Ulipristal acetate, a selective progesterone receptor modulator, induces cell death via inhibition of STAT3/CCL2 signaling pathway in uterine sarcoma.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator and is used for the treatment of uterine leiomyoma (a benign tumor). Uterine sarcoma which is highly malignant cancer with a poor prognosis is clinically resembled with uterine leiomyoma. There has been no experimental research on the effect of UPA on uterine sarcoma. In this study, we examined the efficacy of UPA in uterine sarcoma with in vitro and in vivo animal models. Cytotoxicity of UPA was determined in uterine sarcoma cell lines (MES-SA, SK-UT-1, and SK-LMS-1). Apoptotic genes and signaling pathways affected by UPA were analyzed by complementary DNA (cDNA) microarray of uterine sarcoma cell lines and western blot, respectively. An in vivo efficacy of UPA was examined with uterine sarcoma cell line- and patient-derived xenograft (PDX) mice models. UPA inhibited cell growth in uterine sarcoma cell lines and primary culture cells from a PDX mouse (PDX-C). cDNA microarray analysis revealed that CCL2 was highly down-regulated by UPA. Phosphorylation and the total expression of STAT3 were inhibited by UPA. UPA also inhibited CCL2 and STAT3 in PDX-C. The inhibitory effect of UPA had not changed in the overexpression of PR and treatment of progesterone. In vivo efficacy studies with cell line-derived xenografts and a PDX model with leiomyosarcoma, a typical uterine sarcoma, demonstrated that UPA significantly decreased tumor growth. UPA had significant anti-tumor effects in uterine sarcoma through the inhibition of STAT3/CCL2 signaling pathway and might be a potential therapeutic agent to treat this disease.

Next step in the development of mesoprogestins: the preclinical profile of EC313.

Introduction: The pharmacological target for progesterone, different progestins, and Selective Progesterone Receptor Modulators (SPRMs) is the nuclear progesterone receptor (PR). EC313 is a new member of a subgroup of SPRMs, mesoprogestins, which combine especially PR- agonistic and PR-antagonistic activities in one molecule. Methods: The suitable in vivo-model for the differentiation of SPRMs from the subgroup of mesoprogestins is the estrogen-primed juvenile rabbit endometrium assay (McPhail Assay). Remarkably, in contrast to other well-known SPRMs with no agonistic effects in this test, EC313 shows clear partial PR-agonistic effects that are higher than that of the well-known mesoprogestin Asoprisnil which already demonstrated remarkable clinical effectiveness for the treatment of uterine fibroids and endometriosis. The findings from the guinea pig studies presented here can be the impetus for further preclinical development of EC313. This model shows the same features for the termination of pregnancy by antiprogestins such as Mifepristone and Ulipristal acetate (UPA) in humans. Moreover, it is possible to distinguish between progestational and anti-progestational activities in the same experiment. Results: The EC313 treatment reveals PR dominance in the genital tract and inhibits unopposed estrogenic effects. In very high doses (30.0 mg/animal/day subcutaneously (s.c.)) given twice on pregnancy days 43 and 44, no premature labor was induced (in contrast to UPA, dosed at 10.0 and 30. mg/animal/day s.c.). The anti-ovulatory activity of EC313 exceeds that of Ulipristal acetate or Mifepristone. EC313 binds to the steroid receptors in vitro with a similar affinity as the natural ligand progesterone. At the glucocorticoid receptor (GR) EC313 acts as a weak inhibitor. Minor activities at the human androgen receptor (AR) and mineralocorticoid receptor (MR) are considered negligible. No binding to the estradiol receptor was detected. In contrast to some in vitro-receptor findings, estrogenic, anti-estrogenic, androgenic, anti-androgenic, glucocorticoid, and anti-glucocorticoid actions were absent in vivo. The tissue selectivity of EC313 was demonstrated previously by reducing the growth and proliferation of uterine fibroids in animal models (lowest effective dosage 0.1 mg/kg/day s.c.).. As shown in this article, the anti-fibroid activity of EC313 was confirmed with a 10 times lower dosage (0.01 mg/kg/day s.c.). It was also shown that EC313 reduces the growth of endometriotic lesions in a human xenograft immune-deficient (NOD-SCID) mice model with a comparatively very low dosage range. In the aforementioned EC313 activity model, UPA was tested as the reference compound, the clinical effectiveness of which has already been demonstrated. Discussion: For an explanation of these findings, the possibility is discussed that the mixed agonistic/antagonistic feature of EC313 is tissue target-specific based on its super-additive synergism characteristic for active bifunctional agents. In conclusion, the specific pharmacodynamic profile of this compound opens the possibility for the development of a drug with a distinct pharmaco-endocrinological profile against uterine fibroids, endometriosis, and other PR-dependent gynecological diseases.

Highlights on Medical Treatment of Uterine Fibroids.

Uterine fibroids (leiomyomas or myomas) are the most frequent benign tumors in women. Heavy menstrual bleeding with resultant anemia, dysmenorrhea, chronic pelvic pain, infertility, urinary symptoms and constipation are generally associated with uterine fibroids (UFs). Although strategies mainly resort to surgical intervention, medical treatments are considered the first-line treatment to preserve fertility and avoid surgery. The aim of this review is to offer available and the newest medical treatment options for symptomatic UFs. Various medical therapies are now available for women with uterine fibroids, although each therapy has its own advantages and disadvantages. Our topic specifically explores gonadotropin-releasing hormone (GnRH) analogs and selective progesterone receptor modulators (SPRMs), but also provides the reader with useful advice on the therapies for fibroids available after the recent European Medicines Agency (EMA) warning (EMA/160220/2020). The treatment options depend on the personal treatment objectives of the patients, in addition to treatment effectiveness and necessity for recurrent interventions.

90 YEARS OF PROGESTERONE: Selective progesterone receptor modulators in gynaecological therapies.

Abnormal uterine bleeding (AUB) is a chronic, debilitating and common condition affecting one in four women of reproductive age. Current treatments (conservative, medical and surgical) may be unsuitable, poorly tolerated or may result in loss of fertility. Selective progesterone receptor modulators (SPRMs) influence progesterone-regulated pathways, a hormone critical to female reproductive health and disease; therefore, SPRMs hold great potential in fulfilling an unmet need in managing gynaecological disorders. SPRMs in current clinical use include RU486 (mifepristone), which is licensed for pregnancy interruption, and CDB-2914 (ulipristal acetate), licensed for managing AUB in women with leiomyomas and in a higher dose as an emergency contraceptive. In this article, we explore the clinical journey of SPRMs and the need for further interrogation of this class of drugs with the ultimate goal of improving women's quality of life.

Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure.

BACKGROUND: Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis. OBJECTIVE AND RATIONALE: We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments. SEARCH METHODS: We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment. OUTCOMES: Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response. WIDER IMPLICATIONS: Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.

Ulipristal Acetate Prior to Surgery for Endometriosis.

Selective progesterone receptor modulators may have a role in the treatment of endometriosis. The aim of this report is to review the effect of ulipristal acetate (UPA) on endometriosis lesions and symptoms in women treated prior to surgery. A pathology review of eutopic endometrium and endometriotic lesions was conducted by two gynecologic pathologists. The main outcome measures reported are pain reduction, amenorrhea, and pathologic progesterone receptor modulator-associated endometrial changes (PAECs). Overall, fifteen women with endometriosis received UPA over a 27-month study period. UPA was administered in an intermittent fashion in the majority of patients while 27% of patients had continuous treatment, between 6 and 24 months. Eleven (73%) patients reported amenorrhea on UPA and 11 (92%) of 12 patients with pain reported pain reduction or resolution. Fourteen patients (93%) proceeded with surgical management. Thirteen (93%) patients underwent excision of suspected endometriosis at surgery. Twelve cases (86%) had concurrent eutopic endometrium specimens and PAEC was identified in 58% (n = 7). Among the 14 cases that underwent surgery, a total of 49 extraovarian sites were sampled. Endometriosis was definitively identified in 31 (63%) of these sites. Three cases (21%) showed morphologic features similar to PAEC within foci of endometriosis. All cases of PAEC-like features in endometriosis also had PAEC in the endometrium. These patients had all noted pain reduction and amenorrhea preoperatively. In conclusion, PAECs may be found in endometriosis lesions in patients treated with UPA. Further prospective investigation is required to evaluate the efficacy and safety of SPRMs in women with endometriosis.

The Biological Impact of Ulipristal Acetate on Cellular Networks Regulating Uterine Leiomyoma Growth.

Uterine Fibroids (UFs), or leiomyomas, represent the most frequent pelvic tumor in reproductive-aged women. Although of benign origin, UFs decrease fertility and cause significant reproductive dysfunctions. Compared to normal myometrium, UFs are characterized by a clinical and molecular heterogeneity as demonstrated by the presence of multiple genetic alterations and altered signaling pathways. Recently, selective progesteronereceptor modulators (SPRM), as ulipristal acetate (UPA), have demonstrated their clinical benefits by reducing tumor growth and extracellular matrix deposition. For these reasons, UPA is used in the clinical practice as an intermittent treatment for women symptomatic for UFs or, sometimes, before a myomectomy. However, drug effects on signaling pathways frequently upregulated in UFs remain largely unknown. In fact, the mechanisms of action of the UPA on UFs and on the surrounding areas are not yet understood. To learn more about UPA molecular mechanisms, UF samples were treated ex vivo with UPA and profiled for drug effects on selected markers. During this preliminary ex vivo UPA administration, significant changes were observed in the expression levels of proteins related to cell cycle regulation, cytoskeleton remodeling, and drug resistance. The UPA administration reduced cofilin, Erk and Src phosphorylation, p27 and ezrin protein levels, but not Akt phosphorylation and cyclin D1 and ß-catenin levels. This preliminary ex vivo biological analysis provided new insights into the mechanism of action of UPA in the treatment of UFs, which could better explain the biological functioning of the drug on UFs.

Autophagy up-regulation by ulipristal acetate as a novel target mechanism in the treatment of uterine leiomyoma: an in vitro study.

OBJECTIVE: To assess the effect of ulipristal acetate (UPA) on the autophagic process of uterine leiomyoma cells. DESIGN: In vitro study in primary cultures of leiomyoma and myometrial cells isolated from biopsy specimen, and gene expression evaluation in biopsy material. SETTING: Cellular pathology laboratory. PATIENT(S): Premenopausal women (without hormonal treatment) undergoing myomectomy or hysterectomy for symptomatic leiomyomas. INTERVENTION(S): Surgical specimens collected from uterine leiomyomas and matched normal myometria. MAIN OUTCOME MEASURE(S): After treatment of myometrial and leiomyoma cells with UPA, autophagy was evaluated by Western blot analysis of the typical biochemical markers, LC3-II, LC3-II:LC3-I ratio, and p62/SQSTM1. The expression level of Atg7 and Atg4D proteins was also assessed by Western blot. RESULT(S): The increase of LC3-II protein, LC3-II:LC3-I ratio, and p62/SQSTM1 protein indicates that UPA treatment up-regulates the autophagic response in leiomyoma cells, whereas these markers were almost unchanged in myometrial cells. Consistently, an increased level of Atg7 and Atg4D proteins was observed only in UPA-treated leiomyoma cells. The autophagic machinery is put into motion selectively in these cells, despite that the basal messenger RNA levels of LC3, SQSTM1, and ATG7 in leiomyoma biopsy specimen were not significantly different from those found in normal myometrial biopsy material. CONCLUSION(S): In vitro UPA treatment stimulates the autophagic response selectively in leiomyoma cells, which adds a novel indication for the clinical use of this selective P receptor (PR) modulator. Autophagy up-regulation may potentially contribute to the leiomyoma shrinkage occurring in UPA-treated patients and warrants further study.

Uterine fibroid management: Today and tomorrow.

Current treatments for fibroids are mainly surgical and expensive, so alternatives need to be found. It is, therefore, vital to develop and evaluate alternatives to surgical procedures, especially when fertility preservation is the goal. Selective progesterone receptor modulators (SPRMs) are synthetic compounds that have either an agonistic or antagonistic impact on target tissues determined by their binding to progesterone receptors. Their mixed activity depends on recruitment of cofactors that regulate transcription along so-called genomic pathways, as well as nongenomic interactions with other signaling pathways. There is no doubt that surgery remains indicated in some instances, but we must now establish whether use of SPRMs (notably ulipristal acetate) allows less invasive surgery or even complete avoidance of surgery. Long-term intermittent administration of ulipristal acetate will undoubtedly change our approach to the management of uterine fibroids according to the International Federation of Gynecology and Obstetrics classification, which provides a comprehensive basis for different treatment options. When considering less invasive techniques (uterus-sparing options like myomectomy), the choice is guided by the size, number and location of fibroids, as well as the personal experience of the gynecologist and available equipment. There is now a growing body of evidence pointing to the crucial role of progesterone pathways in the pathophysiology of uterine fibroids. SPRMs should, therefore, be considered an alternative to surgical therapy, or at least an adjunct to surgery, as illustrated in the algorithms. © 2019 Japan Society of Obstetrics and Gynecology.

Uterine fibroids: an update on current and emerging medical treatment options.

Uterine fibroids are the most common gynecological disorder, classically requiring surgery when symptomatic. Although attempts at finding a nonsurgical cure date back to centuries, it is only around the middle of the last century that serious attempts at a medical treatment were carried out. Initially, both progestins and estrogen-progestin combinations have been utilized, although proof of their usefulness is lacking. A major step forward was achieved when peptide analogs of the GnRH were introduced, first those with superagonist properties and subsequently those acting as antagonists. Initially, the latter produced side effects preventing their routine utilization; eventually, this problem was overcome following the synthesis of cetrorelix. Because both types of analogs produce hypoestrogenism, their use is limited to a maximum of 6 months and, for this reason, today they are utilized as an adjuvant treatment before surgery with overall good results. Over the last decade, new, nonpeptidic, orally active GnRH-receptor blockers have also been synthesized. One of them, Elagolix, is in the early stages of testing in women with fibroids. Another fundamental development has been the utilization of the so-called selective progesterone receptor modulators, sometimes referred to as "antiprogestins". The first such compound to be applied to the long-term treatment of fibroids was Mifepristone; today, this compound is mostly used outside of Western Countries, where the substance of choice is Ulipristal acetate. Large clinical trials have proven the effectiveness of Ulipristal in the long-term medical therapy of fibroids, although some caution must be exercised because of the rare occurrence of liver complications. All selective progesterone receptor modulators produce unique endometrial changes that are today considered benign, reversible, and without negative consequences. In conclusion, long-term medical treatment of fibroids seems possible today, especially in premenopausal women.

Functional genomic analysis of the human receptive endometrium transcriptome upon administration of mifepristone at the time of follicle rupture.

The aim of this study was to analyze the effects of progesterone withdrawal on gene transcription in receptive endometrium by the administration of a single dose of 50 mg of the anti-progesterone receptor mifepristone (MFP) at the time of follicle rupture (FR). Six volunteer ovulatory women were studied, taking endometrial biopsies of three control and three MFP-treated women on days LH+2 (C-LH+2) and LH+7 (T-MFP), respectively. The biopsies were prepared for RNA isolation or histological and immunohistochemistry studies. The genomic data from 14 women (C-LH+7) were included as a historical control. The functional genomic analysis of the differentially expressed genes showed that MFP interfered negatively with the bio-functions decidualization of uterus and implantation of blastocyst and embryo. The results of this study confirm but also give new information on how MFP affects endometrial gene expression when administered at the time of FR and the dose used in emergency contraception.

Fibroid management in premenopausal women.

Uterine fibroids are the most common tumors affecting premenopausal women, responsible for bleeding, pain, and reduced quality of life. When symptomatic, their management mainly involves surgery, which is all too often radical (hysterectomy). While surgical options sparing the uterus (hysteroscopic and laparoscopic myomectomy) and other non-surgical approaches do indeed exist, drug-based therapies are associated with lower costs and morbidity rates. Since progesterone is required for fibroid growth, gonadotropin agonists have been used to control bleeding and decrease fibroid volume, but they only represent a temporary remedy due to adverse events. Ulipristal acetate (UPA), a selective progesterone receptor modulator, is indicated for fibroid management. It is safe, provides fast control of bleeding, and causes sustained fibroid volume reduction in the vast majority of cases (80%). Indeed, UPA-treated fibroids shrink by a combination of inhibition of cell proliferation, stimulation of cell death, and fibrosis resorption. In the case of symptom recurrence, repeated intermittent 3-month courses of daily UPA considerably maximize the impact of treatment, sometimes resulting in complete disappearance of treated fibroids. Despite the therapeutic dose of UPA being very well tolerated, patients with liver anomalies or disorders should be excluded at screening according to European Medicines Agency-Pharmacovigilance Risk Assessment Committee (PRAC) recommendations. We therefore propose new algorithms for fibroid management in premenopausal women with symptomatic fibroids, depending on their localization, the patient's wishes, and clinical response, while monitoring liver enzymes and bilirubin, as recommended by the PRAC, in order to minimize the risks of possible liver toxicity.

Non-surgical management of uterine myoma / 中国实用妇科与产科杂志

Uterine fibroids are benign diseases with high incidence and unknown pathogenesis.Currently,fibroid excavation or hysterectomy is the most commonly used treatment,but for women who require conservative treatment or with fertility requirements,there is still no optimal treatment option.At present,GnRH agonists/antagonists,selective progesterone receptor antagonists,levonorgestrel sustained release,uterine artery embolization,high-intensity focused ultrasound and other non-traditional surgical treatments provide new treatment options for conservative treatment of uterine fibroids from different angles.

Vilaprisan for treating uterine fibroids.

INTRODUCTION: The medical strategy to antagonize myoma size and related-symptoms is to reduce estrogen and progesterone activity on myomas. This can be obtained with the GnRH agonist (GnRHa) or with compounds that antagonize progesterone stimulatory activity on myomas. Selective progesterone receptor modulators (SPRMs) bind progesterone receptor (PR), leading to both agonist and antagonist effects. The result of SPRMs's action is tissue-specific and it depends on the particular affinity and strength of each SPRM. Area covered: Ulipristal acetate (UPA) is the first SPRM registered for myoma treatment. UPA reduces heavy uterine bleeding within 7 days from the onset of treatment, whereas a longer time is required with GnRHa treatment. Vilaprisan is a novel powerful SPRM. Phase I and II studies give encouraging results on the efficacy of vilaprisan at different doses. Like other SPRMs, vilaprisan induces benign changes of endometrium (PR modulator-associated endometrial changes, PAECs). These disappear as treatment is discontinued. Unlike GnRHa treatment, neither UPA nor vilaprisan induce hypoestrogenism and associated symptoms. Phase III studies are ongoing to confirm efficacy and safety of vilaprisan in long-term treatment of symptomatic fibroids. Expert opinion: It is fundamental to underline the rapidity of action (only 3 days) in the control of myoma-related bleeding.

Emerging treatment options for uterine fibroids.

INTRODUCTION: Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Current management strategies involve mainly surgical interventions, but the choice of treatment is guided by patient age and desire to preserve fertility or avoid 'radical' surgery such as hysterectomy. Areas covered: There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids, leading to increasing use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate. We searched all published studies on medical management of fibroids with SPRMs. Expert opinion: The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.

[New medical treatments for painful endometriosis: CNGOF-HAS Endometriosis Guidelines]. / Place des nouveaux traitements médicaux dans l'endométriose douloureuse, RPC Endométriose CNGOF-HAS.

OBJECTIVE: The objective of this work is to evaluate the place of new treatments in the management of endometriosis outside the context of infertility. METHODS: A review of the literature was conducted by consulting Medline data until July 2017. RESULTS: Dienogest is effective compared to placebo in short term (NP2) and long term (NP4) for the treatment of painful endometriosis. In comparison with GnRH agonists, dienogest is also effective in terms of decreased pain and improved quality of life in non-operated patients (NP2) as well as for recurrence of lesions and symptomatology postoperatively (NP2). Data on GnRH antagonists, selective progesterone receptor modulators as well as selective inhibitors (anti-TNF-α, matrix metalloprotease inhibitors, angiogenesis growth factor inhibitors) are insufficient to provide evidence of interest in clinical practice for the management of painful endometriosis (NP3). CONCLUSION: Dienogest is recommended as second-line therapy for the management of painful endometriosis (Grade B). Because of lack of evidence, aromatase inhibitors, elagolix, SERM, SPRM and anti-TNF-α are not recommended for the management of painful endometriosis (Grade C).

The past, present, and future of selective progesterone receptor modulators in the management of uterine fibroids.

Uterine fibroids are common in women of reproductive age and can have a significant impact on quality of life and fertility. Although a number of international obstetrics/gynecology societies have issued evidence-based clinical practice guidelines for the management of symptomatic uterine fibroids, many of these guidelines do not yet reflect the most recent clinical evidence and approved indication for one of the key medical management options: the selective progesterone receptor modulator class. This article aims to share the clinical experience gained with selective progesterone receptor modulators in Europe and Canada by reviewing the historical development of selective progesterone receptor modulators, current best practices for selective progesterone receptor modulator use based on available data, and potential future uses for selective progesterone receptor modulators in uterine fibroids and other gynecologic conditions.

The current place of medical therapy in uterine fibroid management.

Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid "radical" surgery. Surgical and non-surgical approaches include hysterectomy myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization, and magnetic resonance-guided focused ultrasound surgery. The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids, and the efficacy of long-term intermittent use of selective progesterone receptor modulators such as ulipristal acetate was recently demonstrated by randomized controlled studies.

Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids.

Uterine fibroids (UFs, AKA leiomyoma) are the most important benign neoplastic threat to women's health, with costs up to hundreds of billions of health care dollars worldwide. Uterine fibroids caused morbidities exert a tremendous health toll, impacting the quality of life of women of all ethnicities, especially women of color. Clinical presentations include heavy vaginal bleeding, pelvic pain, bulk symptoms, subfertility, and obstetric complications. Current management strategies heavily lean toward surgical procedures; nonetheless, the choice of treatment is generally subject to patient's age and her desire to preserve future fertility. Women with UF who desire to maintain future fertility potential face a dilemma because of the limited treatment choices that are currently available to help them achieve that goal. Recently, ulipristal acetate the first of the promising family of oral selective progesterone receptor modulators has been approved for UF treatment in Europe, Canada, and several other countries and is under review for possible approval in the USA. In this review article, we discuss recent advances in the management options against UF with a bend toward oral effective long-term treatment alternatives who are particularly suited for those seeking to preserve their future fertility potential. We also explore the transformative concept of primary and secondary UF prevention using these new anti-UF agents. We envision a remarkable shift in the management of UF in future years from surgical/invasive treatment to orally administrated options; clearly, this potential shift will require additional intense clinical research.

The history and use of the progesterone receptor modulator ulipristal acetate for heavy menstrual bleeding with uterine fibroids.

Progesterone receptor modulators (PRM) or selective progesterone receptor modulators have two remarkable effects in treated women. They considerably suppress endometrial bleeding by incompletely understood mechanisms, and when administered in women with symptomatic fibroids, they produce a significant and potentially long-term decrease in fibroid volume. The crucial advantage of this therapy lies with the absence of suppression of ovarian oestrogen secretion, which is in contrast to GnRH agonists. Long-term treatments have proven to be useful, especially in women approaching the menopausal transition. However, their use is associated with endometrial modifications called PRM-associated endometrial changes (PAECs). Although these abnormalities are now described as benign, the treatment is best administered in an intermittent manner where the PAECs rapidly disappear, while the beneficial effects on fibroid size and uterine bleeding are maintained or even improved in the long term.