Aromatase inhibitors for uterine fibroids

  • Review
  • Intervention

Authors


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 fibroids 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 fibroids 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 fibroid 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).

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.

Résumé scientifique

Les inhibiteurs de l'aromatase pour des fibromes utérins

Contexte

Les fibromes utérins, également connus sous le nom de léiomyomes utérins ou myomes utérins , sont les tumeurs bénignes les plus fréquentes chez les femmes en âge de procréer. Bien que généralement bénignes, les fibromes utérins peuvent avoir un impact majeur sur la santé des femmes et la qualité de vie en contribuant à des saignements utérins anormaux et en provoquant des symptômes de pression pelviennes (comme une augmentation de la fréquence urinaire, des douleurs pelviennes et de la constipation). Des traitements traditionnels des fibromes symptomatiques incluent une variété des techniques chirurgicales. Cependant, cette approche pourrait ne pas être envisageable en raison des taux de récidive élevés ainsi que la possibilité de formation d'adhérences en postopératoire entrainant des douleurs et de l'infertilité. Des traitements médicaux, plus sûrs et efficaces, ont été attendus pendant longtemps. Des études in vitro et des essais cliniques ont suggéré que l'utilisation des inhibiteurs de l'aromatase (AI), une classe d’anti-œstrogènes, pourrait inhiber la croissance d’un fibrome et éliminer le recours à une intervention chirurgicale.

Objectifs

Évaluer l'efficacité et l'innocuité des inhibiteurs de l'aromatase ( AI) chez les femmes présentant des fibromes utérins.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans les bases de données suivantes (des origines au 21 août 2013): Registre spécialisé du groupe Cochrane sur les troubles menstruels et l'hypofertilité, le registre Cochrane des essais contrôlés (CENTRAL) ( La bibliothèque Cochrane ), MEDLINE, EMBASE, CINAHL et PsycINFO. En outre, les références bibliographiques des essais inclus ont été examinées et des experts dans le domaine ont été contactés.

Critères de sélection

Nous avons inclus des essais contrôlés randomisés (ECR) chez des femmes en âge de procréer comparant les effets d'une AI versus placebo, l'absence de traitement ou tout traitement médical ou chirurgical.

Recueil et analyse des données

La sélection des essais éligibles, l'évaluation de la qualité des essais et l'extraction des données ont été réalisées indépendamment par deux auteurs de la revue. Si les données étaient disponibles, nous avions prévu de calculer les rapports de cotes (RC) pour l'analyse des données dichotomiques et les différences moyennes pour les données continues, avec des intervalles de confiance (IC) à 95%.

Résultats principaux

Seul un essai impliquant 70 participants a été inclus. Cet essai n'avait pas rendu compte de notre principal critère de jugement de la revue (le soulagement des symptômes de fibromes utérins). Les seuls résultats secondaires rapportés par cet essai étaient les effets indésirables (bouffées de chaleur) et la réduction de la taille des fibromes. Moins de femmes ont signalé des bouffées de chaleur dans le groupe létrozole que dans le groupe traité par des agonistes de la gonadolibérine (GnRH). La différence était significative (0/33 vs 26/27, P < 0,05). L’utilisation de létrozole réduit le volume des fibromes par 46% et celle d'un agoniste de la GnRH par 32% après 12 semaines de traitement. Ces proportions n’étaient pas significativement différentes. L'essai inclus ne rapportait pas de données sur le volume des fibromes dans une forme permettant le calcul d'un rapport des cotes. En plus, il était ouvert et incluait seulement 60/70 femmes dans l'analyse.

Conclusions des auteurs

Des preuves sont insuffisantes pour soutenir l'utilisation d'AI médicaments dans le traitement des femmes présentant des fibromes utérins.

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.

Résumé simplifié

Les inhibiteurs de l'aromatase pour les femmes présentant des fibromes utérins

Question

Les inhibiteurs de l'aromatase sont-ils sûrs et efficaces pour le traitement des fibromes utérins?

Contexte

Les fibromes utérins sont les tumeurs bénignes les plus fréquentes chez les femmes en âge de procréer. Les fibromes utérins peuvent avoir un impact majeur sur la santé des femmes et sur leur qualité de vie en provoquant des saignements abondants ou irréguliers, de l'hypofertilité ou des symptômes de pression pelvienne. Les traitements chirurgicaux traditionnels ont des taux de récidive élevés des complications postopératoires (comme de la douleur, de l'infertilité); par conséquent, de plus sûrs et plus efficaces traitements médicaux ont été recherchés. Il a été suggéré que les inhibiteurs de l'aromatase peuvent réduire les fibromes utérins en bloquant la production d'œstrogène. Une revue des preuves a été effectuée par des chercheurs dans la Collaboration Cochrane en août 2013 pour tous les essais contrôlés randomisés pertinents et une seule étude éligible a été trouvée.

Caractéristiques de l’étude

Un seul ECR, composée de 70 participantes, a été trouvé. L'étude a été effectuée dans des hôpitaux en Iran et en Allemagne. Des changements des symptômes en relation avec les fibromes et les sources de financement de l’étude n'ont pas été rapportés.

Résultats clés

Les auteurs de la revue ont conclu que, à ce jour, les preuves sont insuffisantes pour tirer des conclusions définitives sur l'efficacité et l'innocuité des médicaments AI dans le traitement des femmes présentant des fibromes utérins.

Notes de traduction

Traduit par: French Cochrane Centre 9th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

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 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 definitive 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 long-term 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 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).

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 disease-free 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, 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).

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.

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:

  • 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 meta-analysis.

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'.

Measures of treatment effect

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.

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 intention-to-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.

Assessment of reporting biases

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

Data synthesis

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.

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

Description of studies

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

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.

Figure 1.

Study flow diagram.

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.

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.

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 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

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.

Selective reporting

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

Other potential sources of bias

The risk of other potential sources of bias was unclear.

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.

Quaity of life

This was not reported in the included study.

Cost-effectiveness

This was not reported in the included study.

Discussion

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.

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.

Data and analyses

Download statistical data

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)

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)
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)
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.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Parsanezhad 2010

MethodsRCT 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

InterventionsAromatase 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
  • Reduction of fibroid volume

  • Occurrence of hot flushes

  • Hormonal changes

  • Ovarian and follicular changes

NotesTrials 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom table
Allocation concealment (selection bias)Unclear riskUnspecified
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blind
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor-blind
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk60 randomised women were included in analysis (85.7%); no ITT
Selective reporting (reporting bias)Unclear riskNo prior protocol available

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Badawy 2012Focused on uterine adenomyosis, not uterine fibroids
Nassar 2009Withdrawn before enrolment

Ancillary