CLIMACTERIC 2015;18:177–181
Ulipristal acetate in the management of symptomatic uterine fibroids: facts and pending issues F. R. Pérez-López Department of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University Hospital, Zaragoza, Spain
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Key words: UTERINE FIBROIDS, UTERINE MYOMAS, ULIPRISTAL ACETATE, HYSTERECTOMY, SELECTIVE PROGESTERONE RECEPTOR MODULATOR
ABSTRACT Various treatment options have been proposed for the management of human symptomatic uterine fibroids (or myomas). Despite this, the most popular one is surgery (myomectomy or hysterectomy). Ulipristal acetate (UA) is a selective progesterone receptor modulator. In women programmed for surgical treatment for uterine fibroids, oral UA treatment (5 or 10 mg/day) controls symptoms, reduces tumor size and improves quality of life as compared to placebo and is not inferior to monthly intramuscular injection of leuprolide acetate for 3 months. Women treated with up to 4 courses of UA (10 mg/day for 3 months) followed or not by norethisterone acetate (10 mg/day for 10 days or placebo) reported a high rate of bleeding control, and improved quality of life, pain anxiety and depression. Median fibroid volume after successive courses of UA treatment ranged from 63% to 72% as compared to baseline value. Endometrium showed benign histological changes without hyperplasia, while adverse events were mild or moderate throughout the several courses of treatment. There is a need for global cost assessment of UA treatment for uterine fibroids, including those women that do not reach their expected outcome and need other complementary explorations or treatments. Studies are needed in non-Caucasian women, in infertile patients and in cases of fibroids associated with adenomyosis. Furthermore, assessment of long-term UA treatment should include endometrial, cardiocirculatory and neurological endpoints.
INTRODUCTION Uterine fibroids (myomas or leiomyomas) are the most common benign female tumor, with a maximal prevalence in the perimenopausal years. Indeed, as many as 40–50% of Caucasian women have fibroids. This prevalence may be even higher in Afro-descendant women (up to 70% in perimenopausal women), with a more dramatic clinical presentation (larger and more symptomatic fibroids) and an earlier age of appearance as compared to Caucasian women1,2. As ovarian production of steroid hormones decreases in postmenopausal years, uterine fibroids regress after menopause and there is a spontaneous resolution of clinical symptoms. Fibroids arise from the uterine smooth muscle and relate to gene mutations and/or complex chromosome alterations, re-organizations, and changes in vascular growth factors3,4.
Uterine fibroids are responsive (increase their growth/size and symptoms) to hormonal factors including estrogens, progestogens and insulin-growth factor I (IGF-I)5,6. IGF-I stimulates uterine myoma cell growth, enhancing proliferation and inhibiting apoptosis, while progesterone (alone or in combination with estradiol) down-regulates IGF-I mRNA and protein expression in fibroid cells6. Fibroid cells produce abnormal regulation of growth factors and cytokines that have negative effects over the endometrium7. Asymptomatic fibroids do not impair quality of life or increase the risk of complications. The severity of symptomatic fibroids is related to their size and location. The most common symptoms include: heavy menstrual bleeding (HMB) or menorrhagia, pain and pelvic pressure, bowel and bladder dysfunction, pain during sexual intercourse, and infertility. HMB is the most common symptom associated with fibroids
Correspondence: Professor F. R. Pérez-López, Department of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University Hospital, Zaragoza, Spain. E-mail: [email protected] SHORT REVIEW © 2014 International Menopause Society DOI: 10.3109/13697137.2014.981133
Received 20-10-2014 Accepted 22-10-2014
Ulipristal acetate in management of symptomatic uterine fibroids that are located in or near the lining of the uterus. However, symptoms can also be related to other causes, including endometrial hyperplasia or cancer, polyps, adenomyosis, pelvic vascular alterations and endocrine disorders. Therefore, an appropriate clinical assessment is mandatory1,8–10. Blood supply may be insufficient in rapidly growing fibroids and therefore degenerate, producing pain, cramping, ischemic acute pain, pelvic pressure, discomfort during sexual intercourse, urinary symptoms and/or painful bowel movements. They have no significant risk for malignant transformation as genetic alterations of myomas and leiomyosarcomas suggest different pathogenic pathways1.
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GENERAL MANAGEMENT OF UTERINE FIBROIDS Symptomatic fibroids have been traditionally managed by surgery, either by hysterectomy or myomectomy. In recent years, alternative therapeutic options are available including different non-surgical interventions (e.g. uterine artery embolization, high-intensity focused ultrasonic myolysis)1,11. However, many women do not desire to be managed with invasive interventions. In this sense, a large number of pharmacologic approaches have also been proposed to control fibroid-related HMB, inter-menstrual bleeding, pelvic pain and impaired quality of life. Pharmacological treatments of uterine fibroids may temporarily reduce/relief symptoms. Despite this, they are not devoid of adverse effects and fibroids may re-grow after medication withdrawal12. The effectiveness of progestogens or progestogen-releasing intrauterine systems in premenopausal women with symptomatic uterine fibroids is limited at reducing HMB or fibroid size13. Progestogens have a moderate effect over heavy uterine bleeding, reduction of myoma size, and hemoglobin increase prior to surgery. Levonorgestrel-releasing intrauterine systems reduce increased menstrual bleeding and aid the restoration of hemoglobin level, although the effect over fibroid anatomy is minimal or nil. Gonadotropin-releasing hormone agonists (GnRHa) (leuprolide, triptorelin, buserelin, goserelin) have been used for 3–6 months prior to fibroid surgery and, in selected cases, to reduce fibroid size, HMB and correct pre-operative anemia in order to allow a high rate of laparoscopic or vaginal surgical procedures12,14,15. However, they produce significant side-effects (menopausal symptoms and bone loss) and fibroid re-growth to previous size within weeks after treatment withdrawal. Adverse hypoestrogenic effects may be neutralized or reduced with estrogen or tibolone add-back therapy and/or the use of bone antiresorptive agents. Preclinical and placebo-controlled trials have demonstrated the efficacy of progesterone antagonists (e.g. mifepristone) and selective progesterone receptor modulators (SPRMs) in reducing fibroid and uterine volume and suppressing associated bleeding. A meta-analysis of 11 randomized, controlled trials including women with symptomatic fibroids reported that mifepristone, at doses ranging from 2.5 to 25 mg/day
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Pérez-López for 3–6 months, reduces fibroid size and related symptoms (uterine bleeding, pelvic pain, pelvic pressure, anemia and dysmenorrhea). In addition, there was no significant difference in the rate of atypical endometrial hyperplasia between patients under hormonal treatment and those receiving placebo; however, there are large individual variations related to fibroid size reduction15. In this sense, Engman and colleagues16 have examined the expression of genes related to this heterogeneous response. They reported that, among good responders to mifepristone (50 mg, every other day for 12 weeks prior to surgery), there was overexpression of the glutathione-s transferase mu 1 (GSTM1) gene as compared to non-responders. These findings support the different hormone fibroid responses and that gene research may lead to the finding of a reliable biomarker that will help stratify patients and optimize therapy. A new option is vaginal mifepristone treatment (10 mg/day for 3 months) which may be effective at reducing fibroid symptoms and volume17.
ULIPRISTAL ACETATE IN THE MANAGEMENT OF SYMPTOMATIC UTERINE FIBROIDS Ulipristal acetate is a SPRM and effective emergency contraceptive that has been studied for other indications including uterine fibroids, endometrial pathology, endometriosis and a potential use in neurology- and oncology-related diseases19,20. UA has a high affinity for progesterone receptors A and B and less affinity for the glucocorticoid receptor as compared to mifepristone21,22. It has pro-apoptotic and anti-proliferative effects over myoma uterine cells23 and initial clinical studies have shown a well-balanced relationship between efficacy and tolerability in the management of symptomatic uterine fibroids24,25. Women with symptomatic uterine fibroids have been treated with UA in phase-II studies and randomized, controlled trials, showing an interesting clinical profile and improvement of impaired quality of life related to fibroids. In the PEARL-I (PGL4001 vs. placebo) trial, premenopausal women (18–50 years) with symptomatic fibroids were randomly assigned before surgery to receive oral UA (5 mg or 10 mg/day) or placebo for up to 13 weeks26. Women had uterine size equivalent to a 16 week gestation, with at least one fibroid of 3 cm but not exceeding 10 cm upon magnetic resonance imaging, and excessive uterine bleeding and anemia. This study demonstrated control of bleeding in 91%, 92% and 19%, respectively for 5 mg UA, 10 mg UA and placebo. Amenorrhea was obtained in 73%, 82%, and 6%, while fibroid volume changes were 21%, 12% and 3%, respectively. The most common side-effects among those treated with UA were headache and breast tenderness, although with a similar rate to the control group. Benign endometrial histological changes were registered among the UA-treated group which disappeared 6 months post-treatment. Barlow and colleagues27 reported the vaginal bleeding characteristics (secondary outcome) in the PEARL-I study for those women who did not have a rapid onset of amenorrhea and had
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Ulipristal acetate in management of symptomatic uterine fibroids irregular bleeding (26.9% for women treated with 5 mg/day and 28.7% for those with 10 mg/day). Bleeding assessment was performed before randomization, during and after treatment in those women who did not have surgery. Women in the placebo group persisted with abnormal bleeding; although four of the 48 women spontaneously improved their bleeding pattern and one developed amenorrhea. In some patients treated with UA, abnormal bleeding (prolonged, frequent or irregular) was related to submucous fibroids. Thus, the presence of submucous fibroids could limit the efficacy of UA at controlling bleeding. The PEARL-II (PGL4001 versus GnRHa in uterine myomas) was a non-inferiority, randomized study that compared the same oral UA doses (5 mg/day and 10 mg/day) used in the PEARL-I study but now compared to monthly intramuscular doses of the GnRHa leuprolide acetate (3.75 mg) for the treatment of women with symptomatic fibroids28. Primary outcome was to assess efficacy at controlling bleeding and uterine size at 13 weeks of treatment. Primary outcome results for the three arms of the study were similar (bleeding control in 89–98% of patients), although median time to amenorrhea was within 1 week for UA treatments as compared to 3 weeks with leuprolide acetate. At the end of the study, all three hormonal treatments reduced the size of the largest fibroids, the median reductions being 36% for low-dose UA, 42% for high-dose UA and 53% for leuprolide acetate. In addition, the GnRHa produced a significantly greater reduction of uterine volume (47%) as compared to UA treatment (20–22%). Moderate to severe hot flushes affected 11% and 10% of women treated with the low and high UA doses as compared to 40% of women treated with the GnRHa. Endometrial thickness was doubled as compared to GnRHa treatment (9.4 and 10.7 mm for patients treated with 5 and 10 mg/day, respectively), and a case of simple hyperplasia was detected in a woman receiving 5 mg/day of UA. Six months after treatments, there were no significant differences in endometrial thickness in women not submitted to hysterectomy. Reduced fibroid volume persisted for a longer period of follow-up in the UA-treated women as compared to those treated with the GnRHa. Menstruation resumed 1 month after UA treatment and 1.5 months after GnRHa therapy was discontinued. In 2012, UA was licensed by the European Medicines Agency for the treatment of symptomatic fibroids (5 mg/day) during a maximum of 3 months for the preoperative management of symptomatic fibroids. Donnez and colleagues29 recently reported the efficacy and safety of cyclical UA treatment (10 mg/day), up to four courses, in an open-label assessment of symptomatic women with at least one fibroid of 3–10 cm diameter (PEARL-III and PEARL-III extension studies). Each 3-month cycle of UA treatment was followed by a double-blind randomization to oral norethisterone acetate (NETA; 10 mg/day) or placebo for 10 days. During the initial UA cycle, amenorrhea occurred in 79% of women and there was a median fibroid volume reduction of 45%, with similar rates of amenorrhea in successive cycles. Endometrial assessment showed benign histological
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Pérez-López changes without hyperplasia, whereas the NETA group did not display changes in fibroid volume and endometrial characteristics. On the other hand, UA did not shrink fibroids in all women with successive cycles of treatment, although the drug produced a high rate of bleeding control. Cyclical UA, with or without NETA treatment, may also improve quality of life, pain anxiety and depression. Adverse events were mild or moderate throughout the several courses of treatment and not greater than those reported in the pivotal studies (PEARL-I and -II)26,28. In addition, all endometrial biopsies reported benign changes without hyperplasia and NETA administration did not influence fibroid size. Pregnancy rate and live birth rate were reported in a small group of patients who desired to conceive30. Twenty-one out of 52 patients included in the PEARL-II and -III trials tried to conceive, of whom 15 became pregnant, with a total of 18 pregnancies. Of these, 12 ended in live births and six in miscarriages. Pregnant women did not have myoma re-growth during pregnancy. In a small case–control study carried out in premenopausal women with symptomatic intramural fibroids, the effect of oral UA (5 mg/day for 3 months) on fibroid volume and vascularity was compared to that of bilateral uterine artery embolization using ultrasound assessment. After 3 months of UA treatment, fibroid volume decreased to a similar level to that found in women 3 months after uterine embolization. Three months after treatments, Doppler vascular indices showed that the vascularization index, the flow index and the vascularization flow index decreased as compared to respective baseline values. In addition, UA decreased fibroid vascularization but yet to a lesser extent than uterine embolization31. More detailed studies are needed to compare the short- and long-term results of these two therapeutic approaches.
PENDING ISSUES Although preoperative UA treatment improves fibroid-related symptoms and reduces fibroid and uterine volume with less frequent side-effects reported than with other hormone therapies (e.g. GnRH analogs), its long-term use for symptomatic fibroids, cost-effectiveness ratio and degree of female acceptance are still issues to be analyzed. Although some cost–benefit models support pre-surgical UA use32, the costeffectiveness as a pre-surgical treatment should be assessed under different national health systems. Moreover, costs related to long-term treatment (e.g. follow-up and complementary explorations) need to be calculated and compared to non-pharmacological therapy. Studies in this regard are warranted. Since there are differences in the prevalence and severity of symptoms related to ethnicity, studies assessing the effect of UA on women with African ancestry are highly recommended. To date, available evidence has been obtained from Caucasian women. On the other hand, although quality of life has been assessed in the PEARL trials, the efficacy of any new treatment
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Ulipristal acetate in management of symptomatic uterine fibroids shows ‘better results’ in highly selected populations which are not confirmed among ‘unselected’ patients and related to emotions, cultural factors and subjective health33. Thus, future UA evaluations should include other tools and endpoints (global health, life satisfaction, psychological well-being, self-esteem) apart from quality of life. There is a need for comparative studies between UA and vaginal mifepristone18. The effect of UA in women with symptomatic uterine fibroids should also be compared with other non-surgical treatments, including uterine artery embolization, myolysis and ablation by high-intensity focused ultrasound guided with magnetic resonance imaging or ultrasound. Combined treatment (UA plus non-surgical interventions, e.g. uterine artery embolization, ultrasound focused myolysis) should be considered as an alternative for selected patients. Another issue that need exploration is the effect of UA in women with symptomatic fibroids who are infertile. It seems that fertility capacity is not affected in women with fibroids that do not distort the uterine cavity34. The endpoint among infertile women should be assessed in relation to fertility outcomes. The effects of UA in women with adenomyosis or both uterine fibroids and adenomyosis have not been established. Finally, assessment of long-term UA treatment should include endometrial, cardio-circulatory and neurological endpoints.
Pérez-López
TAKE-HOME MESSAGES • UA is a SPRM highly effective for the control of symptoms of uterine fibroids and the reduction of their size in symptomatic women programmed for surgical management. These changes are associated with significant improvement of quality of life. • UA cyclic treatment associated with NETA is highly effective in reducing/neutralizing uterine fibroid-related symptoms. • UA can induce unusual specific endometrial changes which warrant follow-up. • Economic assessment of long-term UA use (including drug treatment and the cost of complementary follow up) should be evaluated. • Clinical outcomes of UA treatment should be compared with surgical and other non-surgical interventions. • The efficacy of UA treatment and related outcomes in women with infertility or adenomyosis remains to be determined. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
References 1. Pérez-López FR, Ornat L, Ceausu I, et al. EMAS position statement: management of uterine fibroids. Maturitas 2014; 79:106–16 2. Qi L, Nassir R, Kosoy R, et al. Relationship between hysterectomy and admixture in African American women. Am J Obstet Gynecol 2013;208:279.e1–7 3. Bulun SE. Uterine fibroids. N Engl J Med 2013;369:1344–55 4. Tal R, Segars JH. The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy. Hum Reprod Update 2013;20:194–216 5. Maruo T, Ohara N, Wang J, Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update 2004;10:207–20 6. Yamada T, Nakago S, Kurachi O, et al. Progesterone downregulates insulin-like growth factor-I expression in cultured human uterine leiomyoma cells. Hum Reprod 2004;19: 815–21 7. Doherty L, Mutlu L, Sinclair D, Taylor H. Uterine fibroids: clinical manifestations and contemporary management. Reprod Sci 2014;21:1067–92 8. Latthe P, Mignini L, Gray R, Hills R, Khan K. Factors predisposing women to chronic pelvic pain: systematic review. BMJ 2006;332:749–55 9. Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM–COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet 2011;113:3–13
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10. Dreisler E, Poulsen LG, Antonsen SL, et al; European Menopause and Andropause Society. EMAS clinical guide: assessment of the endometrium in peri and postmenopausal women. Maturitas 2013;75:181–90 11. Patel A, Malik M, Britten J, Cox J, Catherino WH. Alternative therapies in management of leiomyomas. Fertil Steril 2014; 102:649–55 12. Lethaby A, Vollenhoven B. Fibroids (uterine myomatosis, leiomyomas). Clin Evid (Online) 2011;2011. pii: 0814 13. Sangkomkamhang US, Lumbiganon P, Laopaiboon M, Mol BW. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst Rev 2013;2:CD008994 14. U.S. Food and Drug Administration. FDA Drug Safety Communication: Ongoing safety review of GnRH agonists and possible increased risk of diabetes and certain cardiovascular diseases. May 3, 2010. Available at: http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ ucm209842.htm. Accessed September 28, 2014 15. Zhang Y, Sun L, Guo Y, et al. The impact of preoperative gonadotropin-releasing hormone agonist treatment on women with uterine fibroids: a meta-analysis. Obstet Gynecol Surv 2014;69:100–8 16. Shen Q, Hua Y, Jiang W, Zhang W, Chen M, Zhu X. Effects of mifepristone on uterine leiomyoma in premenopausal women: a meta-analysis. Fertil Steril 2013;100:1722–6.e1–10 17. Engman M, Varghese S, Lagerstedt Robinson K, et al. GSTM1 gene expression correlates to leiomyoma volume regression in response to mifepristone treatment. PLoS One 2013;8:e80114
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Ulipristal acetate in management of symptomatic uterine fibroids 18. Yerushalmi GM, Gilboa Y, Jakobson-Setton A, et al. Vaginal mifepristone for the treatment of symptomatic uterine leiomyomata: an open-label study. Fertil Steril 2014;101: 496–500 19. Richardson AR, Maltz FN. Ulipristal acetate: review of the efficacy and safety of a newly approved agent for emergency contraception. Clin Ther 2012;34:24–36 20. Brazert M, Korman MP, Pawelczyk LA. [Applicability of selective progesterone receptor modulators in the treatment of uterine leiomyomata and their future role in the field of gynecology]. Ginekol Pol 2013;84:794–800 21. Attardi BJ, Burgenson J, Hild SA, Reel JR, Blye RP. CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB-2914. Mol Cell Endocrinol 2002;188:111–23 22. Blithe DL, Nieman LK, Blye RP, Stratton P, Passaro M. Development of the selective progesterone receptor modulator CDB-2914 for clinical indications. Steroids 2003;68:1013–17 23. Horak P, Mara M, Dundr P, et al. Effect of a selective progesterone receptor modulator on induction of apoptosis in uterine fibroids in vivo. Int J Endocrinol 2012;2012:436174 24. Levens ED, Potlog-Nahari C, Armstrong AY, et al. CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial. Obstet Gynecol 2008;111:1129–36 25. Nieman LK, Blocker W, Nansel T, et al. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study. Fertil Steril 2011;95:767–72.e1–e2 26. Donnez J, Tatarchuk TF, Bouchard P, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409–20
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Pérez-López 27. Barlow DH, Lumsden MA, Fauser BC, Terrill P, Bestel E. Individualized vaginal bleeding experience of women with uterine fibroids in the PEARL I randomized controlled trial comparing the effects of ulipristal acetate or placebo. Hum Reprod 2014;29:480–9 28. Donnez J, Tatarchuk TF, Bouchard P, et al; PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409–20 29. Donnez J, Vázquez F, Tomaszewski J, et al; PEARL III and PEARL III Extension Study Group. Long-term treatment of uterine fibroids with ulipristal acetate. Fertil Steril 2014;101: 1565–73.e1–18 30. Luyckx M, Squifflet JL, Jadoul P, Votino R, Dolmans MM, Donnez J. First series of 18 pregnancies after ulipristal acetate treatment for uterine fibroids. Fertil Steril 2014 Sep 17. Epub ahead of print 31. Czuczwar P, Wozniak S, Szkodziak P, et al. Comparison of influence of ulipristal acetate and uterine artery embolization on fibroid volume and vascularity indices assessed by 3D ultrasound: a prospective observational study. Ultrasound Obstet Gynecol 2014 Sep 24. Epub ahead of print 32. Nagy B, Timár G, Józwiak-Hagymásy J, et al. The costeffectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids. Eur J Obstet Gynecol Reprod Biol 2014;175:75–81 33. Curhan KB, Sims T, Markus HR, et al. Just how bad negative affect is for you health depends on culture. Psychol Sci 2014 Oct 10. Epub ahead of print 34. Yan L, Ding L, Li C, Wang Y, Tang R, Chen ZJ. Effect of fibroids not distorting the endometrial cavity on the outcome of in vitro fertilization treatment: a retrospective cohort study. Fertil Steril 2014;101:716–21
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Ulipristal acetate in the management of symptomatic uterine fibroids: facts and pending issues F. R. Pérez-López Department of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University Hospital, Zaragoza, Spain
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Key words: UTERINE FIBROIDS, UTERINE MYOMAS, ULIPRISTAL ACETATE, HYSTERECTOMY, SELECTIVE PROGESTERONE RECEPTOR MODULATOR
ABSTRACT Various treatment options have been proposed for the management of human symptomatic uterine fibroids (or myomas). Despite this, the most popular one is surgery (myomectomy or hysterectomy). Ulipristal acetate (UA) is a selective progesterone receptor modulator. In women programmed for surgical treatment for uterine fibroids, oral UA treatment (5 or 10 mg/day) controls symptoms, reduces tumor size and improves quality of life as compared to placebo and is not inferior to monthly intramuscular injection of leuprolide acetate for 3 months. Women treated with up to 4 courses of UA (10 mg/day for 3 months) followed or not by norethisterone acetate (10 mg/day for 10 days or placebo) reported a high rate of bleeding control, and improved quality of life, pain anxiety and depression. Median fibroid volume after successive courses of UA treatment ranged from 63% to 72% as compared to baseline value. Endometrium showed benign histological changes without hyperplasia, while adverse events were mild or moderate throughout the several courses of treatment. There is a need for global cost assessment of UA treatment for uterine fibroids, including those women that do not reach their expected outcome and need other complementary explorations or treatments. Studies are needed in non-Caucasian women, in infertile patients and in cases of fibroids associated with adenomyosis. Furthermore, assessment of long-term UA treatment should include endometrial, cardiocirculatory and neurological endpoints.
INTRODUCTION Uterine fibroids (myomas or leiomyomas) are the most common benign female tumor, with a maximal prevalence in the perimenopausal years. Indeed, as many as 40–50% of Caucasian women have fibroids. This prevalence may be even higher in Afro-descendant women (up to 70% in perimenopausal women), with a more dramatic clinical presentation (larger and more symptomatic fibroids) and an earlier age of appearance as compared to Caucasian women1,2. As ovarian production of steroid hormones decreases in postmenopausal years, uterine fibroids regress after menopause and there is a spontaneous resolution of clinical symptoms. Fibroids arise from the uterine smooth muscle and relate to gene mutations and/or complex chromosome alterations, re-organizations, and changes in vascular growth factors3,4.
Uterine fibroids are responsive (increase their growth/size and symptoms) to hormonal factors including estrogens, progestogens and insulin-growth factor I (IGF-I)5,6. IGF-I stimulates uterine myoma cell growth, enhancing proliferation and inhibiting apoptosis, while progesterone (alone or in combination with estradiol) down-regulates IGF-I mRNA and protein expression in fibroid cells6. Fibroid cells produce abnormal regulation of growth factors and cytokines that have negative effects over the endometrium7. Asymptomatic fibroids do not impair quality of life or increase the risk of complications. The severity of symptomatic fibroids is related to their size and location. The most common symptoms include: heavy menstrual bleeding (HMB) or menorrhagia, pain and pelvic pressure, bowel and bladder dysfunction, pain during sexual intercourse, and infertility. HMB is the most common symptom associated with fibroids
Correspondence: Professor F. R. Pérez-López, Department of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University Hospital, Zaragoza, Spain. E-mail: [email protected] SHORT REVIEW © 2014 International Menopause Society DOI: 10.3109/13697137.2014.981133
Received 20-10-2014 Accepted 22-10-2014
Ulipristal acetate in management of symptomatic uterine fibroids that are located in or near the lining of the uterus. However, symptoms can also be related to other causes, including endometrial hyperplasia or cancer, polyps, adenomyosis, pelvic vascular alterations and endocrine disorders. Therefore, an appropriate clinical assessment is mandatory1,8–10. Blood supply may be insufficient in rapidly growing fibroids and therefore degenerate, producing pain, cramping, ischemic acute pain, pelvic pressure, discomfort during sexual intercourse, urinary symptoms and/or painful bowel movements. They have no significant risk for malignant transformation as genetic alterations of myomas and leiomyosarcomas suggest different pathogenic pathways1.
Climacteric Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
GENERAL MANAGEMENT OF UTERINE FIBROIDS Symptomatic fibroids have been traditionally managed by surgery, either by hysterectomy or myomectomy. In recent years, alternative therapeutic options are available including different non-surgical interventions (e.g. uterine artery embolization, high-intensity focused ultrasonic myolysis)1,11. However, many women do not desire to be managed with invasive interventions. In this sense, a large number of pharmacologic approaches have also been proposed to control fibroid-related HMB, inter-menstrual bleeding, pelvic pain and impaired quality of life. Pharmacological treatments of uterine fibroids may temporarily reduce/relief symptoms. Despite this, they are not devoid of adverse effects and fibroids may re-grow after medication withdrawal12. The effectiveness of progestogens or progestogen-releasing intrauterine systems in premenopausal women with symptomatic uterine fibroids is limited at reducing HMB or fibroid size13. Progestogens have a moderate effect over heavy uterine bleeding, reduction of myoma size, and hemoglobin increase prior to surgery. Levonorgestrel-releasing intrauterine systems reduce increased menstrual bleeding and aid the restoration of hemoglobin level, although the effect over fibroid anatomy is minimal or nil. Gonadotropin-releasing hormone agonists (GnRHa) (leuprolide, triptorelin, buserelin, goserelin) have been used for 3–6 months prior to fibroid surgery and, in selected cases, to reduce fibroid size, HMB and correct pre-operative anemia in order to allow a high rate of laparoscopic or vaginal surgical procedures12,14,15. However, they produce significant side-effects (menopausal symptoms and bone loss) and fibroid re-growth to previous size within weeks after treatment withdrawal. Adverse hypoestrogenic effects may be neutralized or reduced with estrogen or tibolone add-back therapy and/or the use of bone antiresorptive agents. Preclinical and placebo-controlled trials have demonstrated the efficacy of progesterone antagonists (e.g. mifepristone) and selective progesterone receptor modulators (SPRMs) in reducing fibroid and uterine volume and suppressing associated bleeding. A meta-analysis of 11 randomized, controlled trials including women with symptomatic fibroids reported that mifepristone, at doses ranging from 2.5 to 25 mg/day
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Pérez-López for 3–6 months, reduces fibroid size and related symptoms (uterine bleeding, pelvic pain, pelvic pressure, anemia and dysmenorrhea). In addition, there was no significant difference in the rate of atypical endometrial hyperplasia between patients under hormonal treatment and those receiving placebo; however, there are large individual variations related to fibroid size reduction15. In this sense, Engman and colleagues16 have examined the expression of genes related to this heterogeneous response. They reported that, among good responders to mifepristone (50 mg, every other day for 12 weeks prior to surgery), there was overexpression of the glutathione-s transferase mu 1 (GSTM1) gene as compared to non-responders. These findings support the different hormone fibroid responses and that gene research may lead to the finding of a reliable biomarker that will help stratify patients and optimize therapy. A new option is vaginal mifepristone treatment (10 mg/day for 3 months) which may be effective at reducing fibroid symptoms and volume17.
ULIPRISTAL ACETATE IN THE MANAGEMENT OF SYMPTOMATIC UTERINE FIBROIDS Ulipristal acetate is a SPRM and effective emergency contraceptive that has been studied for other indications including uterine fibroids, endometrial pathology, endometriosis and a potential use in neurology- and oncology-related diseases19,20. UA has a high affinity for progesterone receptors A and B and less affinity for the glucocorticoid receptor as compared to mifepristone21,22. It has pro-apoptotic and anti-proliferative effects over myoma uterine cells23 and initial clinical studies have shown a well-balanced relationship between efficacy and tolerability in the management of symptomatic uterine fibroids24,25. Women with symptomatic uterine fibroids have been treated with UA in phase-II studies and randomized, controlled trials, showing an interesting clinical profile and improvement of impaired quality of life related to fibroids. In the PEARL-I (PGL4001 vs. placebo) trial, premenopausal women (18–50 years) with symptomatic fibroids were randomly assigned before surgery to receive oral UA (5 mg or 10 mg/day) or placebo for up to 13 weeks26. Women had uterine size equivalent to a 16 week gestation, with at least one fibroid of 3 cm but not exceeding 10 cm upon magnetic resonance imaging, and excessive uterine bleeding and anemia. This study demonstrated control of bleeding in 91%, 92% and 19%, respectively for 5 mg UA, 10 mg UA and placebo. Amenorrhea was obtained in 73%, 82%, and 6%, while fibroid volume changes were 21%, 12% and 3%, respectively. The most common side-effects among those treated with UA were headache and breast tenderness, although with a similar rate to the control group. Benign endometrial histological changes were registered among the UA-treated group which disappeared 6 months post-treatment. Barlow and colleagues27 reported the vaginal bleeding characteristics (secondary outcome) in the PEARL-I study for those women who did not have a rapid onset of amenorrhea and had
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Ulipristal acetate in management of symptomatic uterine fibroids irregular bleeding (26.9% for women treated with 5 mg/day and 28.7% for those with 10 mg/day). Bleeding assessment was performed before randomization, during and after treatment in those women who did not have surgery. Women in the placebo group persisted with abnormal bleeding; although four of the 48 women spontaneously improved their bleeding pattern and one developed amenorrhea. In some patients treated with UA, abnormal bleeding (prolonged, frequent or irregular) was related to submucous fibroids. Thus, the presence of submucous fibroids could limit the efficacy of UA at controlling bleeding. The PEARL-II (PGL4001 versus GnRHa in uterine myomas) was a non-inferiority, randomized study that compared the same oral UA doses (5 mg/day and 10 mg/day) used in the PEARL-I study but now compared to monthly intramuscular doses of the GnRHa leuprolide acetate (3.75 mg) for the treatment of women with symptomatic fibroids28. Primary outcome was to assess efficacy at controlling bleeding and uterine size at 13 weeks of treatment. Primary outcome results for the three arms of the study were similar (bleeding control in 89–98% of patients), although median time to amenorrhea was within 1 week for UA treatments as compared to 3 weeks with leuprolide acetate. At the end of the study, all three hormonal treatments reduced the size of the largest fibroids, the median reductions being 36% for low-dose UA, 42% for high-dose UA and 53% for leuprolide acetate. In addition, the GnRHa produced a significantly greater reduction of uterine volume (47%) as compared to UA treatment (20–22%). Moderate to severe hot flushes affected 11% and 10% of women treated with the low and high UA doses as compared to 40% of women treated with the GnRHa. Endometrial thickness was doubled as compared to GnRHa treatment (9.4 and 10.7 mm for patients treated with 5 and 10 mg/day, respectively), and a case of simple hyperplasia was detected in a woman receiving 5 mg/day of UA. Six months after treatments, there were no significant differences in endometrial thickness in women not submitted to hysterectomy. Reduced fibroid volume persisted for a longer period of follow-up in the UA-treated women as compared to those treated with the GnRHa. Menstruation resumed 1 month after UA treatment and 1.5 months after GnRHa therapy was discontinued. In 2012, UA was licensed by the European Medicines Agency for the treatment of symptomatic fibroids (5 mg/day) during a maximum of 3 months for the preoperative management of symptomatic fibroids. Donnez and colleagues29 recently reported the efficacy and safety of cyclical UA treatment (10 mg/day), up to four courses, in an open-label assessment of symptomatic women with at least one fibroid of 3–10 cm diameter (PEARL-III and PEARL-III extension studies). Each 3-month cycle of UA treatment was followed by a double-blind randomization to oral norethisterone acetate (NETA; 10 mg/day) or placebo for 10 days. During the initial UA cycle, amenorrhea occurred in 79% of women and there was a median fibroid volume reduction of 45%, with similar rates of amenorrhea in successive cycles. Endometrial assessment showed benign histological
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Pérez-López changes without hyperplasia, whereas the NETA group did not display changes in fibroid volume and endometrial characteristics. On the other hand, UA did not shrink fibroids in all women with successive cycles of treatment, although the drug produced a high rate of bleeding control. Cyclical UA, with or without NETA treatment, may also improve quality of life, pain anxiety and depression. Adverse events were mild or moderate throughout the several courses of treatment and not greater than those reported in the pivotal studies (PEARL-I and -II)26,28. In addition, all endometrial biopsies reported benign changes without hyperplasia and NETA administration did not influence fibroid size. Pregnancy rate and live birth rate were reported in a small group of patients who desired to conceive30. Twenty-one out of 52 patients included in the PEARL-II and -III trials tried to conceive, of whom 15 became pregnant, with a total of 18 pregnancies. Of these, 12 ended in live births and six in miscarriages. Pregnant women did not have myoma re-growth during pregnancy. In a small case–control study carried out in premenopausal women with symptomatic intramural fibroids, the effect of oral UA (5 mg/day for 3 months) on fibroid volume and vascularity was compared to that of bilateral uterine artery embolization using ultrasound assessment. After 3 months of UA treatment, fibroid volume decreased to a similar level to that found in women 3 months after uterine embolization. Three months after treatments, Doppler vascular indices showed that the vascularization index, the flow index and the vascularization flow index decreased as compared to respective baseline values. In addition, UA decreased fibroid vascularization but yet to a lesser extent than uterine embolization31. More detailed studies are needed to compare the short- and long-term results of these two therapeutic approaches.
PENDING ISSUES Although preoperative UA treatment improves fibroid-related symptoms and reduces fibroid and uterine volume with less frequent side-effects reported than with other hormone therapies (e.g. GnRH analogs), its long-term use for symptomatic fibroids, cost-effectiveness ratio and degree of female acceptance are still issues to be analyzed. Although some cost–benefit models support pre-surgical UA use32, the costeffectiveness as a pre-surgical treatment should be assessed under different national health systems. Moreover, costs related to long-term treatment (e.g. follow-up and complementary explorations) need to be calculated and compared to non-pharmacological therapy. Studies in this regard are warranted. Since there are differences in the prevalence and severity of symptoms related to ethnicity, studies assessing the effect of UA on women with African ancestry are highly recommended. To date, available evidence has been obtained from Caucasian women. On the other hand, although quality of life has been assessed in the PEARL trials, the efficacy of any new treatment
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Ulipristal acetate in management of symptomatic uterine fibroids shows ‘better results’ in highly selected populations which are not confirmed among ‘unselected’ patients and related to emotions, cultural factors and subjective health33. Thus, future UA evaluations should include other tools and endpoints (global health, life satisfaction, psychological well-being, self-esteem) apart from quality of life. There is a need for comparative studies between UA and vaginal mifepristone18. The effect of UA in women with symptomatic uterine fibroids should also be compared with other non-surgical treatments, including uterine artery embolization, myolysis and ablation by high-intensity focused ultrasound guided with magnetic resonance imaging or ultrasound. Combined treatment (UA plus non-surgical interventions, e.g. uterine artery embolization, ultrasound focused myolysis) should be considered as an alternative for selected patients. Another issue that need exploration is the effect of UA in women with symptomatic fibroids who are infertile. It seems that fertility capacity is not affected in women with fibroids that do not distort the uterine cavity34. The endpoint among infertile women should be assessed in relation to fertility outcomes. The effects of UA in women with adenomyosis or both uterine fibroids and adenomyosis have not been established. Finally, assessment of long-term UA treatment should include endometrial, cardio-circulatory and neurological endpoints.
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TAKE-HOME MESSAGES • UA is a SPRM highly effective for the control of symptoms of uterine fibroids and the reduction of their size in symptomatic women programmed for surgical management. These changes are associated with significant improvement of quality of life. • UA cyclic treatment associated with NETA is highly effective in reducing/neutralizing uterine fibroid-related symptoms. • UA can induce unusual specific endometrial changes which warrant follow-up. • Economic assessment of long-term UA use (including drug treatment and the cost of complementary follow up) should be evaluated. • Clinical outcomes of UA treatment should be compared with surgical and other non-surgical interventions. • The efficacy of UA treatment and related outcomes in women with infertility or adenomyosis remains to be determined. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
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