Progesterone resistance in endometriosis: A pathophysiological perspective and potential treatment alternatives

Abstract

Background: Endometriosis is a common gynecological disease affecting women of reproductive age. Patients with endometriosis frequently experience severe chronic pain and have higher chances to experience infertility. Progesterone resistance is a major problem that develops during the medical treatment of endometriosis, which often leads to treatment failure of hormonal therapies. Previous studies indicated that the dysregulation of progesterone receptors (PR) is the primary factor leading to progesterone resistance in endometriosis.

Methods: This review article systematically reviewed and summarized findings extracted from previously published papers available on PubMed, encompassing both experimental studies and clinical trials.

Main findings: Various determinants influencing PR expression in endometriosis have been identified, including the environmental toxins, microRNAs, cell signaling pathways, genetic mutations, and the pro-inflammatory cytokines. The selective estrogen/progesterone receptor modulators have emerged as novel therapeutic approaches for treating endometriosis, offering potential improvements in overcoming progesterone resistance.

Conclusion: Concerns and limitations persist despite the newly developed drugs. Therefore, studies on unraveling new therapeutic targets based on the molecular mechanisms of progesterone resistance is warranted for the development potential alternatives to overcome hormonal treatment failure in endometriosis.

Keywords: cell signaling; endometriosis; hormonal therapy; microRNA; progesterone resistance.

FIGURE 1

Epidemiology and treatment of endometriosis. According to WHO announcement in 2023, the prevalence rate of endometriosis is about 10% of reproductive‐aged women worldwide. Endometriosis patients often suffer from many different pain symptoms such as the chronic pelvic pain, dysmenorrhea, dyspareunia, and painful urination and defecation. However, the most serious problem for endometriosis patients is infertility. Nowadays, there are several diagnostic approaches ranging from traditional surgical method to application of imaging‐based devises and examination of biomarkers. The current treatments for endometriosis, including surgical removal and hormonal treatments. As for the novel therapeutic treatment, SERMs and SPRMs are the newly identified drugs, which have been reported to overcome the progesterone resistance in endometriosis. (COCs, combined oral contraceptive pills; MRI, magnetic resonance imaging; SERMs, selective estrogen receptor modulators; SPRMs, selective progesterone receptor modulators; TVUS, transvaginal ultrasonography).

FIGURE 2

Potential mechanisms of causing progesterone resistance in endometriosis. Progesterone resistance in endometriosis has been reported to be associated with exposure of environmental toxin, upregulation of multiple miRNAs, overactive cell signaling pathways, overexpressed KRAS mutation and cytokine effects under chronic inflammation. These regulated pathways eventually result in downregulation of the stimulatory progesterone receptor‐B expression, which further contributes to the development of progesterone resistance in endometriosis. (Dnmt3b, DNA methyltransferase 3b; MEK/ERK, mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase; miR, microRNA; PI3K/AKT, phosphatidylinositol 3 kinase/protein kinase B; PR, progesterone receptor; SIRT1, Sirtuin 1; TCDD, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin; TGF‐β, transforming growth factor‐beta; TNF‐α, tumor necrosis factor‐α; YAP, yes‐associated protein).

FIGURE 3

Potential therapeutic targets for endometriosis treatment. Summary of potential therapeutic approaches outlined in the published literature in the studies of endometriosis. The strategies include blocking the overactive cell signaling pathways through the use of inhibitors, antagonizing certain highly expressed miRNAs with antagomirs, repressing specific aberrantly expressed receptors or enzymes with antagonists or inhibitors, and adopting the antiproliferative properties of cannabinoids. These therapeutic targets collectively aim to alleviate the pathological progressions of endometriosis and concomitantly ease the endometriosis‐associated pain symptoms (EP2/4, prostaglandin E₂ receptors 2/4; IGF‐1, insulin‐like growth factor‐1; MEK/ERK, mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase; miR, microRNA; NTRK2, neurotrophic receptor tyrosine kinase 2; PDK, pyruvate dehydrogenase kinase; PI3K/AKT, phosphatidylinositol 3 kinase/protein kinase B; PR, progesterone receptor; RAMP1, receptor activity‐modifying protein 1; SIRT1, Sirtuin 1; TCDD, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin; TGF‐β, transforming growth factor‐beta; TNF‐α, tumor necrosis factor‐α; YAP, yes‐associated protein).