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Ulipristal Acetate: a novel medical therapy for uterine fibroids

Vikram Sinai Talaulikar MD, MRCOG

Clinical Fellow in Reproductive Endocrinology and Assisted Reproduction, University College London Hospital, London, UK

Uterine fibroids – current management options and the need for an effective medical therapy

Fibroids are the most common tumors of women during their reproductive life and they are found in one out of every four women. They are symptomatic in 50% of the women who have them, with the peak incidence of symptoms occurring among women in their 30s and 40s. Fibroids can cause a variety of symptoms which include menstrual disturbances (commonly menorrhagia and dysmenorrhea), pressure symptoms such as increased urinary frequency, pelvic pain and constipation, they may also interfere with reproduction. Although it is usually assumed that problems associated with fibroids resolve with the onset of the menopause, in reality fibroids can cause symptoms (including abnormal bleeding) even in the menopause.

Although the exact etiology of fibroids is not well established, it is known that these tumors depend on sex hormones for their growth and several risk factors have been identified such as early menarche, nulliparity and family history.

majority of symptomatic uterine fibroids are currently treated by surgical interventions (myomectomy or hysterectomy) or radiological treatments (uterine artery embolization or focused ultrasound surgery). None of these treatments are a panacea for every woman, and what is conspicuous is the lack of an effective long-term medical therapy for a disorder so common among women of reproductive age.

Although hysterectomy constitutes a ‘cure’, the operation remains unacceptable to the woman wishing to retain her fertility potential. Myomectomy is a major operation with associated morbidity and indeed mortality risks. It may also compromise the very same fertility that it seeks to preserve owing to the potential for adhesion formation, and there is a significant risk of recurrence of the fibroids. In recent years, a multitude of additional therapeutic choices have emerged, including laparoscopic and vaginal myomectomy, uterine artery embolization (UAE) and, more recently, magnetic resonance-guided focused ultrasound surgery (MRgFUS). It is, however, abundantly clear that none of these therapies is a panacea and a ‘one size fits all’ approach cannot work. Laparoscopic surgery requires skills that are not commonplace and there are limitations on the size and number of fibroids that can be treated by this modality. Much the same applies to vaginal myomectomy. UAE has a range of complications including premature ovarian failure, chronic vaginal discharge and in rare cases pelvic sepsis, and may have limited efficacy where the fibroids are large. While these treatments have varying degrees of efficacy, they all have major cost implications too. MRgFUS, for example, requires the availability of costly ‘open’ MRI facilities that many units do not have, while the costs of the other procedures including myomectomy and hysterectomy are well reported in the literature.

Given the choice, many women would opt to avoid major surgery such as myomectomy or hysterectomy, or indeed even the less invasive procedures such as UAE or MRgFUS. There is clearly a need for medical therapy that eliminates the need for surgery, is relatively cheap and has efficacy equivalent or superior to surgery.

The status of current medical treatments for uterine fibroids

Gonadotropin-releasing hormone (GnRH) analogues have been the most widely used medical treatment; however, while they do cause fibroid regression, they can only be used in the short term, as temporizing measures in the perimenopausal woman, or preoperatively to reduce fibroid size and influence the type of surgery, restore hemoglobin levels and apparently reduce blood loss at operation. They are notorious for rebound growth of the fibroids upon cessation of therapy, and have major side-effects such as bone mineral density loss and vasomotor symptoms. They are also reasonably expensive and may make subsequent myomectomy more difficult because they can destroy tissue planes. Selective estrogen receptor modulators (SERMs) such as raloxifene have been shown to effectively induce fibroid regression in post-, but not premenopausal women, but experience with these drugs is limited and they are associated with significant side-effects. Progestational agents such as norethisterone (non-proprietary) 5 mg three times a day continuously have also been used in less resourced settings to induce amenorrhea while improving anemia. But side-effects include bloating, fluid retention, breast tenderness, weight change, nausea, headache, drowsiness and mood swings. There is no significant reduction in uterine or fibroid volume. There are also suggestions that the levonorgestrel intrauterine system can cause dramatic reduction in menstrual flow in women with fibroids, but as yet there are no robust randomized trials of its use in these women, where rates of expulsion of the device appear to be high.

What is ulipristal acetate and what is its mechanism of action on fibroids?

Recent biochemical studies have suggested that progesterone and its receptors enhance proliferative activity in fibroids and this has, therefore, raised the possibility that anti-progestational agents and progesterone receptor modulators could be useful in the medical management of fibroids1,2. The first progesterone receptor antagonist, mifepristone (RU-486), emerged on the clinical horizon 25 years ago and since then hundreds of steroidal as well as non-steroidal compounds displaying progesterone antagonist (PA) or mixed agonist/antagonist activity have been synthesized. Ulipristal acetate (UA also known as CDB-2914) belongs to this group of compounds collectively known as selective progesterone receptor modulators (SPRMs). It reversibly blocks the progesterone receptor in its target tissues (uterus, cervix, ovaries, hypothalamus) and acts as a potent, orally active anti-progestational agent. Most gynecologists will be familiar with UA as it has been on the clinical scene for some while as an efficient emergency contraceptive. Recently, it has successfully completed phase III clinical trials for medical treatment of uterine fibroids. It has been licensed in Western Europe for short-term clinical use prior to surgery for fibroids, and has shown efficacy with a significant reduction in uterine bleeding, fibroid volume and improved quality of life, without the side-effects associated with other medications such as GnRH agonists.

UA downregulates the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and their receptors in cultured fibroid cells3 . This can result in the suppression of neovascularization, cell proliferation and survival1 . UA also increases the expression of matrix metalloproteinases and decreases the expression of tissue inhibitor of metalloproteinases and collagens in cultured fibroid cells. This can reduce the collagen deposition in the extracellular spaces of fibroids, impairing tissue integrity1,3,4. UA and other SPRMs have been shown to modulate the ratio of progesterone receptor isoforms (PR-A and PR-B) in the cultured leiomyoma cells5 . They decreased the cell viability; suppressed the expression of growth factors, angiogenic factors and their receptors in those cells; and induced apoptosis. Have clinical trials and other studies found ulipristal acetate effective and safe? In phase II and III clinical trials, a number of issues have been addressed using UA. A randomized, double-blind, placebo-controlled trial of efficacy and tolerability also has demonstrated positive results when ulipristal was administered for 3–6 months, showing good control of bleeding, reduction in fibroid size, and improvement in quality of life in the treatment group6 . In another trial in which ulipristal was given at 10 or 20 mg in comparison against placebo for three cycles, ulipristal showed a 92% reduction in bleeding versus 19% with placebo. Fibroid volume was significantly reduced with UA administration (placebo 6%; UA 29%; p = 0.01). UA eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles: UA, 20%; placebo, 83%; p = 0.001). UA improved the concern scores of the uterine leiomyoma symptom quality of life subscale (p = 0.04). One UA woman developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. Interestingly, there were no differences in serum estradiol levels between the treatment and placebo groups (median estradiol was greater than 50 pg/ml in all groups). However, the numbers studied were small, with 22 patients being allocated and 18 completing the three cycles or 90–120 day trial7 . Ulipristal has recently successfully completed two phase III clinical trials (PEARL I & II) in Europe demonstrating its efficacy and safety for the treatment of symptomatic uterine fibroids in patients eligible for surgery8,9. PEARL I compared treatment with oral UA for up to 13 weeks at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) with placebo (48 women) in patients with fibroids, menorrhagia and anemia8 . All patients received iron supplementation. The co-primary efficacy endpoints were control of uterine bleeding and reduction of fibroid volume at week 13, after which patients could undergo surgery. At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of UA, 92% of those receiving 10 mg of UA, and 19% of those receiving placebo (p <0.001 for the comparison of each dose of UA with placebo). Treatment with UA for 13 weeks effectively controlled excessive bleeding owing to uterine fibroids and reduced the size of the fibroids. PEARL II was a double-blind non-inferiority trial, which randomly assigned 307 patients with symptomatic fibroids and excessive uterine bleeding to receive 3 months of daily therapy with oral UA (at a dose of either 5 or 10 mg) or once-monthly intramuscular injections of the GnRH analogue leuprolide acetate (at a dose of 3.75 mg)9 . The primary outcome was the proportion of patients with controlled bleeding at week 13, with a pre-specified non-inferiority margin of –20%. Uterine bleeding was controlled in 90% of patients receiving 5 mg of UA, in 98% of those receiving 10 mg, while the figure for leuprolide acetate was 89%. Both UA doses were non-inferior to once monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes.

Are there any side-effects associated with the use of ulipristal acetate?

The vast majority of adverse reactions are mild, have not led to discontinuation of the medicinal product and resolved spontaneously. These include hot flushes, headache, functional ovarian cysts, vertigo, nausea, acne, sweating, muscle pain and tiredness.

A National Institute of Health (NIH)-sponsored workshop evaluated endometrial specimens from women receiving mifepristone, asoprisnil and CDB-29141,10-12. Pathologists were blinded to agent, dose and exposure interval. It was concluded that there was little evidence of mitosis consistent with the antiproliferative effect of PRMs. No biopsy demonstrated atypical hyperplasia. There was asymmetry of stromal and epithelial growth and prominent cystically dilated glands with both admixed estrogen (mitotic) and progestin (secretory) epithelial effects. This histology has not been previously encountered in clinical practice. The panel designated these changes as PRM associated endometrial changes (PAECs)1,10-12. Despite the paucity of mitoses, pathologists may associate the cystic glandular dilatation observed with PRMs with simple hyperplasia and should be aware of the potential diagnostic pitfalls of misdiagnosing hyperplasia in women receiving PRMs. In the PEARL II study endometrial biopsy examinations showed no findings of clinical concern in cases receiving UA. At week 13, all histological specimens showed benign endometrium except for one patient in the group receiving 5 mg of UA, whose specimen showed simple hyperplasia9.

Thus, the overall evidence emerging from the recent clinical trials regarding the use of PRMs has been reassuring. Clinicians detecting endometrial thickening in women treated with PRMs need to be aware that administration of PRMs for longer than 3 months may lead to endometrial thickening. This is related to cystic glandular dilation, not endometrial hyperplasia and pathologists need to be aware of PAEC and avoid misclassifying the appearance as hyperplasia. Until safety data from long-term studies are available, an appropriate follow-up should be recommended for patients receiving UA13.

What are the clinical indications for ulipristal therapy for fibroids?

The licensed form of ulipristal acetate is called Esmya™ (manufactured by Gedeon Richter plc., Hungary) and is given as a 5 mg once a day oral tablet, taken for 3 months ahead of surgery. Unfortunately at the present time, the license covers only 3 months of use preceding surgery, and therefore further research is required to define the true impact of UA on fibroids. UA may be less effective in the treatment of massive fibroids as it may achieve a modest reduction in their size. It may act best in a selection of patients with certain fibroid number and size as compared to others. Larger research clinical trials in future with varying dosage and duration of therapy should provide a definitive answer to this question13.

Clinicians detecting endometrial thickening in women treated with UA need to be aware that administration of UA for longer than 3 months may lead to endometrial thickening. This is related to cystic glandular dilation, not endometrial hyperplasia. However, in absence of robust safety data for a period longer than 3 months or on repeat courses of treatment, treatment duration should not exceed 3 months. Clinicians should be aware of the need to investigate, as per usual clinical practice, persistence of endometrial thickening following treatment discontinuation and return of menstruation to exclude any underlying pathological conditions14.


There is undoubtedly an urgent need for simple and effective medical therapies to treat the very common disease of the female reproductive age group that is symptomatic fibroids. Ulipristal acetate and other progesterone receptor modulators are promising candidates, with their simplicity of administration, potentially minimal side-effects profile, and likely low costs. The challenges which remain include the inadequacy of research regarding their long-term efficacy and safety. Key questions include the effectiveness of shrinking large fibroids, whether these fibroids re-grow on cessation of therapy, how quickly they do so, their safety with regards to the endometrium and impact on metabolism, and of course the impact of long-term therapy on reproductive function. The manufacturers have secured a license for the preoperative use of ulipristal acetate in most of Western Europe and the stage is set for definitive clinical trials that should help establish the true role of progesterone receptor modulators in the management of symptomatic uterine fibroids.

Have you prescribed ulipristal acetate pre-operatively for your patients? What has been your experience with ulipristal for treatment of uterine fibroids? We would love to hear from you and share your thoughts with our readers. Please click the "Make a comment" button located to the left of the page.


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