A review of Mamillapalli et al. 2026

One of the greatest mysteries surrounding endometriosis is the lack of correlation between disease progression and symptom severity. We might expect deeper, more extensive lesions to cause greater pain, but this isn’t always the case. Some people with endometriosis have no symptoms at all despite having deep infiltrating endometriosis, and others with minimal lesions have debilitating pain. There are many theories as to why this might be, and Yale researchers decided to tackle gene expression in symptomatic versus asymptomatic endometriosis. Mamillapalli et al. (2026) believed that endometriosis symptom severity may be due to molecular differences between the two groups (differences in gene expression between symptomatic and asymptomatic patients).

The researchers decided to explore this question through a technique called RNA sequencing (a technique that measures which genes are expressed and at what levels (Kukurba and Montgomery, 2015)) and analysed the results using the Weighted Gene Co-expression Network Analysis. They collected biopsies (surgical samples) from 19 patients, 9 symptomatic (with pain) and 10 asymptomatic (without pain) and 27 tissue samples. The researchers focused on four main facets of endometriosis: inflammation, immune dysregulation, cell adhesion and tissue organisation, as well as nerve signalling.

Following RNA sequencing, 890 genes were found to differ between symptomatic and asymptomatic patients: 262 showed more than a twofold difference, with 189 downregulated (expressed at lower levels) and 73 upregulated (expressed at higher levels) in symptomatic samples. What was fascinating about the results discovered was that more genes were downregulated rather than upregulated, which creates more nuance surrounding symptom severity in endometriosis. You may think that if endometriosis symptoms are more severe, then surely more genes involved in inflammation would be expressed. However, the researchers concluded that because certain immune responses have protective functions, reduced activity could potentially contribute to symptom severity.

Additionally, the results showed that seven of the 22 significantly downregulated pathways were associated with immune function. Out of these, the most significantly affected area was T-cell differentiation (immune cells that help coordinate immune responses and recognise abnormal or infected cells (Adu-Berchie, Obuseh and Mooney, 2023)).

So what about the difference between symptomatic and asymptomatic endo patients? The researchers found three genes whose expression differed greatly between the two groups. Firstly IL16! This was the largest finding, with its expression being significantly greater in symptomatic endometriosis cases and also associated with higher pain severity. This gene is largely involved in increased inflammation however, it is also known to carry some immunomodulatory effects (protective effects). Secondly, IL17RA. This gene is a receptor gene involved in IL-17 signalling. It is primarily involved in inflammation and increases the release of pro-inflammatory markers in the body. Last but not least, JAK3 was largely downregulated in symptomatic endometriosis cases, this gene plays a role in immune signalling. Overall, immunohistochemistry (a lab technique that uses antibodies to detect antigens in a tissue sample (HAWES et al., 2009)) showed an increase in IL16 and IL17RA in symptomatic patients, but this shows an association and not a cause.

This research shows great potential in identifying the distinct molecular signature that symptomatic endometriosis carries. This is especially important in future research and the discovery of new, non-hormonal targeted therapies.

However, Mamillapalli et al. (2026) do mention some key limitations to consider when interpreting the paper. Firstly, the researchers preface that the biopsies were received post-surgery, and the sample storage as well as time was not kept consistent from retrieval to the RNA sequencing. Mamillapalli mentions that due to differing conditions, RNA degradation (RNA molecules being broken down (Jackowiak et al., 2011)) may have taken place, reducing the reliability of results. Secondly, the researchers mention that the sample size was too small to draw generalisable conclusions and call for larger research in this domain. Lastly, the variables within the population analysed were not kept consistent, allowing potential confounders to interfere with the results. Finally, this observational study cannot establish whether gene-expression differences cause pain.

While this paper offers the possibility of symptomatic endometriosis having a distinct immune-related molecular profile, larger studies are needed to confirm the findings as well as the potential target these pathways for future research. What do you think about the study?

References

  1. Mamillapalli, R., Li, H.J., Apelian, S., Kumar, M., Wang, S.F., Pondugula, N., de Queiroz Campos, G., Sayeed, S., Cho, Y. and Taylor, H.S. (2026). Endometriosis pain: genes linked to inflammation distinguish symptomatic from asymptomatic disease. Molecular human reproduction, doi:10.1093/molehr/gaag055.

  2. Kukurba, K.R. and Montgomery, S.B. (2015). RNA Sequencing and Analysis. Cold Spring Harbor Protocols, [online] 2015(11), p.pdb.top084970. doi:10.1101/pdb.top084970.

  3. Adu-Berchie, K., Obuseh, F.O. and Mooney, D.J. (2023). T Cell Development and Function. Rejuvenation Research, 26(4), pp.126–138. doi:10.1089/rej.2023.0015.

  4. HAWES, D., SHI, S.-R., DABBS, D.J., TAYLOR, C.R. and COTE, R.J. (2009). Immunohistochemistry. Modern Surgical Pathology, [online] pp.48–70. doi:10.1016/b978-1-4160-3966-2.00016-3.

  5. Jackowiak, P., Nowacka, M., Strozycki, P.M. and Figlerowicz, M. (2011). RNA degradome–its biogenesis and functions. Nucleic Acids Research, 39(17), pp.7361–7370. doi:10.1093/nar/gkr450.