Ulipristal Acetate: Ready for Prime Time?
By Michael A. Thomas, MD
Professor, Director, Division of Reproductive Endocrinology and Infertility, University of Cincinnati College of Medicine
Dr. Thomas reports no financial relationships relevant to this field of study.
Since the beginning of modern time, researchers have been trying to find a hormonal agent that would confer multiple therapeutic effects. This "perfect" drug would prevent pregnancy, shrink fibroids, and lessen the effects of endometriosis thereby treating contraceptive needs, symptomatic leiomyomas, and pelvic pain. What a medicine! Well, that perfect hormonal agent may finally be available. Multiple drugs have been touted as the next best thing over the last 60 years; these contenders have included combination oral contraceptives, progestin-only pills, and intrauterine devices. But the new Swiss Army knife of gynecology that may ameliorate or cure all reproductive ills may rest in the hands of the selective progesterone receptor modulators (SPRMs).
SPRMs, like ulipristal acetate (UPA), have been studied as a treatment option for patients in need of emergency contraception and are predicted to have multiple uses in the field of reproductive medicine.1 Although UPA is FDA-approved as an emergency contraceptive, other potential uses are as a daily oral contraceptive as well as an agent to treat endometriosis and symptomatic uterine fibroids.
UPA, otherwise known as CDB-2914 or VA 2914, is a second-generation SPRM that directly blocks progesterone action in target tissues and, unlike mifepristone (RU 486), has little glucocorticoid receptor activity.2,3 UPA is a SPRM with mixed effects at the level of the progesterone receptor.4 It can exhibit both antagonistic and a partial agonistic effect. When it binds to the progesterone receptor, it prevents endogenous progesterone from occupying this site, inhibiting progesterone receptor-mediated DNA transcription. SPRMs have been demonstrated to inhibit ovulation, decrease proliferation of the endometrium (with possible alteration of implantation potential), and result in amenorrhea.1 UPA can exhibit different effects depending on when it is administered in the menstrual cycle.
SPRMs are an effective form of emergency contraception that can be used up to 120 hours after intercourse.1 When comparing levonorgestrel (LNG) to UPA, LNG acts primarily by blocking or delaying the luteinizing hormone (LH) surge. Its efficacy is limited to the time frame preceding the onset of this surge, with no subsequent effects on follicular dynamics once LH levels increase. In contrast, UPA has the potential to prevent pregnancy even in the presence of increased LH levels in the advanced follicular phase. A single dose of 30 mg of UPA administered immediately prior to ovulation (dominant follicle > 18 mm) was effective in delaying subsequent follicular rupture for 5 days in 60% of subjects, primarily through postponement of the LH peak.5
One group of investigators directly compared the effectiveness of a single 30 mg dose of UPA to 1.5 mg of LNG in a randomized, multicenter, single-blinded, non-inferiority trial, involving 1696 women.6 With the primary outcome being pregnancy rate in women who received emergency contraception within 72 hours of unprotected intercourse, 15 pregnancies occurred in the UPA group (1.8%; 95% confidence interval [CI], 1.0-3.0) compared to 22 in the LNG group (2.6%; CI 1.7-3.9; odds ratio, 0.68). No significant difference in pregnancy rates (P = 0.091) between the UPA and LNG group was observed. Secondary outcome was pregnancy rate from 72-120 hours of intercourse, and in this subgroup of 203 women, a total of three pregnancies were observed, all from the LNG group. A significant number of pregnancies were prevented in the UPA group compared to the LNG group (P = 0.037). When the authors analyzed the pregnancy rates between the groups over the entire 120-hour period, there was no statistical significance (P = 0.091). A meta-analysis including data from a National Institutes of Health (NIH) multicenter study involving an additional 1546 women demonstrated a lower pregnancy rate at the timepoints of 24 (P = 0.035), 72 (P = 0.046), and 120 hours (P = 0.025).7 Unlike LNG, UPA can be used over a 5-day period, and it does not exhibit the same magnitude of decreased efficacy the longer one administers it after intercourse.
Commonly experienced symptoms observed include headache, nausea, and abdominal pain. In the two Phase 3 studies, the rates were 18%, 12%, and 12%, respectively.6,8 Other symptoms include dysmenorrhea, fatigue, and dizziness, as well as a delay in menses that ranged between 2.1 and 2.8 days.1
In 2009, the new drug review application for UPA as an emergency contraceptive agent by FDA discussed the possibility of drug-drug interactions, including agents that induce or inhibit CYP3A4 enzymes. Agents that may induce this enzyme include carbamazepine, phenytoin, barbiturates, griseofulvin, rifampin, oxcarbazepine, and St. John’s wort.3 Inhibitors of this enzyme, such as ketoconazole and itraconazole, possibly could increase blood levels of this agent, as UPA is primarily degraded by the cytochrome P450 system.
UPA is categorized as a pregnancy category X drug, and, therefore, is contraindicated for use during pregnancy.3 In addition, the potential of drug secretion into breast milk is yet unknown, so breastfeeding is not recommended. There is animal evidence that exposure of UPA during organogenesis resulted in fetal loss; however, in the fetuses that survived, no malformations were seen in the offspring. Unlike mifepristone, UPA is not approved for use in termination of pregnancy.
Daily Contraceptive Pill
In addition to use as an emergency contraceptive agent, UPA is being investigated as a potential agent for estrogen-free, long-term contraception. The capacity of UPA to inhibit or prevent ovulation for contraception has been investigated. In a prospective, randomized, placebo-controlled trial of 46 women, 5 or 10 mg of daily UPA was shown to effectively prevent ovulation over a 3-month period (81.8% and 80%, respectively).9 Other investigators have used UPA in a vaginal ring, but up to 32% of 111 treatment cycles of 4 weeks noted evidence of ovulation.10 Though a thickened, cystic-appearing endometrium is occasionally noted with users of oral UPA, PRM-associated endometrial changes (PAEC) confers no evidence of hyperplasia or endometrial cancer when seen on biopsy. Therefore, PAEC is thought to be a benign condition. Although UPA has demonstrable effects on suppressing ovulation, estrogen levels are essentially unchanged, and, therefore, any bone density changes seen secondary to a hypoestrogenic environment are not observed.
The NIH is currently conducting a Phase 2 trial using UPA in 5 and 10 mg doses continuously as a daily administered contraceptive. The 5 mg dose will also be looked at in a 24-day and 4-day sequential pattern.
As of now, Phase 1, 2, and 3 clinical trials using UPA for patients with uterine fibroids have been completed.11 Most of these studies have demonstrated a decrease in bleeding, fibroid volume, and an improvement in quality-of-life parameters without any significant side effects after 13 weeks of administration. When compared to placebo, UPA in doses of 5 mg and 10 mg showed a significant reduction in bleeding, fibroid size, and adverse effects.12 When fibroid patients were given leuprolide acetate (LA), a GnRH agonist, or UPA at similar doses, the LA and the different UPA groups had similar effects on the control of bleeding, but complaint of hot flashes was more significant in those taking LA.13
Although studies in humans have yet to be published, when UPA was given to a rat model with surgically induced endometriosis for 8 weeks, a regression and atrophy of the endometriotic lesions was documented.14 There was also a reduction in cytokines associated with cellular proliferation and inflammation. Whether similar findings in the human will be demonstrated remains to be seen.
UPA is the first SPRM approved for emergency contraception in the United States. It is also currently undergoing Phase 3 trials as treatment for uterine leiomyomas and Phase 2 trials as a long-term contraceptive agent. It has the capability to affect both ovulation and implantation, as evidenced by its effects on progesterone and the role of this hormone in the female reproductive process. Hypothetically, if there is a uterine protective effect, UPA could be used for patients with endometrial hyperplasia or early stages of endometrial cancers. The intrauterine administration of UPA, when placed in a silastic tube, in ovariectomized rhesus macaques that were estrogenized has demonstrated an induction of endometrial atrophy and amenorrhea.15
Muhammad Ali was a self proclaimed G.O.A.T. (Greatest of All Time). He proved worthy of this unofficial honor by years of proven boxing prowess. Whether UPA will be the reproductive equivalent of a G.O.A.T. remains to be seen. However, initial studies have shown that UPA and other second-generation SPRMs may be the future pharmaceutical agents that will allow our patients to improve their lives by protecting them against unwanted pregnancy, the bleeding and mass effect of uterine fibroids, and the menstrual and sexual pain associated with endometriosis.
- Martinez AM, Thomas MA. Ulipristal acetate as an emergency contraceptive agent. Expert Opin Pharmacother 2012;13:1937-1942.
- Bouchard P, et al. Selective progesterone receptor modulators in reproductive medicine: Pharmacology, clinical efficacy and safety. Fertil Steril 2011;96:1175-1189.
- 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.
- Blithe DL, et al. Development of the selective progesterone receptor modulator CDB-2914 for clinical indications. Steroids 2003;68:1013-1017.
- Cheng L, et al. Interventions for emergency contraception. Chochrane Database Syst Rev 2012;8:CD001324.
- Glasier AF, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: A randomized non-inferiority trial and meta-analysis. Lancet 2010;375:555-562.
- Creinin MD, et al. Progesterone receptor modulator for emergency contraception: A randomized controlled trial. Obstet Gynecol 2006;108:1089-1097.
- Fine P, et al. Ulipristal acetate taken 48-120 hours after intercourse for emergency contraception. Obstet Gynecol 2010;115:257-263.
- Chabbert-Buffet N, et al. Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and a prospective, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2007;92:3582-3589.
- Brache V, et al. Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns, and endometrium in normal women. Contraception 2012;85:480-488.
- Islam MS, et al. Uterine leiomyoma: Available medical treatments and new possible therapeutic options. J Clin Endocrinol Metab 2013;98:921-934.
- Donnez J, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409-420.
- Donnez J, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:
- Huniadi CA, et al. The effect of ulipristal on Bax/Bcl-2, cytochrome C, Ki-67 and cyclooxygenase-2 expression in a rat model with surgically induced endometriosis. Eur J Obstet Gynecol Reprod Biol 2013; Apr 22 [Epub ahead of print].
- Brenner RM, et al. Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques. Contraception 2010;81:336-342.