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Thursday 23 May 2019
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Medical treatment of uterine fibroids


Surgical treatments have been the traditional gold standard definitive therapies for symptomatic fibroids; however, not all women want to undergo surgery and a range of non-surgical alternatives, such as medical management, are now available


Vikram Talaulikar MD MRCOG PhD
Ertan Saridogan MD PhD FRCOG

Reproductive Medicine Unit, University College London Hospital NHS Trust, London, UK


Uterine fibroids (also known as myomas or leiomyomas) are benign tumours characterised by the proliferation of uterine smooth muscle cells and associated collagen matrix and are the most common benign tumours in women of reproductive age group. They are estimated to be symptomatic in 50% of women who have them, with the peak incidence of symptoms occurring among women aged 30 to 40.1 Uterine fibroids are thought to result from increased mitotic activity within the myometrium under the influence of female hormones, however what initiates the fibroid growth is not yet clear.

Symptoms from fibroids depend on size and position of the fibroids. Symptoms include bleeding disturbances (usually heavy and prolonged periods, sometimes frequent and unpredictable bleeds), pressure symptoms (bladder and bowel symptoms, bloating, chronic pelvic pain and dyspareunia) and subfertility.2 While bleeding disturbances are more suggestive of submucosal or intramural fibroids which distort the endometrial cavity, pressure symptoms depend on the fibroid size and the extent to which fibroids encroach on the surrounding pelvic structures. The impact of fibroids on fertility remains controversial but most clinicians recommend surgical removal of fibroids distorting the endometrial cavity to improve chances of conception.

Asymptomatic women with small fibroids may benefit from expectant management, especially those approaching the menopause. Surgical treatments such as hysterectomy and myomectomy have been the traditional gold standard definitive therapies for symptomatic fibroids. However, not all women wish to have surgery and would like to consider non-surgical alternatives such as medical management.

Medical treatments for symptomatic fibroids
Women with asymptomatic uterine fibroids may not need any active treatment and only require monitoring with periodic assessments to review fibroid size and symptoms. Current medical therapeutic approaches exploit the observations that uterine fibroids have significantly increased concentrations of both oestrogen and progesterone receptors compared to normal myometrium, and that ovarian steroids influence fibroid growth.3,4 Women with symptomatic uterine fibroids who wish to avoid surgery, who have recurrent fibroids following previous surgery, or are unfit for surgical treatment have different medical treatment options for alleviation of symptoms. Most of the medical treatments produce significant, but usually temporary, reductions in both uterine size and symptoms. Although medical management can be an effective option for selected women, there is limited evidence to support many of the treatments suggested. Treatment choice needs be individualised based on each woman’s unique clinical circumstance.

Non-hormonal pharmacological treatment
Tranexamic acid and non-steroidal anti-inflammatory drugs (NSAIDs) are the two most commonly used non-hormonal medications for bleeding and pain associated with uterine fibroids. Tranexamic acid is a synthetic antifibrinolytic agent and it is often the first line medication for management of menorrhagia in primary care setting.5–7

Eder et al7 evaluated the efficacy and safety of oral, modified-release tranexamic acid in women with heavy menstrual bleeding and fibroids. In women with and without fibroids, mean menstrual blood loss was reduced compared with placebo across all treatment cycles (p<0.001). Within the tranexamic acid group, more statistically significant (p<0.001) reductions in blood loss occurred in women with fibroids than in those without fibroids. Adverse events were similar between treatment groups. Concerns have been raised about possible increased risk of venous thromboembolism with tranexamic acid, however the data available so far have been reassuring. A systematic review included 10 trials involving the efficacy of tranexamic acid for the treatment of heavy uterine bleeding.8 Pregnant, post-menopausal and cancer patients were excluded.

The results indicated that tranexamic acid therapy in women with idiopathic menorrhagia resulted in 34–54% reduction in menstrual blood loss. Following tranexamic acid treatment, patient’s quality of life parameters improved by 46–83% compared with 15–45% for norethisterone treatment. When compared with placebo, tranexamic acid use significantly decreased the blood loss by 70% in women with menorrhagia secondary to an intrauterine device (p<0.001). Limited evidence indicated potential benefit in fibroid patients with menorrhagia. No thromboembolic event was reported in all studies analysed.8

Overall, the data on the therapeutic efficacy of tranexamic acid in patients with symptomatic uterine fibroids are limited and further studies are needed to better define its role in fibroid management.

NSAIDs such as mefenemic acid have been effective in reducing heavy menstrual bleeding and dysmenorrhoea in women without fibroids;9,10 however, there are no robust studies showing similar benefits of NSAIDs for menorrhagia in women with uterine fibroids.

A systematic review investigated the effectiveness of NSAIDs in achieving a reduction in menstrual blood loss in women of reproductive years with heavy menstrual bleeding and included 18 randomised controlled trials (RCTs).9 The authors concluded that NSAIDs reduced heavy menstrual bleeding when compared with placebo but were less effective than tranexamic acid, danazol or levonorgestrel intrauterine system. In the limited number of small studies suitable for evaluation, no significant difference in efficacy was demonstrated between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, contraceptive pill or the Progestasert intrauterine system.9

Combined and progesterone-only contraceptives
A review of the epidemiological and clinical evidence for the association between oral contraceptives and uterine fibroids suggests that both combined and progesterone-only contraceptives may decrease the risk of developing clinically significant fibroids.11

Combined oral contraceptives may control irregular or heavy bleeding associated with uterine fibroids without having much impact on their size.12 Studies investigating the effect of oral progesterone therapy on fibroids have also produced mixed results with some studies showing a decrease in fibroid size while others report no significant change.13–15

Progesterone intrauterine system
The levonorgestrel intrauterine system (LNG-IUS), which first appeared on the market in 1990s, has transformed the management of menorrhagia over the last two decades. It proved highly effective in reducing menstrual blood loss and is now considered an alternative to the surgical treatment of menorrhagia.2 The system consists of a T-shaped intrauterine device sheathed with a reservoir of levonorgestrel that is released at the rate of 20μg/day. It exerts its clinical effect by preventing endometrial proliferation and consequently reduces both the duration of bleeding and the amount of menstrual loss.16,17

A number of studies have reported that LNG-IUS is an effective treatment for menorrhagia and irregular bleeding associated with fibroids.16–22 However, results regarding its effect on fibroid growth have been conflicting.18–20 Although some women with large intramural fibroids experienced spontaneous expulsion of LNG-IUS at various intervals, they requested reinsertion of the device because of remarkable reduction in menorrhagia.21 Significant increases in haemoglobin levels were observed after insertion of the devices, but no significant differences were noted in fibroid volume and uterine volume, as assessed by magnetic resonance imaging (MRI) examination pre-treatment and at 12 months of use.21,22

A systematic review conducted to determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating pre-menopausal women with uterine fibroids included three trials.15 However, data for progestogen-releasing intrauterine systems were available from only one study that compared 29 women with a LNG-IUS versus 29 women with a combined oral contraceptive for treating uterine fibroids. There was a significant reduction of menstrual blood loss in women receiving the LNG-IUS compared with the oral contraceptive. The authors concluded that progestogen-releasing intrauterine systems appear to reduce menstrual blood loss in pre-menopausal women with uterine fibroids. Oral progestogens did not reduce fibroid size or fibroid-related symptoms. The evidence was insufficient to support the use of progestogens or progestogen-releasing intrauterine systems in treating pre-menopausal women with uterine fibroids.15

Overall, fibroids are associated with increased rates of discontinuation of the LNG-IUS, difficulties at the time of fitting and higher device expulsion rates. The IUS also acts as a contraceptive and therefore not an option for women wishing to conceive.

Gonadotropin-releasing hormone (GnRH) analogues
GnRH agonists are synthetic analogues of GnRH that after an initial flare effect, inhibit the hypothalamic–pituitary–ovarian axis. The resulting drop in circulating oestrogen levels is associated with fibroid degeneration, resulting in shrinkage of the fibroid. GnRH agonists have been mainly used for the treatment of fibroids in perimenopausal women or as a pre-operative treatment for three to four months.

There is strong evidence that if given three to four months before myomectomy or hysterectomy, GnRH agonists are associated with reduced fibroid volume, correction of pre-operative anaemia, reduction in intraoperative blood loss, reduced midline incisions and increased vaginal approach to surgery where appropriate.23,24 However the reduction in fibroid size and symptoms is usually temporary and the fibroids often re-grow to pre-treatment size after cessation of GnRH agonists in most women. The risk of fibroid recurrence after a course of GnRH agonists in patients who have subsequently undergone myomectomy is controversial and there are limited data to confirm the association.25–27 GnRH agonists are associated with side effects such as hot flushes, sleep disturbances, vaginal dryness, low mood and loss of bone mass after prolonged use.

Various therapies have been studied as add-back (combined oestrogen and progestin, medroxyprogesterone acetate, tibolone) to reduce such adverse effects to allow longer use of GnRH agonists.27

GnRH antagonists have not been studied in as much detail as the agonists. These agents cause reduction in fibroid volume, but their use is limited by their shorter half life, which necessitates daily administration, and that there are few oral preparations.10

Progesterone receptor modulators (PRMs)
Since the emergence of mifepristone (RU-486), the first progesterone receptor (PR) antagonist, more than 25 years ago, many steroidal, as well as non-steroidal, compounds displaying progesterone antagonist or mixed agonist/antagonist activity have been synthesised. Collectively, they are known as PRMs. Progesterone receptors are present in higher concentrations in fibroids than in normal myometrium and some of the PRMs that have been the subject of recent clinical trials or research studies in relation to fibroids treatment include mifepristone, CDB-4124 (telapristone), CP-8947 and J867 (asoprisnil) and CDB-2914 (ulipristal acetate).

The following mechanisms of action have been proposed for the effect of PRMs on fibroids:

  • Ulipristal downregulates the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and their receptors in cultured fibroid cells28 resulting in suppression of neovascularisation, cell proliferation and survival.29
  • Ulipristal and asoprisnil inhibit proliferation of cultured fibroid cells and induce apoptosis by upregulating cleaved caspase 3 and downregulating Bcl-2.28–30
  • Ulipristal also increases the expression of matrix metalloproteinases (MMPs) and decreases expression of tissue inhibitor of metalloproteinases (TIMPs) and collagens in cultured fibroid cells.2 Other important actions of PRMs include inhibition of myoma cell proliferation, reduction in extracellular matrix (ECM) component production and modulation of the ratio of progesterone receptor isoforms in cultured myoma cells.31 Mifepristone and asoprisnil have also been associated with a decrease in uterine artery blood flow.2

A number of clinical trials have established the potential of PRMs in the treatment of uterine fibroids. They are associated with a reduction in pain, bleeding, size of fibroids and an overall improvement in quality of life. Unlike long-acting GnRH analogues, they do not have the drawbacks of the profound oestrogen deficiency and decrease in bone mineral density.

Mifepristone (RU-486)
Mifepristone was introduced as a drug used for medical termination of pregnancy, with or without misoprostol. Mifepristone is an anti-progestin with high affinity for progesterone receptors.

Early reports of the use of mifepristone for the treatment of fibroids date back to 2002, when De Leo et al used doses ranging from 12.5 to 50mg daily and reported a reduction in uterine/fibroid volume of 40–50%, with amenorrhoea in most subjects.32 This report was corroborated by a paper a year later from a group who used mifepristone at a dose of 5 or 10mg per day for one year, and found that it was effective in decreasing mean uterine volume by 50%, while amenorrhoea occurred in 40–70% of the subjects.33 Adverse effects included vasomotor symptoms, but no change in bone mineral density was noted.

Simple endometrial hyperplasia was noted in 28% of the women.33 These reports were followed by a RCT on the use of mifepristone for the treatment of uterine fibroids. This was a double-blind placebo controlled study of 42 women over a period of six months,34 and the authors reported significantly improved overall quality of life, anaemia rates and reduced uterine volumes. In another RCT, 100 women were assigned to mifepristone 5 or 10mg daily for three months without a placebo group: with both doses, there were equivalent reductions in fibroid and uterine volumes, and symptomatic improvements.35

A systematic review was conducted to determine the efficacy and safety of mifepristone for the management of uterine fibroids in pre-menopausal women.36 Three trials involving 112 participants were included. Comparison interventions included different dosages of mifepristone, placebo and vitamin B tablets. There is evidence that treatment with mifepristone relieves heavy menstrual bleeding compared with placebo. There was no evidence of an effect of mifepristone on the fibroid volume.  The pooled data suggested an increased adverse event (abnormal endometrial histology) in the mifepristone group compared with placebo (OR 31.65; 95% CI 4.83–207.35).36 The authors concluded that mifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reduce fibroid volume.

Despite all the beneficial effects of mifepristone, the endometrial hyperplasia seen in some women limits the use of this drug among those desiring a long-term medical therapeutic option for fibroids.

CDB-4124 (telapristone)
A clinical trial (Phase I/II) evaluated the efficacy of telapristone in symptomatic fibroids. This small three-month study, comprising 30 women, compared oral doses of 12.5, 25 and 50mg telapristone with the GnRH analogue leuprolide and a placebo.37 There was a significant reduction in tumour size and reduced bleeding with telapristone treatment.

J-867 (asoprisnil)
Studies compared the efficacy and safety of three doses (5, 10 and 25mg and placebo) of asoprisnil in 129 women over 12 weeks.38,39 Asoprisnil reduced the uterine and fibroid volumes in a dose-dependent manner. There was a dose-dependent decrease in menorrhagia scores in women with menorrhagia at baseline, while amenorrhea rates increased as the dose increased (28.1% with 5mg, 64.3% with 10mg and 83.3% with 25mg), but with no increase in the rates of unscheduled bleeding in all three asoprisnil groups. Results suggested endometrial thickening to be one of the important side effects of the drug. Overall safety data available so far, however, have been reassuring and its impact on bone mineral density, fertility, recurrence rates of fibroids and endometrial hyperplasia are still under evaluation.2

CDB-2914 (ulipristal acetate)
Ulipristal acetate (UA) is the most studied and popular progesterone receptor modulator for treatment of uterine fibroids.

In a trial in which UA was given at 10mg or 20mg against placebo for three cycles, UA showed a 92% reduction in bleeding versus 19% with placebo.40 Myoma volume was significantly reduced with UA (29% versus 6%; p=0.01). UA eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles 20% on UA versus 83% with placebo; p=0.001). UA also improved the quality of life subscale. One woman on UA developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported.40

A double blind, placebo-controlled trial of efficacy and tolerability has also demonstrated positive results when UA was administered for three to six months, showing good control of bleeding, reduction in fibroid size, and improvement in quality of life in the treatment group.41

Two Phase III clinical trials (PEARL I and II) in Europe demonstrated the efficacy and safety of UA for the treatment of symptomatic uterine fibroids in patients eligible for surgery.42,43 The PEARL I study, a double blind, placebo-controlled trial, demonstrated reductions in menstrual loss in 91% and greater than 20% reductions in fibroid volume in those taking either 5mg or 10mg of ulipristal acetate for 13 weeks, making it useful in reducing fibroid volume prior to surgery. These results were mirrored by the PEARL II study, which demonstrated UA to be as effective as the GnRH agonist leuprolide in controlling uterine bleeding and achieving fibroid shrinkage, with fewer hypoestrogenic side effects. Side effects included benign histologic endometrial changes that disappeared within six months after treatment. Both the 5mg and the 10mg daily doses of UA were non-inferior to once-monthly GnRH analogue treatment in controlling uterine bleeding.42,43

Endometrial hyperplasia and thickening associated with use of PRMs
A National Institute of Health-sponsored workshop evaluated endometrial specimens from women receiving mifepristone, asoprisnil and UA.29,44,45 It was concluded that there was little evidence of mitosis, consistent with the anti-proliferative effect of PRMs. No biopsy demonstrated atypical hyperplasia. There was asymmetry of stromal and epithelial growth and prominent cystically dilated glands with both admixed oestrogen (mitotic) and progestin (secretory) epithelial effects. This histology has not previously been encountered in clinical practice. The panel designated these changes as PRM-associated endometrial changes (PAECs).29,44,45 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.

Some studies have reported endometrial thickening detected on ultrasound after use of high- or low-dose mifepristone.46,47 It has been suggested that, unlike in the situation where there is unopposed oestrogen effect, the endometrial thickening in women on PRMs is related to cystic glandular dilation and not endometrial hyperplasia. The overall evidence emerging from the recent clinical trials regarding the safety of PRMs appears to be reassuring.

Clinicians detecting endometrial thickening in women treated with PRMs need to be aware that administration of PRMs for longer than three 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.

The PEARL III study investigated the efficacy and safety of ulipristal acetate for long-term treatment of symptomatic uterine fibroids.48 A total of 209 women with symptomatic fibroids received repeated intermittent UA courses, each followed by randomised double-blind norethisterone acetate (NETA) or placebo. Patients received up to four three-month courses of UA 10mg daily, immediately followed by ten-day double-blind treatment with NETA (10mg daily) or placebo. After the first UA course, amenorrhoea occurred in 79% of women, with median onset (from treatment start) of four days (interquartile range, 2–6 days).

Median fibroid volume change was –45% (interquartile range, –66%; –25%).48 Amenorrhoea rates were 89%, 88%, and 90% for the 131, 119, and 107 women who received treatment courses 2, 3, and 4, respectively. Median times to amenorrhea were 2, 3, and 3 days for treatment courses 2, 3, and 4, respectively. Median fibroid volume changes from baseline were –63%, –67%, and –72% after treatment courses 2, 3, and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology.48

A double-blind, randomised study (n=451) investigated the efficacy and safety of repeated 12-week courses of 5 or 10mg UA daily for intermittent treatment of symptomatic uterine fibroids. In the 5 and 10mg treatment groups, 62% and 73% of patients, respectively achieved amenorrhoea (defined as lack of bleeding for at least 35 days) during both treatment courses.49 Proportions of patients achieving controlled bleeding (defined as no episode of heavy bleeding and a maximum of eight days of bleeding during at least 56 days of a treatment course) during two treatment courses were >80%. Menstruation resumed after each treatment course and was diminished compared with baseline. After the second treatment course, median reductions from baseline in fibroid volume were 54% and 58% for the patients receiving 5 and 10mg UA, respectively. Pain and quality of life improved in both groups. UA was well tolerated, with less than 5% of patients discontinuing treatment due to adverse events.49

The same group further published their results regarding the efficacy and safety of four repeated 12-week courses of 5 or 10mg daily UA for intermittent treatment of symptomatic uterine fibroids.50 Efficacy results, such as bleeding control and fibroid volume reduction, were in line with previously published data. Pain and quality of life showed marked improvements from screening, even during the off-treatment intervals. The safety profile of UA was confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions.50 The percentage of subjects with endometrial thickness ≥16mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. UA did not increase the occurrence of endometrial features of concern. The frequency of non-physiological changes did not increase with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were reversible after treatment cessation.50

The data regarding long-term use of UA so far appear to be reassuring. The beneficial effects of ulipristal with low rates of adverse events (headaches, flushes, dizziness) demonstrated in all studies make it an attractive alternative to surgery for women with symptomatic of fibroids. Women close to menopause who wish to avoid surgery or who are high risk for surgery are especially likely to benefit from UA therapy. However, it is likely that the PRMs are not useful for the treatment of very large uteri or fibroids because they cause only a modest decrease in their size.

Luyckx et al51 reported their series of 21 patients who attempted to conceive following ulipristal acetate therapy. Fifteen women (71%) succeeded, totalling 18 pregnancies. Among these 18 pregnancies, 12 resulted in the birth of 13 healthy babies and 6 ended in early miscarriage. No re-growth of fibroids was observed during pregnancy.51 There were no maternal complications related to fibroids during pregnancy and all the babies were healthy. One infant had an ectopic kidney, but it was not linked to the treatment. Most deliveries were performed by caesarean section, either because of previous surgery for uterine fibroids, or in an emergency context for preeclampsia or fetal conditions.51 The data are still insufficient to confirm safety of UA prior to pregnancy and further studies are awaited.

Aromatase inhibitors
Aromatase inhibitors block peripheral conversion of androgens to estrogens in both ovarian and peripheral tissues. It has been suggested that aromatase expression is increased in fibroid tissue and thus the role for aromatase inhibitors.

A study of 21 women over 35 years of age, with symptomatic uterine fibroids, assessed the effect of 1mg daily anastrozol on the fibroids.52 Average reduction of uterine volume of 9.32%, attaining up to 32%, and reduction of symptoms of uterine fibroids (menstrual volume, duration of menstruation, and dysmenorrhoea) were noted.52

A systematic review evaluated the effectiveness and safety of aromatase inhibitors in women with uterine fibroids. One trial involving 70 participants was included. Significantly fewer women reported hot flushes in the letrozole group than in the GnRH analogue group (0/33 vs 26/27, p<0.05). Use of letrozole reduced fibroid volume by 46% and use of GnRHa by 32% after 12 weeks of treatment – this difference was not significantly different.53 The current evidence is insufficient to recommend the use of aromatase inhibitors for treatment of symptomatic uterine fibroids.

Selective oestrogen receptor modulators (SERMs)
Tamoxifen and raloxifene are two SERMs that exert tissue-specific agonist and antagonist effects on oestrogen receptors. Raloxifene is the most studied agent in this group of drugs, mainly in postmenopausal women with fibroids.

A Cochrane systematic review studied the effectiveness and safety of selective oestrogen receptor modulators in women with uterine fibroids.54 Three studies involving 215 participants were included; the trial size varied from 25 to 100 women. The SERM in all cases was raloxifene. In one study, women in both arms received GnRH analogue and comparison interventions included no treatment and placebo. Two of the three studies found a significant benefit from raloxifene, but the third study found no benefit at three- or six-month follow-up. The overall quality of the evidence was low or very low. All three studies mentioned adverse reactions but data were limited.54

There is no consistent evidence from the limited number of studies that SERMs reduce the size of fibroids or improve clinical outcomes.

Other pharmacological treatments
Although danazol and gestrinone appear to be effective in treating some symptoms associated with uterine fibroids, there is no reliable evidence available from large RCTs regarding the benefits and/or harms of the use of these drugs for treating uterine fibroids. A systematic review concluded that current evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies with large sample sizes and of high quality.10,55

Many uterine fibroids are asymptomatic and require no intervention. While myomectomy and hysterectomy have been the traditional definitive treatments for symptomatic uterine fibroids, not all women wish to have surgery and many want to retain their uterus. Non-surgical treatment options for symptomatic fibroids include pharmacologic as well as radiologically guided interventions. The range of medical treatments includes tranexamic acid, non-steroidal anti-inflammatory drugs, contraceptive steroids, GnRH analogues, aromatase inhibitors and progesterone receptor modulators. However, it is important to remember that these medical options may not always be a definitive form of treatment and symptoms may return when treatment is stopped.


Key points

  • Women with asymptomatic uterine fibroids may not need any active treatment, only periodic monitoring to review size and symptoms.
  • Symptoms depend on the size and position of the fibroids and range from heavy unpredictable bleeds and bleeding disturbances to chronic pelvic pain and subfertility.
  • NSAIDs are effectve in reducing heavy menstrual bleedng and dysmenorrhea in women without fibroids but robust evidence for the same benefit is lacking in women with uterine fibroids.
  • GnRH analouges are useful for short-term therapy as temporising measures in the perimenopausal women or pre-operatively to reduce fibroid size, restore haemoglobin levels and influence the type of surgery.
  • Progesterone receptor modulators have emerged as an effective treatment option for uterine fibroids. The PEARL trials have demonstrated the safety and efficacy of  ulipristal acetate for controlling excessive bleeding and fibroid size reduction in selected patient groups.



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