Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women’s lives. Because the menstrual cycle repeatably occurs during reproductive ages with dynamic changes and remodeling of reproductive-related tissues, these alterations can accumulate and induce chronic and recurrent conditions. This review focuses on faulty progesterone signaling mechanisms and cellular responses to progesterone in endometriosis, adenomyosis, leiomyoma (uterine fibroids), polycystic ovary syndrome (PCOS), and endometrial hyperplasia. We also summarize the association with gene mutations and steroid hormone regulation in disease progression as well as current hormonal therapies and the clinical consequences of progesterone resistance.

Due to the vital roles of macrophages in the pathogenesis of endometriosis, targeting macrophages could be a promising therapeutic direction. Here, we investigated the efficacy of niclosamide for the resolution of a perturbed microenvironment caused by dysregulated macrophages in a mouse model of endometriosis. Single-cell transcriptomic analysis revealed the heterogeneity of macrophages including three intermediate subtypes with sharing characteristics of traditional “small” or “large” peritoneal macrophages (SPMs and LPMs) in the peritoneal cavity. Endometriosis-like lesions (ELL) enhanced the differentiation of recruited macrophages, promoted the replenishment of resident LPMs, and increased the ablation of embryo-derived LPMs, which were stepwise suppressed by niclosamide. In addition, niclosamide restored intercellular communications between macrophages and B cells. Therefore, niclosamide rescued the perturbed microenvironment in endometriosis through its fine regulations on the dynamic progression of macrophages. Validation of similar macrophage pathogenesis in patients will further promote the clinical usage of niclosamide for endometriosis treatment.

Endometriosis causes severe chronic pelvic pain and infertility. We have recently reported that niclosamide treatment reduces growth and progression of endometriosis-like lesions and inflammatory signaling (NFĸB and STAT3) in a mouse model. In the present study, we examined further inhibitory mechanisms by which niclosamide affects endometriotic lesions using an endometriotic epithelial cell line, 12Z, and macrophages differentiated from a monocytic THP-1 cell line. Niclosamide dose dependently reduced 12Z viability, reduced STAT3 and NFĸB activity, and increased both cleaved caspase-3 and cleaved PARP. To model the inflammatory microenvironment in endometriotic lesions, we exposed 12Z cells to macrophage conditioned media (CM). Macrophages were differentiated from THP-1 cells using 12-O-tetradecanoylphorbol-13-acetate as M0, and then M0 macrophages were polarized into M1 or M2 using LPS/IFNγ or IL4/IL13, respectively. CM from M0, M1 or M2 cultures increased 12Z viability. This effect was blocked by niclosamide, and cell viability returned to that of CM from cells treated with niclosamide alone. To assess proteins targeted by niclosamide in 12Z cells, CM from 12Z cells cultured with M0, M1 or M2 with/without niclosamide were analyzed by cytokine/chemokine protein array kits. CM from M0, M1 and/or M2 stimulated the secretion of cytokines/chemokines from 12Z cells. Production of most of these secreted cytokines/chemokines in 12Z cells was inhibited by niclosamide. Knockdown of each gene in 12Z cells using siRNA resulted in reduced cell viability. These results indicate that niclosamide can inhibit the inflammatory factors in endometriotic epithelial cells stimulated by macrophages by targeting STAT3 and/or NFĸB signaling.

Recently, an unusual family of genes was identified with expression confined to the trophoblast of ruminant ungulate species. The members of this fam