all major endometriosis phenotypes with distinct, subtype-specific morphology.
• Organoid behavior reflects underlying biological heterogeneity, including hormone receptor dynamics and treatment sensitivity.

Importance: 

• Lack of physiologically relevant models limits understanding of subtype-specific endometriosis biology
• Organoids provide a platform to study disease heterogeneity and support development of personalized and mechanism-driven therapies.

What’s done here:

• Organoid cultures established from surgical specimens of Deep infiltrating endometriosis (DIE), endometrioma(OMA) and peritoneal endometriosis (PE).
• Models characterized by morphology, hormone receptor expression, and clinical correlates including hormonal treatment status

Key results:

• Organoid establishment success varied by phenotype: OMA 71.4%; DIE 63.6%; PE 30%.
• Distinct morphological phenotypes (cystic, solid, mixed) correlated with disease subtype
• Progesterone receptor expression preserved in DIE and PE, but reduced in OMA-derived organoids
• Hormonal treatment significantly reduced organoid establishment success (23.1% vs 80.0%) and tissue yield
• Organoids recapitulated key histopathologic and molecular features of original lesions.

Strengths and Limitations:

• Strengths are: being first systematic comparison of organoid generation across endometriosis subtypes; integration of clinical variables (e.g., hormonal therapy) with model performance, demonstration of phenotype-specific biological behavior in vitro.
• Limitations are modest sample size and potential selection bias; the problem of uniform culture conditions may not equallysupport all subtypes; the lack of stromal, immune, and microenvironmental components; also tissue pooling may obscure intra-patient heterogeneity.

From the Editor-in-Chief – EndoNews

"This study advances the field by demonstrating that organoid models can recapitulate the phenotypic and biological diversity of endometriosis across its major subtypes. The observed differences in establishment efficiency, morphology, and progesterone receptor expression underscore that endometriosis is not a uniform entity, but a spectrum of biologically distinct conditions with variable cellular behavior and treatment responsiveness.

Importantly, the reduced success of organoid generation from hormonally treated patients highlights a critical and often overlooked interface between clinical management and experimental modeling. Preclinical systems do not exist in isolation; they are shaped by prior therapies, tissue context, and disease state, all of which must be considered when interpreting translational relevance.

At the same time, these findings expose the inherent limitations of current organoid platforms. While epithelial-driven systems offer valuable mechanistic insights, they incompletely capture the complex microenvironment of endometriosis, where stromal, immune, vascular, and neural components critically interact. As such, organoids should be viewed not as definitive disease models, but as reductionist tools within a broader investigative framework.

Taken together, this work reinforces the need to align experimental models with the clinical reality of endometriosis. Progress will depend on integrating organoid technologies with personalized, multimodal, and multidisciplinary approaches, linking in vitro phenotype with patient-specific disease behavior.

Understanding endometriosis will not come from a single model, but from how well our models reflect its biological diversity.

Lay Summary

A study published in Human Reproduction by Prof. Caroline Ford and colleagues from UNSW Sydney, Australia, demonstrates that patient-derived organoids can model the biological diversity of endometriosis across its major subtypes.

The researchers aimed to determine whether organoid models could be reliably established from different forms of endometriosis, including deep infiltrating disease, ovarian endometrioma, and peritoneal lesions.

To address this, they generated organoid cultures from 28 tissue samples obtained from 23 patients and evaluated their growth, morphology, hormone receptor expression, and cellular composition.

Overall, 78.6% of samples formed three-dimensional organoid structures, and more than half (53.6%) remained viable after cryopreservation.

However, success varied markedly by subtype, with the highest establishment rates observed in ovarian endometriomas (71.4%) and deep infiltrating endometriosis (63.6%), compared to substantially lower success in superficial peritoneal disease (30%).

Importantly, the organoids preserved key biological features of the original lesions. Progesterone receptor expression was maintained in organoids derived from superficial and deep lesions but was significantly reduced in those derived from ovarian endometriomas. In addition, organoids exhibited distinct morphological patterns that aligned with disease phenotype, reflecting underlying biological heterogeneity.

Clinical factors also influenced model performance. Tissue samples obtained from patients receiving hormonal therapy were smaller and significantly less likely to generate successful organoids.

These findings establish organoids as a promising platform to investigate subtype-specific disease mechanisms, including hormone resistance, and support the development of more personalized therapeutic strategies in endometriosis.

Research Source: https://pubmed.ncbi.nlm.nih.gov/41298340/