Uterine fibroids

Introduction

Fibroids are the most common tumour in women of reproductive age (54, 55). Recent years have seen a demographic shift in child­birth trends, with many women delaying starting their families until they reach their third or fourth decade (56, 57).

The repertoire of uterus-preserving treatments for symptomatic fibroids has increased in recent years. The use of uterine artery em­bolization (UAE) was first reported over two decades ago (60). The National Institute for Health and Care Excellence (NICE) in the United Kingdom has reviewed its efficacy and recommends UAE as an alternative treatment to hysterectomy and myomectomy (61). Magnetic MRgFUS (62) is another new technique, but its adoption has been slow, partly due to the high infrastructure costs of setting up such a service and because of its limitations in treating large and/or numerous fibroids (63, 64). Pharmaceutical agents continue to be developed. While it was originally introduced as a premyomectomy treatment (65), ulipristal acetate has recently ac­quired a licence for use as a stand- alone treatment for symptomatic fibroids (66) and is regarded by many as the ‘first-in-class' medical therapy for fibroids (67). Despite the emergence of these new treat­ments for managing symptomatic uterine fibroids, in reality, when the uterus is to be preserved, myomectomy, especially the open abdominal approach, remains the treatment of choice of many gynaecologists.

Incidence, aetiology, and epidemiology of fibroids

Incidence

Although fibroids are undoubtedly the commonest benign tumour in women, their exact incidence is unknown for a variety of reasons including sampling methods, the populations studied, the timing of sampling, and not least because a significant proportion of women with fibroids (often quoted as 50%) are entirely asymptomatic and are not included in studies that identify subjects due to their symp­toms.

Aetiology

Despite considerable research, the aetiology of uterine fibroids is unknown. There is no adequate animal model to aid laboratory enquiry. What is well established is that all the cells within a given fibroid originate from a single cell (the monoclonal origin of fi­broids) (71, 72)—but what actually causes the transformation from a normal myometrial to a leiomyoma cell remains enigmatic. While it is evident that ovarian steroid hormones promote fibroid growth, there is no evidence for differences in circulating concentrations of these hormones between women with and without fibroids. In vitro studies suggest that progesterone rather than oestrogen is the major mitogen for uterine fibroids, and indeed these studies have led to the recent introduction of ulipristal acetate, the first-in-class selective progesterone receptor modulator (SPRM) (see ‘Medical treatment of fibroids'). Peptide growth hormones and a range of growth factors are also thought to influence fibroid growth over and above the sex steroids (see ‘Pathophysiology of fibroids'). Cytogenetic chromo­somal alterations, including translocations, duplications, and dele­tions have also been found in up to 50% of fibroid tumours. The commonest cytogenetic abnormalities are deletions in chromosome 7, and translocations involving chromosomes 7, 12, and 14 (73-75).

Epidemiology

There is a clear-cut racial disparity in age of onset and number and size of fibroids between black, white, and Asian women (76, 77). The reasons for the racial differences are not known, and while epi­demiological factors linked to fibroids are thought to include repro­ductive factors, sex steroids, and lifestyle/environmental factors in addition to racial origin, the available information should be inter­preted with caution. For example, the racial disparity is not reflected in hormonal concentrations or oestrogen receptor expression. In other words, the basis of the racially disparity is not known. The familial predisposition to fibroids is illustrated by a number of obser­vations: female relatives of women with fibroids have a significantly increased risk of developing fibroids; twin pair studies indicate an increased risk of fibroids in monozygotic compared to dizygotic twins (78, 79); and there is a consistent pattern of clinical symptoms, operative findings, and tissue molecular features in families with a prevalence of uterine fibroids compared with those without this prevalence (77). Fibroids are associated with the polycystic ovary syndrome, hypertension, and obesity, while smoking in white (but not black) women appears to be protective (80). There are no dietary factors that have been proven to alter the risk of developing fibroids. Fibroids are commoner in nulliparous women, with the relative risk decreasing with increasing number of term pregnancies. Fibroids initially increase in size in the first trimester of pregnancy and then shrink in size over the next two trimesters. There is therefore an overall relative decrease in uterine fibroid volume during the course of pregnancy (81, 82). The effect of the oral contraceptive pill on the risk of fibroids is unclear, with some studies showing an increased risk, others a decrease, and yet others no association at all.

Pathophysiology of fibroids

The pathophysiology of fibroids is poorly understood. However, it is likely that there is altered smooth muscle cell proliferation in asso­ciation with disordered angiogenesis (83). When compared with the adjacent myometrium, fibroid vasculature appears to be significantly altered (84-86). A dense vascular rim of tissue surrounds smaller fi­broids, but there are fewer blood vessels within the actual fibroid tumour itself (87, 88). The vascular supply within the fibroid tissue increases as the fibroid grows, but does not reach the density of that in the adjacent myometrium. Perhaps due to differences in the levels of angiogenesis promoters and inhibitors within the fibroid tissue, vessels that penetrate the fibroid tissue from the dense perifibroid vascular rim of tissue are abnormally narrow in diameter and lack the normal structure of vessels within the myometrium (89, 90)—it is interesting to speculate that this abnormal and reduced vascula­ture may render the fibroid tissue prone to ischaemic necrosis after UAE (see ‘Radiological treatment of fibroids').

The proliferation of smooth muscle cells also appears to be al­tered in fibroids compared with adjacent myometrium, and there is an exaggerated response to both progesterone and oestrogen. In addition, a variety of growth factors (IGFs, EGF, bFGF, PDGF, TGF- beta) have differential effects on fibroid cells compared with normal myometrial cells via a variety of mechanisms including alteration of receptor levels and signalling pathways (91-95).

Fundamentally, the importance of understanding the pathophysi­ology of fibroids is that this will lead to the development of effective intervention strategies. This is exemplified by the recent emergence of SPRMs as potential effective treatments for fibroids (see ‘Medical management of symptomatic fibroids').

Clinical presentation of fibroids

While 50% of women with fibroids are asymptomatic (96-98), those who are affected experience significant morbidity and reduced quality of life.

Diagnosis and imaging of uterine fibroids

Imaging

Imaging is critical for confirmation of the diagnosis, and is indis­pensable in guiding decisions on clinical management, especially with the increasing demand for uterus-preserving treatments. Thus the goals of imaging include the exclusion of other pathologies, es­pecially malignancy, and the determination of the number, size, and position of the fibroids and the overall dimensions of the uterus. Imaging may also be used to evaluate the vascular supply to the fi­broids, especially when treatments such as UAE are being considered. Considerations when choosing the imaging modality will include individual and global costs of the procedure, and safety aspects if radiation is involved.

Ultrasound

Ultrasound is the most widely used imaging modality as it is rela­tively cheap, is often part of a routine gynaecological examination, is a rapid procedure, and uses no ionizing radiation and therefore can be used during pregnancy. While both the transabdominal ultra­sound (TAUS) and the TVUS approaches may be used, TAUS offers a wide field of view, increased depth of signal penetration, flexibility in transducer movement, and the ability to examine other organs. The TAUS view is more effective than the TVUS approach for the visualization of pedunculated subserosal fibroids extending into the abdominal cavity, and is also more effective when very large fibroids are present (107). During TVUS, the probe is placed in close prox­imity to the organs of interest, and therefore image resolution is im­proved compared to the TAUS approach. TVUS provides a better view of the endometrium (108), does not require use of the bladder as an acoustic window, and is not affected by obesity, bowel gas, or a retroverted uterus (108, 109). TVUS is considered reliable, with a high level of interobserver agreement for measurement of uterine size and endometrial thickness (111). The combination of TVUS and TAUS imaging is the most widely used technique for the detec­tion, mapping, and characterization of fibroids (107). TVUS capabil­ities can be enhanced by the use of hysterosonographic examination (HSE), also known as SIS (110). When used with TVUS, HSE al­lows identification of endometrial pathology, submucosal myomas, and adhesions (107, 109, 110, 111). The combination of imaging modalities may also be effective in the evaluation of submucosal myoma location, breadth of attachment, and extent of protrusion into the uterine cavity (113). The use of colour Doppler allows ultrasound assessment of organ vascularity, which may be useful in distinguishing between solid and cystic masses (5, 34), and in the differential diagnosis of adenomyosis.

Ultrasound is not without limitations. The TAUS approach may be less effective in the measurement of uteri larger than 300 mL in total volume (113). Ultrasound may also be less effective when multiple fibroids are present, as the tumours may produce acoustic shadows (108, 113).

Magnetic resonance imaging

This is arguably currently the best imaging technique for fibroids, allowing for precise mapping of the individual fibroid position, in­cluding assessment of the depth of submucosal fibroid penetration (39). It is also useful for assessment of very large myomas. MRI is an effective companion to ultrasound in the differential diagnosis of adenomyosis. Use of MRI follow-up may confirm the presence of adenomyosis if low-intensity, poorly demarcated lesions are visual­ized with ultrasound (114-116). Magnetic resonance angiography (MRA) may be useful in an assessment of the vascularization of the uterus and fibroids. MRA may be helpful in determining the presence of an extrauterine blood supply to fibroids. Evaluation of fibroid vascularity is beneficial when UAE is considered as a uterine- preserving therapy for symptomatic fibroids (117). The main limita­tion of MRI in the imaging of fibroid disease is the high cost.

Surgical management of symptomatic fibroids

Hysterectomy

Globally, the great majority of symptomatic fibroids continue to be managed surgically, mostly by hysterectomy. Thus, hysterectomy remains the most common major gynaecological operation per­formed worldwide. About 600,000 hysterectomies are carried out in the United States and 40,000 in England per year (118). Forty per cent of women all over the world will have a hysterectomy by the age of 64 and indications for the majority will be to relieve symp­toms due to fibroid disease and improve quality of life. The majority of hysterectomies are carried out abdominally despite evidence that the vaginal route confers many benefits (119). Hysterectomy rates are highest in satisfaction scores compared with other modalities of treatment (120, 121), particularly in the treatment of dysfunctional uterine bleeding, and in the treatment of fibroids it offers a definitive cure with no possibility of recurrence. It is therefore arguably the ideal treatment for a woman whose family is complete, or one who has no desire for future fertility.

The changing demography of childbirth, at least in developed countries such as the United Kingdom, is likely to have a signifi­cant impact on the use of hysterectomy to treat fibroid disease. As an increasing number of women are postponing childbirth to the late third and early fourth decade of life, more women wish uterus/ fertility-preserving treatments, and developments in assisted repro­ductive technology using egg donation mean that women can real­istically expect to be able to carry a pregnancy in their 50s provided they have managed to retain their uterus (122). Radiological treat­ments (see later) and myomectomy offer uterus/fertility-preserving options for the treatment of fibroid disease.

Myomectomy

Most myomectomies are still performed by the open abdominal route. Depending on the size, number, and location of the fibroids, this is an operation that requires considerable skill, and may be as­sociated with significant blood loss (123, 124). In skilled hands, this operation benefits many women who often go on to achieve a preg­nancy, but it can also compromise the fertility if dense adhesions form, either in the pelvis and/or in the uterine cavity, as a result of the procedure. Much has been written about techniques of open myomectomy, including approaches to the minimization of blood loss and the avoidance of both pelvic and intrauterine adhesions (125-127).

Myomectomy can also be performed by minimal access ap­proaches that include laparoscopic and robotic-assisted procedures. Laparoscopic myomectomy is associated with a lower incidence of adhesions, shorter hospital stay, lower costs, and improved quality of life (128, 129), but requires skills that are not always readily avail­able, and there are limitations on the number and size of fibroids that can be treated by this modality. The costs associated with the use of robotic surgery have led to intense debate concerning the clinical and cost-effectiveness of robotically assisted myomectomy over the laparoscopic approach.

Hysteroscopic myomectomy

There is little debate or controversy concerning the hysteroscopic treatment of submucous fibroids. It is widely accepted that submucous and intracavitary fibroids are a common cause of menorrhagia and intermenstrual bleeding, and can contribute to subfertility and/or miscarriage. In skilled hands, hysteroscopic re­section is a relatively simple and safe procedure with proven efficacy in symptom relief (130, 131) and improvement in fertility.

Radiological management of symptomatic fibroids

UAE and MRgFUS are the mainstay radiological treatments of fi­broids, but less frequently used modalities include magnetic resonance-guided transvaginal cryotherapy and radiofrequency ab­lation. In this section, the focus will be on the first two, as the others are rarely used in clinical practice. The indications for both are fibroid-induced severe menorrhagia, dysmenorrhoea, anaemia, and pressure effects on the bladder/bowel. Contraindications to their use include viable pregnancy, suspected malignancy of uterus or ovaries, contrast allergy/renal impairment (UAE), and refusal to accept hys­terectomy under any circumstances. Case series of successful preg­nancies after both treatments have been published, but there has yet to be a head- to- head comparison between the two, or between either and myomectomy with regard to pregnancy outcomes.

UAE for the treatment of symptomatic uterine fibroids was first reported by Ravina and his colleagues in 1995 (132). The technique involves percutaneous femoral artery puncture with radiologic- ally guided selective catheterization of each uterine artery in turn (133). Embolic particles are then injected until the uterine artery is occluded. While non-spherical polyvinyl alcohol particles were the most commonly used in the early years of the UAE, there are now a range of embolic agents with different properties, although com­parative data is scarce (134, 135). There is consensus that complete devascularization of all fibroids is mandatory for effective treatment (136, 137). While partial devascularization can result in a clinical improvement and volume reduction, there is a higher long-term re­currence rate (138).

The advantages of UAE include the ability for total treatment of the uterus (numbers and size of fibroids are irrelevant), its minimal invasiveness, and the fact that it is performed under local anaes­thesia. In addition, it is associated with rapid recovery (2-3 weeks compared with 6- 8 weeks for myomectomy), and should new symp­tomatic fibroids form then the treatment can be repeated (133). There is level 1 evidence to suggest that UAE can achieve similar symptom control as hysterectomy (139, 140, 141), and when com­pared to hysterectomy, costs are lower with UAE, even when fur­ther interventions following UAE are included (142). Hence NICE have approved UAE as an alternative treatment to hysterectomy and myomectomy (143).

Symptom relief after UAE

Symptomatic improvements are often quite dramatic, with some women noticing a reduction in menorrhagia and dysmenorrhoea at the first and certainly by the second menses following treatment. Thus menorrhagia improvement occurs in 85-90% (133) of patients, while improvements in bulk symptoms occur in 70-90% (133). However, women with massive fibroids might find that absolute volume reduction may not live up to their expectation.

Further treatment may be required for recurrent symptoms, and the age of the woman appears to be an important factor. The younger at first treatment, the more likely she is to experience a recurrence, with the risk being 25% over 5 years for patients whose first treat­ment is when aged less than 40 years, and 10% for patients aged 40-50 years (133).

Outcomes for UAE relative to myomectomy

Research to date suggests that quality of life improvement following UAE is similar to that following myomectomy, while major com­plications occurred in 3% in association with UAE versus 8% with myomectomy. Reinterventions at 2 years are required in 14% fol­lowing UAE compared to 3% following myomectomy (144).

Side effects and complications of UAE

These are well documented. The postembolization syndrome is so common that it should perhaps be viewed as an expected side ef­fect of UAE rather than a true complication (133). The syndrome is characterized by low-grade pyrexia, discomfort, and malaise occurring at post-treatment days 3-7, and in the vast majority of cases it settles with conservative measures. True complications in­clude transient amenorrhoea, reported in 5-10% cases, while the incidence of permanent amenorrhoea is related to the patient's age, with reports suggesting an incidence of 7-14% in women over 45 years and 0-3% in younger women. Therefore, a major concern regarding the risk of inadvertent embolization of ovarian vascular supply is the potential negative impact on fertility. Transcervical fibroid expulsion occurs in 0-3%, while endometrial or uterine infection complicates 1-2% of cases. Non-infectious endometritis occurs in 1-2%, and up to 5% of treated women may complain of a chronic vaginal discharge. Fibroid impaction at the cervix can cause significant pain and distress and warrants admission for hysteroscopy and removal of the impacted fibroid (133). Where an UAE service is offered, the potential for complications war­rants close collaboration between interventional radiologists and gynaecologists.

Magnetic resonance-guided focused ultrasound surgery

MRgFUS uses focused high-energy ultrasound to sonicate or ablate fibroid tissue. As with conventional diagnostic ultrasound, ultra­sound waves pass through the anterior abdominal wall without causing any damage/injury, and significant heat only occurs where the waves converge at the focus (145, 146). Magnetic resonance guidance provides continuous imaging of the fibroid and other vital structures such as bowel, bladder, and sacral nerves (147, 148). Thus, MRgFUS is a truly non-invasive procedure, and research so far has reported significant improvements in clinical symptoms and quality-of-life parameters (149, 150). Complication rates are very low, and women can return to work within a day of treatment, which compares very favourably with 13 days after UAE and a minimum of 6 weeks after abdominal myomectomy or hysterectomy (133). However, MRgFUS is a relative new treatment that warrants fur­ther evaluation. It was approved by the United States Food and Drug Administration in 2004, but in the United Kingdom NICE continues to recommend that the procedure be used only in an audit and re­search setting. MRgFUS is a focal treatment rather than global as with UAE, and volume reduction after treatment is small compared with the mean levels seen after both myomectomy and UAE. Again, because it is a focal treatment, very large fibroids are not amenable to treatment given the time that would be required to achieve sonic­ation of the tumours The use of MRI guidance may be prohibitive in terms of cost compared with UAE and other established treatment modalities (151).

Medical management of symptomatic fibroids

There has long been a need for a medical therapy for the treatment of symptomatic uterine fibroids that is simple, effective, safe, and leads to a resolution of symptoms without affecting fertility. Most of the current medical therapeutic approaches exploit the obser­vations that uterine fibroids have significantly increased concen­trations of oestrogen and progesterone receptors compared with normal myometrium (152, 153), 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. Thus GnRH agonists have been used to achieve amenorrhoea and shrink fibroid size in symptomatic women, but their use is restricted due to significant side effects such as bone mineral density loss and vasomotor symptoms. Rebound growth of the fibroids also occurs on cessation of therapy. The authors of this chapter advocate that there is no role for GnRH agonists in the management of fibroid disease because they are not cost-effective (154) and render myomectomy more difficult because they destroy tissue planes (155, 156), increasing rather than reducing periopera­tive blood loss and operating time. When used before myomectomy they may increase the risk of ‘recurrence’ because they obscure smaller fibroids that ‘recur’ when the effects of the GnRH agon­ists wear off (157-159). Cheaper medications with fewer side ef­fects are also available. Selective oestrogen receptor modulators such as raloxifene have been shown to induce fibroid regression in post- but not premenopausal women, and medical therapies aiming to antagonize the oestrogen effects on fibroid growth in premenopausal women have not been successful. Conversely, a series of meticulous in vitro studies using cultured leiomyoma and normal myometrial cells have led to the development of SPRMs. This class of medications have demonstrated two important ef­fects: firstly that they have a differential impact on the leiomyoma cells versus the normal myometrium, with no negative impact on the latter; and secondly that the SPRMs inhibited leiomyoma cell growth via several mechanisms (160-163). This translational re­search has led to the emergence of ulipristal acetate as the first-in­class SPRM for clinical use. Given at a 5 mg or 10 mg daily dose, it is highly effective at reducing menstrual blood loss, effecting amen- orrhoea in 75% of recipients within 10 days, and has many attri­butes that arguably render it not only non-inferior but potentially superior to GnRH analogues. Importantly, it has been associated with improved quality of life (164, 165). The original European li­cence was for pre-myomectomy use of ulipristal acetate to shrink fibroids, to correct anaemia and improve the efficacy of the subse­quent myomectomy. More recently, ulipristal acetate has acquired a licence for use as a stand-alone therapy for up to four treatment cycles of 3 months each, interrupted by a month of non-use (166, 167). To date, most of the research on its clinical use has been in­dustry led, and there is a pressing need for researcher-led studies to replicate the findings described previously. Long-term studies are mandatory especially as progesterone receptors are ubiquitous, being found on the breast, bone, heart, brain, and blood cells as well as the genital organs: the impact of long-term use of SPRMs there­fore warrants further studies. Moreover, ulipristal acetate has been shown to induce changes in the endometrium of a small proportion of women, changes that are reversible upon cessation of ulipristal acetate, and which have been designated progesterone receptor modulator-associated endometrial changes (168-170) by a panel in a NIH-sponsored workshop. Where ulipristal acetate is used prior to myomectomy, its impact on the surgery itself has yet to be care­fully and systematically evaluated.

Conclusion

Fibroids, the most common benign tumour in women, have a major impact on women’s quality of life because of the clinical symptoms they cause, and have significant health-cost implications from their treatments. Controversy prevails as to whether they significantly contribute to problems of reproduction such as subfertility, miscar­riage, and poor pregnancy outcomes. With women increasingly de­laying childbirth until their third and fourth decade of life, when fibroids are more prevalent and symptomatic, a timely and welcome development over the past two decades or so has been the expansion of the repertoire of treatment options available. Interventional radio­logical treatments, the emergence of effective medical therapies, and the refinement of minimally invasive approaches to myomectomy, accompanied by parallel developments in assisted reproductive technologies, all contribute to an era of increasing choice for women where they can postpone/delay childbirth and yet realistically ex­pect to have successful pregnancy at a later stage in life. However, the exact cause of fibroids remains an enigma, and perhaps because of the benign nature of the tumour, research and funding has not been prioritized on fibroids, and the new treatment options warrant further rigorous evaluation.