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

Open AccessPublished:December 21, 2017DOI:https://doi.org/10.1016/j.ajog.2017.12.206
      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.

      Key words

      Introduction

      Uterine fibroids (UF) are common in women of reproductive age, with a prevalence of up to 80% by age 50 years.
      • Baird D.D.
      • Dunson D.B.
      • Hill M.C.
      • et al.
      High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence.
      Although many fibroids are asymptomatic, in 20-50% of cases they can cause abnormal uterine bleeding (AUB), anemia, bulk symptoms, and fertility issues.
      • Vilos G.A.
      • Allaire C.
      • Laberge P.Y.
      • et al.
      The management of uterine leiomyomas.
      Traditionally, surgery has been the mainstay of management for symptomatic UF, with either myomectomy for fertility preservation, or hysterectomy if definitive treatment is desired. Nonsurgical conservative interventions include uterine artery embolization, focused energy delivery systems, and radio frequency myolysis.
      • Vilos G.A.
      • Allaire C.
      • Laberge P.Y.
      • et al.
      The management of uterine leiomyomas.
      Until recently, medical management for UF symptoms has been limited to oral contraceptives, levonorgestrel-releasing intrauterine systems, progestins, nonsteroidal antiinflammatory drugs, tranexamic acid, danazol, and gonadotropin-releasing hormone agonists (GnRHas). Recently, a new class of medications has become available for the treatment of UF: the selective progesterone receptor (PR) modulators (SPRMs). This article reviews the development and use of SPRMs and discusses how they best fit into the management algorithm of patients with symptomatic UF.

      The past

      Traditionally, the dominant thought was that fibroid growth was fueled by estrogen, based on in vitro studies and the clinical observation that the estrogen-reducing GnRHas could reduce fibroid volume and induce amenorrhea. More recently, it has been discovered that progesterone and PRs are required for cellular proliferation and fibroid growth.
      • Ishikawa H.
      • Ishi K.
      • Serna V.A.
      • et al.
      Progesterone is essential for maintenance and growth of uterine leiomyoma.
      Compared to the surrounding myometrium, fibroids express elevated levels of both types of PR: PR-A and PR-B.
      • Tsigkou A.
      • Reis F.M.
      • Lee M.H.
      • et al.
      Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms.
      Progesterone and its receptors therefore represent potential targets for inhibiting UF growth.
      SPRMs are designed to compete at the PR binding site in a tissue-specific manner. Binding of the SPRM to the PR leads to a mix of agonistic and antagonistic effects. The relative strength of these opposing effects may be related to the proportions of PR-A and PR-B in the particular tissue and the SPRM’s specific affinity for each receptor isoform.
      • Bouchard P.
      • Chabbert-Buffet N.
      • Fauser B.C.
      Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety.
      By acting on PRs throughout the reproductive system, SPRMs induce several effects that assist in bleeding control and fibroid shrinkage. These include direct antiproliferative and proapoptotic effects on leiomyoma cells; endometrial changes that reduce bleeding; and inhibition of the pituitary gland’s luteinizing hormone surge, resulting in anovulation and subsequent amenorrhea.
      • Donnez J.
      • Dolmans M.M.
      Uterine fibroid management: from the present to the future.
      The first SPRM, mifepristone, was originally discovered serendipitously in a search for synthetic ligands of the glucocorticoid receptor. Subsequent animal studies revealed that it was more active as an antiprogesterone agent and an abortifacient.
      • Chabbert-Buffet N.
      • Pintiaux A.
      • Bouchard P.
      The imminent dawn of SPRMs in obstetrics and gynecology.
      It was initially developed and commercialized for pregnancy termination and has more recently been investigated as a treatment for UF. Mifepristone has been studied in randomized trials against placebo and leuprolide acetate at doses from 5-50 mg per day. A Cochrane Review
      • Tristan M.
      • Orozco L.J.
      • Steed A.
      • et al.
      Mifepristone for uterine fibroids.
      concluded that mifepristone is effective at controlling bleeding and improving patient quality of life (QoL) in UF; although mifepristone is used to treat UF in some regions, it does not have a formal indication for this use in any jurisdiction.
      Several other SPRMs have been studied in UF, notably asoprisnil, telapristone acetate, vilaprisan, and ulipristal acetate (UPA) (Figure 1). As a class, the SPRMs have been shown to be effective for improving QoL, decreasing menstrual blood loss, and achieving amenorrhea.
      • Murji A.
      • Whitaker L.
      • Chow T.L.
      • Sobel M.L.
      Selective progesterone receptor modulators (SPRMs) for uterine fibroids.
      There have been 2 randomized trials evaluating asoprisnil from 5-20 mg per day. These studies showed that asoprisnil is able to suppress uterine bleeding in a dose-dependent manner in patients with UF.
      • Chwalisz K.
      • Larsen L.
      • Mattia-Goldberg C.
      • et al.
      A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      Its clinical development was halted in 2007 due to a change in priorities by its developer. Telapristone acetate is another SPRM that has shown promise in animal models and preliminary clinical research; its development was briefly suspended in 2009 due to liver toxicity concerns but has now restarted, using a lower dose.
      • Moravek M.B.
      • Yin P.
      • Ono M.
      • et al.
      Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications.
      Vilaprisan is a novel SPRM currently in the late stages of clinical development.
      • Seitz C.
      • Bumbuliene Z.
      • Costa A.R.
      • et al.
      Rationale and design of ASTEROID 2, a randomized, placebo- and active comparator-controlled study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids.
      Figure thumbnail gr1
      Figure 1Summary: timeline of selective progesterone receptor modulators (SPRM) development
      Development of SPRMs began with serendipitous discovery of mifepristone and elucidation of its effects on uterus. Specific SPRMs have been developed and tested in recent years, leading to approval of ulipristal acetate, first SPRM specifically indicated for uterine fibroid (UF) management, in 2013.
      QoL, quality of life.
      Singh. SPRM past, present, and future in UF. Am J Obstet Gynecol 2018.
      The history of the development of SPRMs cannot be separated from the simultaneous evolution of a classification system for the unique endometrial changes accompanying SPRM treatment. The concerns initially arose when early studies reported high rates of endometrial hyperplasia following treatment with mifepristone. However, closer evaluation of the endometrium showed cystic glandular dilatation with little mitotic activity, in keeping with antiproliferative SPRM effects. Description of these endometrial changes did not fit into the secretory or proliferative classification systems of the time. In April 2006, a panel of expert pathologists independently reviewed slides of biopsies obtained following 3 months of treatment with 1 of 4 different SPRMs. They agreed that the histological changes were unique to SPRM treatment and did not pose a safety concern, although they acknowledged the risk that pathologists might overdiagnose hyperplasia based on these specimens. They proposed the term “progesterone receptor modulator-associated endometrial changes” (PAEC), defined to include mild thickening of the endometrium and architectural alterations such as cyst formation, gland cell changes, and vascular changes.
      • Mutter G.L.
      • Bergeron C.
      • Deligdisch L.
      • et al.
      The spectrum of endometrial pathology induced by progesterone receptor modulators.
      • Horne F.M.
      • Blithe D.L.
      Progesterone receptor modulators and the endometrium: changes and consequences.
      UPA is the only SPRM specifically approved and commercialized to date for management of UF. The initial indication for UPA in Europe and Canada was for a single treatment course of 3 months in patients with symptomatic UF who were candidates for surgery. This indication was based in large part on 2 trials that established the safety and efficacy of UPA prior to surgery as compared to either placebo (PEARL I) or the GnRHa leuprolide acetate (PEARL II).
      • Donnez J.
      • Tatarchuk T.F.
      • Bouchard P.
      • et al.
      Ulipristal acetate versus placebo for fibroid treatment before surgery.
      • Donnez J.
      • Tomaszewski J.
      • Vazquez F.
      • et al.
      Ulipristal acetate versus leuprolide acetate for uterine fibroids.
      Across these 2 trials, UPA was superior to placebo and noninferior to leuprolide acetate on key clinical endpoints. Over 80% of UPA patients experienced a normalization of menstrual bleeding, and roughly 70% achieved amenorrhea after a single 3-month course of treatment. The most common adverse events with UPA were headache and breast tenderness, although these did not occur significantly more often than with placebo in PEARL I. Moderate to severe hot flashes were reported in 11% of patients in PEARL II compared to 40% of patients treated with leuprolide acetate (P < .001), albeit without add-back therapy.

      Fibristal (ulipristal acetate) [product monograph]. Markham, Ontario, Canada: Actavis Specialty Pharmaceuticals; Co; 2016.

      The VENUS-I trial was designed to reflect the US population and satisfy US Food and Drug Administration requirements. Similar to PEARL I, VENUS-I compared 5- and 10-mg UPA doses to placebo, but in a population consisting of 69% African American patients. Preliminary results showed that UPA was superior to placebo for rate of amenorrhea and time to amenorrhea. Furthermore, 3 months of UPA reduced the impact of UF symptoms on patients’ daily activities compared to the baseline evaluation.
      • Simon J.
      • Catherino W.
      • Segars J.
      First US-based phase 3 study of ulipristal acetate (UPA) for symptomatic uterine fibroids (UF): results of VENUS-I.
      Further safety analyses have shown that with the 5- and 10-mg doses of UPA used in the pivotal clinical trials, the alterations seen in PAEC are benign and resolve in most patients within 3 months of UPA discontinuation.
      • Williams A.R.
      • Bergeron C.
      • Barlow D.H.
      • Ferenczy A.
      Endometrial morphology after treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate.
      Concern over PAEC was a key reason for limiting UPA courses to 3 months in the PEARL studies. The 3-month treatment duration was arbitrarily chosen to allow for shedding of nonphysiological endometrium. Since the initial studies, evidence from longer-term trials of UPA now suggests that PAEC is reversible to baseline levels, even with repeated intermittent UPA use.
      • Donnez J.
      • Donnez O.
      • Matule D.
      • et al.
      Long-term medical management of uterine fibroids with ulipristal acetate.
      • Donnez J.
      • Vazquez F.
      • Tomaszewski J.
      • et al.
      Long-term treatment of uterine fibroids with ulipristal acetate.
      • Fauser B.C.
      • Donnez J.
      • Bouchard P.
      • et al.
      Safety after extended repeated use of ulipristal acetate for uterine fibroids.
      Based on PEARL I and PEARL II data, short-term use of UPA has been recommended in clinical practice guidelines as an option for preoperative management of UF.
      • Vilos G.A.
      • Allaire C.
      • Laberge P.Y.
      • et al.
      The management of uterine leiomyomas.
      • Perez-Lopez F.R.
      • Ornat L.
      • Ceausu I.
      • et al.
      EMAS position statement: management of uterine fibroids.
      However, the American Congress of Obstetricians and Gynecologists Practice Bulletin on alternatives to hysterectomy in UF predates the development of UPA; as such its guidance on SPRMs focuses only on mifepristone and notes the efficacy of this agent in relieving symptoms of UF, reducing fibroid volume, and achieving amenorrhea.
      American College of Obstetricians and Gynecologists
      ACOG practice bulletin. Alternatives to hysterectomy in the management of leiomyomas.

      The present

      Although controlling bleeding and reducing fibroid size prior to surgery are still useful clinical goals for many patients, a need remains for management options that might postpone surgical intervention or eliminate the need for surgery altogether. Several clinical trials have now demonstrated that UPA can control fibroid size and symptoms when used in repeated intermittent courses over nearly 2 years. In the first extension of PEARL III, patients who had completed the PEARL III core study, involving a single 3-month 10-mg UPA course, were invited to complete an additional 3 courses of UPA. Each UPA course in the core study and the extension was followed by norethindrone acetate (NETA) or placebo, with the hypothesis that inducing menses with NETA after a UPA course would decrease the incidence of PAEC, which was thought at the time to be of potential clinical concern.
      • Donnez J.
      • Vazquez F.
      • Tomaszewski J.
      • et al.
      Long-term treatment of uterine fibroids with ulipristal acetate.
      Ultimately, compared with placebo, use of NETA to induce menses did not have an effect on the incidence or the time to reversal of PAEC. Patients who had completed a total of 4 courses in this initial PEARL III extension were invited to complete an additional 4 courses of 10-mg UPA, this time without NETA/placebo, for a total of up to 8 courses of UPA. This study was designed to focus on long-term safety, rather than efficacy.
      • Fauser B.C.
      • Donnez J.
      • Bouchard P.
      • et al.
      Safety after extended repeated use of ulipristal acetate for uterine fibroids.
      PEARL IV was designed to evaluate the 5- and 10-mg doses of UPA (without NETA supplementation) for up to 4 treatment courses.
      • Donnez J.
      • Donnez O.
      • Matule D.
      • et al.
      Long-term medical management of uterine fibroids with ulipristal acetate.
      These studies are also complemented by the VENUS-II study in the United States, which evaluated 2 courses of UPA (5 or 10 mg) vs placebo in a group representative of the ethnic makeup of the US patient population and with a higher mean body mass index than seen in the European studies. Taken together, these 3 trials provide data on safety and efficacy of repeated courses of UPA up to 4 courses, with some safety data for up to 8 courses of treatment (Table).
      TableSummary of key studies of long-term ulipristal acetate use in uterine fibroids
      Study namePopulationDesignEndpointsResults
      PEARL III first extension
      • Donnez J.
      • Vazquez F.
      • Tomaszewski J.
      • et al.
      Long-term treatment of uterine fibroids with ulipristal acetate.
      Women with symptomatic UF including HMB (N = 209) who previously received single 3-mo course of UPA in core PEARL III trialUp to 4 courses (3 mo each) of UPA 10 mg daily, immediately followed by double-blind treatment with NETA (10 mg daily) or placeboEfficacy: amenorrhea, fibroid volume

      Safety: endometrial histology (PAEC)
      Amenorrhea rates and median time to amenorrhea:

       1st course: 79%, 4 d

       2nd course: 89%, 2 d

       3rd course: 88%, 3 d

       4th course: 90%, 3 d

      Median fibroid volume reduction from baseline:

       1st course: 45%

       2nd course: 63%

       3rd course: 67%

       4th course: 72%

      PAEC observed:

      11% of patients at baseline

      26% after course 1

      25% after course 4

      No effect of NETA on rate of PAEC
      PEARL III second extension
      • Fauser B.C.
      • Donnez J.
      • Bouchard P.
      • et al.
      Safety after extended repeated use of ulipristal acetate for uterine fibroids.
      Women with symptomatic UF including HMB (N = 64) who completed 4 courses of UPA in PEARL III core trial and first extension (as above)Up to 4 additional 3-mo courses (8 total) of UPA 10 mg daily, but without continuation of NETA/placebo from core trial and first extensionSafety: endometrial histology, laboratory parameters, general safetyPAEC observed:

       18% of patients at baseline (1st course of initial study)

       21% after course 4

       16% after course 8

       9% after treatment cessation

      No changes in laboratory results outside normal ranges at any time

      Adverse event profile consistent with other trials
      PEARL IV
      • Donnez J.
      • Donnez O.
      • Matule D.
      • et al.
      Long-term medical management of uterine fibroids with ulipristal acetate.
      Women with symptomatic UF including HMB (N = 451)Double-blind randomized administration of 4 courses of UPA 5 or 10 mg daily (each course 3 mo)Efficacy: amenorrhea, controlled bleeding, fibroid volume, QoL, pain

      Safety: endometrial and general safety, laboratory parameters
      Amenorrhea rates:

      For courses 1, 2, 3, and 4, respectively:

       5-mg dose: 72%, 74%, 73%, 70%

       10-mg dose: 83%, 82%, 78%, 75%

      Median volume reduction of 3 largest fibroids, from baseline:

       5-mg dose: 65%

       10-mg dose: 67%

      PAEC:

      For 5- and 10-mg doses, respectively:

       8% and 8% at baseline

       16% and 19% after course 2

       16% and 10% after course 4

       9% and 6% after treatment cessation

      Adverse event profile consistent with that observed with shorter-term UPA use
      VENUS-II

      Allergan. Press release: Allergan and Gedeon Richter announce positive phase III results for ulipristal acetate 5 and 10 mg in the treatment of uterine fibroids. Available at: https://www.allergan.com/news/news/thomson-reuters/allergan-and-gedeon-richter-announce-positive-phas. Accessed August 22, 2017.

      Women with symptomatic UF including HMB (N = 432); 67% of patients were African American (in contrast to European PEARL trials where patients were predominantly Caucasian)Double-blind randomized administration of UPA 5 mg, UPA 10 mg, or placebo for 2 3-mo coursesEfficacy: amenorrhea, QoL

      Safety: general safety
      Amenorrhea rates:

      For courses 1 and 2, respectively:

       Placebo: 0%, 8%

       5-mg UPA: 35%, 41%

       10-mg UPA: 55%, 57%

      Fibroid volume reduction: not reported

      Improvement from baseline in UFS-QOL revised activities subscale:

       5-mg UPA: 48%

       10-mg UPA: 57%

       Placebo: 13%

      Adverse event profile consistent with that observed with shorter-term UPA use
      HMB, heavy menstrual bleeding; NETA, norethindrone acetate; PAEC, progesterone receptor modulator-associated endometrial changes; QoL, quality of life; UF, uterine fibroids; UFS-QOL, Uterine Fibroid Symptom and Health-related Quality of Life Questionnaire; UPA, ulipristal acetate.
      Singh. SPRM past, present, and future in UF. Am J Obstet Gynecol 2018.
      The PEARL III and IV data and preliminary findings from VENUS-II demonstrated that repeated courses of UPA are safe and effective at maintaining long-term control of fibroid symptoms, with a therapeutic effect lasting for at least 3 months beyond treatment cessation. In the PEARL trials, at least 70% of patients reached the primary endpoint of amenorrhea during each course of treatment. Median time to amenorrhea was 4-6 days. Bleeding control occurred in >73% of subjects, and the intensity of menstrual bleeding declined with each successive course of treatment. Fibroid volume also decreased with each treatment course, and this decrease was maintained through the 3-month posttreatment follow-up (Table). In terms of long-term safety, overall adverse events were similar in rate and severity to those seen in the shorter-term trials; the most common were headaches and hot flashes. Nonphysiological endometrial changes returned to baseline rates within 3 months after the final treatment course.
      • Donnez J.
      • Donnez O.
      • Matule D.
      • et al.
      Long-term medical management of uterine fibroids with ulipristal acetate.
      • Donnez J.
      • Vazquez F.
      • Tomaszewski J.
      • et al.
      Long-term treatment of uterine fibroids with ulipristal acetate.
      • Fauser B.C.
      • Donnez J.
      • Bouchard P.
      • et al.
      Safety after extended repeated use of ulipristal acetate for uterine fibroids.
      Preliminary data from the US-based VENUS-II trial are generally consistent with the PEARL findings, with amenorrhea rates up to 57% and significant improvements in QoL following 2 courses of treatment.

      Allergan. Press release: Allergan and Gedeon Richter announce positive phase III results for ulipristal acetate 5 and 10 mg in the treatment of uterine fibroids. Available at: https://www.allergan.com/news/news/thomson-reuters/allergan-and-gedeon-richter-announce-positive-phas. Accessed August 22, 2017.

      These studies were conducted such that each treatment course was separated by 1 menses. The subsequent UPA course commenced at the beginning of the second menses. Average bleeding scores for menses occurring between treatment courses were lower compared to baseline (pictorial blood-loss assessment chart, PBAC) and decreased with each successive treatment course.
      The PEARL III trial provides additional insights into how UPA treatment can best be managed in the clinical setting. In the core study and the first extension, patients were randomized to receive either NETA or a placebo at the end of each UPA course. Although induction of menses with NETA following a course of UPA did not have any effect on the incidence of PAEC, patients treated with NETA had a shorter time to the return of menses after UPA cessation (median of 14 vs 25 days after the first UPA course, P < .001) as well as a reduction in bleeding volume (PBAC days 1-8 of 59 vs 123, P = .006).
      • Donnez J.
      • Vazquez F.
      • Tomaszewski J.
      • et al.
      Long-term treatment of uterine fibroids with ulipristal acetate.
      Based on the findings from trials of long-term UPA use, the indication for UPA was amended from 2015 through 2016 in most jurisdictions to permit repeated intermittent courses of UPA, regardless of any plans for future surgery.

      Fibristal (ulipristal acetate) [product monograph]. Markham, Ontario, Canada: Actavis Specialty Pharmaceuticals; Co; 2016.

      Esmya (ulipristal acetate) [product information]. Melbourne, Australia: Vifor Pharma Pty Ltd; 2017.

      Esmya (ulipristal acetate) [product information]. Budapest, Hungary: Gedeon Richter PLC; 2016.

      Although the clinical trials on which the new indication was based used a maximum of 4 courses of UPA, the respective product labels place no restriction on the number of courses for long-term use.

      Fibristal (ulipristal acetate) [product monograph]. Markham, Ontario, Canada: Actavis Specialty Pharmaceuticals; Co; 2016.

      Esmya (ulipristal acetate) [product information]. Melbourne, Australia: Vifor Pharma Pty Ltd; 2017.

      Esmya (ulipristal acetate) [product information]. Budapest, Hungary: Gedeon Richter PLC; 2016.

       Treating the patient with symptomatic UF today

      The key clinical question now becomes: based on the clinical data for long-term treatment and a new indication, where do SPRMs fit into the treatment of patients with symptomatic UF? We propose an algorithm (Figure 2), based on clinical trial data, international guidelines and algorithms,
      • Donnez J.
      • Dolmans M.M.
      Uterine fibroid management: from the present to the future.
      and our own experience. The clinical data set for long-term UPA in UF is fairly limited, consisting primarily of the PEARL and VENUS trials. However, clinical practice is constantly evolving, and as such existing algorithms should be updated by incorporating both the latest clinical data and experts’ perspectives and experience. The quality of evidence driving this algorithm was rated using the criteria described in the report of the Canadian Task Force on Preventive Health Care (Appendix).
      Figure thumbnail gr2
      Figure 2Treatment options for symptomatic uterine fibroids
      Based on type/location of fibroids, patient’s desire for future fertility, and degree of anemia at baseline, UPA may be useful as bridge to surgery, as strategy for potentially avoiding surgery altogether, or for symptom management in patients for whom surgery is not anticipated. Data from
      • Donnez J.
      • Dolmans M.M.
      Uterine fibroid management: from the present to the future.
      and Donnez J, Arriagada P, Donnez O, Dolmans M-M. Current management of myomas: the place of medical therapy with the advent of selective progesterone receptor modulators. Curr Opin Obstet Gynecol 2015;6:422-31.
      AUB, abnormal uterine bleeding; FIGO, International Federation of Gynecology and Obstetrics; Hb, hemoglobin; QoL, quality of life.
      Singh. SPRM past, present, and future in UF. Am J Obstet Gynecol 2018.

       For patients considered candidates for any type of surgery

      For patients considered candidates for any type of surgery (hysterectomy or myomectomy), UPA may be considered preoperatively, as it may confer several clinical benefits, including improved QoL, correction of anemia while awaiting surgery, and reduction of fibroid volume (Level I, A evidence). By shrinking the fibroid(s), preoperative UPA may facilitate the use of a minimally invasive approach. In some cases, large fibroid uteri that would otherwise require morcellation for laparoscopic removal at the time of hysterectomy may become small enough that this is no longer necessary.
      GnRHas are another option for reducing fibroid size, improving fibroid-related symptoms, and correcting anemia prior to surgery. They have been shown to decrease fibroid volume by up to 50% when used presurgically.
      • Lethaby A.
      • Puscasiu L.
      • Vollenhoven B.
      Preoperative medical therapy before surgery for uterine fibroids.
      GnRHas and SPRMs have different mechanisms of action. The choice of which agent to use preoperatively should be made taking into account the route of administration, side-effect profile, type of surgery, and surgeon/patient preference. GnRHas are associated with a greater decrease in fibroid and uterine volume compared to SPRMs.
      • Murji A.
      • Whitaker L.
      • Chow T.L.
      • Sobel M.L.
      Selective progesterone receptor modulators (SPRMs) for uterine fibroids.
      • Lethaby A.
      • Puscasiu L.
      • Vollenhoven B.
      Preoperative medical therapy before surgery for uterine fibroids.
      When compared to no pretreatment, use of a GnRHa is associated with decreased fluid absorption at hysteroscopic myomectomy,
      • Donnez J.
      • Vilos G.
      • Gannon M.J.
      • et al.
      Goserelin acetate (Zoladex) plus endometrial ablation for dysfunctional uterine bleeding: a 3-year follow-up evaluation.
      • Muzii L.
      • Boni T.
      • Bellati F.
      • et al.
      GnRH analog treatment before hysteroscopic resection of submucous myomas: a prospective, randomized, multicenter study.
      and decreased blood loss and transfusions at laparotomic/laparoscopic myomectomy
      • Lethaby A.
      • Puscasiu L.
      • Vollenhoven B.
      Preoperative medical therapy before surgery for uterine fibroids.
      • de Milliano I.
      • Twisk M.
      • Ket J.C.
      • et al.
      Pre-treatment with GnRHa or ulipristal acetate prior to laparoscopic and laparotomic myomectomy: a systematic review and meta-analysis.
      (Level I, A). The primary advantage of UPA over GnRHas is the rapid control of uterine bleeding (5-7 days with 10- and 5-mg UPA doses, respectively, vs 21 days for leuprolide, P < .01).
      • Donnez J.
      • Tomaszewski J.
      • Vazquez F.
      • et al.
      Ulipristal acetate versus leuprolide acetate for uterine fibroids.
      The data on surgical outcomes with UPA are still emerging and discussed below.

       For patients with International Federation of Gynecology and Obstetrics classification type 0 or 1

      For patients with International Federation of Gynecology and Obstetrics classification
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      type 0 or 1 (submucosal) fibroids, UPA can be considered preoperatively for hysteroscopic myomectomy to control bleeding symptoms and shrink fibroids. Based on initial reports, the difficulty of hysteroscopy is not increased by UPA pretreatment, and in fact the ease of surgery and chance of a complete primary resection may be improved.
      • Ferrero S.
      • Racca A.
      • Tafi E.
      • et al.
      Ulipristal acetate before high complexity hysteroscopic myomectomy: a retrospective comparative study.
      • Sancho J.M.
      • Delgado V.S.
      • Valero M.J.
      • et al.
      Hysteroscopic myomectomy outcomes after 3-month treatment with either ulipristal acetate or GnRH analogs: a retrospective comparative study.
      • Murji A.
      • Wais M.
      • Lee S.
      • et al.
      A multicenter study evaluating the effect of ulipristal acetate during myomectomy.
      However, further study and evaluation will be required to assess short- and long-term outcomes.

       For patients with symptomatic, cavity-distorting fibroids wishing to maintain fertility or address fibroid-related infertility

      Anemia prior to elective surgery has been associated with adverse outcomes in gynecologic surgery.
      • Richards T.
      • Musallam K.M.
      • Nassif J.
      • et al.
      Impact of preoperative anemia and blood transfusion on postoperative outcomes in gynecological surgery.
      If the patient is anemic (hemoglobin <12 g/dL), initiate menstrual suppression plus iron supplementation (Level II-2, C). If the patient is not anemic, it may be appropriate to proceed directly to surgical management. However, if surgery is expected to be delayed for several months, UPA pretreatment can be considered to bridge to surgery, improve QoL, and shrink fibroids (Level I, A). This may help facilitate a minimally invasive surgical approach. Based on preliminary reports, UPA pretreatment does not affect the surgical experience in laparoscopic myomectomy.
      • Murji A.
      • Wais M.
      • Lee S.
      • et al.
      A multicenter study evaluating the effect of ulipristal acetate during myomectomy.
      • Ferrero S.
      • Alessandri F.
      • Vellone V.G.
      • et al.
      Three-month treatment with ulipristal acetate prior to laparoscopic myomectomy of large uterine myomas: a retrospective study.
      • Luketic L.
      • Shirreff L.
      • Kives S.
      • et al.
      Does ulipristal acetate affect surgical experience at laparoscopic myomectomy?.
      Regardless of prior anemia status, the uterine cavity should be imaged as part of the preoperative workup (Level III, B). UPA has the potential to affect the cavity not only through its effects on overall fibroid size, but also by inducing migration of fibroids in some cases.
      • Willame A.
      • Marci R.
      • Petignat P.
      • Dubuisson J.
      Myoma migration: an unexpected "effect" with ulipristal acetate treatment.
      If the cavity is normal, the patient may attempt natural or assisted conception without the need for surgery and myomectomy may not be indicated (Level II-2, D). If the cavity has not been restored, myomectomy is recommended (Level III, C).
      • Carranza-Mamane B.
      • Havelock J.
      • Hemmings R.
      • et al.
      The management of uterine fibroids in women with otherwise unexplained infertility.

       Patients with symptomatic fibroids who have completed their childbearing

      Patients with symptomatic fibroids who have completed their childbearing should undergo appropriate workup for their AUB and other symptoms. With mounting clinical data suggesting improvements in fibroid-related bleeding and QoL, patients can be offered 1-2 courses of UPA (Level I, A). The response to treatment should be assessed based on the signs/symptoms that are most relevant for the patient. For example, if a patient’s main concerns were bleeding and anemia but not bulk-related symptoms, control of bleeding and resolution of anemia could be considered a positive clinical response. If UPA results in a positive clinical response (ie, appropriate symptom control for the patient), suspend treatment until symptoms recur as there are data that clinical benefits can be seen up to 6 months following treatment cessation (Level II-3, B). When symptoms recur, patients can restart pulsatile courses of UPA as required (Level III, B). This can be especially useful in perimenopausal women to help transition into menopause while avoiding surgery.
      • Nogales F.F.
      • Crespo-Lora V.
      • Cruz-Viruel N.
      • et al.
      Endometrial changes in surgical specimens of perimenopausal patients treated with ulipristal acetate for uterine leiomyomas.
      If the response after the first 1-2 UPA courses is incomplete, consider another 1-2 courses or proceed to further workup as for a patient with no response. In the case of an insufficient or undetectable response, repeat the workup to rule out other causes of AUB and symptoms (eg, malignancy); consider switching to a GnRHa or other medical option, or proceed to surgical management if appropriate.
      Based on the authors’ clinical experience, the following practical guidance may be useful with short-term or repeated courses of UPA.

       Before starting UPA

      The patient should undergo appropriate workup for AUB.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      • Singh S.
      • Best C.
      • Dunn S.
      • et al.
      Abnormal uterine bleeding in pre-menopausal women.
      American College of Obstetricians and Gynecologists
      Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. ACOG committee opinion no. 557.
      If bleeding does not improve during treatment, the physician should continue to investigate other potential causes. Although inhibition of ovulation is one of the mechanisms of action of SPRMs, an ovulation rate of up to 20% was found at fibroid-treatment doses.
      • Chabbert-Buffet N.
      • Pintiaux-Kairis A.
      • Bouchard P.
      VA2914 Study Group
      Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial.
      Consequently, patients should be counselled about the need for concurrent use of nonhormonal contraception as data on pregnancies occurring on UPA are limited.

      Fibristal (ulipristal acetate) [product monograph]. Markham, Ontario, Canada: Actavis Specialty Pharmaceuticals; Co; 2016.

       Between UPA courses or after the final course

      Patients and physicians should be advised that the first menses after UPA cessation can be heavy. This is not necessarily an indication that the treatment has been unsuccessful–bleeding should decline significantly in subsequent menses. Using NETA after a course of UPA, as in PEARL III,
      • Donnez J.
      • Vazquez F.
      • Tomaszewski J.
      • et al.
      Long-term treatment of uterine fibroids with ulipristal acetate.
      may decrease the flow of the first menstrual period and make it more predictable. For example, PBAC bleeding score in the first menses was 59 after NETA, compared to 123 without (with scores >100 considered heavy menstrual bleeding). Tranexamic acid can also be helpful for controlling excessive bleeding in between treatment courses.
      It should be noted that not all patients will experience a favorable response to UPA treatment, even with repeated courses. For example, in the PEARL IV study, 14% of patients experienced amenorrhea without a significant volume reduction, 8% showed volume reduction but not amenorrhea, and 5% of participants failed to achieve either endpoint.
      • Donnez J.
      • Donnez O.
      • Matule D.
      • et al.
      Long-term medical management of uterine fibroids with ulipristal acetate.
      However, based on the current data, we are unable to predict factors associated with poor clinical response.

       Recommendations for monitoring

      Unless clinically indicated, it is not necessary to perform repeated ultrasounds solely to monitor fibroid size after UPA treatment. Similarly, repeated endometrial biopsies are not required for monitoring PAEC resolution, unless otherwise indicated (eg, AUB).

       Volume reduction

      Clinical trial data demonstrated fibroid volume reductions of roughly 30% after a single UPA course and up to 70% after 4 courses. These data were gathered by magnetic resonance imaging or ultrasound under the stringent environments of study protocols. Clinical experience in nonresearch settings has varied, in part due to differing practices in ultrasound fibroid measurement and misapplication of linear data to the calculation of spherical/ovoid volumes. For example, a 30% volume reduction for a spherical fibroid 10 cm in diameter would yield a diameter of 8.9 cm. Ultimately, the absolute reduction in fibroid size is less clinically important than patient-reported symptoms and QoL. However, it should be noted that in rare cases a rapid increase in fibroid size may be observed, particularly in perimenopausal women. This finding should be investigated, as it may indicate the presence of sarcoma. Nonresponders should be reevaluated for alternative management strategies and further assessment for undiagnosed pathology or conditions.

       Awareness of PAEC

      With either short- or long-term intermittent use of UPA, clinicians and pathologists should be aware of the likely development of PAEC. (Rates of PAEC development observed in clinical trials are summarized in the Table.) In particular, when submitting pathology specimens, clinicians should alert the pathologist that patients have been treated with a SPRM. All evidence suggests that PAEC is benign and readily reversible after treatment cessation, even with repeated courses of UPA, as seen in PEARL III and IV. Unless otherwise indicated, there is no need for ongoing ultrasound or endometrial biopsy to monitor PAEC. Most patients will likely have undergone endometrial biopsy prior to UPA initiation as part of the recommended workup for AUB,
      • Singh S.
      • Best C.
      • Dunn S.
      • et al.
      Abnormal uterine bleeding in pre-menopausal women.
      which can provide baseline data for future reference. However, if this has not already been done there is no specific requirement for a baseline biopsy prior to UPA initiation, or for a standard posttreatment biopsy. During treatment courses, ultrasound measurement of endometrial thickness is not clinically indicated. In clinical trials, there was no difference in mean endometrial thickness at the end of the first treatment course between UPA and placebo groups (mean 8-mm thickness). However, 11% of patients in UPA groups had endometrial thickness >16 mm.
      • Donnez J.
      • Tatarchuk T.F.
      • Bouchard P.
      • et al.
      Ulipristal acetate versus placebo for fibroid treatment before surgery.
      • Donnez J.
      • Tomaszewski J.
      • Vazquez F.
      • et al.
      Ulipristal acetate versus leuprolide acetate for uterine fibroids.

      The future

      Because of the clinical data showing the safety and efficacy of both short- and longer-term UPA use, we can now envision a model in which medical treatments can be used with the goal of postponing or eliminating the need for surgery. Indeed, in a multicenter study of 1473 patients treated with a single preoperative course of UPA, only 39% proceeded with the previously planned surgery, as of the 15-month follow-up.
      • Fernandez H.
      • Schmidt T.
      • Powell M.
      • et al.
      Real-world data of 1473 patients treated with ulipristal acetate for uterine fibroids: Premya study results.
      There may also be a role for UPA and other medical options in secondary prevention of UF recurrence after successful surgery in patients at high risk of UF regrowth. Further clinical trials will be required to elucidate this potential.
      • Donnez J.
      • Dolmans M.M.
      Uterine fibroid management: from the present to the future.
      One key issue to be addressed more fully in the future is the impact of UPA treatment on subsequent pregnancy outcomes. The desire for fertility is a key decision point when considering management options for UF. Certain therapeutic options are not recommended for women who may wish to become pregnant, either because of known detrimental or as yet undetermined effects on fertility (eg, uterine artery embolization
      • Torre A.
      • Paillusson B.
      • Fain V.
      • et al.
      Uterine artery embolization for severe symptomatic fibroids: effects on fertility and symptoms.
      ) or a lack of data on subsequent pregnancy outcomes (eg, focused energy methods).
      • Vilos G.A.
      • Allaire C.
      • Laberge P.Y.
      • et al.
      The management of uterine leiomyomas.
      Understanding pregnancy outcomes after UPA use, whether short-term or repeated intermittent courses, is therefore crucial for informed decision-making when retaining fertility or addressing fibroid-related infertility is one of the treatment goals. The data set for UPA and pregnancy outcomes is still developing, but the current evidence includes a case series of 18 pregnancies after UPA use in the PEARL clinical trials,
      • Luyckx M.
      • Squifflet J.L.
      • Jadoul P.
      • et al.
      First series of 18 pregnancies after ulipristal acetate treatment for uterine fibroids.
      as well as multiple independent case reports.
      • Luyckx M.
      • Pirard C.
      • Fellah L.
      • et al.
      Long-term nonsurgical control with ulipristal acetate of multiple uterine fibroids, enabling pregnancy.
      • Monleon J.
      • Martinez-Varea A.
      • Galliano D.
      • Pellicer A.
      Successful pregnancy after treatment with ulipristal acetate for uterine fibroids.
      • Murad K.
      Spontaneous pregnancy following ulipristal acetate treatment in a woman with a symptomatic uterine fibroid.
      Although many of these patients underwent surgery between discontinuing UPA and becoming pregnant, in several cases UPA was the only intervention. Further reports from clinical trials and real-world use will be useful to expand on our understanding of pregnancy outcomes and appropriate patient selection. Although myomectomy remains the first-line option for enhancing fertility in women with fibroids and otherwise unexplained fertility issues,
      • Falcone T.
      • Parker W.H.
      Surgical management of leiomyomas for fertility or uterine preservation.
      it is possible to envision an algorithm that would first attempt treatment with an SPRM, reserving myomectomy for patients with inadequate response to medical intervention.
      Due to their tissue-specific effects on the myometrium, endometrium, and pituitary, SPRMs are of interest in other gynecologic conditions in addition to UF. A promising area for further investigation is SPRM use for endometriosis or adenomyosis. In these conditions, SPRMs could potentially alleviate the pain and other symptoms caused by ectopic endometrial tissue through 2 complementary mechanisms: reduction of endometrial proliferation and menstrual suppression.
      • Bouchard P.
      • Chabbert-Buffet N.
      • Fauser B.C.
      Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety.
      A phase II trial of UPA in adenomyosis is currently underway (NCT02587000).
      Through its inhibition of ovulation, UPA is also effective as an emergency contraceptive and is approved and marketed for this use in several jurisdictions, albeit at a much higher dose (30 mg) than is used for UF management. These anovulatory effects may also hold promise for the development of long-term contraceptives, which could be of particular value for women who are unable to use estrogen-containing products.
      • Murdoch M.
      • Roberts R.
      Selective progesterone receptor modulators and their use within gynecology.
      Proof of concept for SPRMs as estrogen-free contraceptives is provided by a study that established that mifepristone 5 mg was effective at preventing pregnancy, with a more favorable bleeding pattern than a progesterone-only pill (levonorgestrel).
      • Lakha F.
      • Ho P.C.
      • Van der Spuy Z.M.
      • et al.
      A novel estrogen-free oral contraceptive pill for women: multicenter, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
      It should be noted that at the doses of UPA typically used in the UF trials (5 and 10 mg), rates of anovulation were only in the range of 80%.
      • Chabbert-Buffet N.
      • Pintiaux-Kairis A.
      • Bouchard P.
      VA2914 Study Group
      Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial.
      Further study will be required to determine whether the reliability of UPA as a long-term contraceptive can be improved. Currently there are no SPRMs with an indication for long-term contraception anywhere in the world.
      As clinicians and researchers continue to refine the use of UPA and other medical options for UF management, it may become possible to develop new medications–or new regimens for existing medications–that can provide effective treatment of UF and related conditions while minimizing endometrial changes and other side effects. Two novel SPRMs (oral vilaprisan and orally or vaginally administered telapristone acetate) are currently in development for management of UF.
      • Seitz C.
      • Bumbuliene Z.
      • Costa A.R.
      • et al.
      Rationale and design of ASTEROID 2, a randomized, placebo- and active comparator-controlled study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids.
      Additional new agents or therapeutic strategies may also emerge based on new insights into the effects of PR and their tissue-specific effects.
      In summary, past and present clinical experience with UPA in the treatment of UF has expanded the range of possibilities for management of UF symptoms, management of fibroid-related infertility, and treatment of other gynecologic conditions. With further experience and additional clinical data, it is possible to envision a future with fewer invasive procedures, better patient outcomes, and more choices for patients and clinicians.

      Acknowledgment

      The authors thank John Ashkenas, PhD (SCRIPT, Toronto, Ontario, Canada) for editorial assistance.

      Appendix

      AppendixKey to evidence statements and grading of recommendations, using ranking of Canadian Task Force on Preventive Health Care
      Quality of evidence assessmentClassification of recommendations
      I: Evidence obtained from at least 1 properly randomized controlled trial

      II-1: Evidence from well-designed controlled trials without randomization

      II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from >1 center or research group

      II-3: Evidence obtained from comparisons between times or places with or without intervention; dramatic results in uncontrolled experiments (eg, results of treatment with penicillin in 1940s) could also be included in category

      III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees
      A. There is good evidence to recommend clinical preventive action

      B. There is fair evidence to recommend clinical preventive action

      C. Existing evidence is conflicting and does not allow to make recommendation for or against use of clinical preventive action; however, other factors may influence decision-making

      D. There is fair evidence to recommend against clinical preventive action

      E. There is good evidence to recommend against clinical preventive action

      I. There is insufficient evidence (in quantity or quality) to make recommendation; however, other factors may influence decision-making

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      Linked Article

      • Re: The past, present, and future of selective progesterone receptor modulators in the management of uterine fibroids
        American Journal of Obstetrics & GynecologyVol. 219Issue 4
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          With interest we have read the review of Singh et al1 on the place of selective progesterone receptor modulators in the management of uterine fibroids (UF). After summarizing the evidence on ulipristal acetate (UPA) they proposed an algorithm in which UPA plays an important role as medical pretreatment for hysteroscopic and laparoscopic fibroid surgery and for intermittent long-term use to prevent surgery.1 However, in our opinion the currently available evidence does not support the implementation of this policy in daily practice (yet).
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      • The past, present, and future of selective progesterone receptor modulators in the management of uterine fibroids: an alternative perspective
        American Journal of Obstetrics & GynecologyVol. 219Issue 2
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          We read with interest the comprehensive review by Singh et al1 that highlighted the positive aspects of selective progesterone receptor modulators and particularly ulipristal acetate (UPA) for the medical management of fibroid tumors. However, in our view, as with most other reviews on this topic, the picture that is presented is rather 1-sided, and none of the potential downsides or unknowns is explored.
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        American Journal of Obstetrics & GynecologyVol. 219Issue 2
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          We would like to thank Dr Odejinmi et al for their comments. They present 3 questions related to our recent publication1: (1) the generalizability of selective progesterone receptor modulators (SPRMs) treatment trials among various populations, (2) the health economics of SPRM treatment, and (3) the potential challenges of surgery after SPRM treatment.
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        American Journal of Obstetrics & GynecologyVol. 219Issue 4
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          We would like to thank Dr Middelkoop and Dr Huirne for their comments related to our recent publication.1 Their letter raises several issues that we would like to address.
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