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EMAS position statement: Management of uterine fibroids

      Abstract

      Introduction

      Uterine fibroids (also termed leiomyomas or myomas) are the most common tumors of the female reproductive tract.

      Aim

      The aim of this position statement is to provide and critically appraise evidence on the management of women with uterine fibroids.

      Methods

      Literature review and consensus of expert opinion.

      Results and conclusions

      Many uterine fibroids are asymptomatic and require no intervention, although it is advisable to follow up patients to document stability in size and growth. Fibroid-associated symptoms include heavy menstrual bleeding and pain or pelvic discomfort. The association between infertility and fibroids increases with age. Fibroids do not increase the risk of malignant uterine disease and leiomyosarcomas are extremely rare (less than one in 1000). It is unknown at present whether leiomyosarcoma represents de novo growth or malignant transformation from benign uterine fibroids. Treatment options for symptomatic fibroids include pharmacologic, surgical and radiologically guided interventions. The range of medical treatments allows flexible management of fibroid-related symptoms; the options include tranexamic acid, non-steroidal anti-inflammatory drugs, contraceptive steroids, gonadotropin-releasing hormone analogs, antiprogesterone, and selective progesterone receptor modulators. However, these medical options do not remove the tumors and symptoms may return when treatment is stopped. Surgical and radiologically guided procedures may be tailored to age, general health, and individual patient wishes. Hysterectomy is the most effective treatment, although in some cases myomectomy may be sufficient to control symptoms. Alternatives to surgery include uterine artery embolization, myolysis and ablation by high-intensity focused ultrasound (guided with magnetic resonance imaging or ultrasound). The choice of treatment depends on fibroid size, the underlying symptoms and their severity and the woman's desire for subsequent fertility and pregnancy, as well as efficacy and need for repeated interventions.

      Keywords

      1. Introduction

      Uterine fibroids (also termed leiomyomas or myomas) are the most common tumors of the female reproductive tract. While they may be asymptomatic they can cause abnormal bleeding, pelvic pressure symptoms and infertility. Fibroid growth and regression vary throughout life. Thus, they tend to grow during the patient's reproductive years and regress after the menopause. They affect millions of women and are the leading cause of hysterectomy.
      Fibroids are benign tumors characterized by the proliferation of uterine muscle cells and the production of a collagenous matrix. They consist of smooth-muscle cells which cells carry the MED12 (or HMGA2) mutation, suggesting that their origin is a myometrial stem cell [
      • Bulun S.E.
      Uterine fibroids.
      ,
      • Ono M.
      • Yin P.
      • Navarro A.
      • et al.
      Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth.
      ,
      • Bertsch E.
      • Qiang W.
      • Zhang Q.
      • et al.
      MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma.
      ]. The mitotic activity of fibroids is generally low, although the proliferative rate of the fibroid tissue is greater than that of the adjacent myometrium. The collagenous matrix is variable in quantity. It has been proposed that there is an inverse relationship between the percentage of tumor matrix and microvascular density which leads to interstitial ischemia and myocyte atrophy [
      • Flake G.P.
      • Moore A.B.
      • Sutton D.
      • et al.
      The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation.
      ]. Angiogenic growth factors and glycosylated calcitonin may also be involved in fibroid development and growth, and contribute to their abnormal vasculature [
      • Nikitenko L.L.
      • Cross T.
      • Campo L.
      • et al.
      Expression of terminally glycosylated calcitonin receptor-like receptor in uterine leiomyoma: endothelial phenotype and association with microvascular density.
      ,
      • Tal R.
      • Segars J.H.
      The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy.
      ].
      Both experimental studies and clinical observations suggest that uterine fibroids are estrogen dependent tumors. Furthermore, experimental and clinical evidence suggests that progesterone has an equally important role as estradiol in regulating fibroid growth [
      • Maruo T.
      • Ohara N.
      • Wang J.
      • Matsuo H.
      Sex steroidal regulation of uterine leiomyoma growth and apoptosis.
      ,
      • Islam M.S.
      • Protic O.
      • Giannubilo S.R.
      • et al.
      Uterine leiomyoma: available medical treatments and new possible therapeutic options.
      ]. Progesterone and progestins increase mitotic activity in leiomyomas and thereby their rate of growth. Other endocrine, paracrine and biochemical factors are associated with fibroid growth and development and require assessment as potential therapeutic targets [
      • Bulun S.E.
      Uterine fibroids.
      ,
      • Ono M.
      • Yin P.
      • Navarro A.
      • et al.
      Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth.
      ].
      The traditional management of symptomatic fibroids has been surgery (hysterectomy or myomectomy). However, some women do not want invasive surgery and wish to retain their uterus and fertility [
      • Borah B.J.
      • Nicholson W.K.
      • Bradley L.
      • Stewart E.A.
      The impact of uterine leiomyomas: a national survey of affected women.
      ]. Fortunately in this respect, during the last few years new medical and surgical uterine-conserving alternatives have become available as technological advances have been made. Pharmacological management of symptomatic uterine fibroids has benefited from the introduction of new compounds, although the indications and treatment duration are limited by their side-effects.
      The aim of this position statement is to provide recommendations to help decision-making in the management of women with fibroids.

      2. Prevalence and risk factors

      A large proportion of women with fibroids are unaware they have these tumors simply because they are asymptomatic and do not seek medical attention. Therefore, the reported prevalence of fibroids varies between studies, as it depends on how participants are recruited and screened. In general, the prevalence of symptomatic fibroids peaks in the perimenopausal years and declines after the menopause. Their prevalence is high, at up to 70% of women aged 50 years, and the figure is even higher among black women [
      • Baird D.D.
      • Dunson D.B.
      • Hill M.C.
      • Cousins D.
      • Schectman J.M.
      High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence.
      ,
      • Wise L.A.
      • Palmer J.R.
      • Harlow B.L.
      • et al.
      Reproductive factors, hormonal contraception, and risk of uterine leiomyomata in African-American women: a prospective study.
      ].
      Nulliparity, early menarcheal age, older age at first term pregnancy, obesity, diabetes, hypertension and family history are associated with an increased risk of fibroids. Leiomyomas may enlarge during the first trimester of pregnancy, but with no further growth in the second and third trimesters, despite increases in circulating progesterone [
      • Hammoud A.O.
      • Asaad R.
      • Berman J.
      • Treadwell M.C.
      • Blackwell S.
      • Diamond M.P.
      Volume change of uterine myomas during pregnancy: do myomas really grow?.
      ,
      • Neiger R.
      • Sonek J.D.
      • Croom C.S.
      • Ventolini G.
      Pregnancy-related changes in the size of uterine leiomyomas.
      ]. Parity is inversely related to the risk of fibroids, but only among white women [
      • Chen C.R.
      • Buck G.M.
      • Courey N.G.
      • Perez K.M.
      • Wactawski-Wende J.
      Risk factors for uterine fibroids among women undergoing tubal sterilization.
      ]. Fibroids shrink postpartum. Thus one study of 171 women with one initial fibroid found that 36% had no identifiable fibroid at the time of postpartum ultrasound, and 79% of the remaining fibroids decreased in size [
      • Laughlin S.K.
      • Herring A.H.
      • Savitz D.A.
      • et al.
      Pregnancy-related fibroid reduction.
      ].
      The effect of the combined oral contraceptive pill is uncertain as the evidence is conflicting. Depot progestogens may reduce the risk of fibroids [
      • Okolo S.
      Incidence, aetiology and epidemiology of uterine fibroids.
      ]. There is some evidence that caffeine intake, for instance in the form of coffee, is associated with an increased risk of fibroids but smokers are at reduced risk [
      • Wise L.A.
      • Palmer J.R.
      • Harlow B.L.
      • et al.
      Risk of uterine leiomyomata in relation to tobacco, alcohol and caffeine consumption in the Black Women's Health Study.
      ,
      • Laughlin S.K.
      • Schroeder J.C.
      • Baird D.D.
      New directions in the epidemiology of uterine fibroids.
      ]. Overt hypothyroidism was found to be associated with fibroids [
      • Ott J.
      • Kurz C.
      • Braun R.
      • Promberger R.
      • Seemann R.
      • Vytiska-Binstorfer E.
      • Walch K.
      Overt hypothyroidism is associated with the presence of uterine leiomyoma: a retrospective analysis.
      ]. With regard to dietary risk factors dairy products and omega-3 fatty acid intake increase risk, but high fruit intake may reduce risk in black women [
      • Wise L.A.
      • Radin R.G.
      • Palmer J.R.
      • Kumanyika S.K.
      • Boggs D.A.
      • Rosenberg L.
      Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata.
      ,
      • Wise L.A.
      • Palmer J.R.
      • Ruiz-Narvaez E.
      • Reich D.E.
      • Rosenberg L.
      Is the observed association between dairy intake and fibroids in African Americans explained by genetic ancestry?.
      ,
      • Wise L.A.
      • Radin R.G.
      • Kumanyika S.K.
      • Ruiz-Narváez E.A.
      • Palmer J.R.
      • Rosenberg L.
      Prospective study of dietary fat and risk of uterine leiomyomata.
      ].
      Exposure to endocrine disrupters, and intake of soybean milk, food additives and sweeteners may all increase the risk of fibroids [
      • Yu L.
      • Moore A.B.
      • Castro L.
      • et al.
      Estrogen regulates MAPK-related genes through genomic and nongenomic interactions between IGF-1-I receptor tyrosine kinase and estrogen receptor-alpha signaling pathways in human uterine leiomyoma cells.
      ,
      • Shen Y.
      • Xu Q.
      • Xu J.
      • Ren M.L.
      • Cai Y.L.
      Environmental exposure and risk of uterine leiomyoma: an epidemiologic survey.
      ].

      3. Clinical presentation

      Most fibroids are asymptomatic, and will not produce pelvic symptoms or discomfort. However, fibroids may cause heavy menstrual bleeding (HMB) or painful menstruation, abdominal discomfort or bloating, back ache, painful defecation, painful sexual intercourse, and uncomfortable pelvic pressure; they may also increase the frequency of urinary tract infections. Many of these women may nonetheless delay medical consultation for a period of years. This is often because they fear the possible consequences of such a consultation which include cancer diagnosis, surgery (and the subsequent alteration of their sexual function), and loss of self-image and/or personal control. Women with severe symptoms will take time off work and experience a reduced quality of life [
      • Borah B.J.
      • Nicholson W.K.
      • Bradley L.
      • Stewart E.A.
      The impact of uterine leiomyomas: a national survey of affected women.
      ]. However, clinical symptoms tend to reduce or disappear after the menopause [
      • Flake G.P.
      • Moore A.B.
      • Sutton D.
      • et al.
      The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation.
      ].
      Co-morbid conditions that are highly prevalent among women with uterine fibroids around the time of the menopause and sometimes may be associated with similar clinical symptoms include polyps, adenomyosis, endometrial hyperplasia and ovulatory disturbances [
      • Munro M.G.
      • Critchley H.O.
      • Broder M.S.
      • Fraser I.S.
      FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM–COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age.
      ,
      • Dreisler E.
      • Poulsen L.G.
      • Antonsen S.L.
      • et al.
      EMAS clinical guide: assessment of the endometrium in peri and postmenopausal women.
      ].

      3.1 Bleeding problems

      Bleeding problems such as HMB and inter-menstrual bleeding can lead to iron deficiency and anemia. Why fibroids cause bleeding problems is uncertain. However, abnormal bleeding tends to be associated with submucous fibroids which distort the uterine cavity and may lead to endometrial and vascular dysfunction. It has been said that submucous fibroids are associated with more severe symptoms in general than fibroids in other locations, but menorraghia and anemia are no more likely to be reported in women with at least one submucous fibroid than in those with fibroids only in other locations [
      • Bachmann G.A.
      • Bahouth L.A.
      • Amalraj P.
      • Mhamunkar V.
      • Hoes K.
      • Ananth C.V.
      Uterine fibroids: correlations of anemia and pain to fibroid location and uterine weight.
      ,
      • Puri K.
      • Famuyide A.O.
      • Erwin P.J.
      • Stewart E.A.
      • Laughlin-Tommaso S.K.
      Submucosal fibroids and the relation to heavy menstrual bleeding and anemia.
      ].
      Assessment of excessive bleeding may be carried with pictograms, weighing menstrual protection, objective measurement of menstrual blood loss with the alkaline haematin method and assessment of hemoglobin and ferritin, or a combination of these measures [
      • Schumacher U.
      • Schumacher J.
      • Mellinger U.
      • Gerlinger C.
      • Wienke A.
      • Endrikat J.
      Estimation of menstrual blood loss volume based on menstrual diary and laboratory data.
      ,
      • Napolitano M.
      • Dolce A.
      • Celenza G.
      • et al.
      Iron-dependent erythropoiesis in women with excessive menstrual blood losses and women with normal menses.
      ]. For practical purposes, a subjective definition of HMB (i.e., excessive menstrual blood loss that is not tolerated by the patient and adversely affects quality of life) rather than objective measures can be used by the clinician as the basis for further investigation.

      3.2 Pelvic symptoms

      Fibroids may cause pelvic pain such as dysmenorrhea, dyspareunia, pelvic pressure and pelvic heaviness or discomfort. The location and size of the fibroids may influence the pain characteristics. Some do not produce any type of pain, especially those which are small. Torsion of pedunculated subserosal fibroids may produce acute pain, and submucosal fibroids may be associated with intermittent uterine contractions. Large fibroids can cause pelvic pressure symptoms and affect bowel and bladder function although differential diagnosis should be made with other common causes such as pelvic adhesions, endometriosis and adenomyosis, and pelvic floor disorders [
      • Munro M.G.
      • Critchley H.O.
      • Broder M.S.
      • Fraser I.S.
      FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM–COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age.
      ,
      • Kavvadias T.
      • Baessler K.
      • Schuessler B.
      Pelvic pain in urogynaecology: Part I: Evaluation, definitions and diagnoses.
      ,
      • Moshesh M.
      • Olshan A.F.
      • Saldana T.
      • Baird D.
      Examining the relationship between uterine fibroids and dyspareunia among premenopausal women in the United States.
      ].

      3.3 Infertility

      Fibroid location influences fertility. In patients consulting for infertility uterine morphology should be studied by magnetic resonance imaging which is a better procedure than transvaginal ultrasound and hysterosalpingography to plan clinical management. It seems that intramural, but not subserosal, fibroids may be associated with reduced fertility and increased risk of miscarriage. Submucosal or deeply infiltrating intramural fibroids may alter the endometrial cavity and interfere with implantation and pregnancy outcome [
      • Kroon B.
      • Johnson N.
      • Chapman M.
      • Yazdani A.
      • Hart R.
      Australasian CREI Consensus Expert Panel on Trial evidence (ACCEPT) group. Fibroids in infertility – consensus statement from ACCEPT (Australasian CREI Consensus Expert Panel on Trial evidence).
      ]. The effects of multiple or different size fibroids on fertility is unclear due to the low quality of the available evidence [
      • Metwally M.
      • Farquhar C.M.
      • Li T.C.
      Is another meta-analysis on the effects of intramural fibroids on reproductive outcomes needed?.
      ]. Small fibroids not affecting the endometrial cavity do not seem to impact the in vitro fertility rate [
      • Somigliana E.
      • De Benedictis S.
      • Vercellini P.
      • et al.
      Fibroids not encroaching the endometrial cavity and IVF success rate: a prospective study.
      ].
      On the other hand, given that the prevalence of fibroids increases with age, women who delay pregnancy are more likely to have fibroids than their younger counterparts. While there is a statistical association between infertility and uterine fibroids, this is likely to be largely due to age alone, and it is not clear whether there is a direct cause–effect relationship between fibroids and infertility. Observational studies have reported inconclusive or contradictory results [
      • Metwally M.
      • Cheong Y.C.
      • Horne A.W.
      Surgical treatment of fibroids for subfertility.
      ].

      4. General management of uterine fibroids

      Uterine fibroids may be diagnosed by pelvic clinical examination and ultrasound. Sometimes it is not possible clinically to accurately determine whether a pelvic mass involves the uterus or not, but ultrasound is a simple way to confirm this. In cases where the uncertain, magnetic resonance (MR) imaging or computed tomography may help [
      • Shwayder J.
      • Sakhel K.
      Imaging for uterine myomas and adenomyosis.
      ]. Sonohysterography, hysterosalpingography or hysteroscopy may assist in identifying submucosal fibroids. Management depends on size, number and location as well as whether the fibroids are causing symptoms. Fig. 1 shows the different management and therapeutic options.
      Figure thumbnail gr1
      Fig. 1Suggested flowchart for the management of uterine fibroids.

      4.1 Asymptomatic patients: conservative management

      Asymptomatic women with small fibroids may benefit from expectant management, especially those approaching the menopause. An enlarged uterus rarely causes ureteric compression sufficient to compromise renal function. Women eligible for expectant management may be followed up to check for any change in uterine size or symptoms. While there are no standard guidelines as to frequency of follow up, annual review would appear prudent. Thus, when the woman is asymptomatic and does not want to become pregnant, there is no reason to consider treatment [
      • Lefebvre G.
      • Vilos G.
      • Allaire C.
      • et al.
      The management of uterine leiomyomas.
      ,
      • Laughlin S.K.
      • Stewart E.A.
      Uterine leiomyomas: individualizing the approach to a heterogeneous condition.
      ,
      • Pritts E.A.
      • Olive D.L.
      When should uterine fibroids be treated?.
      ].

      4.2 Symptomatic patients

      For women with symptomatic fibroids (pain or pelvic discomfort, heavy bleeding), rapid growth or highly vascularized fibroids, treatment should be instituted after appropriate assessment. A wide variety of medical therapies are available (see Section 5). Medical treatments may shrink but will not eradicate fibroids which will tend to regrow once therapy is stopped. Surgery (myomectomy or hysterectomy) is indicated if the fibroids are large, rapidly growing or if symptoms are not responding to medical therapies. What option is used depends on a woman's desire to retain her uterus and her fertility goals.
      Newer treatment options include uterine artery embolization via interventional radiologic techniques. Other new therapies such as high-intensity focused ultrasound, MR-guided laser ablation and ligation of the uterine arteries (detailed below) show promise, but need further evaluation.

      5. Medical treatments and interventions

      Premenopausal women with symptomatic uterine fibroids have different medical treatment options for the alleviation of symptoms, and may choose to delay surgery or the use of other invasive techniques, or even to avoid them altogether. Most of the medical treatments may produce significant – though temporary – reductions in both uterine size and symptoms. These interventions may make surgery easier and in some cases may render it unnecessary, especially where, in the interim, the patient becomes menopausal. However, pharmacological treatments do not eradicate fibroids and are not devoid of side-effects.

      5.1 Non-hormonal pharmacological treatment

      The two commonly used non-hormonal options are tranexamic acid and non-steroidal anti-inflammatory drugs (NSAIDs). Tranexamic acid is a synthetic antifibrinolytic agent which has been used as a first-line non-hormonal therapy for HMB due to dysfunctional uterine causes or associated with fibroids [
      • Fraser I.S.
      • Porte R.J.
      • Kouides P.A.
      • Lukes A.S.
      A benefit-risk review of systemic haemostatic agents: Part 2: In excessive or heavy menstrual bleeding.
      ,
      • Freeman E.W.
      • Lukes A.
      • VanDrie D.
      • et al.
      A dose–response study of a novel, oral tranexamic formulation for heavy menstrual bleeding.
      ,
      • Eder S.
      • Baker J.
      • Gersten J.
      • Mabey R.G.
      • Adomako T.L.
      Efficacy and safety of oral tranexamic acid in women with heavy menstrual bleeding and fibroids.
      ].
      Eder et al. [
      • Eder S.
      • Baker J.
      • Gersten J.
      • Mabey R.G.
      • Adomako T.L.
      Efficacy and safety of oral tranexamic acid in women with heavy menstrual bleeding and fibroids.
      ] reported the efficacy and safety of modified-release tranexamic acid in women with HMB and fibroids. Within the tranexamic acid group, more statistically significant (p < 0.001) reductions in menstrual blood loss compared with placebo occurred in women with fibroids than in those without. However, further studies are needed to better define the potential benefit in women whose HMB is associated with fibroids. Tranexamic acid may increase the rate venous thromboembolism, although the rate is low; most studies have found the incidence of thrombosis in treated and untreated women [
      • Naoulou B.
      • Tsai M.C.
      Efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding: a systematic review.
      ]. In a case series of 490 women Ip et al. [
      • Ip P.P.
      • Lam K.W.
      • Cheung C.L.
      • et al.
      Tranexamic acid-associated necrosis and intralesional thrombosis of uterine leiomyomas: a clinicopathologic study of 147 cases emphasizing the importance of drug-induced necrosis and early infarcts in leiomyomas.
      ] reported that infarct-type necrosis and thrombosis of leiomyoma was more commonly observed in patients treated with tranexamic acid. However this requires further confirmation.
      NSAIDs may reduce HMB and dysmenorrhea in women without fibroids [
      • Lethaby A.
      • Duckitt K.
      • Farquhar C.
      Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding.
      ]. However, there are no controlled trials showing the benefits of NSAIDs for HMB in women with fibroids. NSAIDs may reduce the pain associated with fibroids.

      5.2 Systemic combined and progestin-only contraceptives

      Epidemiologic studies suggest that both combined and progestin-only contraceptives may decrease the risk of developing clinically significant fibroids [
      • Qin J.
      • Yang T.
      • Kong F.
      • Zhou Q.
      Oral contraceptive use and uterine leiomyoma risk: a meta-analysis based on cohort and case–control studies.
      ]. Combined oral contraceptives may control spotting or HMB associated with uterine fibroids without affecting their size [
      • Hoellen F.
      • Griesinger G.
      • Bohlmann M.K.
      Therapeutic drugs in the treatment of symptomatic uterine fibroids.
      ]. A recent meta-analysis suggests that uterine fibroids should not be considered a contraindication for combined oral contraceptive use [
      • Qin J.
      • Yang T.
      • Kong F.
      • Zhou Q.
      Oral contraceptive use and uterine leiomyoma risk: a meta-analysis based on cohort and case–control studies.
      ].
      Clinical studies using progestins for the treatment of uterine fibroids have reported mixed results. While some studies with small numbers of cases reported a decrease in fibroid size during oral progestin therapy [
      • Venkatachalam S.
      • Bagratee J.S.
      • Moodley J.
      Medical management of uterine fibroids with medroxyprogesterone acetate (Depo Provera): a pilot study.
      ,
      • Ichigo S.
      • Takagi H.
      • Matsunami K.
      • Suzuki N.
      • Imai A.
      Beneficial effects of dienogest on uterine myoma volume: a retrospective controlled study comparing with gonadotropin-releasing hormone agonist.
      ], the review by Sangkomkamhang et al. [
      • Sangkomkamhang U.S.
      • Lumbiganon P.
      • Laopaiboon M.
      • Mol B.W.
      Progestogens or progestogen-releasing intrauterine systems for uterine fibroids.
      ] concluded that oral progestins did not reduce fibroid size or fibroid-related symptoms. However, progestins may reduce endometrial hyperplasia-related HMB associated with fibroids.

      5.3 Levonorgestrel intrauterine system

      The levonorgestrel intrauterine system (LNG IUS) acts by inducing endometrial atrophy [
      • Sangkomkamhang U.S.
      • Lumbiganon P.
      • Laopaiboon M.
      • Mol B.W.
      Progestogens or progestogen-releasing intrauterine systems for uterine fibroids.
      ,
      • Lethaby A.E.
      • Cooke I.
      • Rees M.
      Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding.
      ]. The LNG IUS is an effective treatment for HMB and irregular bleeding associated with fibroids and increases hemoglobin levels, but there are conflicting results concerning the effect on fibroid growth [
      • Socolov D.
      • Blidaru I.
      • Tamba B.
      • Miron N.
      • Boiculese L.
      • Socolov R.
      Levonorgestrel releasing-intrauterine system for the treatment of menorrhagia and/or frequent irregular uterine bleeding associated with uterine leiomyoma.
      ,
      • Kriplani A.
      • Awasthi D.
      • Kulshrestha V.
      • Agarwal N.
      Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma.
      ,
      • Depypere H.T.
      • Hillard T.
      • Erkkola R.
      • et al.
      A 60-month non-comparative study on bleeding profiles with the levonorgestrel intrauterine system from the late transition period to estrogen supplemented menopause.
      ]. A multicentre, open, single-group, non-comparative phase 3 clinical study, 394 women between 46 and 51 years fitted with a LNG IUS found no significant change in size. Thus at study entry 83/394 (21.1%) women had one or two intramural fibroids (mean ± SD diameter of the largest fibroid was 21 ± 9 mm). At 60 months of follow up the mean diameter was 22 ± 10 mm [
      • Depypere H.T.
      • Hillard T.
      • Erkkola R.
      • et al.
      A 60-month non-comparative study on bleeding profiles with the levonorgestrel intrauterine system from the late transition period to estrogen supplemented menopause.
      ]. In cell culture, levonorgestrel inhibits proliferation and induces apoptosis of fibroid cells [
      • Xu Q.
      • Qiu L.
      • Zhu L.
      • Luo L.
      • Xu C.
      Levonorgestrel inhibits proliferation and induces apoptosis in uterine leiomyoma cells.
      ].
      A systematic review concluded that progestogen-releasing intrauterine systems appear to reduce menstrual blood loss in premenopausal women with uterine fibroids [
      • Sangkomkamhang U.S.
      • Lumbiganon P.
      • Laopaiboon M.
      • Mol B.W.
      Progestogens or progestogen-releasing intrauterine systems for uterine fibroids.
      ]. However, the LNG IUS does not significantly reduce fibroid size and is more likely to be expelled [
      • Jiang W.
      • Shen Q.
      • Chen M.
      • et al.
      Levonorgestrel-releasing intrauterine system use in premenopausal women with symptomatic uterine leiomyoma: a systematic review.
      ,
      • Youm J.
      • Lee H.J.
      • Kim S.K.
      • Kim H.
      • Jee B.C.
      Factors affecting the spontaneous expulsion of the levonorgestrel-releasing intrauterine system.
      ]. In addition, there is some concern about the long-term cardiovascular effects of levonorgestrel, but this requires further study [
      • Pérez-López F.R.
      Long-term consequences of LNG-IUS vs. hysterectomy for menorrhagia.
      ].

      5.4 Gonadotropin-releasing hormone agonists

      Gonadotropin-releasing hormone (GnRH) agonists have been used for the treatment of fibroids in perimenopausal women or as a preoperative treatment for 3–4 months, when they are used to reduce fibroid-related bleeding and anemia, uterine volume and fibroid size, to facilitate or enable endoscopic or transvaginal surgery [
      • Muzii L.
      • Boni T.
      • Bellati F.
      • et al.
      GnRH analogue treatment before hysteroscopic resection of submucous myomas: a prospective, randomized, multicenter study.
      ]. In some cases a change from an abdominal procedure to vaginal surgery is possible after pre-treatment with GnRH agonists. The risk of fibroid recurrence after a course of GnRH agonists in patients who have undergone myomectomy is controversial and data are scarce on postoperative fertility [
      • Hoellen F.
      • Griesinger G.
      • Bohlmann M.K.
      Therapeutic drugs in the treatment of symptomatic uterine fibroids.
      ,
      • Lethaby A.
      • Vollenhoven B.
      • Sowter M.
      Efficacy of pre-operative gonadotrophin hormone releasing analogues for women with uterine fibroids undergoing hysterectomy or myomectomy: a systematic review.
      ].
      The benefits of GnRH agonists are limited by their side-effects, which include hot flashes, sleep disturbances, vaginal dryness, depression and loss of bone mass after prolonged use. Various therapies have been studied as add-back (combined estrogen and progestin, medroxyprogesterone acetate, tibolone) to reduce these adverse effects, in order to allow longer use of GnRH agonists [
      • Lethaby A.E.
      • Vollenhoven B.J.
      An evidence-based approach to hormonal therapies for premenopausal women with fibroids.
      ]. The improvements resulting from GnRH agonist treatment disappear soon after stopping.
      A meta-analysis of the use of GnRH analogs before hysteroscopic submucous myomectomy concluded that there is insufficient evidence to support their use and that randomized trials are needed [
      • Kamath M.S.
      • Kalampokas E.E.
      • Kalampokas T.E.
      Use of GnRH analogues pre-operatively for hysteroscopic resection of submucous fibroids: a systematic review and meta-analysis.
      ].

      5.5 Antagonists of progesterone receptors

      Progesterone receptors are present in higher concentrations in fibroids than in normal myometrium. Mifepristone (RU-486) is a progesterone receptor antagonist that has been used, at different doses, to improve fibroid-associated symptoms. Mifepristone (2.5 or 5 mg) for 3–6 months is associated with increases in health-related quality of life, which has been explained by the reduction of both pain and HMB. The effect of mifepristone on fibroid volume remains uncertain with conflicting results and there are concerns regarding endometrial hyperplasia [
      • Shen Q.
      • Hua Y.
      • Jiang W.
      • Zhang W.
      • Chen M.
      • Zhu X.
      Effects of mifepristone on uterine leiomyoma in premenopausal women: a meta-analysis.
      ,
      • Feng C.
      • Meldrum S.
      • Fiscella K.
      Improved quality of life is partly explained by fewer symptoms after treatment of fibroids with mifepristone.
      ,
      • Eisinger S.H.
      • Fiscella J.
      • Bonfiglio T.
      • Meldrum S.
      • Fiscella K.
      Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata.
      ,
      • Tristan M.
      • Orozco L.J.
      • Steed A.
      • Ramírez-Morera A.
      • Stone P.
      Mifepristone for uterine fibroids.
      ]. Mifepristone (2.5 mg/day) for 6 months in women with at least moderate symptoms, with uterine volume of 160 ml or more, or at least one fibroid of >2.5 cm in diameter results in modest reductions in uterine size and improvements in symptoms and quality of life without endometrial hyperplasia [
      • Eisinger S.H.
      • Fiscella J.
      • Bonfiglio T.
      • Meldrum S.
      • Fiscella K.
      Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata.
      ].
      An analysis of three randomized controlled trials of mifepristone in women with confirmed uterine fibroids showed that it may reduce HMB (compared with placebo), although it has no effect on fibroid volume. This treatment was associated with an increase of abnormal endometrial histology compared with placebo, including endometrial hyperplasia at the end of the therapy [
      • Tristan M.
      • Orozco L.J.
      • Steed A.
      • Ramírez-Morera A.
      • Stone P.
      Mifepristone for uterine fibroids.
      ].
      There is little information on the effect of vaginal mifepristone in women with symptomatic fibroids, although Yerushalmi et al. [
      • Yerushalmi G.M.
      • Gilboa Y.
      • Jakobson-Setton A.
      • et al.
      Vaginal mifepristone for the treatment of symptomatic uterine leiomyomata: an open-label study.
      ] recently reported that a course of 10 mg/day for 3 months reduced fibroid volume and the number of bleeding days, and improved quality of life.

      5.6 Selective progesterone receptor modulators

      Selective progesterone receptor modulators (SPRMs) act through progesterone receptors and behave as agonists or antagonists in various target organs. They include onapristone, asoprisnil and ulipristal, all of which are under evaluation for the treatment of fibroids. The results suggest that short-term treatment can reduce fibroid-associated symptoms and anemia. Ulipristal is licensed in the USA and in the European Union for the preoperative treatment of uterine fibroids as an oral daily tablet of 5 mg.
      Asoprisnil is an orally active SPRM which has been studied in a randomized double-blind, placebo-controlled trial with a small number of women scheduled for hysterectomy for fibroids. They were treated with 10 or 25 mg asoprisnil or placebo for 12 weeks before surgery. Asoprisnil moderately reduced uterine artery blood flow, decreased the frequency and intensity of bleeding in both groups of treated women, compared with the placebo group. In this short-term study no serious adverse events were reported [
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      ].
      Ulipristal acetate has been studied in premenopausal women with symptomatic fibroids. A daily dose of 10 or 20 mg for 3 months reduced total fibroid volume, compared with placebo. Treatment was associated with amenorrhea, and increased hemoglobin levels and quality of life [
      • Nieman L.K.
      • Blocker W.
      • Nansel T.
      • et al.
      Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study.
      ]. A randomized controlled trial evaluated ulipristal treatment (5 or 10 mg/day for 13 weeks) in women with symptomatic fibroids. It effectively controlled HMB and reduced the size of fibroids compared with placebo. Rates of amenorrhea were high in women treated with ulipristal, occurring very early after initiation of treatment. Side-effects included benign histologic endometrial changes that disappeared within 6 months after treatment [
      • Donnez J.
      • Tatarchuk T.F.
      • Bouchard P.
      • et al.
      Ulipristal acetate versus placebo for fibroid treatment before surgery.
      ]. Both the 5 mg and the 10 mg daily doses of ulipristal acetate were non-inferior to once-monthly GnRH analog treatment in controlling uterine bleeding [
      • Donnez J.
      • Tomaszewski J.
      • Vázquez F.
      • et al.
      Ulipristal acetate versus leuprolide acetate for uterine fibroids.
      ]. As ulipristal treatment does not suppress estrogen synthesis, its use is not associated with menopausal symptoms and bone loss, unlike GnRH agonists [
      • Donnez J.
      • Tomaszewski J.
      • Vázquez F.
      • et al.
      Ulipristal acetate versus leuprolide acetate for uterine fibroids.
      ,
      • Biglia N.
      • Carinelli S.
      • Maiorana A.
      • D’Alonzo M.
      • Lo Monte G.
      • Marci R.
      Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids.
      ] Ulipristal was superior to placebo as a preoperative treatment of uterine fibroids, reducing fibroid-associated bleeding and fibroid size, without the side-effects of GnRH analogs. There is also some evidence that repeated 3-month ulipristal treatment may control bleeding and shrink symptomatic fibroids [
      • Donnez J.
      • Vázquez F.
      • Tomaszewski J.
      • et al.
      Long-term treatment of uterine fibroids with ulipristal acetate.
      ]. Their effect on fibroid size may persist longer after cessation of treatment compared with GnRH agonist therapy [
      • Hoellen F.
      • Griesinger G.
      • Bohlmann M.K.
      Therapeutic drugs in the treatment of symptomatic uterine fibroids.
      ].

      5.7 Other pharmacological treatments

      Danazol and gestrinone appear to be effective in treating some symptoms associated with fibroids, but they both have side-effects. In addition, there is very limited information and there are no randomized controlled trials on the risks and benefits of using these drugs for the treatment of fibroid-associated symptoms.
      Currently, there is limited evidence for the use of raloxifene in premenopausal women for the treatment of fibroids and there is no evidence to support the use of tamoxifen [
      • Deng L.
      • Wu T.
      • Chen X.Y.
      • Xie L.
      • Yang J.
      Selective estrogen receptor modulators (SERMs) for uterine leiomyomas.
      ].
      Aromatase inhibitors (letrozole, exemestane and anastrozole) are not approved for the treatment of uterine fibroids, despite some favorable effects [
      • Varelas F.K.
      • Papanicolaou A.N.
      • Vavatsi-Christaki N.
      • Makedos G.A.
      • Vlassis G.D.
      The effect of anastrazole on symptomatic uterine leiomyomata.
      ,
      • Parsanezhad M.E.
      • Azmoon M.
      • Alborzi S.
      • et al.
      A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status.
      ,
      • Brito L.G.
      • Candido-dos-Reis F.J.
      • Magario F.A.
      • Sabino-de-Freitas M.M.
      Effect of the aromatase inhibitor anastrozole on uterine and leiomyoma Doppler blood flow in patients scheduled for hysterectomy: a pilot study.
      ,
      • Song H.
      • Lu D.
      • Navaratnam K.
      • Shi G.
      Aromatase inhibitors for uterine fibroids.
      ]. However, some studies, though with small numbers of patients, have reported a reduction in HMB and pelvic pain as well as a decrease in fibroid volume [
      • Hilario S.
      • Bozzini N.
      • Borsari R.
      • Baracat E.
      Action of aromatase inhibitor for treatment of uterine leiomyoma in perimenopausal patients.
      ,
      • Duhan N.
      • Madaan S.
      • Sen J.
      Role of the aromatase inhibitor letrozole in the management of uterine leiomyomas in premenopausal women.
      ]. In addition, short-term letrozole treatment (2.5 mg/day for 12 weeks) has been reported as effective as GnRH analogs in reducing fibroid volume [
      • Parsanezhad M.E.
      • Azmoon M.
      • Alborzi S.
      • et al.
      A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status.
      ]. Further trials are required.
      A systematic review concluded that current evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies with large sample sizes and of high quality [
      • Liu J.P.
      • Yang H.
      • Xia Y.
      • Cardini F.
      Herbal preparations for uterine fibroids.
      ].

      6. Surgical treatments and interventions

      In premenopausal women with fibroids and severe symptoms which do not respond to medical treatments, surgery – either hysterectomy or myomectomy – is the conventional option. The three common approaches are abdominal open surgery, laparoscopy or robot-assisted surgery. Classical vaginal hysterectomy or hysteroscopic myomectomy can also be performed.

      6.1 Hysterectomy

      Symptomatic uterine fibroids have been, and still are, one of the most common indications for hysterectomy. It eliminates the symptoms and removes the lesions. Hysterectomy should be considered when other therapeutic options have failed and the patient does not want to retain her uterus and accepts the risks of surgery [
      • Royal College of Obstetricians and Gynaecologists
      Consent advice 4: abdominal hysterectomy for benign conditions.
      ]. The procedure can be performed via the vaginal, abdominal or laparoscopic route, taking into account uterine size, patient preference and available facilities. Vaginal hysterectomy is the most cost-effective option [
      • Sculpher M.
      • Manca A.
      • Abbott J.
      • Fountain J.
      • Mason S.
      • Garry R.
      Cost effectiveness analysis of laparoscopic hysterectomy compared with standard hysterectomy: results from a randomised trial.
      ]. Laparoscopic and vaginal surgery are associated with less postoperative pain, a shorter hospital stay, better cosmetic results and quicker return to ordinary activities than abdominal hysterectomy. Some women may elect for subtotal hysterectomy. However there appear to be no significant differences in the outcome, although in some women cyclical bleeding may persist after subtotal hysterectomy [
      • Nieboer T.E.
      • Johnson N.
      • Lethaby A.
      • et al.
      Surgical approach to hysterectomy for benign gynaecological disease.
      ]. It seems that subtotal hysterectomy does not lead to better sexual, urinary or bowel function when compared with total abdominal hysterectomy [
      • Lethaby A.
      • Mukhopadhyay A.
      • Naik R.
      Total versus subtotal hysterectomy for benign gynaecological conditions.
      ]. Furthermore women will need to continue with cervical screening.The evidence regarding robot-assisted hysterectomy for fibroids is limited and requires further evaluation [
      • Manoucheri E.
      • Fuchs-Weizman N.
      • Cohen S.L.
      • Wang K.C.
      • Einarsson J.I.
      MAUDE – analysis of robotic-assisted gynecologic surgery.
      ,
      • Kannisto P.
      • Harter P.
      • Heitz F.
      • Traut A.
      • du Bois A.
      • Kurzeder C.
      Implementation of robot-assisted gynecologic surgery for patients with low and high BMI in a German gynecological cancer center.
      ,
      • O’Neill M.
      • Moran P.S.
      • Teljeur C.
      • et al.
      Robot-assisted hysterectomy compared to open and laparoscopic approaches: systematic review and meta-analysis.
      ].

      6.2 Abdominal myomectomy

      Perioperative morbidity of abdominal myomectomy and hysterectomy are similar [
      • Sawin S.W.
      • Pilevsky N.D.
      • Berlin J.A.
      • Barnhart K.T.
      Comparability of perioperative morbidity between abdominal myomectomy and hysterectomy for women with uterine leiomyomas.
      ]. However, myomectomy of very large fibroids may be associated with significant perioperative complications such as bleeding requiring transfusion and bowel or bladder injury. It seems that complications are more common with a uterine size equivalent to that of 20 gestational weeks or more, when 10 or more fibroids are removed and when a midline skin incision is needed [
      • Pundir J.
      • Krishnan N.
      • Siozos A.
      • et al.
      Peri-operative morbidity associated with abdominal myomectomy for very large fibroid uteri.
      ].

      6.3 Laparoscopic myomectomy

      Laparoscopic myomectomy has medical, social and economic advantages over abdominal open surgery, including less postoperative pain and a shorter recovery time [
      • Mettler L.
      • Schollmeyer T.
      • Lehmann-Willenbrock E.
      • Dowaji J.
      • Zavala A.
      Treatment of myomas by laparoscopic and laparotomic myomectomy and laparoscopic hysterectomy.
      ,
      • Jin C.
      • Hu Y.
      • Chen X.C.
      • et al.
      Laparoscopic versus open myomectomy – a metaanalysis of randomized controlled trials.
      ]. Laparoscopic myomectomy of subserous and intramural fibroids with retention of the fibroid pseudocapsule permits the preservation of myometrial and endometrial integrity, and has few complications. In addition, the fertility rate and pregnancy outcomes are more favorable with laparoscopic myomectomy than after abdominal myomectomy when there is no other cause of infertility [
      • Kubinova K.
      • Mara M.
      • Horak P.
      • Kuzel D.
      • Dohnalova A.
      Reproduction after myomectomy: comparison of patients with and without second-look laparoscopy.
      ]. The time to conception after laparoscopic myomectomy is shorter than after abdominal myomectomy, although the pregnancy rate is similar [
      • Soriano D.
      • Desolle L.
      • Poncelet C.
      • Benifla J.L.
      • Madelenat P.
      • Darai E.
      Pregnancy outcome after laparoscopic and laparoconverted myomectomy.
      ,
      • Hackethal A.
      • Westermann A.
      • Tchartchian G.
      • et al.
      Laparoscopic myomectomy in patients with uterine myomas associated with infertility.
      ]. Uterine rupture during pregnancy following laparoscopic myomectomy is rare [
      • Paul P.G.
      • Koshy A.K.
      • Thomas T.
      Pregnancy outcomes following laparoscopic myomectomy and single-layer myometrial closure.
      ]. However, laparoscopic myomectomy should be considered with caution for women with fibroids of more than 5 cm in diameter, those with several fibroids and those with deep intramural myomas [
      • Banas T.
      • Klimek M.
      • Fugiel A.
      • Skotniczny K.
      Spontaneous uterine rupture at 35 weeks’ gestation, 3 years after laparoscopic myomectomy, without signs of fetal distress.
      ,
      • Parker W.H.
      • Iacampo K.
      • Long T.
      Uterine rupture after laparoscopic removal of a pedunculated myoma.
      ]. In such cases, a prospective comparative study reported better results with radiofrequency thermal ablation (see Section 8.4) than with laparoscopic myomectomy [
      • Brucker S.Y.
      • Hahn M.
      • Kraemer D.
      • Taran F.A.
      • Isaacson K.B.
      • Krämer B.
      Laparoscopic radiofrequency volumetric thermal ablation of fibroids versus laparoscopic myomectomy.
      ].
      In April 2014 the US Food and Drug Administration discouraged the use of laparoscopic power morcellation during hysterectomy or myomectomy for the treatment of women with uterine fibroids because of the potential for dissemination of an unsuspected uterine sarcoma [
      • US Food and Drug Administration
      Laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication.
      ].

      6.4 Robot-assisted myomectomy

      Robot-assisted laparoscopic myomectomy is a new alternative to traditional surgery. The evidence suggests that is associated with less blood loss, lower complication rates and shorter hospital stays than abdominal myomectomy, although the cost is higher [
      • Advincula A.P.
      • Xu X.
      • Goudeau 4th, S.
      • Ransom S.B.
      Robot-assisted laparoscopic myomectomy versus abdominal myomectomy: a comparison of short-term surgical outcomes and immediate costs.
      ,
      • Mansour F.W.
      • Kives S.
      • Urbach D.R.
      • Lefebvre G.
      Robotically assisted laparoscopic myomectomy: a Canadian experience.
      ,
      • Ranisavljevic N.
      • Mercier G.
      • Masia F.
      • Mares P.
      • De Tayrac R.
      • Triopon G.
      Robot-assisted laparoscopic myomectomy: comparison with abdominal myomectomy.
      ]. In a retrospective analysis of fertility, higher preterm delivery rates were associated with a greater number of myomas removed and anterior location of the largest incision [
      • Pitter M.C.
      • Gargiulo A.R.
      • Bonaventura L.M.
      • Lehman J.S.
      • Srouji S.S.
      Pregnancy outcomes following robot-assisted myomectomy.
      ]. Thus cost effectiveness of robot-assisted laparoscopic myomectomy requires further evaluation.

      6.5 Hysteroscopic myomectomy

      In women with infertility and asymptomatic submucosal fibroids, hysteroscopic myomectomy seems the only reasonable treatment option. Hysteroscopic myomectomy for submucosal fibroids greater than 2 cm and for intramural fibroids distorting the endometrial cavity may be considered in subfertile women [
      • Brady P.C.
      • Stanic A.K.
      • Styer A.K.
      Uterine fibroids and subfertility: an update on the role of myomectomy.
      ]. Although the technique is widely used, there is little evidence from randomized trials to support the intervention in women whose infertility is unexplained [
      • Casini M.L.
      • Rossi F.
      • Agostini R.
      • Unfer V.
      Effects of the position of fibroids on fertility.
      ,
      • Bosteels J.
      • Kasius J.
      • Weyers S.
      • Broekmans F.J.
      • Mol B.W.
      • D’Hooghe T.M.
      Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities.
      ]. Hysteroscopy-related complications include uterine perforation, hemorrhage, cervical laceration and fluid overload while long term sequelae include adhesions.

      6.6 Ligation of uterine arteries

      Laparoscopic ligation of the uterine arteries is better tolerated although is less efficacious than uterine artery embolization (see Section 7) [
      • Helal A.
      • Mashaly Ael-M
      • Amer T.
      Uterine artery occlusion for treatment of symptomatic uterine myomas.
      ]. It reduces the size of the fibroids as well as symptoms, but again the results obtained with uterine artery embolization are better, and there is less risk of recurrence. Laparoscopic ligation of the uterine arteries has also been used immediately before myomectomy to reduce intraoperative complications [
      • Chang W.C.
      • Huang P.S.
      • Wang P.H.
      • et al.
      Comparison of laparoscopic myomectomy using in situ morcellation with and without uterine artery ligation for treatment of symptomatic myomas.
      ,
      • Vercellino G.
      • Erdemoglu E.
      • Joe A.
      • et al.
      Laparoscopic temporary clipping of uterine artery during laparoscopic myomectomy.
      ].
      Transvaginal bilateral uterine artery ligation has been proposed in centers lacking high-level medical technology. Clinical and patient satisfaction has been reported to be acceptable at 3-year follow-up [
      • Akinola O.I.
      • Fabamwo A.O.
      • Akinola R.A.
      • Ottun T.A.
      • Akinniyi A.
      • Akpan A.E.
      Uterine artery ligation for the treatment of fibroids.
      ].

      6.7 Endometrial ablation

      Endometrial ablation can be used separately or can be combined with hysteroscopic resection in women with HMB who do not wish to preserve their fertility. Second-generation endometrial ablation (thermal ablation, radiofrequency ablation, microwave ablation) are as effective as the LNG IUS, although satisfaction is higher with hysterectomy [
      • Agdi M.
      • Tulandi T.
      The benefits of intrauterine balloon: an intrauterine manipulator and balloon proved useful in myomectomy.
      ,
      • Bhattacharya S.
      • Middleton L.J.
      • Tsourapas A.
      • et al.
      Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis.
      ,
      • Fergusson R.J.
      • Lethaby A.
      • Shepperd S.
      • Farquhar C.
      Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.
      ,
      • Kroft J.
      • Liu G.
      First- versus second-generation endometrial ablation devices for treatment of menorrhagia: a systematic review, meta-analysis and appraisal of economic evaluations.
      ].

      7. Uterine artery embolization

      Uterine artery embolization (UAE) involves the placement of an angiographic catheter into the uterine arteries via a common femoral artery approach and injection of embolic particles larger than 500 μm, in most cases polyvinyl alcohol particles or tris-acryl gelatin icrospheres, until the flow becomes sluggish in both uterine arteries. The mechanism of UAE's action is the marked reduction of uterine blood flow at the arteriolar level, which produces ischemic injury to the fibroids, causing them to undergo necrosis and shrink, while the normal myometrium is able to recover. Immediately after the procedure, most patients experience moderate to severe ischemic pain for 8–12 h, but this gradually decreases during the next 12 h. Patients can usually return to normal activities within 8–14 days. A relatively common complication of UAE is vaginal expulsion of an infarcted fibroid, reported in up to 10% of cases. This complication is more frequently seen with submucosal or intramural fibroids. The most serious complication of UAE is intrauterine infection, but this has been reported after less than 1% of procedures [
      • Tropeano G.
      • Amoroso S.
      • Scambia G.
      Non-surgical management of uterine fibroids.
      ].
      UAE is an option for women with symptomatic fibroids, who no longer desire fertility but who wish to avoid surgery or are poor surgical or anesthetic risks. A multicenter study carried out in the United Kingdom assessed the cost-effectiveness of UAE and hysterectomy in women with symptomatic fibroids. The women were followed from the initial procedure to the menopause. Endpoints were costs of interventions and complications and quality of life expressed as quality-adjusted life years (QALYs). UAE was a cheaper treatment and had more QALYs, even after accounting for repeat procedures and complications. Short-term, but not long-term, quality of life was better in patients who underwent UAE because of the need for further procedures. The authors concluded that UAE is cost-effective in women who wish to preserve their uterus [
      • Wu O.
      • Briggs A.
      • Dutton S.
      • et al.
      Uterine artery embolisation or hysterectomy for the treatment of symptomatic uterine fibroids: a cost–utility analysis of the HOPEFUL study.
      ]. The cost and QALYs of UAE have also been compared with both hysterectomy and myomectomy in Hong Kong women with symptomatic fibroids [
      • You J.H.
      • Sahota D.S.
      • Yuen P.M.
      Uterine artery embolization, hysterectomy, or myomectomy for symptomatic uterine fibroids: a cost–utility analysis.
      ]. This study showed that hysterectomy is more cost-effective than the other two treatments among women with no preference for uterus-conserving interventions.
      The Randomized Trial of Embolization versus Surgical Treatment for Fibroids (REST) found no differences between groups on quality-of-life measures at one year [
      • Edwards R.D.
      • Moss J.G.
      • Lumsden M.A.
      • et al.
      Committee of the randomized trial of embolization versus surgical treatment for fibroids: uterine-artery embolization versus surgery for symptomatic uterine fibroids.
      ]. The UAE group had shorter hospital stays and recovery times than the hysterectomy group. There were no differences between the groups in the rate of major complications (15% for the UAE and 20% for the surgical group). In cost and cost-effectiveness studies, hospital costs associated with UAE were lower, largely because of shorter length of stay. However, this needs to be balanced against the need for additional interventions such as hysterectomy or repeated UAEs due to recurrent symptoms. Thus a randomized trial of 157 women found that the 5-year intervention rate for treatment failure or complications was higher for UAE (32%) than for surgery (4%) [
      • Moss J.G.
      • Cooper K.G.
      • Khaund A.
      • et al.
      Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results.
      ]. The authors concluded that the initial cost benefit of UAE over surgery at 12 months was substantially reduced because of subsequent interventions, with treatments being cost neutral at 5 years.
      Gupta et al. [
      • Gupta J.K.
      • Sinha A.
      • Lumsden M.A.
      • Hickey M.
      Uterine artery embolization for symptomatic uterine fibroids.
      ] carried out a meta-analysis of the benefits and risks of UAE versus other medical or surgical interventions for symptomatic uterine fibroids. Patient satisfaction with the procedures and the rate of complications were similar for UAE and surgery at 2 and 5 years. There was some evidence that myomectomy may be associated with better fertility outcomes in the small sample of women who wished to retain their fertility. UAE was associated with reduced length of the treatment, shorter hospital stay, lower rate of blood transfusion and less time to resumption of normal activities as compared with surgical procedures. However, there were higher rates of complications after UAE, such as more unscheduled readmissions after discharge and an increased surgical reintervention rate. These surgical procedures should be included in the final costs of UAE.
      In premenopausal women both hysterectomy and UAE may lead to loss of ovarian reserve [
      • Hehenkamp W.J.
      • Volkers N.A.
      • Broekmans F.J.
      • et al.
      Loss of ovarian reserve after uterine artery embolization: a randomized comparison with hysterectomy.
      ]. Embolization particles have been found in the ovaries and blood flow is reduced [
      • Payne J.F.
      • Robboy S.J.
      • Haney A.F.
      Embolic microspheres within ovarian arterial vasculature after uterine artery embolization.
      ,
      • Ryu R.K.
      • Chrisman H.B.
      • Omary R.A.
      • et al.
      The vascular impact of uterine artery embolization: prospective sonographic assessment of ovarian arterial circulation.
      ]. Results from randomized trials and prospective series suggest that reduction of the ovarian reserve, after UAE, occurs mainly in women aged 45 or more [
      • Kaump G.R.
      • Spies J.B.
      The impact of uterine artery embolization on ovarian function.
      ].
      The fertility rate after UAE has been studied in women with severe symptomatic fibroids and infertility. Torre et al. [
      • Torre A.
      • Paillusson B.
      • Fain V.
      • Labauge P.
      • Pelage J.P.
      • Fauconnier A.
      Uterine artery embolization for severe symptomatic fibroids: effects on fertility and symptoms.
      ] carried out a prospective study in 66 women who had been previously treated with abdominal myomectomy but whose fibroids had recurred, and who wished to maintain their reproductive capacity. All the women underwent embolization of both uterine arteries. The procedure improved HMB, and reduced both pain and dominant fibroid size. Although the ovarian reserve was not altered by UAE, among the 31 women who tried to conceive, there was only one pregnancy, and that ended in miscarriage. However, this low rate of fertility cannot be generalized to patients without previous surgery and extensive fibroid recurrence.
      In a small sample of selected women, the long-term effects of UAE on ovarian reserve has been compared with findings in women treated with laparoscopic myomectomy. Serum anti-müllerian hormone levels and antral follicle count were significantly lower in women who had undergone UAE than in women who had undergone surgical myomectomy, although serum FSH and estradiol levels were similar in the two groups [
      • Arthur R.
      • Kachura J.
      • Liu G.
      • Chan C.
      • Shapiro H.
      Laparoscopic myomectomy versus uterine artery embolization: long-term impact on markers of ovarian reserve.
      ]. Furthermore, studies in sheep suggest that UAE could lead to intrauterine growth retardation [
      • Yamagami T.
      • Yoshimatsu R.
      • Matsumoto T.
      • et al.
      Fertility after uterine artery embolization: investigation using a sheep model.
      ].
      While UAE appears to be an option for women who wish to retain their uterus, use of the procedure needs to be balanced against the need for further interventions and the loss of ovarian reserve with scarce data on pregnancy outcome.

      8. Fibroid lysis

      Ablation with high-intensity focused ultrasound (HIFU) is a minimally invasive treatment which is performed under the guidance of either MR or ultrasound. HIFU has been used to treat a variety of solid benign and malignant lesions. It produces focal fibroid coagulation and necrosis without alteration of surrounding normal myometrium. Myolysis is not indicated for women who want to become pregnant. Patients contemplating pregnancy should be informed that the effects of the procedure on fertility and on pregnancy are uncertain.

      8.1 Magnetic resonance-guided high-intensity focused ultrasound

      Magnetic resonance-guided MR-guided HIFU is an alternative to surgery and UAE. It is non-invasive, requires no general anesthetic or hospitalization, and uses high-intensity ultrasound waves to destroy fibroids, by heating, without damaging adjacent normal structures. It is an ambulatory procedure without incisions, allowing women to return to work after one or two days. Better results are achieved for intramural fibroids, so MR-guided HIFU is not recommended for pedunculated subserosal fibroids. The presence of bowel loops or abdominal wall scars in the projected pathway of the ultrasound beam may preclude use of the technique. Common symptoms during the procedure are short-term lower abdominal pain, leg pain and buttock pain. Patients are usually discharged home 1 h after the procedure. It seems that the use of GnRH agonist therapy beforehand improves the effect of the thermoablative treatment [
      • Smart O.C.
      • Hindley J.T.
      • Regan L.
      • Gedroyc W.G.
      Gonadotrophin-releasing hormone and magnetic-resonance-guided ultrasound surgery for uterine leiomyomata.
      ].
      Froeling et al. [
      • Froeling V.
      • Meckelburg K.
      • Schreiter N.F.
      • et al.
      Outcome of uterine artery embolization versus MR-guided high-intensity focused ultrasound treatment for uterine fibroids: long-term results.
      ] compared the long-term outcomes of UAE and MR-guided HIFU for symptomatic uterine fibroids. The rate of theater intervention was significantly lower after UAE (12.2%) than after MR-guided HIFU (66.7%), and both total health-related quality of life and severity of symptoms were better in women treated with UAE. The procedure is not possible when there is bowel interposition in the ultrasound beam path. Thus, a study of 783 women found that bowel interposition affected 60.4% of women and differences in technical eligibility for MR-guided HIFU (38.9%) and UAE (99.2%) were significant (P < 0.001) [
      • Fröling V.
      • Kröncke T.J.
      • Schreiter N.F.
      • et al.
      Technical eligibility for treatment of magnetic resonance-guided focused ultrasound surgery.
      ]. However, in some patients with bowel loops anterior to the uterus, therapeutic HIFU ablation of uterine fibroids may be possible after bowel compression with a degassed water balloon on the abdominal wall under a real-time MR guidance and control [
      • Zhang L.
      • Chen W.Z.
      • Liu Y.J.
      • et al.
      Feasibility of magnetic resonance imaging-guided high intensity focused ultrasound therapy for ablating uterine fibroids in patients with bowel lies anterior to uterus.
      ]. This technique needs further assessment.
      MR-guided HIFU is cost-effective when compared with traditional techniques, hysterectomy, myomectomy and uterine artery embolization. Indeed, its low overall cost may lead to the technique becoming the first therapeutic option for symptomatic fibroids. A meta-analysis of 38 studies concluded that MR-guided HIFU a safe, efficient and cost-effective technique for the treatment of symptomatic uterine fibroids that improves quality of life and fertility [
      • Gizzo S.
      • Saccardi C.
      • Patrelli T.S.
      • et al.
      Magnetic resonance-guided focused ultrasound myomectomy: safety, efficacy, subsequent fertility and quality-of-life improvements. A systematic review.
      ]. It has comparable results to other treatment strategies. In a recent U.S. survey in which women were informed about different treatments, 60% rated focused ultrasound as their top choice [
      • Borah B.J.
      • Nicholson W.K.
      • Bradley L.
      • Stewart E.A.
      The impact of uterine leiomyomas: a national survey of affected women.
      ].

      8.2 Ultrasound-guided high-intensity focused ultrasound

      Ultrasound-guided HIFU ablation is a new non-invasive treatment of uterine fibroids [
      • Wang W.
      • Wang Y.
      • Wang T.
      • Wang J.
      • Wang L.
      • Tang J.
      Safety and efficacy of US-guided high-intensity focused ultrasound for treatment of submucosal fibroids.
      ]. The technique allows a check on the immediate efficacy of the procedure; then, if viable residual tissue is detected, there is the option to repeat the ablation immediately. Heterogeneous and markedly homogeneous hyperintense fibroids, as classified by MR, may be treated with ultrasound-guided HIFU [
      • Zhao W.P.
      • Chen J.Y.
      • Zhang L.
      • et al.
      Feasibility of ultrasound-guided high intensity focused ultrasound ablating uterine fibroids with hyperintense on T2-weighted MR imaging.
      ]. Contrast-enhanced ultrasonography may also be used to monitor gradual shrinkage of the treated fibroids or later growth [
      • Wang Y.
      • Wang W.
      • Ye H.
      Contrast-enhanced ultrasonography assessment of therapeutic efficacy for ultrasound-guided high-intensity focused ultrasound ablation of uterine fibroids: comparison with contrast-enhanced magnetic resonance.
      ].
      Large-scale clinical trials are needed to assess the role and limitations of these techniques.

      8.3 Transcervical real-time intrauterine sonography with radiofrequency ablation

      A device is available that combines real-time intrauterine sonography with radiofrequency ablation, which takes place under real-time visualization. A graphical interface delineates the boundaries of both ablation and thermal spread, which means that thermal injury to the serosa can be avoided, and the risk of adhesion and injury to bowel or bladder can be minimized. Overall, the procedure is well tolerated, with patients recording low pain scores; it may be carried out with the patient under local anesthetic or sedation. The procedure takes about 30 min [
      • Garza-Leal J.G.
      • Toub D.
      • Hernández León I.
      • et al.
      Transcervical, intrauterine ultrasound-guided radiofrequency ablation of uterine fibroids with the VizAblate System: safety, tolerability, and ablation results in a closed abdomen setting.
      ]. Further studies are needed.

      8.4 Laparoscopic ultrasound-guided radiofrequency ablation

      Laparoscopic ultrasound-guided radiofrequency thermal ablation of fibroids seems to be safe and to have a high rate of patient satisfaction. It reduces menstrual bleeding and has a low rate of re-intervention. It has been shown to improve quality of life at one- and two-year follow-up [
      • Bergamini V.
      • Ghezzi F.
      • Cromi A.
      • et al.
      Laparoscopic radiofrequency thermal ablation: a new approach to symptomatic uterine myomas.
      ,
      • Garza-Leal J.G.
      • Hernandez Leon I.
      • Castillo Saenz L.
      • Lee B.B.
      Laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation of symptomatic uterine leiomyomas: feasibility study using the Halt 2000 Ablation System.
      ,
      • Robles R.
      • Aguirre V.A.
      • Argueta A.I.
      • Guerrero M.R.
      Laparoscopic radiofrequency volumetric thermal ablation of uterine myomas with 12 months of follow-up.
      ,
      • Chudnoff S.G.
      • Berman J.M.
      • Levine D.J.
      • Harris M.
      • Guido R.S.
      • Banks E.
      Outpatient procedure for the treatment and relief of symptomatic uterine myomas.
      ]. Its main advantage is that it allows direct placement of the device close to the fibroid. A prospective randomized controlled trial in women who wanted to retain their uterus reported that radiofrequency thermal ablation allowed treatment of more fibroids with less blood loss and a shorter hospital stay than laparoscopic myomectomy [
      • Brucker S.Y.
      • Hahn M.
      • Kraemer D.
      • Taran F.A.
      • Isaacson K.B.
      • Krämer B.
      Laparoscopic radiofrequency volumetric thermal ablation of fibroids versus laparoscopic myomectomy.
      ].

      9. Specific considerations

      9.1 Fibroids and menopausal hormone therapy

      Asymptomatic fibroids are not a contraindication to menopausal hormone therapy. The data are limited and show that menopausal hormone therapy does not significantly increase fibroid volume, but it can increase the risk of abnormal bleeding in women with submucosal fibroids [
      • Colacurci N.
      • De Franciscis P.
      • Cobellis L.
      • Nazzaro G.
      • De Placido G.
      Effects of hormone replacement therapy on postmenopausal uterine myoma.
      ,
      • Yang C.H.
      • Lee J.N.
      • Hsu S.C.
      • Kuo C.H.
      • Tsai E.M.
      Effect of hormone replacement therapy on uterine fibroids in postmenopausal women – a 3-year study.
      ].

      9.2 Fibroid degeneration

      Fibroids can undergo various types of benign degeneration. The most common is hyaline degeneration, consisting of mucopolysaccharide deposits around muscle fibers. ‘Red degeneration’ corresponds to vascular infarction, is associated with acute pain and mainly occurs in pregnancy. Fat degeneration is very rare and is asymptomatic. Calcification is seen in postmenopausal women, especially those of older age [
      • Hendrickson M.R.
      • Tavassoli F.A.
      • Kempson R.L.
      • et al.
      Mesenchymal tumours and related lesions.
      ].

      9.3 Unusual fibroid complications and malignancies

      In perimenopausal women rapid uterine growth may be due to an unexpected pregnancy. Unusual complications include massive hemoperitoneum resulting from spontaneous rupture or avulsion of fibroids or due to rupture of a vessel overlying an uterine fibroid, degenerative changes mimicking an ovarian cancer, or an undiagnosed uterine sarcoma. The presenting symptoms, clinical assessment, ultrasound examination and MR imaging can help to establish the differential diagnosis, and in particular to distinguish between benign and malignant causes [
      • Namimoto T.
      • Yamashita Y.
      • Awai K.
      • et al.
      Combined use of T2-weighted and diffusion-weighted 3-T MR imaging for differentiating uterine sarcomas from benign leiomyomas.
      ,
      • Thomassin-Naggara I.
      • Dechoux S.
      • Bonneau C.
      • et al.
      How to differentiate benign from malignant myometrial tumours using MR imaging.
      ].
      It is unknown at present whether leiomyosarcoma represents de novo growth or malignant transformation from benign uterine fibroids. This rare malignant tumor (less than one in 1000) is characterized by a rapid increase of uterine size, abnormal bleeding, pain and general symptoms sometimes related to metastases. Leiomyosarcomas express a variety of genes which are related to both disease progression and metastasis formation [
      • Davidson B.
      • Abeler V.M.
      • Førsund M.
      • et al.
      Gene expression signatures of primary and metastatic uterine leiomyosarcoma.
      ].
      Hereditary myomatosis and renal cell cancer is an autosomal dominant syndrome defined by uterine fibroids, piloleiomyoma and papillary type 2 renal cancer related to a germline mutation in the fumarate hydratase gene. This syndrome is very rare, affecting only some 180 families worldwide, but it is exceptionally aggressive [
      • Lehtonen H.J.
      Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics.
      ].
      Pseudo-Meigs’ syndrome is a rare clinical condition characterized by the presence of a uterine fibroid associated with ascites, with or without hydrothorax [
      • Chourmouzi D.
      • Papadopoulou E.
      • Drevelegas A.
      Magnetic resonance imaging findings in pseudo-Meigs’ syndrome associated with a large uterine leiomyoma: a case report.
      ].

      10. Conclusions

      Uterine fibroids are the most common tumors of the female reproductive tract. Fibroid-associated symptoms include HMB, pain or pelvic discomfort and infertility. Treatment options for symptomatic fibroids include pharmacologic, surgical and radiologically guided interventions. A wide range is now available and some require further evaluation. Thus women can now retain their uterus and their fertility. The choice of treatment depends on fibroid size, the underlying symptoms and their severity and the woman's desire for subsequent fertility and pregnancy, as well as efficacy and need for repeated interventions.

      11. Summary recommendations

      • Women with asymptomatic uterine fibroids require follow-up, with periodic assessment to document stability in size and growth.
      • Women with symptomatic uterine fibroids generally complain of heavy menstrual bleeding and pelvic pain; infertility may be an associated problem.
      • There is no effective non-invasive (medical) treatment that permanently removes fibroids.
      • Tranexamic acid, combined and progestin-only contraceptives may be useful in the management of fibroid-associated bleeding problems.
      • Progesterone receptor modulators are an important addition to the medical armamentarium, although they are advocated currently only for short-term use preoperatively.
      • Hysterectomy has a high degree of satisfaction in premenopausal women who have no wish to preserve their fertility.
      • Myomectomy may be indicated for infertility-associated fibroids.
      • Nonsurgical treatments include uterine artery embolization and high-intensity focused ultrasound but the impact of these treatments on fertility and pregnancy success is still uncertain.

      Contributors

      FRPL, LO and MR prepared the initial draft, which was circulated to EMAS board members for comment and approval; production was coordinated by MR and FRPL.

      Competing interests

      The authors have no conflicting interests to declare.

      Funding

      None was sought or secured for writing this statement.

      Provenance and peer review

      EMAS position statement.

      References

        • Bulun S.E.
        Uterine fibroids.
        N Engl J Med. 2013; 369: 1344-1355
        • Ono M.
        • Yin P.
        • Navarro A.
        • et al.
        Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth.
        Proc Natl Acad Sci USA. 2013; 110: 17053-17058
        • Bertsch E.
        • Qiang W.
        • Zhang Q.
        • et al.
        MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma.
        Mod Pathol. 2014; ([in press], PMID: 24390224)
        • Flake G.P.
        • Moore A.B.
        • Sutton D.
        • et al.
        The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation.
        Obstet Gynecol Int. 2013; 2013: 528376
        • Nikitenko L.L.
        • Cross T.
        • Campo L.
        • et al.
        Expression of terminally glycosylated calcitonin receptor-like receptor in uterine leiomyoma: endothelial phenotype and association with microvascular density.
        Clin Cancer Res. 2006; 12: 5648-5658
        • Tal R.
        • Segars J.H.
        The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy.
        Hum Reprod Update. 2014; 202: 194-216
        • Maruo T.
        • Ohara N.
        • Wang J.
        • Matsuo H.
        Sex steroidal regulation of uterine leiomyoma growth and apoptosis.
        Hum Reprod Update. 2004; 10: 207-220
        • Islam M.S.
        • Protic O.
        • Giannubilo S.R.
        • et al.
        Uterine leiomyoma: available medical treatments and new possible therapeutic options.
        J Clin Endocrinol Metab. 2013; 98: 921-934
        • Borah B.J.
        • Nicholson W.K.
        • Bradley L.
        • Stewart E.A.
        The impact of uterine leiomyomas: a national survey of affected women.
        Am J Obstet Gynecol. 2013; 209: 319.e1-319.e20
        • Baird D.D.
        • Dunson D.B.
        • Hill M.C.
        • Cousins D.
        • Schectman J.M.
        High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence.
        Am J Obstet Gynecol. 2003; 188: 100-107
        • Wise L.A.
        • Palmer J.R.
        • Harlow B.L.
        • et al.
        Reproductive factors, hormonal contraception, and risk of uterine leiomyomata in African-American women: a prospective study.
        Am J Epidemiol. 2004; 159: 113-123
        • Hammoud A.O.
        • Asaad R.
        • Berman J.
        • Treadwell M.C.
        • Blackwell S.
        • Diamond M.P.
        Volume change of uterine myomas during pregnancy: do myomas really grow?.
        J Minim Invasive Gynecol. 2006; 13: 386-390
        • Neiger R.
        • Sonek J.D.
        • Croom C.S.
        • Ventolini G.
        Pregnancy-related changes in the size of uterine leiomyomas.
        J Reprod Med. 2006; 51: 671-674
        • Chen C.R.
        • Buck G.M.
        • Courey N.G.
        • Perez K.M.
        • Wactawski-Wende J.
        Risk factors for uterine fibroids among women undergoing tubal sterilization.
        Am J Epidemiol. 2001; 153: 20-26
        • Laughlin S.K.
        • Herring A.H.
        • Savitz D.A.
        • et al.
        Pregnancy-related fibroid reduction.
        Fertil Steril. 2010; 94: 2421-2423
        • Okolo S.
        Incidence, aetiology and epidemiology of uterine fibroids.
        Best Pract Res Clin Obstet Gynaecol. 2008; 22: 571-588
        • Wise L.A.
        • Palmer J.R.
        • Harlow B.L.
        • et al.
        Risk of uterine leiomyomata in relation to tobacco, alcohol and caffeine consumption in the Black Women's Health Study.
        Hum Reprod. 2004; 19: 1746-1754
        • Laughlin S.K.
        • Schroeder J.C.
        • Baird D.D.
        New directions in the epidemiology of uterine fibroids.
        Semin Reprod Med. 2010; 28: 204-217
        • Ott J.
        • Kurz C.
        • Braun R.
        • Promberger R.
        • Seemann R.
        • Vytiska-Binstorfer E.
        • Walch K.
        Overt hypothyroidism is associated with the presence of uterine leiomyoma: a retrospective analysis.
        Eur J Obstet Gynecol Reprod Biol. 2014; 177: 19-22
        • Wise L.A.
        • Radin R.G.
        • Palmer J.R.
        • Kumanyika S.K.
        • Boggs D.A.
        • Rosenberg L.
        Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata.
        Am J Clin Nutr. 2011; 94: 1620-1631
        • Wise L.A.
        • Palmer J.R.
        • Ruiz-Narvaez E.
        • Reich D.E.
        • Rosenberg L.
        Is the observed association between dairy intake and fibroids in African Americans explained by genetic ancestry?.
        Am J Epidemiol. 2013; 178: 1114-1119
        • Wise L.A.
        • Radin R.G.
        • Kumanyika S.K.
        • Ruiz-Narváez E.A.
        • Palmer J.R.
        • Rosenberg L.
        Prospective study of dietary fat and risk of uterine leiomyomata.
        Am J Clin Nutr. 2014; 99: 1105-1116
        • Yu L.
        • Moore A.B.
        • Castro L.
        • et al.
        Estrogen regulates MAPK-related genes through genomic and nongenomic interactions between IGF-1-I receptor tyrosine kinase and estrogen receptor-alpha signaling pathways in human uterine leiomyoma cells.
        J Signal Transduct. 2012; : 204236
        • Shen Y.
        • Xu Q.
        • Xu J.
        • Ren M.L.
        • Cai Y.L.
        Environmental exposure and risk of uterine leiomyoma: an epidemiologic survey.
        Eur Rev Med Pharmacol Sci. 2013; 17: 3249-3256
        • Munro M.G.
        • Critchley H.O.
        • Broder M.S.
        • Fraser I.S.
        FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM–COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age.
        Int J Gynaecol Obstet. 2011; 113: 3-13
        • Dreisler E.
        • Poulsen L.G.
        • Antonsen S.L.
        • et al.
        EMAS clinical guide: assessment of the endometrium in peri and postmenopausal women.
        Maturitas. 2013; 75: 181-190
        • Bachmann G.A.
        • Bahouth L.A.
        • Amalraj P.
        • Mhamunkar V.
        • Hoes K.
        • Ananth C.V.
        Uterine fibroids: correlations of anemia and pain to fibroid location and uterine weight.
        J Reprod Med. 2011; 56: 463-466
        • Puri K.
        • Famuyide A.O.
        • Erwin P.J.
        • Stewart E.A.
        • Laughlin-Tommaso S.K.
        Submucosal fibroids and the relation to heavy menstrual bleeding and anemia.
        Am J Obstet Gynecol. 2014; 210: 38.e1-38.e7
        • Schumacher U.
        • Schumacher J.
        • Mellinger U.
        • Gerlinger C.
        • Wienke A.
        • Endrikat J.
        Estimation of menstrual blood loss volume based on menstrual diary and laboratory data.
        BMC Women's Health. 2012; 12: 24
        • Napolitano M.
        • Dolce A.
        • Celenza G.
        • et al.
        Iron-dependent erythropoiesis in women with excessive menstrual blood losses and women with normal menses.
        Ann Hematol. 2014; 93: 557-563
        • Kavvadias T.
        • Baessler K.
        • Schuessler B.
        Pelvic pain in urogynaecology: Part I: Evaluation, definitions and diagnoses.
        Int Urogynecol J. 2011; 22: 385-393
        • Moshesh M.
        • Olshan A.F.
        • Saldana T.
        • Baird D.
        Examining the relationship between uterine fibroids and dyspareunia among premenopausal women in the United States.
        J Sex Med. 2014; 11: 800-808
        • Kroon B.
        • Johnson N.
        • Chapman M.
        • Yazdani A.
        • Hart R.
        Australasian CREI Consensus Expert Panel on Trial evidence (ACCEPT) group. Fibroids in infertility – consensus statement from ACCEPT (Australasian CREI Consensus Expert Panel on Trial evidence).
        Aust N Z J Obstet Gynaecol. 2011; 51: 289-295
        • Metwally M.
        • Farquhar C.M.
        • Li T.C.
        Is another meta-analysis on the effects of intramural fibroids on reproductive outcomes needed?.
        Reprod Biomed Online. 2011; 23: 2-14
        • Somigliana E.
        • De Benedictis S.
        • Vercellini P.
        • et al.
        Fibroids not encroaching the endometrial cavity and IVF success rate: a prospective study.
        Hum Reprod. 2011; 26: 834-839
        • Metwally M.
        • Cheong Y.C.
        • Horne A.W.
        Surgical treatment of fibroids for subfertility.
        Cochrane Database Syst Rev. 2012; 11: CD003857
        • Shwayder J.
        • Sakhel K.
        Imaging for uterine myomas and adenomyosis.
        J Minim Invasive Gynecol. 2014; 21: 362-376
        • Lefebvre G.
        • Vilos G.
        • Allaire C.
        • et al.
        The management of uterine leiomyomas.
        J Obstet Gynaecol Can. 2003; 25: 396
        • Laughlin S.K.
        • Stewart E.A.
        Uterine leiomyomas: individualizing the approach to a heterogeneous condition.
        Obstet Gynecol. 2011; 117: 396-403
        • Pritts E.A.
        • Olive D.L.
        When should uterine fibroids be treated?.
        Curr Obstet Gynecol Rep. 2012; 1: 71-80
        • Fraser I.S.
        • Porte R.J.
        • Kouides P.A.
        • Lukes A.S.
        A benefit-risk review of systemic haemostatic agents: Part 2: In excessive or heavy menstrual bleeding.
        Drug Saf. 2008; 31: 275-282
        • Freeman E.W.
        • Lukes A.
        • VanDrie D.
        • et al.
        A dose–response study of a novel, oral tranexamic formulation for heavy menstrual bleeding.
        Am J Obstet Gynecol. 2011; 205: 319.e1-319.e7
        • Eder S.
        • Baker J.
        • Gersten J.
        • Mabey R.G.
        • Adomako T.L.
        Efficacy and safety of oral tranexamic acid in women with heavy menstrual bleeding and fibroids.
        Women's Health (Lond, Engl). 2013; 9: 397-403
        • Naoulou B.
        • Tsai M.C.
        Efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding: a systematic review.
        Acta Obstet Gynecol Scand. 2012; 91: 529-537
        • Ip P.P.
        • Lam K.W.
        • Cheung C.L.
        • et al.
        Tranexamic acid-associated necrosis and intralesional thrombosis of uterine leiomyomas: a clinicopathologic study of 147 cases emphasizing the importance of drug-induced necrosis and early infarcts in leiomyomas.
        Am J Surg Pathol. 2007; 3: 1215-1224
        • Lethaby A.
        • Duckitt K.
        • Farquhar C.
        Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding.
        Cochrane Database Syst Rev. 2013; 1: CD000400
        • Qin J.
        • Yang T.
        • Kong F.
        • Zhou Q.
        Oral contraceptive use and uterine leiomyoma risk: a meta-analysis based on cohort and case–control studies.
        Arch Gynecol Obstet. 2013; 288: 139-148
        • Hoellen F.
        • Griesinger G.
        • Bohlmann M.K.
        Therapeutic drugs in the treatment of symptomatic uterine fibroids.
        Expert Opin Pharmacother. 2013; 14: 2079-2085
        • Venkatachalam S.
        • Bagratee J.S.
        • Moodley J.
        Medical management of uterine fibroids with medroxyprogesterone acetate (Depo Provera): a pilot study.
        J Obstet Gynaecol. 2004; 24: 798-800
        • Ichigo S.
        • Takagi H.
        • Matsunami K.
        • Suzuki N.
        • Imai A.
        Beneficial effects of dienogest on uterine myoma volume: a retrospective controlled study comparing with gonadotropin-releasing hormone agonist.
        Arch Gynecol Obstet. 2011; 284: 667-670
        • Sangkomkamhang U.S.
        • Lumbiganon P.
        • Laopaiboon M.
        • Mol B.W.
        Progestogens or progestogen-releasing intrauterine systems for uterine fibroids.
        Cochrane Database Syst Rev. 2013; 2: CD008994
        • Lethaby A.E.
        • Cooke I.
        • Rees M.
        Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding.
        Cochrane Database Syst Rev. 2005; 4: CD002126
        • Socolov D.
        • Blidaru I.
        • Tamba B.
        • Miron N.
        • Boiculese L.
        • Socolov R.
        Levonorgestrel releasing-intrauterine system for the treatment of menorrhagia and/or frequent irregular uterine bleeding associated with uterine leiomyoma.
        Eur J Contracept Reprod Health Care. 2011; 16: 480-487
        • Kriplani A.
        • Awasthi D.
        • Kulshrestha V.
        • Agarwal N.
        Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma.
        Int J Gynaecol Obstet. 2012; 116: 35-38
        • Depypere H.T.
        • Hillard T.
        • Erkkola R.
        • et al.
        A 60-month non-comparative study on bleeding profiles with the levonorgestrel intrauterine system from the late transition period to estrogen supplemented menopause.
        Eur J Obstet Gynecol Reprod Biol. 2010; 153: 176-180
        • Xu Q.
        • Qiu L.
        • Zhu L.
        • Luo L.
        • Xu C.
        Levonorgestrel inhibits proliferation and induces apoptosis in uterine leiomyoma cells.
        Contraception. 2010; 82: 301-308
        • Jiang W.
        • Shen Q.
        • Chen M.
        • et al.
        Levonorgestrel-releasing intrauterine system use in premenopausal women with symptomatic uterine leiomyoma: a systematic review.
        Steroids. 2014; 86C: 69-78
        • Youm J.
        • Lee H.J.
        • Kim S.K.
        • Kim H.
        • Jee B.C.
        Factors affecting the spontaneous expulsion of the levonorgestrel-releasing intrauterine system.
        Int J Gynaecol Obstet. 2014; ([in press])
        • Pérez-López F.R.
        Long-term consequences of LNG-IUS vs. hysterectomy for menorrhagia.
        Climacteric. 2014; 14: 308-309
        • Muzii L.
        • Boni T.
        • Bellati F.
        • et al.
        GnRH analogue treatment before hysteroscopic resection of submucous myomas: a prospective, randomized, multicenter study.
        Fertil Steril. 2010; 94: 1496-1499
        • Lethaby A.
        • Vollenhoven B.
        • Sowter M.
        Efficacy of pre-operative gonadotrophin hormone releasing analogues for women with uterine fibroids undergoing hysterectomy or myomectomy: a systematic review.
        BJOG. 2002; 109: 1097-1108
        • Lethaby A.E.
        • Vollenhoven B.J.
        An evidence-based approach to hormonal therapies for premenopausal women with fibroids.
        Best Pract Res Clin Obstet Gynaecol. 2008; 22: 307-331
        • Kamath M.S.
        • Kalampokas E.E.
        • Kalampokas T.E.
        Use of GnRH analogues pre-operatively for hysteroscopic resection of submucous fibroids: a systematic review and meta-analysis.
        Eur J Obstet Gynecol Reprod Biol. 2014; 177C: 11-18
        • Shen Q.
        • Hua Y.
        • Jiang W.
        • Zhang W.
        • Chen M.
        • Zhu X.
        Effects of mifepristone on uterine leiomyoma in premenopausal women: a meta-analysis.
        Fertil Steril. 2013; 100: 1722-1726
        • Feng C.
        • Meldrum S.
        • Fiscella K.
        Improved quality of life is partly explained by fewer symptoms after treatment of fibroids with mifepristone.
        Int J Gynaecol Obstet. 2010; 109: 121-124
        • Eisinger S.H.
        • Fiscella J.
        • Bonfiglio T.
        • Meldrum S.
        • Fiscella K.
        Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata.
        Eur J Obstet Gynecol Reprod Biol. 2009; 146: 215-218
        • Tristan M.
        • Orozco L.J.
        • Steed A.
        • Ramírez-Morera A.
        • Stone P.
        Mifepristone for uterine fibroids.
        Cochrane Database Syst Rev. 2012; 8: CD007687
        • Yerushalmi G.M.
        • Gilboa Y.
        • Jakobson-Setton A.
        • et al.
        Vaginal mifepristone for the treatment of symptomatic uterine leiomyomata: an open-label study.
        Fertil Steril. 2014; 101: 496-500
        • Wilkens J.
        • Chwalisz K.
        • Han C.
        • et al.
        Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
        J Clin Endocrinol Metab. 2008; 93: 4664-4671
        • Nieman L.K.
        • Blocker W.
        • Nansel T.
        • et al.
        Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study.
        Fertil Steril. 2011; 95 (e1–e2): 767-772
        • Donnez J.
        • Tatarchuk T.F.
        • Bouchard P.
        • et al.
        Ulipristal acetate versus placebo for fibroid treatment before surgery.
        N Engl J Med. 2012; 366: 409-420
        • Donnez J.
        • Tomaszewski J.
        • Vázquez F.
        • et al.
        Ulipristal acetate versus leuprolide acetate for uterine fibroids.
        N Engl J Med. 2012; 366: 421-432
        • Biglia N.
        • Carinelli S.
        • Maiorana A.
        • D’Alonzo M.
        • Lo Monte G.
        • Marci R.
        Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids.
        Drug Des Dev Ther. 2014; 8: 285-292
        • Donnez J.
        • Vázquez F.
        • Tomaszewski J.
        • et al.
        Long-term treatment of uterine fibroids with ulipristal acetate.
        Fertil Steril. 2014; 101 (e18): 1565-1573
        • Deng L.
        • Wu T.
        • Chen X.Y.
        • Xie L.
        • Yang J.
        Selective estrogen receptor modulators (SERMs) for uterine leiomyomas.
        Cochrane Database Syst Rev. 2012; 10: CD005287
        • Varelas F.K.
        • Papanicolaou A.N.
        • Vavatsi-Christaki N.
        • Makedos G.A.
        • Vlassis G.D.
        The effect of anastrazole on symptomatic uterine leiomyomata.
        Obstet Gynecol. 2007; 110: 643-649
        • Parsanezhad M.E.
        • Azmoon M.
        • Alborzi S.
        • et al.
        A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status.
        Fertil Steril. 2010; 93: 192-198
        • Brito L.G.
        • Candido-dos-Reis F.J.
        • Magario F.A.
        • Sabino-de-Freitas M.M.
        Effect of the aromatase inhibitor anastrozole on uterine and leiomyoma Doppler blood flow in patients scheduled for hysterectomy: a pilot study.
        Ultrasound Obstet Gynecol. 2012; 40: 119-120
        • Song H.
        • Lu D.
        • Navaratnam K.
        • Shi G.
        Aromatase inhibitors for uterine fibroids.
        Cochrane Database Syst Rev. 2013; 10: CD009505
        • Hilario S.
        • Bozzini N.
        • Borsari R.
        • Baracat E.
        Action of aromatase inhibitor for treatment of uterine leiomyoma in perimenopausal patients.
        Fertil Steril. 2009; 91: 240-243
        • Duhan N.
        • Madaan S.
        • Sen J.
        Role of the aromatase inhibitor letrozole in the management of uterine leiomyomas in premenopausal women.
        Eur J Obstet Gynecol Reprod Biol. 2013; 171: 329-332
        • Liu J.P.
        • Yang H.
        • Xia Y.
        • Cardini F.
        Herbal preparations for uterine fibroids.
        Cochrane Database Syst Rev. 2013; 4: CD005292
        • Royal College of Obstetricians and Gynaecologists
        Consent advice 4: abdominal hysterectomy for benign conditions.
        RCOG Press, London2009
        • Sculpher M.
        • Manca A.
        • Abbott J.
        • Fountain J.
        • Mason S.
        • Garry R.
        Cost effectiveness analysis of laparoscopic hysterectomy compared with standard hysterectomy: results from a randomised trial.
        Br Med J. 2004; 328: 134
        • Nieboer T.E.
        • Johnson N.
        • Lethaby A.
        • et al.
        Surgical approach to hysterectomy for benign gynaecological disease.
        Cochrane Database Syst Rev. 2009; 3: CD003677
        • Lethaby A.
        • Mukhopadhyay A.
        • Naik R.
        Total versus subtotal hysterectomy for benign gynaecological conditions.
        Cochrane Database Syst Rev. 2012; 4: CD004993
        • Manoucheri E.
        • Fuchs-Weizman N.
        • Cohen S.L.
        • Wang K.C.
        • Einarsson J.I.
        MAUDE – analysis of robotic-assisted gynecologic surgery.
        J Minim Invasive Gynecol. 2014; (pii: S1553-4650(14)00027-2)
        • Kannisto P.
        • Harter P.
        • Heitz F.
        • Traut A.
        • du Bois A.
        • Kurzeder C.
        Implementation of robot-assisted gynecologic surgery for patients with low and high BMI in a German gynecological cancer center.
        Arch Gynecol Obstet. 2014; 290: 143-148
        • O’Neill M.
        • Moran P.S.
        • Teljeur C.
        • et al.
        Robot-assisted hysterectomy compared to open and laparoscopic approaches: systematic review and meta-analysis.
        Arch Gynecol Obstet. 2013; 287: 907-918
        • Sawin S.W.
        • Pilevsky N.D.
        • Berlin J.A.
        • Barnhart K.T.
        Comparability of perioperative morbidity between abdominal myomectomy and hysterectomy for women with uterine leiomyomas.
        Am J Obstet Gynecol. 2000; 183: 1448-1455
        • Pundir J.
        • Krishnan N.
        • Siozos A.
        • et al.
        Peri-operative morbidity associated with abdominal myomectomy for very large fibroid uteri.
        Eur J Obstet Gynecol Reprod Biol. 2013; 167: 219-224
        • Mettler L.
        • Schollmeyer T.
        • Lehmann-Willenbrock E.
        • Dowaji J.
        • Zavala A.
        Treatment of myomas by laparoscopic and laparotomic myomectomy and laparoscopic hysterectomy.
        Min Invas Ther Allied Technol. 2004; 13: 58-64
        • Jin C.
        • Hu Y.
        • Chen X.C.
        • et al.
        Laparoscopic versus open myomectomy – a metaanalysis of randomized controlled trials.
        Eur J Obstet Gynecol Reprod Biol. 2009; 145: 14-21
        • Kubinova K.
        • Mara M.
        • Horak P.
        • Kuzel D.
        • Dohnalova A.
        Reproduction after myomectomy: comparison of patients with and without second-look laparoscopy.
        Minim Invasive Ther Allied Technol. 2012; 21: 118-124
        • Soriano D.
        • Desolle L.
        • Poncelet C.
        • Benifla J.L.
        • Madelenat P.
        • Darai E.
        Pregnancy outcome after laparoscopic and laparoconverted myomectomy.
        Eur J. Obstet Gynecol Reprod Biol. 2003; 108: 194-198
        • Hackethal A.
        • Westermann A.
        • Tchartchian G.
        • et al.
        Laparoscopic myomectomy in patients with uterine myomas associated with infertility.
        Minim Invasive Ther Allied Technol. 2011; 20: 338-345
        • Paul P.G.
        • Koshy A.K.
        • Thomas T.
        Pregnancy outcomes following laparoscopic myomectomy and single-layer myometrial closure.
        Hum Reprod. 2006; 21: 3278-3281
        • Banas T.
        • Klimek M.
        • Fugiel A.
        • Skotniczny K.
        Spontaneous uterine rupture at 35 weeks’ gestation, 3 years after laparoscopic myomectomy, without signs of fetal distress.
        J Obstet Gynaecol Res. 2005; 31: 527-530
        • Parker W.H.
        • Iacampo K.
        • Long T.
        Uterine rupture after laparoscopic removal of a pedunculated myoma.
        J Minim Invasive Gynecol. 2007; 14: 362-364
        • Brucker S.Y.
        • Hahn M.
        • Kraemer D.
        • Taran F.A.
        • Isaacson K.B.
        • Krämer B.
        Laparoscopic radiofrequency volumetric thermal ablation of fibroids versus laparoscopic myomectomy.
        Int J Gynecol Obstet. 2014; 125: 261-265
        • US Food and Drug Administration
        Laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication.
        2014 (http://www.fda.gov/medicaldevices/safety/alertsandnotices/ucm393576.htm [accessed 05.06.14])
        • Advincula A.P.
        • Xu X.
        • Goudeau 4th, S.
        • Ransom S.B.
        Robot-assisted laparoscopic myomectomy versus abdominal myomectomy: a comparison of short-term surgical outcomes and immediate costs.
        J Minim Invasive Gynecol. 2007; 14: 698-705
        • Mansour F.W.
        • Kives S.
        • Urbach D.R.
        • Lefebvre G.
        Robotically assisted laparoscopic myomectomy: a Canadian experience.
        J Obstet Gynaecol Can. 2012; 34: 353-358
        • Ranisavljevic N.
        • Mercier G.
        • Masia F.
        • Mares P.
        • De Tayrac R.
        • Triopon G.
        Robot-assisted laparoscopic myomectomy: comparison with abdominal myomectomy.
        J Gynecol Obstet Biol Reprod (Paris). 2012; 41: 439-444
        • Pitter M.C.
        • Gargiulo A.R.
        • Bonaventura L.M.
        • Lehman J.S.
        • Srouji S.S.
        Pregnancy outcomes following robot-assisted myomectomy.
        Hum Reprod. 2013; 28: 99-108
        • Brady P.C.
        • Stanic A.K.
        • Styer A.K.
        Uterine fibroids and subfertility: an update on the role of myomectomy.
        Curr Opin Obstet Gynecol. 2013; 25: 255-259
        • Casini M.L.
        • Rossi F.
        • Agostini R.
        • Unfer V.
        Effects of the position of fibroids on fertility.
        Gynecol Endocrinol. 2006; 22: 106-109
        • Bosteels J.
        • Kasius J.
        • Weyers S.
        • Broekmans F.J.
        • Mol B.W.
        • D’Hooghe T.M.
        Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities.
        Cochrane Database Syst Rev. 2013; 1: CD009461
        • Helal A.
        • Mashaly Ael-M
        • Amer T.
        Uterine artery occlusion for treatment of symptomatic uterine myomas.
        JSLS. 2010; 14: 386-390
        • Chang W.C.
        • Huang P.S.
        • Wang P.H.
        • et al.
        Comparison of laparoscopic myomectomy using in situ morcellation with and without uterine artery ligation for treatment of symptomatic myomas.
        J Minim Invasive Gynecol. 2012; 19: 715-721
        • Vercellino G.
        • Erdemoglu E.
        • Joe A.
        • et al.
        Laparoscopic temporary clipping of uterine artery during laparoscopic myomectomy.
        Arch Gynecol Obstet. 2012; 286: 1181-1186
        • Akinola O.I.
        • Fabamwo A.O.
        • Akinola R.A.
        • Ottun T.A.
        • Akinniyi A.
        • Akpan A.E.
        Uterine artery ligation for the treatment of fibroids.
        Acta Obstet Gynecol Scand. 2009; 88: 59-62
        • Agdi M.
        • Tulandi T.
        The benefits of intrauterine balloon: an intrauterine manipulator and balloon proved useful in myomectomy.
        Am J Obstet Gynecol. 2008; 199: 581.e1
        • Bhattacharya S.
        • Middleton L.J.
        • Tsourapas A.
        • et al.
        Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis.
        Health Technol Assess. 2011; 15 (1–252): iii-xvi
        • Fergusson R.J.
        • Lethaby A.
        • Shepperd S.
        • Farquhar C.
        Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.
        Cochrane Database Syst Rev. 2013; 11: CD000329
        • Kroft J.
        • Liu G.
        First- versus second-generation endometrial ablation devices for treatment of menorrhagia: a systematic review, meta-analysis and appraisal of economic evaluations.
        J Obstet Gynaecol Can. 2013; 35: 1010-1019
        • Tropeano G.
        • Amoroso S.
        • Scambia G.
        Non-surgical management of uterine fibroids.
        Hum Reprod Update. 2008; 14: 259-274
        • Wu O.
        • Briggs A.
        • Dutton S.
        • et al.
        Uterine artery embolisation or hysterectomy for the treatment of symptomatic uterine fibroids: a cost–utility analysis of the HOPEFUL study.
        BJOG. 2007; 114: 1352-1362
        • You J.H.
        • Sahota D.S.
        • Yuen P.M.
        Uterine artery embolization, hysterectomy, or myomectomy for symptomatic uterine fibroids: a cost–utility analysis.
        Fertil Steril. 2009; 91: 580-588
        • Edwards R.D.
        • Moss J.G.
        • Lumsden M.A.
        • et al.
        Committee of the randomized trial of embolization versus surgical treatment for fibroids: uterine-artery embolization versus surgery for symptomatic uterine fibroids.
        N Engl J Med. 2007; 356: 360-370
        • Moss J.G.
        • Cooper K.G.
        • Khaund A.
        • et al.
        Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results.
        BJOG. 2011; 118: 936-944
        • Gupta J.K.
        • Sinha A.
        • Lumsden M.A.
        • Hickey M.
        Uterine artery embolization for symptomatic uterine fibroids.
        Cochrane Database Syst Rev. 2012; 5: CD005073
        • Hehenkamp W.J.
        • Volkers N.A.
        • Broekmans F.J.
        • et al.
        Loss of ovarian reserve after uterine artery embolization: a randomized comparison with hysterectomy.
        Hum Reprod. 2007; 22: 1996-2005
        • Payne J.F.
        • Robboy S.J.
        • Haney A.F.
        Embolic microspheres within ovarian arterial vasculature after uterine artery embolization.
        Obstet Gynecol. 2002; 100: 883-886
        • Ryu R.K.
        • Chrisman H.B.
        • Omary R.A.
        • et al.
        The vascular impact of uterine artery embolization: prospective sonographic assessment of ovarian arterial circulation.
        J Vasc Interv Radiol. 2001; 12: 1071-1074
        • Kaump G.R.
        • Spies J.B.
        The impact of uterine artery embolization on ovarian function.
        J Vasc Interv Radiol. 2013; 24: 459-467
        • Torre A.
        • Paillusson B.
        • Fain V.
        • Labauge P.
        • Pelage J.P.
        • Fauconnier A.
        Uterine artery embolization for severe symptomatic fibroids: effects on fertility and symptoms.
        Hum Reprod. 2014; 29: 490-501
        • Arthur R.
        • Kachura J.
        • Liu G.
        • Chan C.
        • Shapiro H.
        Laparoscopic myomectomy versus uterine artery embolization: long-term impact on markers of ovarian reserve.
        J Obstet Gynaecol Can. 2014; 36: 240-247
        • Yamagami T.
        • Yoshimatsu R.
        • Matsumoto T.
        • et al.
        Fertility after uterine artery embolization: investigation using a sheep model.
        Reprod Sci. 2010; 17: 350-357
        • Smart O.C.
        • Hindley J.T.
        • Regan L.
        • Gedroyc W.G.
        Gonadotrophin-releasing hormone and magnetic-resonance-guided ultrasound surgery for uterine leiomyomata.
        Obstet Gynecol. 2006; 108: 49-54
        • Froeling V.
        • Meckelburg K.
        • Schreiter N.F.
        • et al.
        Outcome of uterine artery embolization versus MR-guided high-intensity focused ultrasound treatment for uterine fibroids: long-term results.
        Eur J Radiol. 2013; 82: 2265-2269
        • Fröling V.
        • Kröncke T.J.
        • Schreiter N.F.
        • et al.
        Technical eligibility for treatment of magnetic resonance-guided focused ultrasound surgery.
        Cardiovasc Intervent Radiol. 2014; 37: 445-450
        • Zhang L.
        • Chen W.Z.
        • Liu Y.J.
        • et al.
        Feasibility of magnetic resonance imaging-guided high intensity focused ultrasound therapy for ablating uterine fibroids in patients with bowel lies anterior to uterus.
        Eur J Radiol. 2010; 73: 396-403
        • Gizzo S.
        • Saccardi C.
        • Patrelli T.S.
        • et al.
        Magnetic resonance-guided focused ultrasound myomectomy: safety, efficacy, subsequent fertility and quality-of-life improvements. A systematic review.
        Reprod Sci. 2014; 21: 465-476
        • Wang W.
        • Wang Y.
        • Wang T.
        • Wang J.
        • Wang L.
        • Tang J.
        Safety and efficacy of US-guided high-intensity focused ultrasound for treatment of submucosal fibroids.
        Eur Radiol. 2012; 22: 2553-2558
        • Zhao W.P.
        • Chen J.Y.
        • Zhang L.
        • et al.
        Feasibility of ultrasound-guided high intensity focused ultrasound ablating uterine fibroids with hyperintense on T2-weighted MR imaging.
        Eur J Radiol. 2013; 82: e43-e49
        • Wang Y.
        • Wang W.
        • Ye H.
        Contrast-enhanced ultrasonography assessment of therapeutic efficacy for ultrasound-guided high-intensity focused ultrasound ablation of uterine fibroids: comparison with contrast-enhanced magnetic resonance.
        J Med Ultrasound. 2014; 22: 22-28
        • Garza-Leal J.G.
        • Toub D.
        • Hernández León I.
        • et al.
        Transcervical, intrauterine ultrasound-guided radiofrequency ablation of uterine fibroids with the VizAblate System: safety, tolerability, and ablation results in a closed abdomen setting.
        Gynecol Surg. 2011; 8: 327-334
        • Bergamini V.
        • Ghezzi F.
        • Cromi A.
        • et al.
        Laparoscopic radiofrequency thermal ablation: a new approach to symptomatic uterine myomas.
        Am J Obstet Gynecol. 2005; 192: 768-773
        • Garza-Leal J.G.
        • Hernandez Leon I.
        • Castillo Saenz L.
        • Lee B.B.
        Laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation of symptomatic uterine leiomyomas: feasibility study using the Halt 2000 Ablation System.
        J Minim Invasive Gynecol. 2011; 18: 364-371
        • Robles R.
        • Aguirre V.A.
        • Argueta A.I.
        • Guerrero M.R.
        Laparoscopic radiofrequency volumetric thermal ablation of uterine myomas with 12 months of follow-up.
        Int J Gynaecol Obstet. 2013; 120: 65-69
        • Chudnoff S.G.
        • Berman J.M.
        • Levine D.J.
        • Harris M.
        • Guido R.S.
        • Banks E.
        Outpatient procedure for the treatment and relief of symptomatic uterine myomas.
        Obstet Gynecol. 2013; 121: 1075-1082
        • Colacurci N.
        • De Franciscis P.
        • Cobellis L.
        • Nazzaro G.
        • De Placido G.
        Effects of hormone replacement therapy on postmenopausal uterine myoma.
        Maturitas. 2000; 35: 167-173
        • Yang C.H.
        • Lee J.N.
        • Hsu S.C.
        • Kuo C.H.
        • Tsai E.M.
        Effect of hormone replacement therapy on uterine fibroids in postmenopausal women – a 3-year study.
        Maturitas. 2002; 43: 35-39
        • Hendrickson M.R.
        • Tavassoli F.A.
        • Kempson R.L.
        • et al.
        Mesenchymal tumours and related lesions.
        in: Tavassoli F.A. Devilee P. Pathology and genetics of tumours of the breast and female genital organs. IARC Press, Lyon, France2003: 233-244
        • Namimoto T.
        • Yamashita Y.
        • Awai K.
        • et al.
        Combined use of T2-weighted and diffusion-weighted 3-T MR imaging for differentiating uterine sarcomas from benign leiomyomas.
        Eur Radiol. 2009; 19: 2756-2764
        • Thomassin-Naggara I.
        • Dechoux S.
        • Bonneau C.
        • et al.
        How to differentiate benign from malignant myometrial tumours using MR imaging.
        Eur Radiol. 2013; 23: 2306-2314
        • Davidson B.
        • Abeler V.M.
        • Førsund M.
        • et al.
        Gene expression signatures of primary and metastatic uterine leiomyosarcoma.
        Hum Pathol. 2014; 45: 691-700
        • Lehtonen H.J.
        Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics.
        Fam Cancer. 2011; 10: 397-411
        • Chourmouzi D.
        • Papadopoulou E.
        • Drevelegas A.
        Magnetic resonance imaging findings in pseudo-Meigs’ syndrome associated with a large uterine leiomyoma: a case report.
        J Med Case Rep. 2010; 4: 120