Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms

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.

Impaired fertility in adenomyosis: a murine model reveals endometrial receptivity and progesterone resistance imbalances

“…One proposed molecular cause of progesterone resistance is a reduced expression of progesterone receptors, found in endometriotic lesions and eutopic endometrium from women with endometriosis ( Nie et al 2009 , Shen et al 2015 , Wölfler et al 2016 ). This endometrial progesterone unresponsiveness may negatively influence both the proliferation of endometrial cells and the decidualization of stromal cells, leading to both lesion growth and a non-receptive endometrium ( Maclean & Hayashi 2022 , Zhang & Wang 2023 ). In our mice affected by adenomyosis, the PGR expression was reduced in the stromal and glandular cells of the uterus of 3-month-old mice affected by adenomyosis.…”

The significance of immune microenvironment in patients with endometriosis

“…Furthermore, the endometriotic implants express enzymes, such as aromatase and 17β-hydroxysteroid dehydrogenase type 1, that are involved in estradiol production, and are deficient in 17β-hydroxysteroid dehydrogenase type 2, which normally inactivates estrogen, thus creating a hyperestrogenic milieu [ 47 ]. In endometriotic implants, a cellular resistance to progesterone may further enhance the estradiol effects [ 48 ].…”

“…The levels of PR, particularly the PR-B isoform, are markedly decreased in endometriotic stromal cells, resulting in a loss of paracrine signaling [ 51 ]. PR deficiency is probably involved in the development of progesterone resistance in patients with endometriosis [ 48 , 52 ]. Samples from our study were collected from patients that underwent surgical treatment, but they were not further divided into different groups according to the presurgical treatment.…”

Postmenopausal endometriosis: a challenging condition beyond menopause

“…These changes may include the development of progestin-resistant receptors or alterations in the signaling pathways that respond to progestins. As a result, the effectiveness of progestins, which primarily act through progesterone receptors, may be compromised in these lesions 99 . Progestins are synthetic forms of progesterone and are often used in premenopausal women to regulate the menstrual cycle, treat conditions like endometriosis, and provide hormonal balance.…”