Unlocking the potential of tranilast: Targeting fibrotic signaling pathways for therapeutic benefit.

Fibrosis is the excessive deposition of extracellular matrix in an organ or tissue that results from an impaired tissue repair in response to tissue injury or chronic inflammation. The progressive nature of fibrotic diseases and limited treatment options represent significant healthcare challenges. Despite the substantial progress in understanding the mechanisms of fibrosis, a gap persists translating this knowledge into effective therapeutics. Here, we discuss the critical mediators involved in fibrosis and the role of tranilast as a potential antifibrotic drug to treat fibrotic conditions. Tranilast, an antiallergy drug, is a derivative of tryptophan and has been studied for its role in various fibrotic diseases. These include scleroderma, keloid and hypertrophic scars, liver fibrosis, renal fibrosis, cardiac fibrosis, pulmonary fibrosis, and uterine fibroids. Tranilast exerts antifibrotic effects by suppressing fibrotic pathways, including TGF-ß, and MPAK. Because it disrupts fibrotic pathways and has demonstrated beneficial effects against keloid and hypertrophic scars, tranilast could be used to treat other conditions characterized by fibrosis.

MicroRNA in Fibrotic Disorders: A Potential Target for Future Therapeutics.

Fibrotic disorders are defined by accumulating excessive extracellular matrix (ECM) components, especially collagens, in various organs, leading to tissue scarring and organ dysfunction. These conditions are associated with significant challenges in the healthcare system because of their progressive nature and limited treatment options. MicroRNAs (miRNAs) are small non-coding RNA molecules (approximately 22 nucleotides) that modulate gene expression by selectively targeting mRNAs for degradation or translational repression. MiRNAs have recently been identified as potential targets for therapeutic developments in fibrotic disorders. They play vital roles in inducing fibrotic phenotype by regulating fibroblast activation and ECM remodeling. Multiple strategies for targeting specific miRNAs in fibrotic disorders have been explored, including antisense oligonucleotides, small molecule modulators, and natural compounds. This review discussed the role of miRNAs in different fibrotic disorders, including cardiac fibrosis, liver fibrosis, kidney fibrosis, lung fibrosis, dermal fibrosis, and primary myelofibrosis, with recent advances in developing miRNA-based therapeutics.

Targeting fibrotic signaling pathways by EGCG as a therapeutic strategy for uterine fibroids.

Fibrosis is characterized by excessive accumulation of extracellular matrix, which is a key feature of uterine fibroids. Our prior research supports the tenet that inhibition of fibrotic processes may restrict fibroid growth. Epigallocatechin gallate (EGCG), a green tea compound with powerful antioxidant properties, is an investigational drug for uterine fibroids. An early phase clinical trial showed that EGCG was effective in reducing fibroid size and its associated symptoms; however, its mechanism of action(s) has not been completely elucidated. Here, we probed effects of EGCG on key signaling pathways involved in fibroid cell fibrosis. Viability of myometrial and fibroid cells was not greatly affected by EGCG treatment (1-200 µM). Cyclin D1, a protein involved in cell cycle progression, was increased in fibroid cells and was significantly reduced by EGCG. EGCG treatment significantly reduced mRNA or protein levels of key fibrotic proteins, including fibronectin (FN1), collagen (COL1A1), plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF), and actin alpha 2, smooth muscle (ACTA2) in fibroid cells, suggesting antifibrotic effects. EGCG treatment altered the activation of YAP, ß-catenin, JNK and AKT, but not Smad 2/3 signaling pathways involved in mediating fibrotic process. Finally, we conducted a comparative study to evaluate the ability of EGCG to regulate fibrosis with synthetic inhibitors. We observed that EGCG displayed greater efficacy than ICG-001 (ß-catenin), SP600125 (JNK) and MK-2206 (AKT) inhibitors, and its effects were equivalent to verteporfin (YAP) or SB525334 (Smad) for regulating expression of key fibrotic mediators. These data indicate that EGCG exhibits anti-fibrotic effects in fibroid cells. These results provide insight into mechanisms behind the observed clinical efficacy of EGCG against uterine fibroids.

Green Tea and Benign Gynecologic Disorders: A New Trick for An Old Beverage?

Green tea is harvested from the tea plant Camellia sinensis and is one of the most widely consumed beverages worldwide. It is richer in antioxidants than other forms of tea and has a uniquely high content of polyphenolic compounds known as catechins. Epigallocatechin-3-gallate (EGCG), the major green tea catechin, has been studied for its potential therapeutic role in many disease contexts, including pathologies of the female reproductive system. As both a prooxidant and antioxidant, EGCG can modulate many cellular pathways important to disease pathogenesis and thus has clinical benefits. This review provides a synopsis of the current knowledge on the beneficial effects of green tea in benign gynecological disorders. Green tea alleviates symptom severity in uterine fibroids and improves endometriosis through anti-fibrotic, anti-angiogenic, and pro-apoptotic mechanisms. Additionally, it can reduce uterine contractility and improve the generalized hyperalgesia associated with dysmenorrhea and adenomyosis. Although its role in infertility is controversial, EGCG can be used as a symptomatic treatment for menopause, where it decreases weight gain and osteoporosis, as well as for polycystic ovary syndrome (PCOS).

Green Tea in Reproductive Cancers: Could Treatment Be as Simple?

Green tea originates from the tea plant Camellia sinensis and is one of the most widely consumed beverages worldwide. Green tea polyphenols, commonly known as catechins, are the major bioactive ingredients and account for green tea's unique health benefits. Epigallocatechin-3-gallate (EGCG), is the most potent catechin derivative and has been widely studied for its pro- and anti-oxidative effects. This review summarizes the chemical and chemopreventive properties of green tea in the context of female reproductive cancers. A comprehensive search of PubMed and Google Scholar up to December 2022 was conducted. All original and review articles related to green tea or EGCG, and gynecological cancers published in English were included. The findings of several in vitro, in vivo, and epidemiological studies examining the effect of green tea on reproductive cancers, including ovarian, cervical, endometrial, and vulvar cancers, are presented. Studies have shown that this compound targets specific receptors and intracellular signaling pathways involved in cancer pathogenesis. The potential benefits of using green tea in the treatment of reproductive cancers, alone or in conjunction with chemotherapeutic agents, are examined, shedding light on new therapeutic strategies for the management of female reproductive cancers.

A Systematic Review of Vitamin D and Fibroids: Pathophysiology, Prevention, and Treatment.

Uterine fibroids are the most common tumor of reproductive-age women worldwide and cause significant morbidity in affected women. Vitamin D has emerged as a potential therapy for uterine fibroids based on experimental and epidemiologic evidence. The objective of this systematic review was to evaluate the role of vitamin D in the pathophysiology of uterine fibroids and its efficacy for prevention and treatment of fibroids. A comprehensive search was conducted of Cochrane Library, Embase, PubMed, Scopus, and Web of Science from inception to March 2022. English-language publications that evaluated vitamin D and uterine fibroids in humans, whether experimental or clinical, were considered. The search yielded 960 publications, and 89 publications met inclusion criteria: 23 preclinical studies, 25 clinical studies, and 41 review articles. Preclinical studies indicated that the vitamin D receptor was decreased in fibroid cells. Vitamin D treatment of fibroid cells decreased proliferation, extracellular matrix protein expression, and Wnt/ß-catenin signaling. Fourteen clinical studies (n = 3535 participants) assessed serum vitamin D level in women with ultrasound-proven fibroids, and all found an inverse correlation between serum vitamin D level and presence of fibroids. Five clinical studies (n = 472 patients) evaluated treatment of fibroids with vitamin D. Four of five studies showed vitamin D significantly inhibited fibroid growth. One pilot study (n = 109 patients) of vitamin D for secondary prevention of fibroids demonstrated smaller recurrent fibroids in the treated group. These studies provide evidence for vitamin D as a therapy for uterine fibroids and underscore the need for well-designed, randomized, placebo-controlled clinical trials.

Rural women participation in farm and off-farm activities and household income in Bangladesh.

The present study was mainly an impact of farm and off-farm activities on household income and participation of rural women in the Thakurgaon district of Bangladesh. The specific aim was to compare the rural women's participation considering their socioeconomic characteristics, income contribution to household income, and its influencing factors. An Independent Sample T-test was used to compare socioeconomic differences. Pearson's correlation test was used to determine the relationship between women's personal income and household income. The propensity Score Matching (PSM) model was used for impact evaluation of off-farm activities. The result of the t-test showed that off-farm activities were significantly ahead for women from the farm women in terms of socioeconomic variables. There was positive and a strong correlation between women's personal income from off-farm activities and their household income. The result of PSM shows that off-farm activities have a positive and significant impact on rural women's income. Estimation of the binary Probit model and marginal effects of related explanatory variables revealed that educational status, family size, work experiences, personal income, saving, and training, significantly affected rural women's involvement in off-farm activities. Therefore, to increase the pace of work, the participation of rural women in off-farm activities needs to be made more effective and efficient, for which government and non-government organizations need to take necessary steps in area-based development (such as work environment, credit facilities, communication, infrastructure, etc.).

Natural Products and Disease Prevention, Relief and Treatment.

This Special Issue focusses on the role of natural products in disease prevention, relief and treatment [...].

The role of Hippo pathway signaling and A-kinase anchoring protein 13 in primordial follicle activation and inhibition.

OBJECTIVE: To determine whether the mechanotransduction and pharmacomanipulation of A-kinase anchoring protein 13 (AKAP13) altered Hippo signaling pathway transcription and growth factors in granulosa cells. Primary ovarian insufficiency is the depletion or dysfunction of primordial ovarian follicles. In vitro activation of ovarian tissue in patients with primary ovarian insufficiency alters the Hippo and phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B/forkhead box O3 pathways. A-kinase anchoring protein 13 is found in granulosa cells and may regulate the Hippo pathway via F-actin polymerization resulting in altered nuclear yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif coactivators and Tea domain family (TEAD) transcription factors. DESIGN: Laboratory studies. SETTING: Translational science laboratory. PATIENT(S): None. INTERVENTION(S): COV434 cells, derived from a primary human granulosa tumor cell line, were studied under different cell density and well stiffness conditions. Cells were transfected with a TEAD-luciferase (TEAD-luc) reporter as well as expression constructs for AKAP13 or AKAP13 mutants and then treated with AKAP13 activators, inhibitors, and follicle-stimulating hormone. MAIN OUTCOME MEASURE(S): TEAD gene activation or inhibition was measured by TEAD-luciferase assays. The messenger ribonucleic acid levels of Hippo pathway signaling molecules, including connective tissue growth factor (CTGF), baculoviral inhibitors of apoptosis repeat-containing 5, Ankyrin repeat domain-containing protein 1, YAP1, and TEAD1, were measured by quantitative real-time polymerase chain reaction. Protein expressions for AKAP13, CTGF, YAP1, and TEAD1 were measured using Western blot. RESULT(S): Increased TEAD-luciferase activity and expression of markers for cellular growth were associated with decreased cell density, increased well stiffness, and AKAP13 activator (A02) treatment. Additionally, decreased TEAD-luc activity and expression of markers for cellular growth were associated with AKAP13 inhibitor (A13) treatment, including a reduced expression of the BIRC5 and ANKRD1 (YAP-responsive genes) transcript levels and CTGF protein levels. There were no changes in TEAD-luc with follicle-stimulating hormone treatment, supporting Hippo pathway involvement in the gonadotropin-independent portion of folliculogenesis. CONCLUSION(S): These findings suggest that AKAP13 mediates Hippo-regulated changes in granulosa cell growth via mechanotransduction and pharmacomanipulation. The AKAP13 regulation of the Hippo pathway may represent a potential target for regulation of follicle activation.

Selective Progesterone Receptor Modulators (SPRMs) and Androgen Receptor Modulators (SARMs) as Treatment for Benign Gynecologic Diseases.

Common benign gynecologic conditions such as uterine fibroids and endometriosis are linked to chronic pelvic pain, abnormal and heavy uterine bleeding, and infertility. Effective medical management of these diseases is an unmet need. The steroid hormones progesterone (P4), estrogen (E2), and testosterone play a major role in reproductive physiology and uterine pathologies. Notably, selective progesterone receptor modulators have shown considerable promise as treatment options for some hormone-dependent conditions. More limited data are available regarding the safety and efficacy of selective androgen receptor modulators. In this report we review current evidence for selective progesterone receptor modulators and selective androgen receptor modulators as treatment options for benign gynecologic conditions.

Simvastatin modulates estrogen signaling in uterine leiomyoma via regulating receptor palmitoylation, trafficking and degradation.

Uterine leiomyomas or fibroids are the most common tumors of the female reproductive tract. Estrogen (E2), a steroid-derived hormone, and its receptors (ERs), particularly ER-α, are important drivers for the development and growth of leiomyomas. We previously demonstrated that simvastatin, a drug used for hyperlipidemia, also possesses anti-leiomyoma properties. The aim of this work is to investigate the impact of simvastatin on ER-α signaling in leiomyoma cells, including its expression, downstream signaling, transcriptional activity, post-translational modification, trafficking and degradation. Primary and immortalized human uterine leiomyoma (HuLM) cells were used for in vitro experiments. Immunodeficient mice xenografted with human leiomyoma tissue explants were used for in vivo studies. Leiomyoma samples were obtained from patients enrolled in an ongoing double-blinded, phase II, randomized controlled trial. Here, we found that simvastatin significantly reduced E2-induced proliferation and PCNA expression. In addition, simvastatin reduced total ER-α expression in leiomyoma cells and altered its subcellular localization by inhibiting its trafficking to the plasma membrane and nucleus. Simvastatin also inhibited E2 downstream signaling, including ERK and AKT pathways, E2/ER transcriptional activity and E2-responsive genes. To explain simvastatin effects on ER-α level and trafficking, we examined its effects on ER-α post-translational processing. We noticed that simvastatin reduced ER-α palmitoylation; a required modification for its stability, trafficking to plasma membrane, and signaling. We also observed an increase in ubiquitin-mediated ER-α degradation. Importantly, we found that the effects of simvastatin on ER-α expression were recapitulated in the xenograft leiomyoma mouse model and human tissues. Thus, our data suggest that simvastatin modulates several E2/ER signaling targets with potential implications in leiomyoma therapy and beyond.

Extracellular matrix and Hippo signaling as therapeutic targets of antifibrotic compounds for uterine fibroids.

BACKGROUND: Uterine fibroids are highly prevalent, collagen-rich, mechanically stiff, fibrotic tumors for which new therapeutic options are needed. Increased extracellular matrix (ECM) stiffness activates mechanical signaling and Hippo/YAP promoting fibroid growth, but no prior studies have tested either as a therapeutic target. We tested the hypothesis that injection of a purified form of collagenase Clostridium histolyticum (CCH) that selectively digests type I and type III collagens would alter ECM stiffness, Hippo signaling, and selectively reduce fibroid cell growth. We also used two FDA-approved drugs, verteporfin and nintedanib, to elucidate the role of Hippo/YAP signaling in uterine fibroid and myometrial cells. METHODS: The clinical trial was registered (NCT02889848). Stiffness of samples was measured by rheometry. Protein expression in surgical samples was analyzed via immunofluorescence. Protein and gene expression in uterine fibroid or myometrial cell lines were measured by real time PCR and western blot, and immunofluorescence. RESULTS: Injection of CCH at high doses (0.1-0.2 mg/cm3 ) into fibroids resulted in a 46% reduction in stiffness in injected fibroids compared to controls after 60 days. Levels of the cell proliferation marker proliferative cell nuclear antigen (PCNA) were decreased in fibroids 60 days after injection at high doses of CCH. Key Hippo signaling factors, specifically the transcriptionally inactive phosphorylated YAP (p-YAP), was increased at high CCH doses, supporting the role of YAP in fibroid growth. Furthermore, inhibition of YAP via verteporfin (YAP inhibitor) decreased cell proliferation, gene and protein expression of key factors promoting fibrosis and mechanotransduction in fibroid cells. Additionally, the anti-fibrotic drug, nintedanib, inhibited YAP and showed anti-fibrotic effects. CONCLUSIONS: This is the first report that in vivo injection of collagenase into uterine fibroids led to a reduction in Hippo/YAP signaling and crucial genes and pathways involved in fibroid growth. These results indicate that targeting ECM stiffness and Hippo signaling might be an effective strategy for uterine fibroids.

Wnt/ß-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities.

Uterine leiomyoma is the most common tumor of the female reproductive system and originates from a single transformed myometrial smooth muscle cell. Despite the immense medical, psychosocial, and financial impact, the exact underlying mechanisms of leiomyoma pathobiology are poorly understood. Alterations of signaling pathways are thought to be instrumental in leiomyoma biology. Wnt/ß-catenin pathway appears to be involved in several aspects of the genesis of leiomyomas. For example, Wnt5b is overexpressed in leiomyoma, and the Wnt/ß-catenin pathway appears to mediate the role of MED12 mutations, the most common mutations in leiomyoma, in tumorigenesis. Moreover, Wnt/ß-catenin pathway plays a paracrine role where estrogen/progesterone treatment of mature myometrial or leiomyoma cells leads to increased expression of Wnt11 and Wnt16, which induces proliferation of leiomyoma stem cells and tumor growth. Constitutive activation of ß-catenin leads to myometrial hyperplasia and leiomyoma-like lesions in animal models. Wnt/ß-catenin signaling is also closely involved in mechanotransduction and extracellular matrix regulation and relevant alterations in leiomyoma, and crosstalk is noted between Wnt/ß-catenin signaling and other pathways known to regulate leiomyoma development and growth such as estrogen, progesterone, TGFß, PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, IGF, Hippo, and Notch signaling. Finally, evidence suggests that inhibition of the canonical Wnt pathway using ß-catenin inhibitors inhibits leiomyoma cell proliferation. Understanding the molecular mechanisms of leiomyoma development is essential for effective treatment. The specific Wnt/ß-catenin pathway molecules discussed in this review constitute compelling candidates for therapeutic targeting.

Mechanical stiffness augments ligand-dependent progesterone receptor B activation via MEK 1/2 and Rho/ROCK-dependent signaling pathways in uterine fibroid cells.

OBJECTIVE: To test whether mechanical substrate stiffness would influence progesterone receptor B (PRB) signaling in fibroid cells. Uterine fibroids feature an excessive extracellular matrix, increased stiffness, and altered mechanical signaling. Fibroid growth is stimulated by progestins and opposed by anti-progestins, but a functional interaction between progesterone action and mechanical signaling has not been evaluated. DESIGN: Laboratory studies. SETTING: Translational science laboratory. PATIENT(S)/ANIMAL(S): Human fibroid cell lines and patient-matched fibroid and myometrial cell lines. INTERVENTION(S): Progesterone receptor B-dependent reporter assays and messenger RNA quantitation in cells cultured on stiff polystyrene plates (3GPa) or soft silicone plates (930KPa). Pharmacologic inhibitors of extracellular signal-related protein kinase (ERK) kinase 1/2 (MEK 1/2; PD98059), p38 mitogen-activated protein kinase (SB202190), receptor tyrosine kinases (RTKs; nintedanib), RhoA (A13), and Rho-associated coiled-coil kinase (ROCK; Y27632). MAIN OUTCOME MEASURE(S): Progesterone-responsive reporter activation. RESULT(S): Fibroid cells exhibited higher PRB-dependent reporter activity with progesterone (P4) in cells cultured on stiff vs. soft plates. Mechanically induced PRB activation with P4 was decreased 62% by PD98059, 78% by nintedanib, 38% by A13, and 50% by Y27632. Overexpression of the Rho-guanine nucleotide exchange factor (Rho-GEF), AKAP13, significantly increased PRB-dependent reporter activity. Collagen 1 messenger RNA levels were higher in fibroid cells grown on stiff vs. soft plates with P4. CONCLUSION(S): Cells cultured on mechanically stiff substrates had enhanced PRB activation via a mechanism that required MEK 1/2 and AKAP13/RhoA/ROCK signaling pathways. These studies provide a framework to explore the mechanisms by which mechanical stiffness affects progesterone receptor activation.

Hop and artichoke extracts inhibit expression of extracellular matrix components in uterine leiomyoma cells.

OBJECTIVE: To screen 14 different plant extracts for their antifibrotic effect on human primary leiomyoma and healthy myometrial cells. DESIGN: Preclinical study. SETTING: University research laboratory. PATIENT(S): Human uterine leiomyoma and matched myometrial tissues were obtained from Caucasian premenopausal women with symptomatic uterine fibroids at the time of hysterectomy. INTERVENTION(S): Primary human leiomyoma and myometrial cells were cultured in the absence or presence of the plant extracts. MAIN OUTCOME MEASURE(S): Quantification of the expression of extracellular matrix components, such as fibronectin 1 (FN1), collagen type I alpha 1 (COL1A1), and versican (VCAN), and the profibrotic growth factor activin A or inhibin beta A subunit (INHBA). RESULT(S): The cells were treated with the 14 extracts for 48 hours, and we measured FN1 messenger RNA (mRNA) expression. Of the 14 extracts, about (ABO) ABO-2 (hop) and ABO-9 (artichoke) significantly reduced FN1 expression in both the cell types. Next, we evaluated the effect of fractions of these 2 extracts on the mRNA expression of FN1 and other extracellular matrix components, such as COL1A1, VCAN, and INHBA, in leiomyoma and myometrial cells. We found that ABO-2 (hop) and ABO-9 (artichoke) as well as their fractions, ABO-AR-2016-015 (fraction of ABO-2) and ABO-AR-2014-168 (fraction of ABO-9), reduced the mRNA expression of FN1, COL1A1, VCAN, and INHBA in primary leiomyoma cells. In primary myometrial cells, the mRNA expression of FN1, COL1A1, VCAN, and INHBA was not greatly affected. CONCLUSION(S): These results suggest that the hop and artichoke extracts possess antifibrotic properties and support additional evaluation using in vivo models.

Simvastatin ameliorates altered mechanotransduction in uterine leiomyoma cells.

BACKGROUND: Uterine leiomyomas, the most common tumors of the female reproductive system, are characterized by excessive deposition of disordered stiff extracellular matrix and fundamental alteration in the mechanical signaling pathways. Specifically, these alterations affect the normal dynamic state of responsiveness to mechanical cues in the extracellular environment. These mechanical cues are converted through integrins, cell membrane receptors, to biochemical signals including cytoskeletal signaling pathways to maintain mechanical homeostasis. Leiomyoma cells overexpress ß1 integrin and other downstream mechanical signaling proteins. We previously reported that simvastatin, an antihyperlipidemic drug, has antileiomyoma effects through cellular, animal model, and epidemiologic studies. OBJECTIVE: This study aimed to examine the hypothesis that simvastatin might influence altered mechanotransduction in leiomyoma cells. STUDY DESIGN: This is a laboratory-based experimental study. Primary leiomyoma cells were isolated from 5 patients who underwent hysterectomy at the Department of Gynecology and Obstetrics of the Johns Hopkins University Hospital. Primary and immortalized human uterine leiomyoma cells were treated with simvastatin at increasing concentrations (0.001, 0.01, 0.1, and 1 µM, or control) for 48 hours. Protein and mRNA levels of ß1 integrin and extracellular matrix components involved in mechanical signaling were quantified by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. In addition, we examined the effect of simvastatin on the activity of Ras homolog family member A using pull-down assay and gel contraction. RESULTS: We found that simvastatin significantly reduced the protein expression of ß1 integrin by 44% and type I collagen by 60% compared with untreated leiomyoma cells. Simvastatin-treated cells reduced phosphorylation of focal adhesion kinase down to 26%-60% of control, whereas it increased total focal adhesion kinase protein expression. Using a Ras homolog family member A pull-down activation assay, we observed reduced levels of active Ras homolog family member A in simvastatin-treated cells by 45%-85% compared with control. Consistent with impaired Ras homolog family member A activation, simvastatin treatment reduced tumor gel contraction where gel area was 122%-153% larger than control. Furthermore, simvastatin treatment led to reduced levels of mechanical signaling proteins involved in ß1 integrin downstream signaling, such as A-kinase anchor protein 13, Rho-associated protein kinase 1, myosin light-chain kinase, and cyclin D1. CONCLUSION: The results of this study suggest a possible therapeutic role of simvastatin in restoring the altered state of mechanotransduction signaling in leiomyoma. Collectively, these findings are aligned with previous epidemiologic studies and other reports and support the need for clinical trials.

Selective Progesterone Receptor Modulators-Mechanisms and Therapeutic Utility.

Selective progesterone receptor modulators (SPRMs) are a new class of compounds developed to target the progesterone receptor (PR) with a mix of agonist and antagonist properties. These compounds have been introduced for the treatment of several gynecological conditions based on the critical role of progesterone in reproduction and reproductive tissues. In patients with uterine fibroids, mifepristone and ulipristal acetate have consistently demonstrated efficacy, and vilaprisan is currently under investigation, while studies of asoprisnil and telapristone were halted for safety concerns. Mifepristone demonstrated utility for the management of endometriosis, while data are limited regarding the efficacy of asoprisnil, ulipristal acetate, telapristone, and vilaprisan for this condition. Currently, none of the SPRMs have shown therapeutic success in treating endometrial cancer. Multiple SPRMs have been assessed for efficacy in treating PR-positive recurrent breast cancer, with in vivo studies suggesting a benefit of mifepristone, and multiple in vitro models suggesting the efficacy of ulipristal acetate and telapristone. Mifepristone, ulipristal acetate, vilaprisan, and asoprisnil effectively treated heavy menstrual bleeding (HBM) in patients with uterine fibroids, but limited data exist regarding the efficacy of SPRMs for HMB outside this context. A notable class effect of SPRMs are benign, PR modulator-associated endometrial changes (PAECs) due to the actions of the compounds on the endometrium. Both mifepristone and ulipristal acetate are effective for emergency contraception, and mifepristone was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of Cushing's syndrome due to its additional antiglucocorticoid effect. Based on current evidence, SPRMs show considerable promise for treatment of several gynecologic conditions.