Aromatase inhibitors for uterine fibroids.

Aromatase inhibitors for uterine fibroids (Review) Song H, Lu D, Navaratnam K, Shi G

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 10 http://www.thecochranelibrary.com

Aromatase inhibitors for uterine fibroids (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS . . . . . . . . . . . . . . .

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[Intervention Review]

Aromatase inhibitors for uterine fibroids Huan Song1 , DongHao Lu1 , Kate Navaratnam2 , Gang Shi3 1

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 2 Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 3 Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China

Contact address: Gang Shi, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20, 3rd Section of Ren Min Nan Road, Chengdu, Sichuan, 610041, China. [email protected]. [email protected]. Editorial group: Cochrane Menstrual Disorders and Subfertility Group. Publication status and date: New, published in Issue 10, 2013. Review content assessed as up-to-date: 23 October 2012. Citation: Song H, Lu D, Navaratnam K, Shi G. Aromatase inhibitors for uterine fibroids. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD009505. DOI: 10.1002/14651858.CD009505.pub2. Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Uterine fibroids, also called uterine leiomyomas or myomas, are the most common benign tumours in women of reproductive age. Albeit generally benign, uterine broids can have a major impact on women’s health and quality of life by contributing to abnormal uterine bleeding and causing pelvic pressure symptoms (such as increased urinary frequency, pelvic pain and constipation). Traditional treatments for symptomatic broids include a variety of surgical techniques. However, because of the high recurrence rate, as well as possible pain and infertility caused by the formation of postoperative adhesions, this approach may not be advisable. Safer and more effective medical therapy has long been awaited. Both in vitro studies and clinical trials have suggested that use of the aromatase inhibitors (AIs), a class of anti-oestrogens, might inhibit

broid growth, thereby eliminating the need for surgery.

Objectives To evaluate the effectiveness and safety of aromatase Inhibitors (AIs) in women with uterine fibroids. Search methods We searched the following databases (from inception to August 21, 2013): Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL and PsycINFO. In addition, the reference lists of included trials were searched, and experts in the field were contacted. Selection criteria Randomised controlled trials (RCTs) in women of reproductive age comparing the effects of any AI versus placebo, no treatment or any medical treatment/surgery were included. Data collection and analysis Selection of eligible trials, assessment of trial quality and data extraction were performed independently by two review authors. If data were available, we planned to calculate odds ratios (ORs) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CIs). Aromatase inhibitors for uterine fibroids (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results Only one trial involving 70 participants was included. This trial did not report our primary review outcome (relief of symptoms of fibroids). The only secondary review outcomes reported by this trial were adverse effects (hot flushes) and reduction in fibroid size. Significantly fewer women reported hot flushes in the letrozole group than in the GnRHa group (0/33 vs 26/27, P < 0.05). Use of letrozole reduced fibroid volume by 46% and use of a gonadotrophin-releasing hormone (GnRH) agonist (GnRHa) by 32% after 12 weeks of treatment; these proportions were not significantly different. The included trial did not report data on fibroid volume in a form that permitted calcuation of an odds ratio. Morevoer it was unblinded and included only 60/70 women in analysis. Authors’ conclusions Evidence is insufficient to support the use of AI drugs in the treatment of women with uterine fibroids.

PLAIN LANGUAGE SUMMARY Aromatase inhibitors for women with uterine fibroids Review question Are aromatase Inhibitors safe and effective for treating uterine fibroids? Background Uterine fibroids are the most common benign tumours in women of reproductive age. By causing heavy or irregular bleeding, subfertility or pelvic pressure symptoms, uterine fibroids have a major impact on women’s health and on their quality of life. Traditional surgical treatments have a high recurrence rate and high risk of postoperative complications (e.g. pain, infertility); therefore, safer and more effective medical therapy has been sought. It has been suggested that aromatase inhibitors may shrink uterine fibroids by blocking the production of oestrogen. A review of the evidence was conducted by researchers in The Cochrane Collaboration, who searched in August 2013 for all relevant randomised controlled trials and found only one eligible study. Study characteristics Only one RCT study, consisting of 70 participants, was found. The study was conducted in teaching hospitals in Iran and Germany. It did not report on changes in fibroid-related symptoms or on the source of study funding. Key results The review authors concluded that, to date, evidence is insufficient to allow any conclusions to be drawn about the effectiveness and safety of AI drugs in treating women with uterine fibroids.

BACKGROUND Description of the condition Uterine fibroids, also called uterine leiomyomas or myomas, are the most common benign tumours in women of reproductive age. Studies report that about 70% to 80% of women have uterine fibroids, varying with populations and diagnostic method used, but only approximately 25% of them experience symptoms that interfere with daily living (Cramer 1990; Day 2003; Walker 2005).

Generally, the severity of symptoms depends on the size, number and location of the fibroids (Cramer 1990). Symptoms associated with uterine fibroids include heavy or irregular bleeding, infertility and recurrent abortion. Fibroids can grow large enough to affect other pelvic structures, resulting in pressure symptoms such as increased urinary frequency, pelvic pain and constipation (Stewart 2001). Many women with significant symptoms require further therapy. Fibroids are the most common indication for gynaecological surgery, accounting for more than 200,000 hysterectomies annually in the United States (Walker 2005). Thus they have a


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substantial impact on women’s health and quality of life.

Description of the intervention Therapeutic options for women with fibroids need to be guided by the size and location of the fibroids, symptoms and the age and reproductive wishes of the woman. Traditional treatments for fibroids include a variety of surgical techniques. Hysterectomy (removal of the uterus) has long been regarded as the de nitive management approach as it resolves bleeding and removes the risk of uterine cancer (Lepine 1997; Wallach 2004). The principal mode of treatment for women with symptomatic fibroids who wish to preserve their fertility is myomectomy (surgical resection of one or more fibroids from the uterine wall), performed during laparotomy (open surgery), by laparoscopy (minimally invasive surgery) or by hysteroscopy (surgery in the uterine cavity by scope with access through the cervix) (Donnez 2002; Stewart 2001). The primary disadvantage of myomectomy is a recurrence rate of 50%. Also, possible postoperative formation of adhesions can cause complications such as pain and infertility. Recently, more conservative approaches have been introduced such as uterine artery embolisation (UAE) (Gupta 2012) and magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) (Yoon 2013). These are approved by the U.S. Food and Drug Administration (FDA) (Hindley 2004; Pron 2003). However, albeit obtaining a similar patient satisfaction rate, together with a shorter recovery period, relative to hysterectomy and myomectomy (Gupta 2012), UAE is associated with higher rates of minor complications and an increased likelihood that surgical re-intervention will be required within two to five years of the initial procedure (Moss 2011). Moreover, ongoing concerns surround the impact of UAE on fertility and pregnancy (Firouznia 2009; Singh 2007). In addition, for MRgFUS, published evidence is limited. Further studies are needed to determine the long-term efficacy of this procedure and to evaluate its efficacy and safety compared with other treatments for uterine fibroids. Effective medical therapy may reduce the need for surgery and may be cost-effective. However, the long-term effectiveness of medical therapy for fibroids may be limited by fibroid recurrence. The only FDA-approved medical therapy is a gonadotrophin-releasing hormone (GnRH) agonist that is used preoperatively with iron. GnRH agonists reduce both bleeding and bulk-related symptoms, but because of the systemic hypoestrogenism caused by this drug, significant menopausal side effects have been reported, and this has limited their application. In contrast to their success in preclinical studies, to date selective oestrogen receptor modulators (a class of compounds that act on the oestrogen receptor) have yielded disappointing results in clinical trials and are not recommended by a Cochrane review (Wu 2007). Other drugs such as danazol or progesterone can shrink fibroids but are not appropriate for longterm use because of adverse effects (Ke 2009).

Aromatase is an enzyme that catalyses the conversion of androgens via hydroxylation (a chemical process that introduces a hydroxyl group into an organic compound) to oestrogens. It is a microsomal enzyme of the cytochrome P450 superfamily and the product of the CYP19 gene located on chromosome 15q21 (Cole 1990). Aromatase enzyme activity has been identified in a variety of tissues, including ovary, breast, endometrium, myometrium, adipose tissue, brain, skin, bone and vascular endothelium, among others (Simpson 2003). Because estradiol and estrone are the final products in the steroidogenic pathway, aromatase is considered a target for selective inhibition. Aromatase inhibitors (AIs) represent a class of anti-oestrogens that block the synthesis of oestrogen. Two types of AIs are available: irreversible steroidal inhibitors, for example, exemestane, which form a permanent bond with the aromatase enzyme complex; and non-steroidal inhibitors, for example, anastrozole and letrozole, which inhibit the enzyme by reversible competition. AIs fall into three generations of evolution. First-generation agents, namely, aminoglutethimide and testolactone, have been used extensively in the treatment of oestrogen receptor-positive postmenopausal breast cancer (Gershanovich 1998). The second generation includes formestane and fadrazole, and the third generation consists of anastrazole, letrozole, eximestane and vorozole. Letrozole and anastrazole were the first AIs used commonly in clinical practice. Both suppress up to 97% to 99% of aromatase activity (Goss 2001) with subsequent substantial reductions in circulating levels of oestrogen (Buzdar 2002). Both letrozole and anastrazole are rapidly absorbed after oral administration, are cleared by the liver and have a mean half-life of approximately 45 hours. Subsequently, their clinical effects are expected to diminish substantially after 10 days, on average. In premenopausal women, AIs have been reported to be well tolerated and to reduce the symptoms and the size of uterine fibroids (Gurates 2008; Hilário 2009). The most commonly reported adverse effects are hypoestrogenic symptoms, such as hot flushes and osteoporosis (bone mineral density loss). Less commonly reported effects include headache, back pain, leg cramps and joint disorders (Felson 2005). However, these effects are usually mild. More frequent adverse events have been reported after prolonged daily use in older women compared with short-term use in younger women. The FDA has reported other adverse events associated with dietary supplements illegally containing AIs, such as a decreased rate of bone maturation and growth, decreased sperm production, infertility, aggressive behaviour, adrenal insufficiency, kidney failure and liver dysfunction (FDA 2010). The first wide-scale clinical use of the aromatase inhibition concept was seen in the treatment of metastatic breast cancer, and the ’third-generation’ AIs have now become standard adjuvant endocrine treatment for oestrogen receptor-positive postmenopausal breast cancer (Howell 2005). Investigations undertaken to look for other applications are ongoing. A systematic review concluded that AIs might be effective in treating endometriosis-related chronic


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pelvic pain in both reproductive-age and postmenopausal women (Pavone 2012). It has been suggested that AIs may have a role in ovulation induction in anovulatory women (Pavone 2013), as well as in subfertile women with polycystic ovary syndrome (Franik 2012; Misso 2012).

the value of in situ oestrogen inhibition by AIs becomes more pronounced in postmenopausal women because GnRH agonists are ineffective in this age group. Kaunitz et al reported that for an obese postmenopausal woman with persistent uterine bleeding, use of anastrozole was associated with reduction in fibroid size, endometrial thinning and cessation of bleeding (Kaunitz 2007).

How the intervention might work Uterine fibroids are sex steroid hormone-dependent, benign tumours that develop during the reproductive period and are usually suppressed with menopause. Besides the ovary, leiomyomal tissue itself is a source of oestrogen. Oestrogen secreted by leiomyomal tissue may reach a sufficient concentration within the local compartment to support its own growth, allowing independence from ovarian oestrogen (Bulun 2005). Moreover, both aromatase and 17b-hydroxysteroid dehydrogenase (17b-HSD) type I are overexpressed in uterine fibroids compared with myometrium. Sumitani 2000 indicates that leiomyoma cells convert circulating androstenedione into estrone (via aromatase) and then into the active form of oestrogen, estradiol (via 17b-HSD type I). Aromatase seems to be the key enzyme in this process in that inhibition of aromatase activity blocks proliferation. Aromatase activity is significantly stimulated by a cyclic adenosine monophosphate (cAMP) analogue, prostaglandin E2 (PGE2), or by a combination of a glucocorticoid and a cytokine (interleukin (IL)-1) (Bulun 1994; Han 2008; Shozu 2002; Sumitani 2000). Aromatase mRNA has been detected in more than 90% of fibroids (Bulun 1994) but was undetectable in myometrial tissues from diseasefree uteri. Ishikawa et al found that leiomyoma tissues from African American women contained the highest levels of aromatase expression, which may result in elevated tissue concentrations of oestrogen and may account for their higher prevalence and earlier incidence (Ishikawa 2009). On the basis of the hypothesis discussed previously, AIs are used as treatment for uterine fibroids. Theoretically, AIs provide several advantages over GnRH agonists because the former drugs directly inhibit oestrogen synthesis in the fibroids and ovary, as opposed to the indirect inhibition induced by GnRH agonists. Serum oestrogen levels begin to decrease as early as the first day of AI intake; therefore, a rapid effect is likely. Also, because AIs create a condition of complete suppression of oestrogen in the fibroids but partial suppression in the ovary, the risk of systemic side effects is relatively low. Gurates et al conducted a prospective clinical trial that enrolled 16 premenopausal women with symptomatic uterine fibroids. Investigators found that letrozole significantly decreased fibroid size and promptly relieved heavy menstrual bleeding without changing bone mineral density (Gurates 2008). Hilário et al reported that anastrozole was effective in reducing the volume of fibroids in a population of 20 participants, thereby controlling symptoms without changing serum follicle-stimulating hormone or estradiol levels (Hilário 2009). Varelas et al found similar results with anastrozole (Varelas 2007) in 45 participants. Additionally,

Why it is important to do this review Traditionally, uterine fibroids have been managed surgically. An increasing demand for medical therapy can eliminate the need for surgery, thereby preserving the uterus and future fertility. A comfortable and non-invasive approach used to reduce fibroids may be preferable for most women and could reduce the burden on healthcare systems. Several clinical studies have examined AIs as treatment for uterine fibroids (Gurates 2008; Hilário 2009; Kaunitz 2007; Varelas 2007). However, weakness in study design has been a common problem, and systematic evaluation of the risks and benefits of AIs is required.

OBJECTIVES To evaluate the effectiveness and safety of aromatase inhibitors (AIs) in women with uterine fibroids.

METHODS

Criteria for considering studies for this review

Types of studies We included all randomised controlled trials (RCTs) of the use of aromatase inhibitors in the treatment of uterine fibroids. Only the first phase of cross-over studies was eligible. Quasi-RCTs were excluded.

Types of participants Women of reproductive age with confirmed uterine fibroids diagnosed by ultrasound scanning, computerised tomography (CT), magnetic resonance imaging (MRI) or a combination of these procedures.


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Types of interventions • • • •

Aromatase inhibitors versus placebo Aromatase inhibitors versus no treatment Aromatase inhibitors versus medical treatment Aromatase inhibitors versus surgery

Commercially available aromatase inhibitors include anastrozole (Arimidex), letrozole (Femara), exemestane (Aromasin), vorozole (Rivizor), formestane (Lentaron), fadrozole (Afema) and testolactone (Teslac). Additional interventions were permitted provided they were available to both study groups. The minimum length of treatment was three months.

Types of outcome measures

Primary outcomes

• Relief of symptoms: menstrual loss, as measured by objective assessments (e.g. menstrual volume, duration of flow); presence or severity of dysmenorrhoea, as assessed subjectively by participant or with the use of a scale

Secondary outcomes

• Adverse events: hot flushes, joint disorders (arthritis and arthralgia, or joint pain), hypercholesterolaemia, osteoporosis and fractures • Reduction in fibroid size: measured by ultrasonography or MRI • Recurrence rate: recurrence measured by ultrasonography or MRI, or recurrence of symptoms after they had subsided. Recurrence could occur both during treatment and after cessation of treatment (follow-up should last at least six months) • Live birth and pregnancy rates for women with a fertility desire after treatment (follow-up should last at least one year) • Quality of life • Cost-effectiveness: direct medical cost and indirect medical cost

Search methods for identification of studies A comprehensive and exhaustive search strategy was developed with the assistance of the Cochrane Menstrual Disorders and Subfertility Group Trials Search Co-ordinator. The strategy was used in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press and in progress) (see Appendix 1). Relevant trials were identified from electronic databases and other resources. It is the intention of the review authors that a new search for RCTs will be performed and the review will be updated every two years.

Electronic searches We searched the following electronic databases, from inception to August 21, 2013. • The Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register. • The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue) (see Appendix 2). • English language electronic databases: MEDLINE, EMBASE and PsycINFO (see Appendix 3, Appendix 4, Appendix 5). EMBASE was searched only one year back as the UK Cochrane Centre had handsearched EMBASE to this point, and these trials were already included in CENTRAL. • Chinese language electronic databases: Chinese Biomedical Literature Database (CBM), Chinese Medical Current Contents (CMCC)-using the corresponding Chinese terms: “uterine fibroid” AND “letrozole”, “Femara”. • Using comparable search terms, the following databases: ◦ CINAHL; ◦ The Cochrane Library (www.cochrane.org/index.htm) for DARE, the Database of Abstracts of Reviews of Effects (reference lists from non-Cochrane reviews on similar topics); ◦ Current Controlled Trials (www.controlled-trials.com/ ); ◦ ClinicalTrials.gov (http://clinicaltrials.gov/ct2/home); ◦ World Health Organization International Clinical Trials Registry Platform search portal (www.who.int/trialsearch/ Default.aspx); ◦ Citation indexes (http://scientific.thomson.com/ products/sci/); ◦ Conference abstracts on the ISI Web of Knowledge (http://isiwebofknowledge.com/); ◦ LILACS (Latin American and Caribbean Health Science Literature) (http://bases.bireme.br/cgi-bin/wxislind.exe/ iah/online/?IsisScript=iah/iah.xis&base=LILACS&lang=i& form=F); and ◦ OpenSIGLE (grey Literature in Europe) (http:// opensigle.inist.fr/). In the MEDLINE and EMBASE search strategies, we used filters for identifying randomised trials as follows. • MEDLINE search: combined with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0, Chapter 6, 6.4.11) (Higgins 2011). • EMBASE search: combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/mehodology/filters.html#random).

Searching other resources We also:


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• searched the references lists of all included studies and relevant reviews to identify further relevant articles; • contacted the study authors and area experts in the relevant field for potential studies; and • handsearched the following relevant Chinese journals: ◦ Chinese Journal of Obstetrics and Gynecology (from 1953 to August 2013); ◦ Chinese Journal of Practical Gynecology and Obstetrics (from 1985 to August 2013); ◦ Journal of Practical Obstetrics and Gynecology (from 1985 to August 2013); and ◦ Maternal and Child Health Care of China (from 1986 to August 2013).

Data collection and analysis We performed statistical analysis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0) (Higgins 2011). Review Manager 5.1 was used to analyse the data. Selection of studies The title, abstract and keywords of every record retrieved were scrutinised independently by HS (Huan Song) and KN (Kate Navaratnam) to determine which studies required further assessment. The full text was retrieved when the information given in titles, abstracts and keywords suggested that the study: • used an aromatase inhibitor as an intervention; and • had a prospective design and a control group. If any doubt arose regarding these criteria after scanning of the titles and abstracts, the full article was retrieved for clarification. Disagreements were resolved by discussion with a third review author, DL (Donghao Lu). The authors of clinical trials were contacted to provide missing data and other necessary information. Data extraction and management The following information was extracted from the study included in the review. It is presented in the table ’Characteristics of included studies’.

Trial characteristics

• Randomisation • Allocation concealment • Trial design: multicentre or single centre; single phase or cross-over design • Number of women randomly assigned, excluded and analysed • Duration, timing and location of the trial • Source of funding

Baseline characteristics of the studied groups

• Age of the women • Investigative work-up • Previously administered treatment(s)

Intervention

• Type of intervention and control • Dose regimen

Outcomes

• • • •

Outcomes reported How outcomes were defined How outcomes were measured Timing of outcome measurement

All data were extracted independently by two review authors (HS, KN) using forms designed according to Cochrane guidelines. We planned to seek additional information from study authors on trial methodology and trial data for trials that appeared to meet the eligibility criteria but for which aspects of methodology were unclear or data were provided in an unsuitable form for metaanalysis. Differences of opinion were noted and resolved by consensus.

Assessment of risk of bias in included studies Sources of bias were considered on a study-by-study basis by two review authors (HS, KN). Risk of bias assessment as independently performed by the two review authors (HS, KN) in keeping with the quality criteria specified by the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0) (Higgins 2011). The following risk of bias domains were assessed. • Sequence generation: randomisation method (e.g. by computer, random number tables, drawing of lots). • Allocation concealment: adequate (e.g. by third party, sealed opaque envelopes); inadequate (e.g. open list of allocation codes); not clear (e.g. not stated, ’envelopes’ stated without further description). • Blinding of participants, personnel and outcome assessors. • Whether an intention-to-treat analysis was performed. • Incomplete outcome data. • Selective outcome reporting. • Other sources of bias. Disagreements were noted and resolved by a third review author (DL). The risk of bias table is included in the table ’Characteristics of included studies’.


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Measures of treatment effect

Data synthesis

For dichotomous outcomes (e.g. recurrence, adverse events), we planned to record the number of participants experiencing the event in each group of the trial. We planned to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous data. For continuous outcomes (e.g. fibroid size), we planned to extract the final value and the standard deviation of the outcomes of interest, as well as the number of women assessed at the endpoint in each treatment arm and at the end of follow-up. From these data, we planned to calculate mean differences (MDs) with 95% CIs. In the case of outcomes with continuous data in different scales, we planned to use standardised mean differences (SMDs) with 95% CIs. If medians and ranges were reported, we planned to extract the data and report them in tables.

For dichotomous outcomes (e.g. adverse events), we planned to calculate pooled ORs using the inverse-variance, random-effects method. For continuous outcomes (e.g. fibroid size), we planned to caclulate pooled MDs or SMDs with 95% CIs, using a random-effects model. If in the future, any trials have multiple treatment groups, the ’shared’ comparison group will be divided into the number of treatment groups, and comparisons between each treatment group and the split comparison group will be treated as independent comparisons.

Unit of analysis issues We planned to assess non-standard designs, such as cluster randomised trials, to avoid unit of analysis errors.

Dealing with missing data We tried to contact the authors of primary studies through e-mail, to obtain missing data or to resolve any queries that arose. When possible, we planned to extract data to allow an intentionto-treat analysis (this analysis includes all participants in the groups to which they were originally randomly assigned). If the numbers randomly assigned were inconsistent with the numbers analysed, we planned that the percentage loss to follow-up would be calculated and reported in the Characteristics of Included Studies table.

Assessment of heterogeneity Only one study was included in this review; therefore, heterogeneity assessment was not necessary. If necessary in the future, tests for heterogeneity will be carried out using the Chi2 test, with significance set at P < 0.1. The I2 statistic will be used to estimate the total variation across studies due to heterogeneity, where < 25% will be considered as low-level, 25% to 50% as moderate-level, and > 50% as high-level heterogeneity (Higgins 2011). If high levels of heterogeneity (I2 > 50%) are seen for the primary outcomes, we will explore possible sources of heterogeneity using the sensitivity and subgroup analyses described below.

Subgroup analysis and investigation of heterogeneity We planned subgroup analyses as follows. • Different types of control groups (placebo, no treatment, different medical treatment, or different surgical procedures). • Duration of therapy (< 6 months, 6 to 12 months, > 12 months). • Location of fibroid (intramural, subserous, submucous). • Number of fibroids (single, multiple). If applicable in future updates of this review, factors such as age, length of follow-up and adjusted and unadjusted analysis might be considered in the investigation of any heterogeneity.

Sensitivity analysis A sensitivity analysis was not warranted in this version of the review. If required in future updates, we plan to perform sensitivity analyses by repeating the analyses to explore the influence of the following factors on effect size. • Exclusion of unpublished studies. • Exclusion of lower-quality studies (those at high or unclear risk of bias related to randomisation, blinding or attrition). • Use of different rating scales to assess symptom relief: exclusion of studies using unpublished rating scales or scales with no established reliability or validity. • Use of a fixed-effect model.

RESULTS

Assessment of reporting biases

Description of studies

If sufficient studies were identified, we planned to assess the potential for publication bias using a funnel plot (Egger 1997).

The characteristics of identified studies have been briefly summarised in tables.


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Results of the search A total of 84 citations (excluding duplicates) were obtained from the electronic search strategy in August 2013. We considered three to be potentially eligible for our systematic review. No additional articles were found by handsearching of reference lists and journals. After full text analysis of these three, only one RCT of an aromatase inhibitor versus gonadotrophin-releasing hormone agonist in women with uterine fibroids was identified. See Figure 1 for details of the screening and selection process.


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Figure 1. Study flow diagram.


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Included studies Study design The only eligible trial was published in 2010 (Parsanezhad 2010). It used a two-arm parallel-group design in multicentres (Iran and Germany). A total of 70 participants were initially randomly assigned to the intervention (aromatase inhibitor) group or the control (long-acting GnRHa) group, resulting in a total of 35 in each group. Participants The included trial recruited symptomatic premenopausal women with a single intramural uterine fibroid ≥ 5 cm, or with a fibroid measuring ≥ 5 cm who had additional fibroid(s) with diameter < 2 cm, as defined by transvaginal ultrasound scans. Age ranged from 18 to 42 years. Interventions The AI (letrozole) was administered orally (2.5 mg/d), regardless of the day of menstrual period, while the GnRH agonist triptorelin (Diphereline; Ipsen Pharma, Paris, France) was administered IM at a dose of 3.75 mg monthly, starting after complete pretreatment work-up. All participants underwent baseline measurement, performed in the early follicular phase. The length of treatment was 12 weeks, during which measurements were performed at weeks

2, 4, 6 and 12. Further medical treatment was not mentioned. We did not identify any study that assessed the effectiveness of AIs other than letrozole, or that compared AIs with placebo or surgery. Outcome measures The primary outcome of our review-relief of symptoms-was not reported by the included study. Outcomes reported included reduction in fibroid volume (as determined by transvaginal ultrasound) and ovarian and follicular changes (as determined by transvaginal ultrasound). The only adverse event reported was the occurrence of hot flushes.

Excluded studies The study Badawy 2012 was excluded because it targeted uterine adenomyosis, instead of uterine fibroids. Another study, Nassar 2009, which was intended to evaluate AIs for prevention of growth of uterine fibroids in perimenopausal women, was excluded because it had been withdrawn before enrolment as a result of lack of recruitment.

Risk of bias in included studies Figure 2 summarised the risk of bias in the included study.


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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for the included study.

Allocation A random table was applied for randomisation in Parsanezhad 2010. Regarding the allocation concealment, which was unspecified, we attempted to contact the authors to obtain additional details. However, after repeated attempts, no reply was received from authors. Therefore, the sequence generation was assessed as ’unclear’ for allocation concealment.

by a person who did not take part in any decision making regarding medication administration during the study. Therefore, the risk of performance bias was judged as high, whereas the risk detection bias was deemed low.

Incomplete outcome data Blinding Parsanezhad 2010 stated that because of the technical reason that GnRHa was supplied in vials and aromatase inhibitors in tablets, instead of by a double-blind study design, an assessor-blind design was applied. Thus preparation and administration were performed

Intention-to-treat (ITT) analyses were not performed in Parsanezhad 2010. The withdrawal rate after randomisation was 14.3% (10/70, two from the letrozole group and eight from the triptorelin group), mainly because of irregular follow-up visits. Therefore, the risk of attrition bias was judged as unclear.


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Selective reporting No protocol was available for the included study; therefore, the risk of selective reporting was unclear.

Quaity of life This was not reported in the included study. Cost-effectiveness This was not reported in the included study.

Other potential sources of bias The risk of other potential sources of bias was unclear.

DISCUSSION Effects of interventions Summary data were extracted from the included study, in which an aromatase inhibitor (letrozole) was administered orally (2.5 mg/ d), regardless of the day of the menstrual period. In this study, all outcomes were measured at baseline and during treatment at 2, 4, 6 and 12 weeks after the start of treatment. Nevertheless, according to our review protocol, only measures obtained at week 12 were taken into account. This study did not report standard deviations for all continuous parameters at each time point. Because we failed to obtain additional details about those data from the study authors, no MDs or 95% CIs could be calculated. Therefore, we have been able to include only measures reported in the article. Primary outcomes Relief of symptoms This was not reported in the included study. Secondary outcomes Adverse events With respect to adverse events, only the occurrence of hot flushes was reported in the included study. 96.3% of women in the GnRHa group experienced hot flushes with various degrees of severity, and no women in the aromatase inhibitor group reported hot flushes of any severity . The way the presence or severity of hot flushes was defined was not mentioned in the report. Analysis showed a statistically significant difference (P = 0.00). However, because one group reported no events (the AI group reported no cases of hot flushes), no OR could be calculated. Reduction in fibroid size The volume of fibroid was measured by transvaginal ultrasound. Data presenting the reduction in fibroid volume (cm3 ) from baseline in both groups at week 12 showed that, for the GnRHa group, mean fibroid volume was reduced from 95.29 to 63.66; and for the aromatase inhibitor group, a reduction from 108.18 to 58.86 was noted. Correspondingly, because data were presented as the percentage change from baseline, the total volume of fibroids declined by 33.2% at week 12 in the GnRHa group (P = 0.02) and by 45.6% at week 12 in the aromatase inhibitor group (P = 0.00). Analysis indicated no significant difference regarding the reduction in fibroid volume between those two groups. Standard deviations were not reported, so an odds ratio could not be calculated. Recurrence rate This was not reported in the included study. Live birth and pregnancy rates for participants with a fertility desire after treatment This was not reported in the included study.

Summary of main results This systematic review found no evidence to support relief of symptoms associated with uterine fibroids treated with AIs. The only RCT (Parsanezhad 2010) did not report disease-related symptoms, such as heavy menstrual loss or dysmenorrhoea. With respect to side effects, letrozole was associated with significantly decreased odds of hot flushes during 12 weeks’ treatment in the included study as compared with the GnRHa group. However, we obtained little evidence to allow any conclusions to be drawn about tolerance/safety because data about other adverse events (joint disorders, hypercholesterolaemia, osteoporosis, fractures raising) and the side effects of other AIs except for letrozole were not reported. Regarding reduction in fibroid size, the included study showed that AIs did not differ significantly from GnRHa in terms of fibroid shrinkage, and this led to a 45.6% reduction in fibroid volume after 12 weeks’ treatment. Because of its short-term follow-up period, the current study provides no evidence to support the effectiveness of AIs in raising or lowering the odds of recurrence of uterine fibroids. Finally, because no study reported on economic evaluations, it is impossible to determine the cost-effectiveness of AI treatment for women with uterine fibroids.

Overall completeness and applicability of evidence The identified study only partially addressed the objectives of the review. First, the included study overlooked some important outcomes. For example, although it included symptomatic women with fibroids, it did not report relief of symptoms, which was the main outcome measure of our review. Further investigation is warranted to clarify the effectiveness of AI treatment for symptomatic relief in women with uterine fibroids. Second, the included study only compared letrozole with GnRHa. Thus other types of interventions, such as letrozole versus placebo/no treatment, and letrozole versus medical treatment or surgery, should be examined in future studies. Third, only premenopausal participants were involved in this research. Therefore, we should examine the effects of AI treatment in perimenopausal or postmenopausal women, because the current evidence does not cover the whole range of patients.


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Additionally, the follow-up period of the included study was too short to allow estimation of some of the long-term effects of AI treatment, such as rates of recurrence, pregnancy and live birth for women with a desire for fertility after treatment. These outcomes should be explored in further studies; this would result in more complete assessment of AI treatment in women with uterine fibroids. We found that no other systematic review was performed on this topic.

Quality of the evidence This systematic review included only one RCT with only 70 women comparing letrozole versus GnRHa. The study failed to report important clinical outcomes. Another major quality issue was the small sample size. Chance could be a reasonable explanation for the reported findings, and this study was underpowered to determine any treatment effect. In addition, investigators did not report sufficient statistical information to permit calculation of ORs or MDs. Another limitation of this review relates to the methodological quality of the included study. Parsanezhad 2010 applied only assessor-blind design, which introduced the risk of performance bias. Also, authors did not specify details about the allocation concealment method, resulting in unclear risk of selection bias, which undermined the reliability of reported data. Last, a 14.3% loss to follow-up was reported, without application of the intention-to-treat principle.

Potential biases in the review process To prevent bias in the review procedure, the search was guided and developed by the Cochrane Menstrual Disorders and Subfertility Group. No restriction (e.g. on language) was added to the search. Study selection, assessment of risks of bias and data collection were conducted independently by two review authors without blinding. Disagreement was resolved through discussion with the third review author. We dealt with missing information and data by making repeated attempts to contact the primary authors by email. Because we received no reply from them, continuous outcomes for which SDs were not reported were listed as in the original report.

Agreements and disagreements with other studies or reviews

Other clinical trials (Gurates 2008; Hilário 2009; Kaunitz 2007; Varelas 2007) have reported findings similar to those reported by the only RCT eligible for inclusion in our review (Parsanezhad 2010). Investigators reported that treatment with AIs (letrozole and anastrozole) appeared beneficial for women with uterine fibroids, in terms of significantly reducing fibroid size and/or controlling symptoms related to this disorder without inducing changes in hormonal secretion or bone mineral density. However, so far, no RCT has examined the use of AIs for uterine fibroids, other than Parsanezhad 2010. Well-designed RCTs are warranted to confirm or refute the current evidence. In addition, other studies have suggested that letrozole could be used to prevent the flare phenomenon (the first effect of GnRH agonists, which compete with endogenous GnRH molecules for the pituitary receptors and provoke a massive release of gonadotropins into the circulation before desensitising the hypophysis). The increase in gonadotropins, if large enough, can provoke ovulation in women with fibroids (Bedaiwy 2009). It has also been reported that AIs have been successfully used to treat women with rare conditions such as benign metastasising fibroid or intravenous fibroid (fibroids found in veins) (Biri 2008; Nasu 2009; Rivera 2004).

AUTHORS’ CONCLUSIONS Implications for practice At present, no evidence supports the use of AI treatment for women with symptomatic fibroids.

Implications for research Well-designed and well-conducted RCTs with double blinding should be conducted to reduce the risk of bias when the effectiveness of aromatase inhibitors in treating fibroids is evaluated. Comparisons of aromatase inhibitor drugs with other medical treatments or with surgery, and with each other, are needed. Future studies should report relief of symptoms, recurrence, pregnancy and live birth rates for women desiring fertility after treatment, and they should conduct an economic evaluation.

ACKNOWLEDGEMENTS We thank Helen Nagels (Managing Editor), Marian Showell (Trials Search Co-ordinator) and the editorial board of the Cochrane Menstrual Disorders and Subfertility Group (MDSG) for their invaluable assistance in developing this review.


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REFERENCES

References to studies included in this review Parsanezhad 2010 {published data only (unpublished sought but not used)} ∗ Parsanezhad ME, Azmoon M, Alborzi S, Rajaeefard A, Zarei A, Kazerooni T, 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. Fertility and Sterility January 2010;93(1):192–8.

References to studies excluded from this review Badawy 2012 {published data only} Badawy AM, Elnashar AM, Mosbah AA. Aromatase inhibitors or gonadotropin-releasing hormone agonists for the management of uterine adenomyosis: a randomized controlled trial. Acta Obstetricia et Gynecologica Scandinavica 2012;91(4):489–95. Nassar 2009 {unpublished data only} Nassar A. Aromatase inhibitors for treatment of uterine leiomyomas. ClinicalTrials.gov 2009. [: ClinicalTrials.gov: NCT00945360]

Additional references Bedaiwy 2009 Bedaiwy MA, Mousa NA, Casper RF. Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists. Fertility and Sterility 2009;91 Suppl(4):1574–7. Biri 2008 Biri A, Korucuoglu U, Zumrutbas N, Tiras B, Guner H. Intravenous leiomyomatosis treated with aromatase inhibitor therapy. International Journal of Gynaecology and Obstetrics 2008;101(3):299–300. [PUBMED: 18280477] Bulun 1994 Bulun SE, Simpson ER, Word RA. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. The Journal of Clinical Endocrinology and Metabolism 1994;78 (3):736–43. Bulun 2005 Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, et al.Aromatase in endometriosis and uterine leiomyomata. The Journal of Steroid Biochemistry and Molecular Biology 2005;95(1-5):57–62. [PUBMED: 16024248] Buzdar 2002 Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer 2002;95(9):2006–16. Cole 1990 Cole PA, Robinson CR. Conversion of 19-oxo[2 beta2H]androgens into oestrogens by human placental

aromatase. An unexpected stereochemical outcome. The Biochemical Journal 1990;268(3):553–61. Cramer 1990 Cramer SF, Patel A. The frequency of uterine leiomyomas. American Journal of Clinical Pathology 1990;94(4):435–8. Day 2003 Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. American Journal of Obstetrics and Gynecology 2003;188(1):100–7. Donnez 2002 Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate?. Human Reproduction 2002;17(6):101–7. Egger 1997 Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629–34. FDA 2010 FDA. FDA Alert: Aromatase inhibitors in products marketed as dietary supplements: recall. Drugs.com (accessed 25 December 2010). Felson 2005 Felson DT, Cummings SR. Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis and Rheumatism 2005;52(9):2594–8. Firouznia 2009 Firouznia K, Ghanaati H, Sanaati M, Jalali AH, Shakiba M. Pregnancy after uterine artery embolization for symptomatic fibroids: a series of 15 pregnancies. AJR American Journal of Roentgenology 2009;192(6):1588–92. Franik 2012 Franik S, Kremer JAM, Nelen WLDM, Farquhar C. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2012, (12). Gershanovich 1998 Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, et al.Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Annals of Oncology 1998;9(6):639–45. Goss 2001 Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. Journal of Clinical Oncology 2001;19(3):881–94. Gupta 2012 Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database of Systematic Reviews 2012, Issue 5. [DOI: 10.1002/14651858.CD005073.pub3]


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Gurates 2008 Gurates B, Parmaksiz C, Kilic G, Celik H, Kumru S, Simsek M. Treatment of symptomatic uterine leiomyoma with letrozole. Reproductive Biomedicine Online 2008;17(4): 569–74. [PUBMED: 18854113] Han 2008 Han M, Kim JY, Park JE, Kim JM, Lee KS. Effects of letrozole on proliferation and apoptosis in cultured leiomyoma cells treated with prostaglandin E(2). European Journal of Obstetrics, Gynecology, and Reproductive Biology 2008;138(1):83–8. Higgins 2011 Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane–handbook.org. Hilário 2009 Hilário SG, Bozzini N, Borsari R, Baracat EC. Action of aromatase inhibitor for treatment of uterine leiomyoma in perimenopausal patients. Fertility and Sterility 2009;91(1): 240–3. Hindley 2004 Hindley J, Gedroyc WM, Regan L, Stewart E, Tempany C, Hynyen K, et al.MRI guidance of focused ultrasound therapy of uterine fibroids: early results. AJR. American Journal of Roentgenology 2004;183(6):1713–9. Howell 2005 Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al.ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365(9453):60–2. Ishikawa 2009 Ishikawa H, Reierstad S, Demura M, Rademaker AW, Kasai T, Inoue M, et al.High aromatase expression in uterine leiomyoma tissues of African-American women. The Journal of Clinical Endocrinology and Metabolism 2009;94 (5):1752–6. Kaunitz 2007 Kaunitz AM. Aromatase inhibitor therapy for uterine bleeding in a postmenopausal woman with leiomyomata. Menopause 2007;14(5):941–3. Ke 2009 Ke LQ, Yang K, Li CM, Li J. Danazol for uterine fibroids. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD007692.pub2] Lepine 1997 Lepine LA, Hillis SD, Marchbanks PA, Koonin LM, Morrow B, Kieke BA, et al.Hysterectomy surveillanceUnited States, 1980-1993. MMWR. CDC Surveillance Summaries 1997;46(4):1–15. Misso 2012 Misso ML, Wong JL, Teede HJ, Hart R, Rombauts L, Melder AM, et al.Aromatase inhibitors for PCOS: a

systematic review and meta-analysis. Hum Reprod Update 2012 May–Jun;18(3):301–12. Moss 2011 Moss JG, Cooper KG, Khaund A, Murray LS, Murray GD, Wu O, 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 Jul;118(8):936–44. Nasu 2009 Nasu K, Tsuno A, Takai N, Narahara H. A case of benign metastasizing leiomyoma treated by surgical castration followed by an aromatase inhibitor, anastrozole. Archives of Gynecology and Obstetrics 2009;279(2):255–7. Pavone 2012 Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of endometriosis. Fertility and Sterility 2012;98 (6):1370–9. Pavone 2013 Pavone ME, Bulun SE. Clinical review: the use of aromatase inhibitors for ovulation induction and superovulation. Journal of Clinical Endocrinology and Metab 2013;98(5): 1838–44. Pron 2003 Pron G, Bennett J, Common A, Wall J, Asch M, Sniderman K, Ontario Uterine Fibroid Embolization Collaboration Group. The Ontario Uterine Fibroid Embolization Trial. Part 2. Uterine fibroid reduction and symptom relief after uterine artery embolization for fibroids. Fertility and Sterility 2003;79(1):120–7. Rivera 2004 Rivera JA, Christopoulos S, Small D, Trifiro M. Hormonal manipulation of benign metastasizing leiomyomas: report of two cases and review of the literature. The Journal of Clinical Endocrinology and Metabolism 2004;89(7):3183–8. [PUBMED: 15240591] Shozu 2002 Shozu M, Sumitani H, Segawa T, Yang HJ, Murakami K, Kasai T, Inoue M. Overexpression of aromatase P450 in leiomyoma tissue is driven primarily through promoter I.4 of the aromatase P450 gene (CYP19). Journal of Clinical Endocrinology and Metabolism 2002;87(6):2540–8. Simpson 2003 Simpson ER. Sources of estrogen and their importance. The Journal of Steroid Biochemistry and Molecular Biology 2003; 86(3-5):225–30. Singh 2007 Singh SS, Bordman R, Leyland N. Pregnancy after uterine artery embolization for fibroids. Canadian Family Physician 2007;53(2):293–5. Stewart 2001 Stewart EA. Uterine fibroids. Lancet 2001;357(9252):2938. Sumitani 2000 Sumitani H, Shozu M, Segawa T, Murakami K, Yang HJ, Shimada K, et al.In situ estrogen synthesized by


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aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism. Endocrinology 2000;141(10):3852–61. Varelas 2007 Varelas FK, Papanicolaou AN, Vavatsi-Christaki N, Makedos GA, Vlassis GD. The effect of anastrazole on symptomatic uterine leiomyomata. Obstetrics and Gynecology 2007;110(3):643–9. Walker 2005 Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science 2005;308(5728):1589–92. Wallach 2004 Wallach EE, Vlahos NF. Uterine myomas: an overview of development,clinical features, and management. Obstetrics

and Gynecology 2004;104(2):393–406. Wu 2007 Wu T, Chen XY, Xie L, Yang J. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database of Systematic Reviews 2007, Issue 4. [DOI: 10.1002/14651858.CD005287.pub3] Yoon 2013 Yoon SW, Cha SH, Ji YG, Kim HC, Lee MH, Cho JH. Magnetic resonance imaging-guided focused ultrasound surgery for symptomatic uterine fibroids: estimation of treatment efficacy using thermal dose calculations. European Journal of Obstetric and Gynecological Reproductive Biology 2013 Mar 21. ∗ Indicates the major publication for the study


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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Parsanezhad 2010 Methods

RCT duration: 12 weeks, multicentre, 70 participants

Participants

70 enrolled: AI group = 35, GnRHa group = 35 Evaluated: AI group = 33, GnRHa group = 27 Age, years: AI group = 30.94, GnRHa group = 31.00 Volume of fibroid (cm3 ): AI group = 108.18, GnRHa group = 95.29 Diagnosis: intramural uterine fibroid Including premenopausal women with a single intramural uterine fibroid > 5 cm with abnormal uterine bleeding, unexplained infertility, pelvic pain, dysmenorrhoea and pressure effect, or with a fibroid measuring ≥ 5 cm who had additional fibroid(s) with diameter < 2 cm Excluding women who had additional fibroid(s) measuring > 2 cm, who were under treatment with any type of E or P more recently than 1 month and with hormonal implant more recently than 3 months or who had a history of a major medical problem and/or previous medical or surgical treatment for fibroids

Interventions

Aromatase inhibitor (letrozole) was administered orally (2.5 mg/d), regardless of the day of menstrual period, while the GnRH agonist triptorelin (Diphereline; Ipsen Pharma, Paris, France) was administered IM at a dose of 3.75 mg monthly, starting after complete pretreatment work-up.The length of treatment was 12 weeks

Outcomes

Notes

• • • •

Reduction of fibroid volume Occurrence of hot flushes Hormonal changes Ovarian and follicular changes

Trials were performed in teaching hospitals affiliated with Siraz University of Medical Sciebces (Shiraz, Iran) and Diako Teaching Centre, Göttingen University (Bremen, Germany)

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Random table

Allocation concealment (selection bias)

Unspecified

Unclear risk

Blinding of participants and personnel High risk (performance bias) All outcomes


Not blind

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Parsanezhad 2010

(Continued)

Blinding of outcome assessment (detection Low risk bias) All outcomes

Assessor-blind

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

60 randomised women were included in analysis (85.7%); no ITT

Selective reporting (reporting bias)

Unclear risk

No prior protocol available

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Badawy 2012

Focused on uterine adenomyosis, not uterine fibroids

Nassar 2009

Withdrawn before enrolment


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DATA AND ANALYSES This review has no analyses.

APPENDICES Appendix 1. MDSG search strategy Menstrual disorders and subfertility (MDSG) database search strategy for DV1612 12.12.11 Keywords CONTAINS “fibroids”or“fibroid size”or“fibroid volume”or“myoma”or“myomas”or “myomata”or “myomatous uterus”or “uterine fibroids”or“uterine leiomyomas”or “uterine myoma”or“uterine myomas”or “Uterine Neoplasms”or “Leiomyoma”or“leiomyomata”or “Leiomyoma-size” or Title CONTAINS“fibroids”or“fibroid size”or“fibroid volume”or“myoma”or“myomas”or “myomata”or “myomatous uterus”or “uterine fibroids”or“uterine leiomyomas”or “uterine myoma”or“uterine myomas”or “Uterine Neoplasms”or “Leiomyoma”or“leiomyomata”or “Leiomyoma-size” AND Keywords CONTAINS “aromatase inhibition” or “aromatase inhibitor” or “aromatase P450” or “Aminoglutethimide” or “Fadrozole” or“Testolactone” or“Anastrozole” or“arimidex” or “Letrozole” or “Exemestane” or Title CONTAINS “aromatase inhibition” or “aromatase inhibitor” or “aromatase P450” or “Aminoglutethimide” or “Fadrozole” or“Testolactone” or“Anastrozole” or“arimidex” or “Letrozole” or “Exemestane”

Appendix 2. CENTRAL search strategy 1 exp leiomyoma/ or exp myoma/ (346) 2 leiomyoma$.tw. (186) 3 fibroid$.tw. (204) 4 (myom$ or hysteromyom$ or fibromyom$).tw. (499) 5 fibroma$.tw. (21) 6 or/1-5 (801) 7 exp aromatase inhibitors/ or exp aminoglutethimide/ or exp fadrozole/ (367) 8 aromatase inhibitor$.tw. (399) 9 aminoglutethimide$.tw. (153) 10 fadrozole$.tw. (28) 11 Testolactone$.tw. (14) 12 Anastrozole.tw. (287) 13 Arimidex.tw. (142) 14 Letrozole.tw. (340) 15 Femara.tw. (27) 16 Exemestane.tw. (155) 17 Aromasin.tw. (16) 18 (Vorozole or Rivizor or Formestane).tw. (49) 19 (Lentaron or Fadrozole or Afema).tw. (35) 20 or/7-19 (1080) 21 6 and 20 (3)


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Appendix 3. MEDLINE search strategy 1 exp leiomyoma/ or exp myoma/ (18629) 2 leiomyoma$.tw. (10367) 3 fibroid$.tw. (4032) 4 (myom$ or hysteromyom$ or fibromyom$).tw. (18547) 5 fibroma$.tw. (9374) 6 or/1-5 (44248) 7 exp aromatase inhibitors/ or exp aminoglutethimide/ or exp fadrozole/ (6190) 8 aromatase inhibitor$.tw. (5257) 9 aminoglutethimide$.tw. (1376) 10 fadrozole$.tw. (318) 11 Testolactone$.tw. (108) 12 Anastrozole.tw. (1426) 13 Arimidex.tw. (257) 14 Letrozole.tw. (1723) 15 Femara.tw. (85) 16 Exemestane.tw. (858) 17 Aromasin.tw. (31) 18 (Vorozole or Rivizor or Formestane).tw. (241) 19 (Lentaron or Fadrozole or Afema).tw. (332) 20 or/7-19 (9177) 21 6 and 20 (76) 22 randomized controlled trial.pt. (383109) 23 controlled clinical trial.pt. (88933) 24 randomized.ab. (298526) 25 placebo.tw. (164819) 26 clinical trials as topic.sh. (173769) 27 randomly.ab. (211676) 28 trial.ti. (128906) 29 (crossover or cross-over or cross over).tw. (61951) 30 or/22-29 (937533) 31 exp animals/ not humans.sh. (4020652) 32 30 not 31 (865465) 33 21 and 32 (4)

Appendix 4. EMBASE search strategy 1 exp UTERUS MYOMA/ (8706) 2 exp leiomyoma/ (13839) 3 leiomyoma$.tw. (12114) 4 fibroid$.tw. (5510) 5 (myom$ or hysteromyom$ or fibromyom$).tw. (21836)) 6 fibroma$.tw. (9926) 7 or/1-6 (50938) 8 exp aromatase inhibitor/ (19459) 9 exp AMINOGLUTETHIMIDE/ (3589) 10 exp FADROZOLE/ (919) 11 aromatase inhibitor$.tw. (6752) 12 aminoglutethimide$.tw. (1418) 13 fadrozole$.tw. (330) 14 Testolactone$.tw. (117) 15 Anastrozole.tw. (1900) Aromatase inhibitors for uterine fibroids (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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16 Arimidex.tw. (1560) 17 Letrozole.tw. (2487) 18 Femara.tw. (949) 19 Exemestane.tw. (1267) 20 Aromasin.tw. (458) 21 (Vorozole or Rivizor or Formestane).tw. (298) 22 (Lentaron or Fadrozole or Afema).tw. (463) 23 exp LETROZOLE/ (6677) 24 exp ANASTROZOLE/ (6388) 25 or/8-24 (20389) 26 7 and 25 (235) 27 Clinical Trial/ (888046) 28 Randomized Controlled Trial/ (354294) 29 exp randomization/ (63205) 30 Single Blind Procedure/ (18108) 31 Double Blind Procedure/ (117135) 32 Crossover Procedure/ (38161) 33 Placebo/ (223856) 34 Randomi?ed controlled trial$.tw. (92947) 35 Rct.tw. (12365) 36 random allocation.tw. (1290) 37 randomly allocated.tw. (19478) 38 allocated randomly.tw. (1917) 39 (allocated adj2 random).tw. (731) 40 Single blind$.tw. (13795) 41 Double blind$.tw. (139487) 42 ((treble or triple) adj blind$).tw. (324) 43 placebo$.tw. (193823) 44 prospective study/ (247126) 45 or/27-44 (1367917) 46 case study/ (20882) 47 case report.tw. (250792) 48 abstract report/ or letter/ (882471) 49 or/46-48 (1148859) 50 45 not 49 (1331061) 51 26 and 50 (84)

Appendix 5. PsycINFO search strategy 1 exp Gynecological Disorders/ (1294) 2 leiomyoma$.tw. (9) 3 fibroid$.tw. (32) 4 (myom$ or hysteromyom$ or fibromyom$).tw. (62) 5 fibroma$.tw. (17) 6 or/1-5 (1392) 7 aminoglutethimid$.tw. (30) 8 fadrozole$.tw. (35) 9 aromatase inhibitor$.tw. (137) 10 Testolactone$.tw. (2) 11 Anastrozole.tw. (12) 12 Arimidex.tw. (2) 13 Letrozole.tw. (30) Aromatase inhibitors for uterine fibroids (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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14 Femara.tw. (0) 15 Exemestane.tw. (6) 16 Aromasin.tw. (0) 17 (Vorozole or Rivizor or Formestane).tw. (11) 18 (Lentaron or Fadrozole or Afema).tw. (35) 19 or/7-18 (191) 20 6 and 19 (0)

CONTRIBUTIONS OF AUTHORS Huan Song: drafting of review; selection of trials for inclusion or exclusion; extraction of data; assessment of risks of bias. Donghao Lu: drafting of protocol and review; search for trials; data entry into RevMan. Kate Navaratnam: selection of trials for inclusion or exclusion; extraction of data; assessment of risks of bias; language support. Gang Shi: all correspondence; drafting of protocol and review; interpretation of results.

DECLARATIONS OF INTEREST The authors have no conflict of interest to disclose.

SOURCES OF SUPPORT

Internal sources • Department of Obstetrics and Gynaecology, University of Auckland, New Zealand. • Department of Obstetrics & Gynaecology, Sichuan University, Chengdu, China.

External sources • None, Not specified.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW Quality of life was added as a secondary outcome on the suggestion of a peer reviewer. In addition, hormonal change was deleted from secondary outcomes because it is of limited clinical usefulness.


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INDEX TERMS Medical Subject Headings (MeSH) Antineoplastic Agents [adverse effects; ∗ therapeutic use]; Aromatase Inhibitors [adverse effects; ∗ therapeutic use]; Hot Flashes [chemically induced]; Leiomyoma [∗ drug therapy]; Nitriles [adverse effects; therapeutic use]; Triazoles [adverse effects; therapeutic use]; Triptorelin Pamoate [therapeutic use]; Uterine Neoplasms [∗ drug therapy]

MeSH check words Female; Humans


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Fibroids (uterine myomatosis, leiomyomas).

Uterine fibroids: current perspectives.

Treatment of hormone positive uterine leiomyosarcoma with aromatase inhibitors.

New hysteroscopic techniques for submucosal uterine fibroids.

Amniotic fluid embolism after uterine artery embolization for uterine fibroids.

Current evidence on uterine embolization for fibroids.

Elective cesarean hysterectomy for uterine fibroids.

Ulipristal acetate in uterine fibroids.

Uterine fibroids associated with infertility.

EMAS position statement: management of uterine fibroids.

Endocrine-disrupting chemicals and uterine fibroids.

Uterine fibroids and current clinical challenges.

Thermal ablative treatment of uterine fibroids.

Uterine fibroids: clinical manifestations and contemporary management.

Pathogenesis of endometriosis and uterine fibroids.

Novel aromatase inhibitors.

Minimally invasive surgical techniques versus open myomectomy for uterine fibroids.

Add-back therapy with GnRH analogues for uterine fibroids.

Successful pregnancy after treatment with ulipristal acetate for uterine fibroids.

Overcoming the challenges of studying uterine fibroids.

Overview of latest evidence on uterine fibroids.

Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review.

Clinical efficiency investigation of laparoscopic uterine artery occlusion combined with myomectomy for uterine fibroids.

Aromatase inhibitors in male sex.