Zhang, P., & Wang, G. (2023). Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms. International journal of molecular sciences, 24(8). https://doi.org/10.3390/ijms24086992
Zhang P, Wang G. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms. International journal of molecular sciences. 2023;24(8). doi:10.3390/ijms24086992
Zhang, Ping, and Guoyun Wang. "Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms." International journal of molecular sciences, vol. 24, no. 8, 2023.
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Evidence points to progesterone resistance in endometriosis tissue
A 2023 review of lab and tissue studies reports evidence that the uterine lining in women with endometriosis responds poorly to progesterone. The authors name low receptor levels, inflammation, gene changes and toxins as possible causes. Up to 1 out of 3 women with symptomatic endometriosis show no response to progestins.
Key Findings
The review describes progestins as first-line treatment, yet as many as a third of women with symptomatic endometriosis show no response to progestins or low-dose oral contraceptives, supporting progesterone resistance.
Studies that separated the two progesterone receptor forms tended to find lower PR-B in lesions or the uterine lining. PR-A was the main form expressed within lesions.
Progesterone-regulated genes and proteins, some used in embryo attachment, were altered in the endometrium of women with endometriosis. Stromal cells cultured from these women showed altered gene responses despite controlled progesterone levels.
Proposed causes of lower receptor levels or activity include DNA hypermethylation, chronic inflammation, environmental toxicants such as dioxin, the PROGINS gene variant, microRNAs and epithelial-to-mesenchymal transition.
The authors propose that reversing progesterone resistance may yield new therapies. They cite laboratory work: an established diabetes drug in cultured endometriotic stem cells and SCM-198 in mouse models of endometriosis.
Interpretation
The paper is a mechanistic review of tissue samples, cultured cells and animal models. It summarizes proposed molecular mechanisms by which progesterone signaling is altered in endometriosis. The authors present the mechanisms as potential causes and state that they remain to be fully understood. They add that more data are required to learn how receptor levels change in lesions and the uterine lining. One meta-analysis linked the PROGINS variant to endometriosis risk only in European subjects.
RRM Context
RRM looks for the cause of endometriosis. Natural progesterone, made after ovulation, differs from synthetic progestins. Altered progesterone signaling in uterine tissue fits care that works with the cycle and removes disease by excision. NaProTechnology adds cycle-timed hormone support after surgery.
Our editorial summary of this paper, not the article's abstract.
Abstract
Endometriosis is an estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the uterus. Progestins are currently the most commonly used treatment for endometriosis because of their excellent therapeutic effects and limited side effects. However, progestins have been unsuccessful in some symptomatic patients. The inability of the endometrium to respond properly to progesterone is known as progesterone resistance. An increasing body of evidence suggests the loss of progesterone signaling and the existence of progesterone resistance in endometriosis. The mechanisms of progesterone resistance have received considerable scholarly attention in recent years. Abnormal PGR signaling, chronic inflammation, aberrant gene expression, epigenetic alterations, and environmental toxins are considered potential molecular causes of progesterone resistance in endometriosis. The general objective of this review was to summarize the evidence and mechanisms of progesterone resistance. A deeper understanding of how these mechanisms contribute to progesterone resistance may help develop a novel therapeutic regimen for women with endometriosis by reversing progesterone resistance.
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