Clinical Progress in Obstetrics & Gynecology Duru Shah, Sudeshna Ray
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Current Approaches to the Management of FibroidsChapter 1

Isaac Manyonda,
Latika Narang
 
Introduction
Uterine leiomyomas are the most common benign pelvic tumors in women of reproductive age.1 They are symptomatic in approximately 50% of cases, with the peak incidence of symptoms occurring among women in their 30s and 40s.2 Uterine fibroids are estrogen dependent and are most often seen after the menarche, and tend to shrink after the menopause.3 They are more commonly seen in women of African ancestry and afflicted women tend to be nulliparous or of low parity. Common symptoms include menorrhagia (that can lead to anemia and related symptoms), dysmenorrhea, pressure symptoms, abdominal distension, and sub-fertility. Where sub-fertility is an issue, it should always be borne in mind that the fibroid(s) may be incidental rather than the cause, except in cases where the fibroids are sub-mucosal.4,5 Complications of fibroids include degeneration, prolapse of a submucous fibroid, ureteric obstruction, venous thromboembolism, intestinal obstruction (pressure effect from large fibroids) and rarely malignant transformation (indeed there is debate as to whether sarcomatous transformation does occur in a benign fibroid, or the fibroids are incidental in a uterus where a sarcoma develops). Traditional management is surgical, with hysterectomy being offered where the woman has completed her family or where fertility potential is deemed irrecoverable, and myomectomy where fertility is desired. Conventional open myomectomy is most commonly practiced, while the laparoscopic approach is argued by some to provide best prospects for fertility outcomes.6 In more recent years the radiological interventions uterine artery embolization (UAE) and magnetic-resonance-guided focused ultrasound surgery (MRgFUS) have emerged as viable minimally invasive options.7 The unmet need has remained effective medical therapies. While GnRH analogs once held promise, they are not suitable stand-alone or long-term treatments. Selective Progesterone Receptor Modulators are emerging as potential effective medical therapies, and ulipristal acetate has recently secured a European license as the first-in-class drug therapy that has completed Phase III clinical trials.
The positive news regarding this very common tumor is that 50% of afflicted women remain asymptomatic, so that no intervention is required. For the symptomatic 50%, the Holy Grail remains arguably a tablet that is taken orally, 2once a day or even better still once a week, with minimal or no side effects, and no negative impact on fertility. Such an ideal therapy remains elusive.
 
Expectant Management
It is estimated that 50% of women with uterine fibroids are without symptoms. With increasing use of ultrasound and more frequent clinical examinations during cervical screening, an increasing number of women will be diagnosed with asymptomatic fibroids. Such women warrant simple explanations of what fibroids are, what symptoms they may cause, and reassurance that as long as they remain asymptomatic no intervention is required.8 In particular women will need reassurance that these benign tumors have minimal, if any, malignant potential. The practical reality is that once they know they have fibroids, many women inevitably become anxious and become aware of symptoms that they might have previously ignored, and therefore seek intervention. The proportion of women with fibroids who are symptomatic is, therefore, likely to increase over the years.
 
Surgical Management
 
Hysterectomy
Hysterectomy is the most common treatment for symptomatic fibroids, and it is considered definitive or curative, since there is no possibility of recurrence of the fibroids. Hysterectomy is particularly suited to women who have completed their families. It is associated with high patient satisfaction scores, with up to 90% of patients reporting at least moderate satisfaction at 2 years after the procedure.9 However, many women later regret the loss of fertility or have concerns regarding their femininity.10 Moreover, hysterectomy has an approximately 3% incidence of major complications.11 While most hysterectomies the world-over are performed by the abdominal route, alternative approaches to hysterectomy include subtotal (open or laparoscopic), when the cervix is conserved, laparoscopic total hysterectomy and vaginal hysterectomy. A recent Cochrane review concluded that subtotal hysterectomy did not offer improved outcomes for sexual, urinary or bowel function when compared with total abdominal hysterectomy. However, women are more likely to experience ongoing cyclical bleeding up to a year after surgery with subtotal hysterectomy compared to total hysterectomy.12
In general, women with a uterus greater than 16 weeks gestational size are not suitable candidates for a laparoscopic hysterectomy, although some gifted surgeons may well have no difficulty with uteruses larger than this, and therefore, each surgeon should place an upper limit on uterine size based on their preference and expertise.13 Vaginal hysterectomy in the presence of fibroids and/or absence of prolapse also requires expertise that may not be common-place. Allowing for the availability of expertise, the vaginal route does have advantages over the abdominal route. It has been reported that the duration of the procedure and hospital stay were longer after hysterectomy by the abdominal route. Perioperative complications 3were observed in 17% of patients after abdominal hysterectomy versus 7.69% after vaginal hysterectomy.14 However, the operation becomes more challenging as the size and number of fibroids increases: the very large uterus is generally not compatible with removal via the vaginal route, even when the surgeon uses techniques to divide the uterus or morcellate the segments.14
Hysterectomy has been compared to the relatively newer radiological treatment uterine artery embolization (UAE), and to date, there have been three prospective, randomized trials comparing. These include the “REST” (Randomized Trial of Embolization versus Surgical Treatment for Fibroids) trial, the EMMY (EMbolization versus hysterectoMY) trial and the HOPEFUL study.9,10,15,16 All three studies have shown both treatments to have very high clinical success rates and very high rates of patient satisfaction.
 
Myomectomy
For women with symptomatic fibroids desiring uterine conservation, the primary surgical treatment is myomectomy, most procedures being performed via the abdominal route (conventional abdominal myomectomy).
 
Conventional Abdominal Myomectomy
The time-honored conventional (open) abdominal myomectomy probably remains the most commonly performed uterus-preservation surgical procedure. When the fibroids are large, it can be technically challenging. It is an operation associated with considerable blood loss, potentially long hospital stay and recovery, and while evidence has shown improvement in fertility prospects, the risks of adhesion may compromise the very same fertility that the operation is performed to preserve. To optimize outcomes following conventional myomectomy, the authors would suggest the following measures or maneuvers:
  • Intraoperative blood loss reduction: Administer 1g tranexmic acid by slow IV infusion at the time of induction of anesthesia. The authors dilute 20 units vasopressin in 100 mL normal saline, and inject this liberally into the myometrium surrounding the fibroids. The combination of the two creates a very dry operative field that lasts for about 45 minutes.17
  • Uterine incision: In an attempt to minimize the risk of adhesion formation, and based on minimal research evidence available,18 the authors prefer a single, midline, vertical incision to remove as many fibroids as possible.
  • Closure: Following closure of dead space and prior to closure of serosal layer, the authors roll out surgical (oxidized regenerated cellulose hemostatic agent) into a ribbon and place it along the entire length of uterine incision, in the space between the myometrium and the serosa.
A major disadvantage of myomectomy is that 50–60% of patients will present with new myomas detected by ultrasound within 5 years following the procedure.19,20 It has also been reported that more than one-third of these women will require additional surgical intervention for the leiomyomas within 5 years.214
 
Laparoscopic Myomectomy
Some consider laparoscopic myomectomy, the best treatment option for symptomatic women with uterine fibroids who wish to maintain their fertility.6 Tulandi et al recommend laparoscopic myomectomy for fibroids of < 15 cm in size, and no more than three fibroids with a size of 5 cm.6 Compared with laparotomy, laparoscopic myomectomy has the advantages of small incisions, decreased intraoperative bleeding, short hospital stay, less postoperative pain, rapid recovery and good assessment of other abdominal organs. No significant differences were found in terms of fertility and obstetrical outcome between the two groups.22,23 Patient selection and the expertise of the surgeon, especially in laparoscopic suturing, play important role in the success and outcome of the procedure.24
Another advance in the field of laparoscopic surgery is the development of robotic-assisted laparoscopic surgery (RAS). RAS allows the surgeon to be seated comfortably while visualizing the abdominal and pelvic cavities in a three-dimensional view and the procedure can be more precise and accurate. 25 Much of this experience incorporated the “da Vinci surgical system” that was approved in April 2005 by the Food and Drug Administration (FDA) for gynecologic applications.26
However, due to recurrent symptoms, about 25% of women undergoing myomectomy will require further surgery.27
 
Laparoscopic-assisted Myomectomy
This procedure is similar to that of laparoscopic myomectomy, except the suturing and removal of fibroid is performed through a laparotomy incision. There have been no randomized studies so far comparing laparoscopic myomectomy and laparoscopic-assisted myomectomy.28,29
 
Vaginal Myomectomy
Davies et al demonstrated the feasibility of performing myomectomy via the vaginal route in a prospective study published in 1999.30 It was carried out in 35 women with symptomatic fibroids requiring myomectomy, and was completed vaginally in 32 (91.4%) women. None of these women required a hysterectomy.
 
Hysteroscopic Myomectomy
It is an established surgical procedure for women with excessive uterine bleeding, infertility or repeated miscarriages. There is debate as to whether treatment with GnRH agonist before myomectomy offers any significant advantages.31,32 However, a recent review reports that preoperative GnRH agonist use in patients with submucous fibroids appears to be the most clinically relevant indication for their use.33
The choice of the technique for the hysteroscopic removal of submucous fibroids mostly depends on their type and location within the endometrial cavity. The operator has the possibility to choose among several alternative procedures, which are as follows:5
  • Resectoscopic excision by slicing
  • Cutting of the base of fibroid and its extraction
  • Ablation by Nd: yAG laser
  • Vaporization of the fibroid using spherical or cylindrical electrodes.34 The main disadvantage of vaporizing electrodes is the lack of tissue sample for pathology.
  • Intrauterine morcellation, the main advantage with this approach being that it preserves tissue for histological examination.35
  • Office hysteroscopic myomectomy: With the development of smaller diameter hysteroscopes (< 5 mm) with working channels and continuous flow systems, it is possible to treat several uterine pathologies in outpatient settings without cervical dilatation.36
Most studies have shown that hysteroscopic myomectomy is safe and effective in the control of menstrual disorders with a success rate ranging from 70 to 99%. Hysteroscopic myomectomy combined with endometrial ablation has been shown to provide good long-term results and has been shown to lead to an amenorrhic state in up to 95.5% of patients.37,38
Reproductive outcome in infertile women following hysteroscopic myomectomy have been investigated by several authors, but unfortunately the evidence thus far is not of the highest quality. Reported postsurgical pregnancy rates vary from 16.7 to 76.9% with a mean of 45%. This large variation reflects the difficulty in controlling for multiple infertility factors, small sample size, follow-up discrepancies and wide variations in patients’ characteristics (i.e. age, primary or secondary infertility) as well as fibroid characteristics (i.e. number, size, intramural portion and presence of concomitant intramural fibroids).39,40
 
Laparoscopic Thermomyolysis or Cryomyolysis
These procedures are associated with side effects such as severe adhesion formation, fever, blood transfusion and conversion to hysterectomy.41 Data on the safety and efficacy of these procedures are still insufficient.4244
 
Laparoscopic Uterine Artery Occlusion
There is limited published data on laparoscopic uterine artery occlusion (LUAO). In a small retrospective study, 9% of women developed leiomyoma recurrence at a median follow-up of 23.6 months.45 There are at least two studies comparing LUAO to UAE. In a small randomized controlled trial, LUAO achieved shorter hospital stays and reduced procedural pain compared to UAE, while achieving similar 3-month clinical success rates.46 In another study, there was a similar degree of bleeding reduction between the two procedures.47
 
Temporary Transvaginal Uterine Artery Occlusion
In this procedure, the uterine arteries are noninvasively identified through the vagina, guided by audible Doppler ultrasound, when a clamp is then applied to occlude both arteries for 6 hours. This is sufficient time to induce fibroid ischemia 6and death without affecting the myometrium. Blood flow through the uterine arteries returns immediately following removal of the clamp.48 While theoretically attractive, these techniques require complex facilities and considerable skills and there is limited data on their true efficacy in clinical settings.
 
Radiological Treatments
 
Uterine Artery Embolization (UAE)
It is a percutaneous transcatheter embolization technique using embolization material to occlude the uterine arteries. The rapidly growing fibroids are sensitive to the ischemia induced, and undergo infarction and involution, while the normal myometrium derives alternative blood supply from collaterals from the vaginal and ovarian arteries.
The UAE has become widely accepted because of the advantage of its minimal invasiveness. A number of large series have compared embolization with hysterectomy favoring embolization4954 as it leads to 80–90% symptom improvement for menorrhagia, pain and bulk-related symptoms. A register of 1387 patients reported that 84% and 83% of patients had an improvement in their symptoms after UAE at 6 and 24 months respectively. It also reported an improvement in mean health-related quality of life scores (on a scale from 0 to 100) from 44.1 at baseline to 79.5 after UAE at a maximum 3-year follow-up (p < 0.001).55
A randomized controlled trial (RCT) of 157 patients treated by UAE or surgery (hysterectomy or myomectomy) reported symptom improvement in both groups, but this improvement was significantly greater among patients treated by surgery than by UAE (p = 0.004 at 1 month, p = 0.03 at 12 months).56
A major side effect of UAE is severe pain after the procedure.5760 Rare but serious complications include severe infection leading to hysterectomy (1.5%) and ovarian failure (5%).50,59,60 Another RCT reported that 28% (23/81) of UAE-treated patients had required hysterectomy at 5-year follow-up.61,62 Some recent reviews have suggested that UAE may have a negative impact on reproduction, increasing subfertility, miscarriage rates and associated with poor obstetric outcomes, but the evidence is of poor quality, and challenging this are growing number of reported series of successful pregnancy outcomes following UAE. A head-to-head RCT of UAE versus myomectomy is clearly required to resolve these issues.
 
MR Guided Focused Ultrasound (MRgFUS)
Focused US (FUS) is the therapeutic use of US waves to induce focal thermal effects, ablation, or thermocoagulation in vivo.
The efficacy of magnetic resonance image (MRI)-guided transcutaneous focused ultrasound for treatment of uterine fibroids has been shown to be adequate, although further treatment may be required and the effect on subsequent pregnancy is uncertain. The side-effects are generally mild and the evidence on safety is adequate 7to support the use of this procedure provided.63 Transient adverse effects include mild skin burn, nausea, short-term buttock or leg pain, and transient sciatic nerve palsy.6466
A nonrandomized comparative study of 192 patients treated by MRI-guided transcutaneous focused ultrasound or abdominal hysterectomy reported improvements in all Short Form-36 quality of life domains for both treatment groups, although scores at 6 months were better in patients treated by hysterectomy.63
It has recently been demonstrated that the pretreatment of patients who have fibroids measuring 10 cm or greater with GnRHa, before MRgFUS, has a beneficial effect, enhancing the tissue response to high intensity focused ultrasound.67
Another advantage is that it can be used as an outpatient-based treatment and significantly reduces symptoms in more than 75% of women treated with fibroids. Another ongoing evaluation of the clinical application of MRgFUS is its impact on fertility. Rabinovici et al have reported on safe and successful outcomes of pregnancies after MRgFUS.68
 
Medical Management
Most of the current medical therapeutic approaches exploit the observations that uterine fibroids have significantly increased concentrations of estrogen (and more recently progesterone) receptors compared with normal myometrium69,70 and that ovarian steroids influence fibroid growth. Most available therapies are therefore hormonal, or act on the relevant hormones or their receptors to interfere with fibroid growth.
 
GnRH Agonists
In the management of women with fibroid disease, GnRH agonists (GnRHa) are frequently used to reduce volume and vascularity prior to myomectomy71,72 apparently to render the operation easier and reduce operative blood loss, and to enable a transverse suprapubic incision instead of a midline vertical one. They induce amenorrhea and thus aid in the correction of preoperative anemia.73 Other gynecologists use GnRHa to shrink submucous fibroids greater than 5 cm in diameter to facilitate access and reduce blood loss and operating time at transcervical resection.74 GnRHa are also occasionally used as a temporizing measure in women with symptomatic fibroids within the climacteric.75
The authors here argue that GnRHa have a limited, if any, role in the management of fibroid disease because they are not cost-effective,76 render myomectomy more difficult because they destroy tissue planes, the more difficult enucleation in fact increasing rather than reducing perioperative blood loss and operating time.77 When used prior to myomectomy, they increase the risk of “recurrence” because they obscure smaller fibroids that “recur” when the effects of the GnRHa wear off78 and are associated with side effects in situations where they confer no benefits, or where alternative cheaper drugs with fewer side effects are available.8
 
Progesterone, the Progesterone Receptor and Receptor Antagonists/Modulators
Progesterone plays a crucial part in human reproductive physiology. Its physiological effects impact the processes of endometrial differentiation, ovulation, implantation, successful development of the embryo, development of the mammary gland as well as regulation of central signals from the hypothalamic-pituitary (HP) axis. The effects of progesterone on target tissues are mediated via the progesterone receptor (PR), which belongs to the nuclear receptor family.79 The PR exists as three separate isoforms (A, B and C) expressed from a single gene.79 The PR functions as a ligand-activated transcription factor to regulate the expression of specific sets of target genes. PR antagonists oppose the biological actions of progesterone by inhibiting PR activation. Progesterone has dual actions on fibroid growth. It stimulates growth by up-regulating EGF and Bcl-2 and down-regulating tumor necrosis factor-alpha expression while it inhibits growth by down-regulating IGF-I expression.80,81 While it has long been well established that estrogen promotes fibroid tumor growth, recent biochemical and clinical studies have suggested that progesterone and the progesterone receptors may also enhance proliferative activity in fibroids.80,81 These observations have, therefore, raised the possibility that anti-progestins and agents or molecules that modulate the activity of the progesterone receptor could be useful in the medical management of uterine fibroids.
 
Levonorgesterol Intrauterine Device (LNG-IUS)
The LNG-IUS is effective in reducing menstrual blood loss and should be considered as an alternative to surgical treatment.82 Levonorgestrel is released locally at a rate of 20 μg/day. At present there are no RCT's of use of LNG-IUS in treatment of menorrhagic women with uterine leiomyomas. There are of course, reports of its use in these women, with striking reduction in menorrhagia being reported, with consequent rise in hemoglobin.82 However, it has not been shown to cause any significant reduction in leiomyoma volume or uterine volume, as assessed by MRI between pretreatment and 12 months of use.83,84 A theoretical consideration is that while the LNG-IUS does indeed reduce menstrual loss (by inhibiting the proliferation of the endometrium) it could at the same time promote fibroid growth via its actions at the fibroid progesterone receptor. This would be an easy question to answer in any well-designed study of the impact of the LNG-IUS on fibroid disease.
 
Progesterone Receptor Modulators
Since the emergence of mifepristone (RU-486), the first progesterone receptor antagonist, more than 25 years ago hundreds of steroidal as well as nonsteroidal compounds displaying progesterone antagonist (PA) or mixed agonist/antagonist activity have been synthesized. Collectively, they are known as progesterone receptor modulators (PRMs). These compounds have a huge potential for use in the treatment of a number of pathological conditions of the female reproductive system including uterine fibroids, endometriosis, dysfunctional uterine bleeding and as potential contraceptives.9
zoom view
FIG. 1.1: Mechanisms of action of progesterone receptor modulators on uterine fibroids
Some of the PRMs that have been the subject of recent clinical trials/research studies in relation to fibroids treatment include mifepristone, CDB-4124 (telapristone), CP-8947 and J867 (asoprisnil) and CDB-2914 (ulipristal acetate). The potential mechanisms of action of PRMs on fibroids are depicted in Figure 1.1.
 
Evidence for Effectiveness of PRMs in Treatment of Uterine Fibroids
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 overall improvement in quality of life. Unlike long-acting GnRH analogs, they do not have the drawbacks of the profound estrogen deficiency and decrease in bone mineral density.
 
Mifepristone (RU-486)
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 50 mg daily and reported a reduction in uterine/fibroid volume of 40–50%, with amenorrhea in most subjects.85 This report was corroborated by a paper a year later from a group who used mifepristone at a dose of 5 or 10 mg per day for one year, and found that it was effective in decreasing mean uterine volume by 50%, while amenorrhea occurred in 40–70% of the subjects.86 Adverse effects included vasomotor symptoms, but no change in bone mineral density was noted. Hot flashes were increased over baseline in the 10 mg group, but 5 mg per day did not increase the incidence of vasomotor symptoms. Simple hyperplasia was noted in 28% of the women. This study therefore suggested that a dose as low as 5 mg per day of mifepristone may be efficacious 10for the treatment of uterine fibroids, with few side effects.86 Antiglucocorticoid effects of long-term use of mifepristone are usually seen only with doses exceeding 200 mg daily.87 The same group of researchers then followed up their preliminary findings with a randomized controlled trial (RCT) on the use of mifepristone for the treatment of uterine fibroids. This was a small study that included 42 women in a double-blind placebo controlled study design over a period of 6 months.88 They reported that overall quality of life was improved significantly, while anemia rates and uterine volume were reduced significantly. The hyperplasia seen in some women may limit the use of this drug among those desiring a long-term medical therapeutic alternative. However, the apparent effectiveness of mifepristone in reducing myoma volume and improving fibroid-related symptoms and quality of life, and the minimal side-effects, all point to a need for a large RCT with sufficient power to define its true place in the medical management of uterine fibroids. A combination of mifepristone and the LNG-IUS could prove especially useful as the IUS would obviate the development of endometrial hyperplasia while also promoting a reduction in menstrual flow. In yet another recent randomised trial, 100 women were assigned to mifepristone 5 or 10 mg daily for 3 months without a placebo group. With both doses, there were equivalent reductions in fibroid and uterine volumes and symptomatic improvements.89
 
CDB-4124 (Telapristone)
A clinical trial (phase I/II) evaluated the efficacy of telapristone in symptomatic fibroids. This small 3-month study comprising 30 women, compared oral doses of 12.5, 25 and 50 mg telapristone with the GnRH analog Lupron and a placebo.90 There was a significant reduction in tumor size and reduced bleeding with telapristone treatment.
 
J-867 (Asoprisnil)
Asoprisnil has high tissue selectivity and binds to progesterone receptors with a 3-fold greater binding affinity than progesterone.91 The initial phase I studies established that asoprisnil induced a reversible suppression of menstruation, while having variable effects on ovulation.92 The phase II multi-center double-blind placebo controlled studies by the same group of researchers compared the efficacy and safety of 3 doses (5, 10 and 25 mg and placebo) in 129 women over 12 weeks.93,94 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 5 mg, 64.3% with 10 mg and 83.3% with 25 mg), but with no increase in the rates of unscheduled bleeding in all 3 asoprisnil groups. Compared to placebo, hemoglobin levels were improved in all three treatment groups, while adverse effects were evenly distributed. The initial clinical trials of asoprisnil suggested endometrial thickening to be one of the important side effects of the drug. However, overall safety data available so far have been reassuring and its impact on bone mineral density, fertility, recurrence rates of fibroids and endometrial hyperplasia are still under evaluation.11
zoom view
FIG. 1.2: Chemical structure of ulipristal acetate (17-acetoxy-11b-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione)
 
CDB-2914 (Ulipristal Acetate or UA) (Fig. 1.2)
In Phase II and III clinical trials, a number of issues have been addressed using UA. In the first trial95 in which UA was given at 10 mg or 20 mg in comparison against placebo for 3 cycles, UA showed a 92% reduction in bleeding versus 19% with placebo. Leiomyoma 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 concern scores of the uterine leiomyoma symptom quality of life subscale (p = 0.04). One woman on UA developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. UA did not suppress estradiol and 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 3 cycles or 90–120 day trial.95 An even more recent randomized, double blind, placebo controlled trial of efficacy and tolerability has also demonstrated positive results when UA was administered for 3–6 months, showing good control of bleeding, reduction in fibroid size, and improvement in quality of life in the treatment group.96 UA has recently successfully completed two Phase III clinical trials (PEARL I and II) in Europe demonstrating its efficacy and safety for the treatment of symptomatic uterine fibroids in patients eligible for surgery.97,98 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 anemia. All patients received iron supplementation. The co-primary efficacy end points were control of uterine bleeding and reduction of fibroid volume at week 13, after that 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 due to uterine fibroids and reduced the size of the fibroids. PEARL II 12was 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 mg or 10 mg) or once-monthly intramuscular injections of the GnRH analog leuprolide acetate (at a dose of 3.75 mg). 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.98
 
Adverse Effects and Limitations Associated with Long-term Use of PRMs
Endometrial Hyperplasia and Thickening
A National Institute of Health (NIH) sponsored workshop evaluated endometrial specimens from women receiving mifepristone, asoprisnil and UA.80,99,100 Pathologists were blinded to agent, dose and exposure interval. 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 estrogen (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).80,99,100 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.80,101 In another study, biopsies were obtained from 58 premenopausal women participating in clinical trials of the telapristone. Biopsies were obtained at 3 and 6 months, and women were receiving daily doses of oral therapy that ranged from 12.5–50 mg. Out of 174 samples 103 contained histologic changes not seen in the normal menstrual cycle.102 Whereas the majority of the histology was atrophic, novel cystic changes were seen with increasing doses. Cystically dilated glands with mixed secretory and mitotic features were noted.102 These lesions are not considered to be premalignant and no malignancies were found.
A few studies have reported endometrial thickening detected on ultrasound after use of high or low dose Mifepristone.103,104 During 3 months treatment with ulipristal in normal women, no thickening was observed and examination of hysterectomy specimens after 3 months of asoprisnil (10 or 25 mg) showed that when compared with placebo, there was a trend for decreased endometrial thickness.80,105 With use of telapristone in the treatment of fibroids, there was a minimum increase in endometrial thickness of 3.3 and 4.2 mm with the 12.5 and 25 mg doses, respectively, after 3 months of treatment.80 It has been suggested that, unlike in the situation where there is unopposed estrogen effect, the endometrial thickening in women on PRMs is related to cystic glandular dilation and not endometrial 13hyperplasia. 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 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. It is also important to consider the limitations of the current data while describing the effects of PRMs on the endometrium. Most existing studies have described the endometrial changes over short periods (months) of follow-up; however, atypical hyperplasia and possibly malignant changes take years to develop and long-term studies are, therefore, necessary to evaluate such outcomes.
Although breakthrough bleeding has been reported as one of the side effects of PRMs, sufficient data assessing their long term use are not available. It is also argued that PRMs are not useful for treatment of large fibroids as they cause a modest decrease in their size; however, larger clinical trials with varying doses and duration of therapy of PRMs in future will be able to provide a definite answer to this question.
 
Gestrinone
It is a steroid that possesses antiestrogen receptor and antiprogesterone receptor properties in the endometrium. A report from Italy evaluated the use of gestrinone in the treatment of premenopausal women with uterine leiomyomas at a dose of 2.5 mg twice per week over a 6-month period.106 The authors reported a 32–42% reduction in uterine volume. A subsequent study reported up to 60% leiomyoma shrinkage in size.107 However, gestrinone acts as a contraceptive agent and also has several unfavorable side effects, such as mild androgenicity, weight gain, seborrhea, acne, hirsutism and occasional hoarseness.
 
Other Treatment Modalities
 
Endometrial Ablation
Selected women with submucous fibroids, who have completed their families, can be treated by endometrial ablation.108,109 Conventional endometrial ablation techniques cannot be used when the uterine cavity is remarkably enlarged (>12 cm) and distorted as result of submucous or intramural myomas.
Hydrothermal ablation has already been demonstrated to be safe and effective in treating women with menorrhagia and submucous fibroids up to 4 cm in diameter.110
Microwave endometrial ablation (MEA) has also been used for treating menorrhagia effectively. It is now possible to treat even enlarged (12–16 cm in length) and distorted uterine cavity as a result of large submucous fibroids, with the advent of a thinner (4 mm) curved microwave probe.111,112 Available data about the outcome of MEA in patients with menorrhagia caused by submucous myomas are few but encouraging.14
 
Image Guided Thermal Therapy
This can be achieved by using either magnetic resonance thermometry or laser ablation. The laser ablation of fibroids was first described in 1989 as a procedure performed via laparoscopic (intramural or subserosal fibroids) or hysteroscopic route (submucosal fibroids).113 It was found to decrease fibroid volume by 50% to 70% in symptomatic women. In 1999, Law et al first reported percutaneous treatment of uterine fibroids by neodymium: yttrium-aluminum-garnet (Nd: YAG) laser under MR guidance.114
The reduction in mean fibroid volume was 31% at 3 months follow-up, and 41% at the one year follow-up, in the follow-up series study.115
 
Cryotherapy
Cryoablation is the thermal ablation method that causes cell death by rapid freezing followed by rapid thawing.116 The temperature must be lower than –20~50°C to completely destroy tissue. Like laser ablation this was also initially introduced using either laparoscopic or hysteroscopic route.117,118 Reduction of fibroid volume ranged widely from 31% to about 80% in the follow-up studies.119,120
 
Radiofrequency Ablation
Ablation of solid tumors with radiofrequency energy results from heating that is produced when ions follow the oscillations of a high-frequency alternating electric field.121
It was first used in 2005 in the management of uterine fibroids via a surgical laparoscopic approach122,123 and subsequently with US guidance.124126 A large area of necrosis (up to 6 cm in diameter) can be achieved in a single access with RFA, and, therefore, compared to cryotherapy it is relatively time efficient.
 
Acupuncture
The effectiveness of acupuncture for the management of uterine fibroids remains uncertain.127 More evidence is required to establish the efficacy and safety of acupuncture for uterine fibroids. There is a continued need for well-designed RCTs with long-term follow-up.
 
Concluding Remarks
As recently as 20 years ago the choices for the woman with symptomatic fibroids were confined to abdominal hysterectomy and conventional abdominal myomectomy. Now, there is a multitude of additional choices, including laparoscopic and vaginal myomectomy, uterine artery embolization (UAE) and more recently magnetic resonance-guided focused ultrasound surgery (MRgFUS). Developments in purely medical therapies had, until recently, been singularly disappointing, but the emergence of ulipristal acetate as the first-in-class progesterone receptor modulator licensed for clinical use in Western Europe renders it highly likely that 15a definitive and effective stand-alone medical therapy will soon be developed. As yet, however, there is no panacea. UAE and MRgFUS are yet to be subjected to the rigorous evaluation demanded by the modern concept of evidence-based medical care. There are limitations on the size and number of fibroids that can be treated with laparoscopic or vaginal myomectomy. The license for ulipristal acetate dictates that it is used for no more than 3 months preceding surgery and this treatment is therefore not stand-alone, and further clinical trials of its efficacy are urgently required. Fibroid disease is essentially benign and treatment modalities aim not to save lives, but to improve its quality. Therefore, any evaluation and research on these new treatments must include as the main outcomes health-related quality of life, functional clinical outcomes such as symptom relief and impact on fertility, and a cost-effectiveness analysis as dictated by the finite resources for health care.
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