Uterine fibroid management: from the present to the future

1Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. They are monoclonal tumors of uterine smooth muscle, thus originating from the myometrium. They are composed of large amounts of extracellular matrix (ECM) containing collagen, fibronectin and proteoglycans. Leiomyomas occur in 50–60% of women, rising to 70% by the age of 50, and, in 30% of cases, cause morbidity due to abnormal uterine bleeding (heavy menstrual bleeding inducing anemia) and pelvic pressure (urinary symptoms, constipation and tenesmus). Clinical presentations of uterine leiomyomas include pelvic masses, pelvic pain, infertility and obstetric complications.

2The risk factors for uterine fibroids are illustrated in Fig. 1.

3Race constitutes an important risk factor for leiomyoma development. An US study found that the incidence of uterine fibroids was 60% by age 35 among African-American women, increasing to >80% by age 50, while Caucasian women showed a rate of 40% by age 35, increasing to 70% by age 50. Differences in gene expression in uterine fibroids between these two groups may influence these growth rates. Nevertheless, it is clear that African-American women have a greater chance of being affected by uterine fibroids, particularly at an earlier age. Among women of African origin living in Europe, a similar trend has been observed, with more severe symptoms and surgery required at a younger age. Moreover, recurrence rates after surgery (myomectomy) may be as high as 59% after an interval of 4–5 years for women of African origin.

4followed the size of 262 leiomyomas from 72 women for up to 12 months using magnetic resonance imaging (MRI). The average growth rate was 9% over 6 months, but growth rates differed between races when age was taken into account. White women under 35 years of age had faster-growing tumors than white women over 45, who exhibited a comparatively slow growth rate. On the other hand, women of African origin did not show any decrease in myoma growth rates with age.

5Moreover, delaying the first pregnancy until the third decade of life also places women at higher risk of uterine fibroids.

6Menarche at an early age increases the risk of developing fibroids and is also considered a risk factor for other hormonally mediated diseases, such as endometrial and breast cancers.

7Pregnancy has been found to have a protective effect on the development of uterine fibroids, but the mechanism remains unclear. It has been suggested that during post-partum uterine remodeling, small lesions may be subject to selective apoptosis. Furthermore fibroid tissue may be highly susceptible to ischemia during both uterine remodeling and parturition.

8An association has been reported between alcohol and caffeine intake and an increased risk of developing uterine fibroids in a study concerning the health of women of African origin.

9Some specific genetic alterations are linked to fibroid growth. performed whole genome sequencing and gene expression profiling of 38 uterine leiomyomas and corresponding myometrium. The common occurrence of chromothripsis in uterine fibroids suggests that it also plays a role in their genesis and progression.

10General health status may also be predictive of leiomyoma growth, with factors such as obesity and high blood pressure playing a role. A diet rich in red meat appears to increase the risk of developing leiomyomas, while smoking decreases the risk, for unknown reasons.

11Numerous classifications of myomas can be found in the literature. All of them take into account the degree of intramural extension and/or uterine cavity distortion. The fibroid classification adopted by the ESGE (European Society for Gynecological Endoscopy) has the advantage of being very simple (G0 is a pedunculated intrauterine myoma, G1 has its largest part (>50%) in the uterine cavity, and G2 has its largest part (>50%) in the myometrium).

12More recently, the FIGO classification was published, describing eight types of fibroids as well as a hybrid class (association of two types of myomas) (Fig. 2). As different types of fibroids are often present at the same time (depending on the site), this classification offers a more representative ‘map’ of fibroid distribution and will be used further for the establishment of new algorithms.

13Many fibroids are asymptomatic, but in 30–40% of cases, they show a variety of symptoms, depending on the location and size. Fibroids can cause heavy menstrual bleeding with subsequent anemia, which could be life-threatening. African-American women have more severe symptoms in terms of heavy bleeding and anemia compared to white women. Large fibroids can also result in pressure symptoms (bulk symptoms) that may be responsible for bowel and bladder dysfunction, including urgency, increased daytime urinary frequency and urinary incontinence. Abdominal distention or distortion and pelvic pressure on the ureters (causing hydronephrosis) and pelvic blood vessels (particularly pelvic veins) could also interfere with quality of life (QoL).

14Dysmenorrhea and pelvic pain are frequently encountered, impacting on QoL and impairing daily activities. Infertility and recurrent miscarriage may also be symptoms of fibroids, depending on their location and size, especially for submucous and intramural myomas distorting the uterine cavity.

15Fibroids can impair fertility through several possible mechanisms, including: (1) alteration of the local anatomy (anatomic distortion of the uterine cavity), with subsequent alterations to endometrial function; (2) functional changes, such as increased uterine contractility and impairment of the endometrial and myometrial blood supply and (3) changes to the local hormone milieu and paracrine molecular changes induced by fibroids, which could impair gamete transport and/or reduce blastocyst implantation.

16Moreover, fibroids can affect obstetric outcomes. Inflammatory pathways, associated or not with other reproductive disorders, may impair pregnancy outcomes. Fibroids are significantly associated with preterm delivery (<37 weeks), primary cesarean section, breech presentation and lower birthweight infants. Very recently, a higher incidence of short cervix was also observed during pregnancy in women with fibroids.

17Examination of the pelvis may reveal an enlarged uterus or mass. If fibroids are suspected and a woman reports heavy menstrual bleeding, a hemoglobin evaluation will allow detection of iron deficiency anemia.

18An ultrasound is the gold standard test for uterine fibroids. Its widespread availability enables easy and inexpensive confirmation in almost all instances. Moreover, ultrasonography after infusion of saline into the uterine cavity can delineate submucous myomas and indicate the proximity of intramural myomas to the endometrial cavity. The advent of 3D imaging technology has seen 3D ultrasound establishes itself as a useful tool for the investigation of myometrial pathology due to its ability to reconstruct the coronal plane of the uterus.

19A hysteroscopy may be required to differentiate intracavitary myomas and large endometrial polyps. Hysteroscopy is usually performed in an outpatient setting and does not require any anesthesia. Ultrasonography with saline infusion and diagnostic hysteroscopy should be considered more as complementary examinations when hysteroscopic myomectomy is indicated. Of course, in case of irregular bleeding or if the patient has risk factors for endometrial hyperplasia (obesity, chronic anovulation), hysteroscopy may be combined with an endometrial biopsy.

20MRI can provide information on the number of fibroids, their size, vascularization, relationship with the endometrial cavity and serosal surface, and boundaries with normal myometrium (Fig. 3). It should nevertheless be stressed that like ultrasonography, MRI cannot diagnose malignancy with any certainty. While MRI findings can suggest a diagnosis of sarcoma, there is currently no form of preoperative testing which can definitively rule it out. Possibly in the future, new types of imaging will improve the accuracy of detecting sarcoma, which remains a very infrequent condition (1/1500 in women aged <40 years and 1/1100 in women aged 40–44).

21As stressed by, there are areas of uncertainty surrounding the management of myomas, as only a few randomized trials have compared different therapies for fibroids. Moreover, data on their comparative effectiveness in terms of future fertility are lacking. There are also inadequate data on long-term outcomes in women who have undergone hysterectomy according to indication. Prospective data and studies are essential to compare different options and evaluate long-term outcomes with regard to QoL, recurrence of symptoms (bleeding, bulk symptoms), fertility and even complications.

22Indeed, in a cohort study of 30 117 Nurse's Health Study participants undergoing hysterectomy for benign disease, bilateral oophorectomy was found to be associated with increased mortality in patients under 50 years of age who had never used estrogen therapy.

23While guidelines exist in the literature, the risks and benefits of each option should be discussed with the patient. It should also be stressed that many other factors need to be taken into account, including the skill of the surgeons involved, as well as the experience of different centers in the available techniques.

24Current management strategies involve mainly surgical interventions, but the choice of treatment is guided by the patient's age and desired to preserve fertility or avoid ‘radical’ surgery such as hysterectomy. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization (UAE) and other interventions performed under radiologic or ultrasound guidance (Fig. 4).

25Over the last 30 years, advances in instruments and techniques have promoted hysteroscopic myomectomy to the rank of a standard minimally invasive surgical procedure for submucous myomas. Small fibroids (<2 cm) are now routinely removed in an outpatient setting according to the technique described by Bettocchi.

26Depending on personal experience and available equipment, the gynecologist has a choice of several alternative procedures.

27The first involves cutting the base of pedunculated fibroids with either the resectoscopic loop or laser fiber. The base of the pedicle is cut and the fibroid is extracted by forceps or may be left in place.

28The second alternative is a complete excision of fibroids by a one-step procedure. The most commonly used approach is the slicing technique. Repeated and progressive passage of the cutting loop allows the surgeon to cut the myoma into small chips. The operation is considered complete when the fasciculate fibers of the myometrium are visualized. Hysteroscopic resection is effective and safe and should be considered the technique of choice for type 1 myomas. The development of intrauterine morcellators has facilitated the implementation of hysteroscopic myomectomy. If the myoma is large (>3 cm in diameter), there is an increased risk of operative complications (perforation, bleeding and fluid intravasation) and damage to surrounding myometrium due to use of electrosurgery. Interestingly, ) demonstrated that during surgery, myometrial thickness increases when myoma slices are removed, leading to protrusion of the intramural component into the uterine cavity.

29The third alternative is myomectomy by a two-step procedure (for large type 1–3 myomas of according to the FIGO classification, ). After resection or ablation of the protruded portion of the myoma during first-step hysteroscopy, the residual intramural component rapidly migrates to the uterine cavity, with a parallel increase in myometrial thickness, allowing complete and safe myoma excision during second-step hysteroscopy.

30With all the techniques described here, there is risk of fluid (glycine) absorption while using monopolar energy. This risk is avoided by use of bipolar or laser energy with saline solution.

31Hysteroscopic myomectomy is effective for control of bleeding, but failures are reported and are often related to growth of fibroids in other sites, association of fibroids with adenomyosis, and incomplete treatment of large intramural (partially submucous) myomas.

32In terms of reproductive outcomes, most studies are retrospective. They report post-surgery pregnancy rates ranging from 16.7% to 76.9%, with a mean of 45% (. Their robustness could be criticized, but the authors of a recent review acknowledge that the benefits of hysteroscopic removal of submucous myomas for improving the chances of pregnancy ‘cannot be excluded’. In addition, one prospective randomized study has provided good-quality evidence that surgical therapy (hysteroscopic myomectomy) yields higher pregnancy rates than alternative treatments in women with submucous myomas.

33Laparoscopic myomectomy is perceived by many gynecological surgeons to be more difficult, but the advantages are real: less severe post-operative morbidity, faster recovery with laparoscopic procedures and no significant difference between reproductive outcomes after laparoscopic or abdominal myomectomy (by minilaparotomy). However, there have been reports of uterine rupture after laparoscopic myomectomy, thus emphasizing the importance of adequate closure of the myometrial defect. In a review of nine trials including 808 patients, there was no evidence of any difference in recurrence risk between laparoscopy and open myomectomy.

34Usually, a 10 mm scope and two or three ancillary ports are used, although some gynecologists prefer a 5-mm scope. Depending on the site of the myoma, either a vertical (longitudinal) or a transversal incision is made. In the majority of cases, a unipolar hook probe is utilized, but CO2 laser myomectomy is also performed in some departments. In certain cases, uterine artery ligation may be beneficial to reduce intraoperative bleeding. Robotic laparoscopic myomectomy has been evaluated in a few retrospective series but no prospective study has been published yet and considerable scepticism remains about the real advantages of the technique.

35Leiomyomas are usually removed with a morcellator, although some gynecologists propose vaginal removal through the cul-de-sac of Douglas or minilaparotomy to avoid the risk of dispersing tissue fragments during sarcoma morcellation. The risk of uterine fragment dispersion with the subsequent appearance of pelvic adenomyotic masses and parasitic leiomyomas was described in 2006 and remains a concern. This complication can be avoided by extensive peritoneal lavage and careful removal of all the fragments, even if some authors still have misgivings. Indeed, since their first publication, Donnez et al. no longer encountered this complication in a subsequent series of 400 laparoscopic hysterectomies (LHs), when caution was exercised and attention was paid to examine all areas of the abdominal cavity by placing the patient in the Trendelenburg and anti-Trendelenburg position and by extensive lavage. The risk of morcellation of uterine leiomyosarcomas has recently become a ‘hot’ topic, since the Food and Drug Administration (FDA) warned about the use of electromechanical power morcellation. It should nevertheless be stressed that the prevalence of sarcoma in leiomyomas is <0.3% and the debate on the use of electric morcellation has probably been overstated, not only because of the fear of medicolegal issues but also due to emotional reasons. In a recent study, the prevalence of sarcoma was just 0.06% in a series of 10 731 uteri morcellated for myomas during LH. Of course, we should do all we can to improve the diagnosis of sarcoma, but a similar low incidence (1/2000) was observed in a very recent meta-analysis by and in a retrospective study including 4791 women in Norway. Another meta-analysis by concluded that leiomyosarcomas are diagnosed unexpectedly after surgery for what are presumed to be benign fibroids in 1 in 340 women, and that risks increase with age from less than one case per 500 women aged under 30 years to 1 in 98 women aged 75–79 years.

36The technique of power morcellation in a bag was recently suggested to minimize the risk of inadvertent tissue spread, but there is no evidence that this technique will not increase the rate of post-operative complications.

37Contraindications to laparoscopic myomectomy usually include the presence of an intramural myoma >10–12 cm in size or multiple myomas (≥4) in different sites of the uterus, requiring numerous incisions.

38The dimensions and localization of the main myoma are the principal criteria for choosing the laparoscopic approach. Thus, depending on the skill of the surgeon and his/her ability to suture the myometrial defect without delay, either laparoscopy or minilaparotomy may be selected.

39In terms of infertility, several non-controlled studies have suggested that myomectomy yields a decrease in the miscarriage rate in women with myomas distorting the uterine cavity.In a review of prospective and retrospective studies, Donnez and Jadoul reported a pooled pregnancy rate of 49% (95% CI 46–52) in patients who underwent laparoscopic myomectomy. In another review by ), the post-operative pregnancy rate was 57%. These post-myomectomy pregnancy rates have been confirmed by other studies, but the lack of randomized trials represents a serious drawback. However, it should be pointed out that there are no significant differences in cumulative pregnancy rates or obstetric or perinatal outcomes when laparoscopic and abdominal myomectomy are compared.

40Hysterectomy has long been considered standard surgical treatment for symptomatic intramural and submucous fibroids, particularly for women not wishing to conceive or those of premenopausal age (40–50 years). In the US, more than 600 000 hysterectomies are performed each year. In Denmark, the overall hysterectomy rate was around 180/100 000 women during the period 1977–2011.

41Fibroids are the main indication for hysterectomy and, in the last decade, LH has become the ideal surgical approach to replace laparotomy. In some departments, the rate of LH exceeds 90%. Vaginal hysterectomy (VH) still remains indicated in some conditions, depending on the skill and habits of the surgeon.

42Some studies have reported an increased risk of complications after LH, but in a very large series, ) found a similar complication rate after LH, VH and abdominal hysterectomy (0.44% of major complications). In a personal prospective series of 400 cases, no major complications were encountered. Of course, as stressed by the authors, uterine volume of ≥13–14 weeks represents a relative contraindication. A very recent study demonstrated that in some conditions, hospitalization for LH could be less than 5 h.

43Some ‘in bag’ morcellation techniques, one of them called the Sydney technique, were developed to address the concerns of morcellating large myomatous uteri after total or subtotal hysterectomy but, as stressed earlier, no large studies have demonstrated any real benefit in terms of general safety. Moreover, the risk of leiomyosarcoma morcellation during LH must be weighed against procedure-related complications associated with laparotomy, including mortality.

44Both laparoscopic cryomyolysis and thermo-coagulation have the same goal: reduction or suppression of the primary blood supply and induction of myoma shrinkage by causing sclerohyaline degeneration (by very low or very high temperatures).

45For cryomyolysis, a cryoprobe is inserted into the myoma and cooled to a temperature of <90°C. For laparoscopic thermocoagulation, either a monopolar or bipolar probe is inserted into the myoma before delivering the electrical current. In some studies, laser fibers (YAG) have also been used. The limitation of all of these techniques is the lack of histological evaluation of the fibroids.

46Laparoscopic occlusion of the uterine arteries appears to have no specific advantage over vaginal occlusion, as it requires a laparoscopic approach. Moreover, when compared to UAE, the outcomes were found to be inferior in terms of myoma size reduction and devascularization.

47The alternatives to surgical interventions are illustrated on the right-hand side of Fig. 4.

48Although rapidly adopted by enthusiasts, the introduction of UAE has varied widely across the globe. This technique was first used in 1995 to treat uterine fibroids in women wishing to preserve their uterus.

49UAE constitutes complete uterine therapy, as most fibroids are supplied by the uterine arteries. In UAE, percutaneous ablation of the fibromatous uterus is applied to induce ischemic necrosis of the fibroids, while the myometrium revascularizes. Most fibroids are targeted simultaneously. UAE has been shown, in randomized trials, to result in QoL similar to that achieved after surgery, but with a shorter hospital stay and earlier resumption of normal activities.

50Although UAE is highly effective for treating symptoms (reduction in bleeding and fibroid size), the risk of reoperation is a reality: 15–20% after successful embolization and up to 50% in cases of incomplete infarction. Among possible complications, abdominal pain due to ischemic necrosis of fibroids and risk of infection should not be overlooked. The impact of UAE on the ovarian reserve is another concern, but a systematic review of 15 randomized trials and prospective cohort studies demonstrated that loss of ovarian function occurred primarily in women over 45 years of age. In a very recent review, clearly detailed the results and complications of UAE. It was emphasized that a desire for future pregnancy is a relative contraindication, as the lack of data in the literature cannot ensure a good pregnancy outcome. In a randomized controlled trial (RCT) comparing UAE and myomectomy, surgical removal had a more favorable outcome than UAE in terms of pregnancy rate (78% vs 50%), delivery rate (48% vs 19%), and abortion rate (23% vs 64%).

51Gupta's article in the Cochrane Database of Systematic Reviews evaluated seven RCTs comparing UAE and surgery (abdominal hysterectomy or myomectomy). The authors clearly stated that there were limitations in the evidence. The main limitations of the studies were a serious lack of precision due to wide confidence intervals, failure to clearly report methods, and the absence of blinding for subjective outcomes. They also estimated that between 15% and 32% of subjects would require further surgery within two years of UAE.

52Several trials comparing UAE and myomectomy and UAE with focused ultrasound are currently ongoing, whose outcomes are awaited.

53High frequency magnetic resonance-guided focused ultrasound surgery (MRgFUS) is thermal ablation using MRI to visualize the myoma and define the target. Ultrasonic energy is directed to a point inside the fibroid and coagulation tissue necrosis is induced in the myoma. In theory, damage to surrounding tissue is minimal but, in fact, the impact on critical neighboring structures cannot be excluded.

54As stressed by in their review, hyperintensive MRI images are associated with reduced treatment success compared with hypointensive images of fibroids. The principal limitations to the use of MRgFUS are that (i) only a fraction of patients with fibroids meet the inclusion criteria, (ii) future fertility may be compromised and (iii) the financial burden may be too heavy.

55The literature is still scarce on this topic and additional studies are needed to evaluate safety profiles. In a recent study, 30% of women underwent further fibroid surgery or procedures two years after MRgFUS. Screening and MRI-based prediction models for assessing therapeutic responses may reduce the risk of treatment failure. Several non-controlled clinical trials have reported pregnancies after MRgFUS, but a recent review by found a high rate of complications in the 34 documented pregnancies.

56Occlusion of the uterine arteries with a clamp-like device that remains in place for 6 h leads to myoma ischemia by interfering with the blood supply to the uterus. However, this technique is not recommended for women wishing to conceive in the future.

57In a study by, dominant fibroid volume decreased by 24% and heavy bleeding symptoms decreased by 51%. Here too, research with larger populations is needed to prove the efficacy of the technique.

58Fibroids are highly prevalent and represent a high health burden. Indeed, about 30% of women with leiomyomas will request treatment due to morbidities such as heavy menstrual bleeding, abdominal pain, pressure symptoms and/or infertility. Current treatments are mainly surgical and expensive. Among 600 000 hysterectomies performed each year in the USA, 200 000 are for fibroids. In a study by, health care costs for the management of leiomyomas were estimated to be over $2 billion per year. There is no doubt that fibroids have a significant economic impact, but the cost of therapy both to the health care system and women with fibroids must be balanced against the cost of untreated disease conditions, as well as the cost of ongoing or repeated investigations and treatment modalities. Despite the lack of relevant medico-economic evaluations of the different therapeutics, it is likely that reducing the number of hysterectomies and other surgical procedures will reduce costs and morbidity. It is therefore necessary to develop and evaluate alternatives to surgical procedures especially when fertility preservation is the goal.

59Two recent Cochrane Reviews on the use of herbal preparations and aromatase inhibitors concluded that there was no evidence to support the use of herbal preparations or aromatase inhibitors as medical therapy for treating myomas. However, as reviewed by, ), there is evidence to suggest that certain dietary or alternative treatments like phytochemical herbal preparations may be effective. In addition, some synthetic and natural compounds as well as growth factors are now under laboratory investigation, while observational data suggest that increased consumption of fruits, vegetables and low-fat dietary products are associated with a reduced risk of developing fibroids. Nevertheless, some uncertainty remains due to insufficient high-quality studies with large enough sample sizes.

60By inducing a state of hypoestrogenism and temporary menopause with amenorrhea, GnRH agonists have been used to shrink fibroids and restore hemoglobin levels in symptomatic women (Fig. 5). They cannot be used for long periods of time because of their side effects, such as hot flushes and bone loss. A very recent review demonstrated that there is modest evidence that add-back therapy (tibolone, raloxifene, estriol and ipriflavone) can help reduce bone loss and that medroxyprogesterone acetate (MPA) and tibolone may moderate vasomotor symptoms.

61Use of GnRH agonist before surgery is still a matter of debate, but a review by Gutmann and Corson reports that ‘preoperative use of GnRH agonist appears to be relevant and beneficial in patients with submucous fibroids’. Benefits include a resolution of preoperative anemia; a decrease in fibroid size; a reduction of endometrial thickness and vascularization with subsequently improved visibility and reduced fluid absorption and the possibility of surgical scheduling. Conversely, this preoperative treatment is associated with post-injection endometrial bleeding due to the flare-up effect.

62To date, genetic and epigenetic factors, sex steroids, growth factors, cytokines, chemokines and ECM components have been identified as being implicated in the pathogenesis of leiomyomas. Many growth factors and also activin and myostatin play a role in the mechanisms involved in the development of leiomyomas. Of course, estrogen and progesterone and their respective receptors also have a very significant impact on leiomyoma growth. Recently, demonstrated that testosterone was additionally implicated in the growth of uterine fibroids. In vitro studies have also shown that fibroid development depends on miRNA regulation of gene targets which impact cellular processes. The initial event that triggers the first stages of tumorigenesis nevertheless involves somatic mutations.

63In the past, estrogen was considered to be the major growth factor in myoma development. However, already in the 1990s, a number of studies reported increased the expression of both progesterone receptor A (PR-A) and progesterone receptor B (PR-B) in leiomyoma tissue compared with adjacent normal myometrium. Very recently, Tsigkou et al. showed that PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium. Levels of PR-B mRNA in leiomyoma tissue were directly associated with the number of myomas, but inversely correlated with the intensity of symptoms. Moreover, higher proliferative activity, demonstrated by proliferating cell nuclear antigen (PCNA) and the mitotic index, was observed in leiomyomas during the luteal (secretory) phase. There is evidence from preclinical and clinical trials, as well as from histological and pharmacological studies, that progesterone and its receptors play a key role in uterine fibroid growth. In a review, described, in detail, the activation of signaling pathways in leiomyomas by both estrogen and progesterone. Progesterone is able to cause rapid, membrane-initiated effects, independent of gene transcription, that alter the production of second messengers involved in cell signaling transduction pathways. The PI3K/AKT pathway is mediated by progesterone which, through its receptors, can quickly activate this pathway, which is increasingly considered to be a potential promoter of leiomyoma growth. PTEN, on the other hand, should be considered as a negative regulator of AKT. Progesterone and growth factor signaling pathways are interconnected and govern numerous physiological processes such as proliferation, apoptosis and differentiation.

64Progesterone can modulate the expression of growth factor signaling proteins and is implicated in the regulation of genes associated with proliferation and apoptosis, but these genes have not yet been fully identified or studied in detail. There is therefore evidence that progesterone plays a crucial role, but the mechanism by which it promotes proliferation, the repertoire of genes involved, and how it crosstalks with growth factor signaling pathways all need to be investigated in greater depth. The recent discovery of stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma tissue may lead to the development of therapeutics that temper leiomyoma growth as well as those that eradicate them.

65Having established the crucial role of progesterone in the growth and development of myomas, we can modulate the progesterone pathway by use of selective progesterone receptor modulators (SPRMs). SPRMs are synthetic compounds that exert either an agonistic or antagonistic effect on PRs (Fig. 5). Their binding allows these receptors to interact with coactivators and/or corepressors, and this is further impacted by the presence of coregulators in a particular cell type, which will dictate whether an SPRM acts more as an agonist or antagonist. Hence, the mechanism of action of SPRMs on PRs depends on their structure and how they alter the PR conformation, resulting in exposure or inactivation of particular binding domains. Their activity is also mitigated by tissue types and physiological contexts.

66Four members of the family of compound SPRMs have been investigated in phase II clinical trials: mifepristone, asoprisnil, ulipristal acetate (UPA) and telapristone acetate. All were shown to decrease leiomyoma size and reduce uterine bleeding in a dose-dependent manner. However, although three studies showed a myoma volume reduction of ±30%, a review of the literature by (Cochrane Review) found no clear evidence of this. Some follow-up studies have also raised concerns about unopposed estrogenic activity and liver toxicity.

67The latest antiprogestin to be studied in large clinical trials, UPA, has shown promising results in terms of efficiency and safety. UPA was compared to a placebo and to leuprolide acetate (a GnRH agonist) in two randomized trials. In these first clinical studies, uterine bleeding was controlled in more than 90% of patients receiving a three-month course of UPA, and the median times to control bleeding were shorter in the UPA group (5–7 days) than in the GnRH agonist group (21 days). The control of bleeding and subsequent correction of anemia were clinically relevant. Indeed, it has been well documented that preoperative anemia, even to a mild degree, is associated with an increased risk of morbidity and mortality in patients undergoing surgery. UPA was also found to have a sustained effect (up to six months) in women who did not undergo surgery after the three-month study period. By contrast, those treated with GnRH agonist experienced rapid regrowth of their fibroids, whose size reached pre-therapy dimensions by six months post-treatment.

68Importantly, the induced effects of SPRMs on the endometrium, now described as progesterone receptor modulator (PRM)-associated endometrial changes (PAECs) (Fig. 5), present in almost 70% of patients at the end of treatment, have proved to be benign and reversible, as they disappeared two months after the end of therapy. Safety has also been well documented in pharmacokinetic studies following multiple doses.

69The mechanism of action by which SPRMs reduce menstrual blood loss in women with fibroids remains unknown, although a number of possible factors have been proposed by, ). reported that uterine NK cells regulate endometrial bleeding and were suppressed by asoprisnil.

70Because of the sustained effect observed in the first two trials,), additional intermittent (12-week) courses of SPRMs with off-treatment intervals may be an alternative for long-term medical management of fibroids. The results of the first long-term intermittent administration study suggested that more than one course of SPRMs can maximize its potential benefits in terms of bleeding control and fibroid volume reduction.

71The latest clinical trial was initiated to investigate the efficacy and safety of four repeated 12-week courses of either 5 or 10 mg UPA daily for intermittent treatment of symptomatic uterine fibroids. This study demonstrated a similar degree of response in both treatment groups. We will therefore focus on the results in terms of efficacy and safety of this trial using the approved dose of 5 mg UPA in a repeated intermittent therapy setting (four courses). The percentages of subjects identified as being in amenorrhea after individual treatment courses (1, 2, 3 and 4 in the study) were 75.8%, 84.1%, 86.4% and 87.5% in the 5 mg group. The pictorial blood assessment chart (PBAC) score was measured at initial screening and after 1, 2 and 4 courses to assess the level of menstrual bleeding during the off-treatment period. In the 5 mg group, (median) levels at screening were 224.0, dropping significantly with each subsequent course and finally reaching 77.5 after course 4. The percentage of subjects with a clinically significant volume reduction of ≥25% increased from course 1 to course 4 (from 62.3% to 78.1%), and those with a volume reduction of ≥50% also increased from course 1 to course 4, proving that repeated courses considerably maximize the impact of treatment. This was also proved by the volume reduction of the three largest fibroids which was increased from course 1 to course 4 (Fig. 6). The findings of this study therefore demonstrate the efficacy of 5 mg UPA treatment and further confirm the safety of repeated intermittent administration of UPA for symptomatic myomas.

72The safety profile of UPA during multiple treatment courses was well documented in this study. Safety assessments, including vital signs, physical examinations and laboratory analyses, as well as reported adverse events (AEs) both on and off treatment, showed repeated intermittent administration of UPA to be well tolerated. The vast majority of AEs (97.6%) were of mild or moderate severity. Headaches and hot flushes were the most frequently reported AEs (less than 11% of subjects in any treatment course), but the frequency of these events decreased with each additional treatment course. Breast pain or discomfort was observed in 3% of subjects. In this series of 451 women, serious AEs related to medication included five cases of menorrhagia, one bipolar disorder, one spontaneous myoma expulsion, one abdominal pain and one back pain. No safety concerns were identified from physical examination, vital signs, ovarian ultrasound or electrocardiogram (ECG).

73Based on the available data related to endometrial safety after up to four treatment courses, no increased occurrence of more serious conditions of the endometrium, such as hyperplasia with atypia or endometrial carcinoma, was noted. The frequency of SPRM-associated non-physiological endometrial changes (PAEC) did not appear to increase with repeated treatment courses, reaching 13.3% after a fourth treatment course, and returning to pretreatment levels within three months of completion of treatment. These data further confirm the rapid reversibility of PAEC following completion of treatment and subsequent menstruation. It is reassuring that median endometrial thickness (7–8 mm) was similar to screening levels after single and multiple treatment courses and remained stable during post-treatment follow-up (three months after treatment cessation).

74A recent study by Courtoy et al. suggested an important role of UPA in collagen degradation induced by matrix metalloproteinase 2 (MMP-2), offering an explanation for the sustained beneficial effect. Indeed, this study strongly points to multifactorial mechanisms of action involving: (1) a persistently low cell death rate; (2) a limited period of cell death and (3) ECM remodeling concomitant with stimulation of MMP-2 expression.

75An in vitro study demonstrated another possible mechanism of action of UPA: inhibition of activin A expression and function in cultured leiomyoma cells.

76There is a clear need for alternatives to surgery, even the less invasive endoscopic techniques, especially when fertility preservation is the goal. There is no doubt that surgery remains indicated in some instances, but we must now establish whether SPRMs (UPA) allow less invasive surgery or even complete avoidance of surgery. On the other hand, it is clear that long-term intermittent use of UPA will change our approach to the management of uterine fibroids.

77To address the question of which therapy to adopt, it is crucial to consider key factors determining the management of uterine fibroids: patient age, severity of symptoms (pain, bleeding and infertility), wish to preserve the uterus and/or fertility, localization of fibroids according to FIGO classification and myoma volume. The approaches described below are according to the FIGO classification.

78If type 0 myomas are present, cutting the pedicle by hysteroscopy is indicated (Fig. 7).

79In the majority of cases, hysteroscopic myomectomy for type 1 myomas is relatively straightforward for experienced surgeons, especially in case of type 1 myomas less than 3 cm in size (Fig. 8). If a fibroid is of type 1 but larger than 3 cm, or if the patient presents with anemia, pre-hysteroscopic medical therapy (SPRMs or GnRH agonist) is indicated. Results in terms of subsequent fertility after hysteroscopic myomectomy were discussed earlier in this paper.

80Medical therapy may be given in one or two courses of three months. In the vast majority of cases, type 1 myomas respond to this preoperative therapy and regress in size, enabling an easier hysteroscopic approach in better conditions (recovery of hemoglobin). It should be pointed out that in some cases, myomas regress so much that surgery may be avoided.

81In case of type 2 myomas, medical therapy (SPRMs) can be proposed (Fig. 9). Myomas often respond to this preoperative therapy and regress in size. This reduction also allows a hysteroscopic approach that can be planned after the first menstrual bleed. In some cases (if myomas regress so much that they no longer distort the uterine cavity), surgery may not be required. If myomas are multiple (≥2) or of different types (type 2–5), as is frequently observed, medical therapy (SPRMs) can be given in two courses of three months, as described in clinical trials with UPA. After these two courses of three months, there are three possible outcomes.

82The most positive outcome would be that myoma regression is very significant (>50% decrease in volume). The uterine cavity is no longer distorted and the patient can try to conceive naturally or undergo assisted reproductive techniques, if indicated. A first series of pregnancies after UPA treatment was recently described, demonstrating that in some cases, surgical treatment is not required and patients can conceive and deliver healthy offspring (Fig. 10). Other case reports have also been published. In our series of pregnancies, patients were able to have unprotected sexual intercours or to start with ovarian stimulation after the second menstrual bleed. For those having to undergo IVF, a vaginal ultrasound was performed on day 3 of the second menstrual bleed to assess the absence of a thick endometrium. The second outcome would be that myoma regression is significant (≥25% but <50%). However, in some instances, if the uterine cavity remains distorted or if the myoma remains large due to great volume at baseline, the indication for surgery stands. In this case, medical treatment may allow surgery to be performed by a laparoscopic approach once the hemoglobin level is normalized, avoiding laparotomy.

83The least outcome would be that the response to medical therapy is inadequate. In this case, surgery remains indicated.

84In these cases too, medical therapy can be proposed (Fig. 9), taking into account recent clinical trials with SPRMs demonstrating that four courses of three months induce a significant improvement, course upon course (decrease in myoma size and PBAC score). In the vast majority of cases, regression of myoma size (≥25% in 80% of patients) and control of bleeding (in >90% of patients) will allow avoidance of surgery and restoration of hemoglobin levels (Fig. 11).

85When there is no immediate wish to conceive, there is no pressing need for surgery (even if the uterine cavity remains distorted and/or large myomas are still present). In some cases, myomas will all but disappear. In case of symptom recurrence, medical therapy may be reinitiated. Myomectomy should only be considered when the patient wishes to become pregnant, and if really necessary according to the localization and volume of the fibroids still present. This is important to take into account, especially for women of African descent. Indeed, African and African-American women have a greater chance of developing symptomatic myomas at an earlier age than Caucasian women. It is widely known that the rate of recurrence of myomas after myomectomy can reach almost 60% after an interval of 4–5 years, and that the risk of pelvic adhesions is significantly increased after a repeated myomectomy. Medical treatment with SPRMs can thus be beneficial, since long-term intermittent therapy (repeated in case of symptom recurrence during the interval) may help to avoid or at least postpone the need for surgery until the patient wishes to conceive (Fig. 11).

86Surgery therefore remains indicated only when the patient wishes to conceive, and if large myomas (>3–4 cm) distorting the uterine cavity are present, as these could be the cause of her infertility.

87A meta-analysis by evaluating 23 studies showed a significant drop in pregnancy and implantation rates in the presence of myomas, especially submucous and/or intramural myomas distorting the uterine cavity. In another meta-analysis, demonstrated their impact on fertility, even in case of intramural myomas not distorting the uterine cavity. A recent study by confirmed that intramural fibroids >2.85 cm in size significantly decreased the delivery rate of patients undergoing IVF/intracytoplasmic sperm injection (ICSI).

88Moreover, some centers have large cohorts of patients of more than 40 years of age in oocyte donation programs. In this group of women, the prevalence of myomas is higher than in women of 30 years of age.

89It could be proposed that patients with myomas be treated with one or two courses of SPRMs before IVF or oocyte donation, in order to reduce the size of myomas and restore the uterine cavity and subsequently improve implantation rates. Clinical trials evaluating UPA before IVF or oocyte donation should be initiated to investigate this further.

90Isolated type 2 fibroids are relatively rare in premenopausal women. In the majority of cases, patients with symptomatic myomas have an enlarged uterus with multiple myomas or large myomas of type 2–5 (Fig. 12).

91Our latest results led us to slightly modify previously published algorithms for this group of women. Indeed, in subjects treated with 5 mg UPA for four courses of three months, the percentage of patients with a clinically significant volume reduction increased from 62.3% after 1 course to 78.1% after 4 courses, suggesting increased benefits with repeated courses. The percentage of women showing a clinically significant reduction of >50% also increased from course 1 (37.2%) to course 4 (63.8%). Moreover, the median PBAC score during the off-treatment period decreased with each subsequent course.

92In case of a good response (characterized by a clinically significant volume reduction and/or control of bleeding), treatment can be stopped after four courses and the patient is re-evaluated. Repeated therapy may be proposed when the symptoms recur, as no endometrial hyperplasia was diagnosed in subjects who took 5 mg UPA for eight courses of three months. In this context, the goal is to reach menopause without the need for surgery. Data indicating that SPRMs exert an anti-proliferative effect in breast tissue are also reassuring. Some studies reported anti-proliferative effects on the endometrium after SPRM courses of up to six months.

93Endometriosis and adenomyosis are frequently associated with uterine fibroids.

94In theory, induction of amenorrhea in women treated with SPRMs should also relieve endometriosis-associated pain. In mammalian models, SPRMs stop prostaglandin production by endometriotic lesions and this direct effect may also serve to reduce pain.

95Nevertheless, it should be stressed that even if endometriosis and uterine fibroids are both estrogen-dependent diseases, they show a completely different response to progesterone: endometriosis is characterized by progesterone resistance, while fibroids grow under the influence of progesterone. Fig. 13 shows the excellent response (>50% volume reduction) to UPA obtained in fibroids, but the absence of response (or even a slight volume increase) in endometriomas.

96The specific effects of SPRMs have yet to be determined in ectopic endometrium. Indeed, PAECs may be present in lesions, as observed in eutopic endometrium.

97Adenomyomas and adenomyosis are two distinct clinical entities. Adenomyomas may respond very well to SPRMs, but severe full-thickness adenomyosis, characterized by the presence of numerous sites of ectopic endometrium in the myometrium of an enlarged uterus, is a specific entity that might have a completely different response.

98SPRMs will probably be effective in reducing adenomyosis-associated pain by inducing amenorrhea, but are unlikely to be able to significantly reduce the size of the uterus. Clinical trials are ongoing to explore this particular context and the impact of endometrial modifications, as PAECs will also be present in ectopic intramyometrial endometrium.

99SPRMs have opened up new avenues to explore in fibroid medical therapy, to both treat symptoms and postpone or to eliminate the need for surgery. Future clinical trials should focus on prevention strategies, such as preventing occurrence in women genetically predisposed to this condition, and avoiding recurrence after surgery in women at high risk (i.e. those of a young age or with a family history) (Fig. 14).

100Symptomatic uterine fibroids require surgical and/or medical therapy according to the severity of symptoms, age, infertility, wish to preserve the uterus and FIGO classification (Fig. 14). Current strategies involve mainly surgical intervention, such as hysterectomy, myomectomy by hysteroscopy and myomectomy by laparoscopy or laparotomy. Hysterectomy provides the most effective treatment for fibroids, but is not appropriate in many cases. The choice between less invasive techniques (uterine-sparing options such as myomectomy) is guided by the size, number and location of fibroids as well as the personal experience of the gynecologist and available equipment. Other surgical techniques, such as laparoscopic cryomyolysis, thermocoagulation or uterine artery occlusion, are rarely used. Non-surgical interventions, such as UAE and MRgFUS, are also available but the desire for future pregnancy is a relative contraindication.

101On the other hand, the need for medical therapy remains a reality. It is indeed essential that new treatments be developed to be able to offer as there is a pressing need for alternatives to surgical intervention, particularly when fertility preservation is the goal.

102GnRH agonists have been used to shrink fibroids and restore hemoglobin levels in symptomatic women, but because of their side effects, they cannot be used for long periods of time. However, there is now growing evidence of the crucial role of progesterone in pathways in the pathophysiology of uterine fibroids by the use of SPRMs. UPA (one member of the SPRM compound family) has been studied in large clinical trials and its long-term intermittent administration has been evaluated, yielding promising results for new treatment perspectives. It was found that more than one three-month course of UPA maximizes its potential benefits in terms of bleeding control and fibroid volume reduction. Hence, depending on age and symptoms (infertility, bleeding, etc.), SPRMs should be considered an alternative to surgical therapy, or at least an adjunct to surgery, in some circumstances, as illustrated in the algorithms.

103In conclusion, asymptomatic fibroids do not require treatment once the diagnosis is confirmed by ultrasonography or MRI. Women should be made aware of all available treatment options (medical, radiological and surgical) and why they may or may not be appropriate. Gynecologists now have new tools in their armamentarium (Fig. 15) opening up novel strategies for the management of uterine fibroids.