Progestogens or progestogen-releasing intrauterine systems for uterine fibroids

  • Review
  • Intervention

Authors


Abstract

Background

Uterine fibroids are the most common premenopausal benign uterine tumours. Fibroids can cause symptoms including heavy menstrual bleeding, pelvic pressure and pain. Progestogens can be administered by various routes. Intramuscular injection of depot medroxyprogesterone acetate (DMPA) has dual actions (stimulatory or inhibitory) on fibroid cell growth. Progestogen-releasing intrauterine systems (IUS) decrease menstrual blood loss associated with fibroids by inducing endometrial atrophy and reduction of uterine fibroid size. Currently, their effectiveness for the treatment of uterine fibroids has not been evaluated.

Objectives

To determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids.

Search methods

We searched the Menstrual Disorders and Subfertility Group Specialised Register (inception to 17 August 2012), CENTRAL (inception to 17 August 2012) and Database of Abstracts of Reviews of Effects (DARE) in The Cochrane Library, MEDLINE (inception to 17 August 2012), Ovid EMBASE (1 January 2010 to 17 August 2012), Ovid PsycINFO (inception to 17 August 2012), CINAHL database, and trials registers for ongoing and registered trials.

Selection criteria

All identified published or unpublished randomised controlled trials (RCTs) assessing the effect of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids.

Data collection and analysis

We assessed all potentially eligible studies identified as a result of the search strategy. Two review authors extracted data from each included study using an agreed form and assessed the risk of bias. We resolved discrepancies through discussion.

Main results

This review included three studies. However, data for progestogen-releasing intrauterine systems were available from only one study that compared 29 women with a levonorgestrel (LNG)-IUS versus 29 women with a combined oral contraceptive (COC) for treating uterine fibroids. There was a significant reduction of menstrual blood loss (MBL) in women receiving the LNG-IUS compared to the COC using the alkaline hematin test (mean difference (MD) 77.5%, 95% CI 71.3% to 83.67%, 58 women) and a pictorial assessment chart (PBAC) (MD 34.5%, 95% CI 14.9% to 54.1%, 58 women). The reduction in uterine fibroid size was significantly greater in the leuprorelin group at 16 weeks compared to the progestogen lynestrenol group (MD -15.93 mm, 95% CI -18.02 to -13.84 mm, 46 women). There was no RCT evaluating the effect of DMPA on uterine fibroids.

Authors' conclusions

Progestogen-releasing intrauterine systems appear to reduce menstrual blood loss in premenopausal women with uterine fibroids. Oral progestogens did not reduce fibroid size or fibroid- related symptoms. However, there was a methodological limitation and the one included study with data had a small sample size. This evidence is insufficient to support the use of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids.

Résumé scientifique

Progestatifs ou dispositifs intra-utérins libérant de la progestérone pour les fibromes utérins

Contexte

Les fibromes utérins sont les tumeurs utérines bénignes les plus fréquentes chez les femmes préménopausées. Les fibromes peuvent provoquer des symptômes incluant des saignements menstruels abondants, une pression et une douleur pelviennes. Les progestatifs peuvent être administrés par différentes voies. L'injection intramusculaire d'acétate de médroxyprogestérone-dépôt (AMPD) a une double action (stimulante ou inhibitrice) sur la croissance des cellules du fibrome. Les dispositifs intra-utérins libérant de la progestérone (DIU) réduisent les pertes de sang menstruel associées aux fibromes en induisant l'atrophie endométriale et la réduction de la taille du fibrome utérin. À l'heure actuelle, leur efficacité pour le traitement des fibromes utérins n'a pas été évaluée.

Objectifs

Déterminer l'efficacité des progestatifs ou des dispositifs intra-utérins libérant de la progestérone pour le traitement des femmes préménopausées présentant des fibromes utérins.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre spécialisé du groupe Cochrane sur les troubles menstruels et de la fertilité (de son origine jusqu'au 17 août 2012), CENTRAL (de son origine jusqu'au 17 août 2012) et la base de données « Database of Abstract of Reviews of Effectiveness » (DARE) dans The Cochrane Library, MEDLINE (de son origine jusqu'au 17 août 2012), Ovid EMBASE (du 1er janvier 2010 au 17 août 2012), Ovid PsycINFO (de son origine jusqu'au 17 août 2012), la base de données CINAHL, et les registres d'essais en cours et enregistrés.

Critères de sélection

Tous les essais contrôlés randomisés (ECR) publiés ou non publiés ayant été identifiés, évaluant l'effet des progestatifs ou des dispositifs intra-utérins libérant de la progestérone pour le traitement des femmes préménopausées présentant des fibromes utérins.

Recueil et analyse des données

Nous avons évalué toutes les études potentiellement éligibles, ayant été identifiées au moyen de la stratégie de recherche documentaire. Deux auteurs de la revue ont extrait les données de chaque étude incluse à l'aide du formulaire agréé et ont évalué le risque de biais. Les divergences ont été résolues par la discussion.

Résultats principaux

Cette revue a inclus trois études. Cependant, les données relatives aux dispositifs intra-utérins libérant de la progestérone ne provenaient que d'une seule étude qui a comparé 29 femmes prenant du lévonorgestrel par le biais d'un DIU-LNG à 29 femmes prenant un contraceptif oral combiné (COC) pour le traitement des fibromes utérins. Il existait une réduction significative des pertes de sang menstruel (MBL) chez les femmes recevant le DIU-LNG comparé au COC en utilisant le test de l'hématine alcaline (différence moyenne (DM) 77,5 %, IC à 95 % 71,3 % à 83,67 %, 58 femmes) et un tableau d'évaluation graphique (PBAC) (DM 34,5 %, IC à 95 % 14,9 % à 54,1 %, 58 femmes). La réduction de la taille du fibrome utérin était significativement supérieure dans le groupe sous leuproréline au bout de 16 semaines comparativement au groupe sous progestérone lynestrénol (DM -15,93 mm, IC à 95 % -18,02 à -13,84 mm, 46 femmes). Nous n'avons identifié aucun ECR évaluant l'effet de l'AMPD sur les fibromes utérins.

Conclusions des auteurs

Les dispositifs intra-utérins libérant de la progestérone semblent réduire les pertes de sang menstruel chez les femmes préménopausées présentant des fibromes utérins. Les progestatifs oraux n'ont pas réduit la taille des fibromes ou les symptômes liés aux fibromes. Toutefois, il existait une limite méthodologique et l'unique étude incluse avec des données avait une petite taille d'échantillon. Ces preuves sont insuffisantes pour soutenir l'utilisation de progestatifs ou de dispositifs intra-utérins libérant de la progestérone pour le traitement des femmes préménopausées présentant des fibromes utérins.

Plain language summary

Progestogens or progestogen-releasing intrauterine systems for uterine fibroids

Uterine fibroids are common premenopausal benign uterine tumours. Treatment of uterine fibroids includes surgery, medical treatment, or both. Progestogens can be administered by various routes such as orally and by injection. Depot medroxyprogesterone acetate (DMPA is a synthetic progesterone hormone given by intramuscular injection that may inhibit uterine fibroid growth. The progestogen-releasing (levonorgestrel) intrauterine system (LNG-IUS) is a device placed inside the uterus that releases the hormone progesterone and can cause endometrial suppression. In this review, three randomised controlled studies were included. Two randomised controlled studies included 131 women and evaluated the beneficial and harmful effects of the LNG-IUS compared with hysterectomy or a low dose combined oral contraceptive (COC). However, the results were from only one study that compared 29 women with an LNG-IUS versus 29 women with COC for treating uterine fibroids. The LNG-IUS appeared to reduce menstrual blood loss and increase haemoglobin levels in premenopausal women with uterine fibroids. Reduction of fibroid size was not significant. In one study that included 56 women treated with preoperative oral progestogens (lynestrenol) compared with gonadotropin-releasing hormone (GnRH) agonist, the uterine fibroid size was not different. There was no randomised controlled study of DMPA to treat uterine fibroids. The included studies were of poor quality and had small numbers of participants. Indeed, the authors did not recommend the use of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. More high quality randomized controlled studies evaluating progestogens or progestogen-releasing intrauterine systems for treating uterine fibroids that have an adequate sample size are needed.

Résumé simplifié

Progestatifs ou dispositifs intra-utérins libérant de la progestérone pour les fibromes utérins

Les fibromes utérins sont les tumeurs utérines bénignes fréquentes chez les femmes préménopausées. Le traitement des fibromes utérins inclut la chirurgie, le traitement médical, ou les deux. Les progestatifs peuvent être administrés par différentes voies comme la voie orale et par injection. L'acétate de médroxyprogestérone-dépôt (AMPD) est une hormone progestérone synthétique administrée par injection intramusculaire qui est susceptible d'inhiber la croissance du fibrome utérin. Le dispositif intra-utérin libérant de la progestérone (lévonorgestrel) (DIU-LNG) est un dispositif placé à l'intérieur de l'utérus qui libère l'hormone progestérone et peut provoquer la suppression de l'endomètre. Dans cette revue, nous avons inclus trois études contrôlées randomisées. Deux études contrôlées randomisées ont inclus 131 femmes et évalué les effets bénéfiques et nocifs du DIU-LNG comparé à l'hystérectomie ou à un contraceptif oral combiné (COC) à faible dose. Cependant, les résultats ne provenaient que d'une seule étude qui a comparé 29 femmes portant un DIU-LNG à 29 femmes prenant un COC pour le traitement des fibromes utérins. Le DIU-LNG semblait réduire les pertes de sang menstruel et augmenter les taux d'hémoglobine chez les femmes préménopausées présentant des fibromes utérins. La réduction de la taille du fibrome n'était pas significative. Dans une étude qui a inclus 56 femmes traitées par des progestatifs oraux préopératoires (lynestrénol) comparés à l'agoniste de la gonadolibérine (GnRH), la taille du fibrome utérin n'était pas différente. Il n'y avait aucune étude contrôlée randomisée portant sur l'AMPD pour le traitement des fibromes utérins. Les études incluses étaient de mauvaise qualité et comprenaient de faibles effectifs. En effet, les auteurs n'ont pas recommandé l'utilisation de progestatifs ou de dispositifs intra-utérins libérant de la progestérone pour le traitement des femmes préménopausées présentant des fibromes utérins. Il est nécessaire de réaliser d'autres études contrôlées randomisées de grande qualité évaluant les progestatifs ou les dispositifs intra-utérins libérant de la progestérone pour le traitement des fibromes utérins, ayant une taille d'échantillon suffisante.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Summary of findings(Explanation)

Summary of findings for the main comparison. Levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC) for uterine fibroids
  1. 1 There was a small sample sizes and high loss of follow-up rate.
    2 Total population size was less than 400.

Levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC) for uterine fibroids
Patient or population: patients with uterine fibroids
Settings: hospital
Intervention: levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Low dose combined oral contraceptive (COC)Levonorgestrel-releasing intrauterine system (LNG-IUS)
Menstrual blood loss (MBL) reduction at 12 months - MBL reduction by the alkaline hematin test
The alkaline hematin test. Scale from: 0 to 100.
Follow up: mean 12 months
The mean menstrual blood loss (mbl) reduction at 12 months - mbl reduction by the alkaline hematin test in the control groups was
13.4 ml
The mean menstrual blood loss (MBL) reduction at 12 months - MBL reduction by the alkaline hematin test in the intervention groups was
77.5 higher
(71.33 to 83.67 higher)
 58
(1 study)
⊕⊕⊝⊝
low 1,2
 
Menstrual blood loss (MBL) reduction at 12 months - MBL reduction by a pictorial assessment chart (PBAC)
A pictorial assessment chart (PBAC). Scale from: 0 to 100.
Follow up: mean 12 months
The mean menstrual blood loss (mbl) reduction at 12 months - mbl reduction by a pictorial assessment chart (pbac) in the control groups was
53.5 ml
The mean menstrual blood loss (mbl) reduction at 12 months - MBL reduction by a pictorial assessment chart (pbac) in the intervention groups was
34.5 higher
(14.92 to 54.08 higher)
 58
(1 study)
⊕⊕⊝⊝
low 1,2
 
Reduction in fibroid size at 12 months
Ultrasound. Scale from: 0 to 10.
Follow up: mean 12 months
The mean reduction in fibroid size at 12 months in the control groups was
2.4 cm
The mean reduction in fibroid size at 12 months in the intervention groups was
1.9 higher
(8.04 lower to 11.84 higher)
 58
(1 study)
⊕⊕⊝⊝
low 1,2
 
Haemoglobin level - Haemoglobin level at 12 months
Scale from: 0 to 20.
Follow up: mean 12 months
The mean haemoglobin level - haemoglobin level at 12 months in the control groups was
10.2 g/dl
The mean haemoglobin level - haemoglobin level at 12 months in the intervention groups was
1.5 higher
(0.93 to 2.07 higher)
 58
(1 study)
⊕⊕⊝⊝
low 1,2
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Lynestrenol versus leuprorelin (leuprolide) for uterine fibroids

Summary of findings 2. Lynestrenol versus leuprorelin (leuprolide) for uterine fibroids
  1. 1 High loss of follow up rate
    2 Total number of events is less than 300

Lynestrenol versus leuprorelin (leuprolide) for uterine fibroids
Patient or population: patients with uterine fibroids
Settings: hospital
Intervention: lynestrenol versus leuprorelin
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
LeuprorelinLynestrenol versus leuprorelin
Mean decrease of fibroid size at 16 weeks
Ultrasonography. Scale from: 0 to 30.
Follow up: mean 16 weeks
The mean decrease of fibroid size at 16 weeks in the control groups was
20.93 mm
The mean mean decrease of fibroid size at 16 weeks in the intervention groups was
15.93 lower
(18.02 to 13.84 lower)
 46
(1 study)
⊕⊕⊝⊝
low 1,2
 
Haemoglobin level at 16 weeks
Follow up: mean 16 weeks
The mean haemoglobin level at 16 weeks in the control groups was
13.38 g/dl
The mean haemoglobin level at 16 weeks in the intervention groups was
0.18 higher
(0.01 to 0.35 higher)
 45
(1 study)
⊕⊕⊝⊝
low 1,2
 
Pelvic pain - At 28 days
Follow up: mean 28 days
303 per 1000364 per 1000
(170 to 776)
RR 1.2
(0.56 to 2.56)
55
(1 study)
⊕⊕⊝⊝
low 1,2
 
Pelvic pain - At 16 weeks
Follow up: 16 weeks
226 per 1000334 per 1000
(133 to 838)
RR 1.48
(0.59 to 3.71)
49
(1 study)
⊕⊕⊝⊝
low 1,2
 
Other fibroid symptoms (non-pelvic pain) - At 28 days
Follow up: 28 days
344 per 1000454 per 1000
(234 to 880)
RR 1.32
(0.68 to 2.56)
54
(1 study)
⊕⊕⊝⊝
low 1,2
 
Other fibroid symptoms (non-pelvic pain) - At 16 weeks
Follow up: 16 weeks
161 per 1000389 per 1000
(145 to 1000)
RR 2.41
(0.9 to 6.49)
49
(1 study)
⊕⊕⊝⊝
low 1,2
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Uterine fibroids (myomas or leiomyomas) are benign tumours arising from individual smooth muscle cells of the uterus. The prevalence of fibroids depends upon ethnic background and varies widely (between 5% and 77%) based on the method of diagnosis (Borgfeldt 2000; Cramer 1990). The prevalence in women over the age of 45 years is more than 60%, with a higher prevalence in black women than in white women (Andersen 1998; Okolo 2008).

The cause of fibroids is still unclear, but there is certainly a multi-causal origin. Hormonal factors (ovarian steroid hormones estrogen, progesterone), genetic factors, growth factors, and the molecular biology of these benign tumours all appear to play a role (Flake 2003). Estrogen is thought to promote fibroid development and growth (Andersen 1993). Studies have suggested that progesterone may also enhance the growth of fibroids (Manzo 2000; Rein 1995). The mechanisms of action of progesterone in the regulation of fibroid growth, however, are not well defined as yet.

Most fibroids are asymptomatic but some women have significant symptoms that warrant therapy (Stovall 2001). Symptoms attributable to fibroids can generally be classified in three distinct categories, as abnormal uterine bleeding, pelvic pressure (urinary frequency, constipation) and pain, and reproductive dysfunction (subfertility, miscarriage). The common bleeding pattern of fibroids is prolonged or excessively heavy menstruation (Stewart 2001). Pelvic pressure is caused by pressure upon adjacent organs (Wallach 2004).

A diagnosis of fibroids is often suspected based on palpation of an enlarged, irregular uterine contour on pelvic examination. A uterus of more than 12 weeks in size (described as the pregnant uterus) may be palpated on abdominal examination (Stewart 2001). Ultrasonography is typically used to confirm the diagnosis and to exclude the possibility of ovarian neoplasm. Magnetic resonance imaging (MRI) gives better visualisation of individual fibroids but for most clinical indications the extra cost is not justified.

Description of the intervention

There are a wide range of available treatments, including pharmacologic, surgical, and radiographically directed interventions, depending on factors such as the size, location and number of fibroids, race, age, ethnicity, and childbearing concerns. However, there is no defined 'gold standard' for fibroid therapy (David 2005). Progestogen is a natural or synthetic progestational hormone. Progesterone is a natural hormone produced by the ovary. A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. Progestogen can be administered orally, vaginally, and by intramuscular injection. Depot medroxyprogesterone acetate (DMPA) is a three-month injectable synthetic progestin. It is a reliable and reversible contraceptive method, including for women with uterine fibroids (WHO 2004). DMPA is approved for use in more than 100 countries and is used by more than 30 million women throughout the world (World Contraceptive Use 2005). A study has demonstrated a duration-dependent protective effect of DMPA against development of uterine fibroids (Lumbiganon 1996).

The progestin-releasing intrauterine system (IUS) is a long-acting, hormone-releasing intrauterine device. The IUS has primarily been used for contraception. The levonorgestrel-releasing intrauterine system (LNG-IUS) consists of a small, T-shaped polyethylene frame and a reservoir of synthetic progesterone. Studies of the LNG-IUS show that it provides a broad spectrum of non-contraceptive benefits including reduction of menstrual blood loss, reduction of uterine volume, and reduction of uterine fibroid size (Singer 1994; Starczewski 2000). However, some studies report no reduction in uterine volume or fibroid size (Kaunitz 2007).

How the intervention might work

Progesterone may have dual actions, stimulatory and inhibitory, on fibroid cell growth depending on the local growth factor conditions around each fibroid. Evidence shows that epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-I) act as local factors which stimulate fibroid growth. Progesterone augments EGF and integral membrane protein (Bcl-2) but inhibits IGF-I and tumour necrosis factor (TNFalpha) (Maruo 2004; Maruo 2007). The IUS causes the uterine endometrium to atrophy by making the uterine mucosa thin, stroma swollen, endometrial glands atrophic, and epithelial cells inactive (Silverberg 1986). These mechanisms explain the effect of decreasing menstrual blood loss.

Why it is important to do this review

Studies have suggested that fibroid growth is steroid hormone dependent (Marsh 2006). However, there are many forms of medical and surgical management for uterine fibroids. The LNG-IUS is effective in reducing menstrual blood loss (Lethaby 2005) but its efficacy in treating the heavy menstrual bleeding related to fibroids is unclear. Progestins have been used for many years in some countries in the treatment of uterine fibroids, however the lack of high quality studies has been a common problem when systematic evaluation of their benefits and harms is required. In view of the wide range of potential treatments, a comprehensive review is important.

Objectives

To determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids.

Methods

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials (RCTs) were considered for inclusion.

Types of participants

1. Premenopausal women with uterine fibroids diagnosed by clinical manifestation and physical signs and confirmed by ultrasound scanning, computed tomography (CT), or MRI, or a combination of more than one of the procedures.

2. Premenopausal women with fibroid-related symptoms and palpable uterine fibroids without confirmation by imaging technology were included and compared in sensitivity analyses.

3. Premenopausal women without any symptoms but determined to have uterine fibroids during routine gynaecological examination and confirmed by imaging techniques were also included.

The diagnostic criteria produced by the International Federation of Gynecology and Obstetrics (FIGO 2001) or the International Gynecology and Obstetrics Association were used.

Types of interventions

Experimental interventions included oral progestogens, depot medroxyprogesterone acetate (DMPA) intramuscular injections, or progestin-releasing intrauterine devices (IUS). The control interventions included no treatment, placebo, medical therapy, or surgical procedures.

Types of outcome measures

Primary outcomes

1. Improvement in uterine fibroid-related symptoms, abnormal uterine bleeding measured by objective disease measures such as haemoglobin, haematocrit, or ferritin levels; pain assessed subjectively by the individual or with a visual analogue scale (VAS)

2. Reduction in fibroid size

Secondary outcomes

3. Quality of life

4. Recurrence rate with the possibility of necessitating additional therapy

5. Adverse events such as acne, weight gain, bloating, breast tenderness, and expulsion of the IUS

6. Cost effectiveness

Search methods for identification of studies

We searched for all published and unpublished RCTs of progestogens or progestin-releasing IUSs, without language restrictions and in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Coordinator. The original search was on 6 August 2010, and it was updated on 17 August 2012.

Electronic searches

We searched the:

  • MDSG Specialised Register (from inception to 17 August 2012) in liaison with the Trials Search Coordinator;

  • Cochrane Central Register of Controlled Trials (CENTRAL) (from inception to 17 August 2012) in Ovid;

  • Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (from inception to 17 August 2012);

  • Ovid EMBASE (1 January 2010 to 17 August 2012), EMBASE was only searched one year back as the UK Cochrane Centre has handsearched EMBASE to this point and these trials are already in CENTRAL;

  • Ovid PsycINFO (from inception to 17 August 2012).

The MEDLINE search was combined with the Cochrane highly sensitive search strategy for identifying randomized trials, which appears in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0 (Chapter 6, 6.4.11).

The EMBASE search was combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) at http://www.sign.ac.uk/mehodology/filters.html#random

Searching other resources

Trials registers for ongoing and registered trials: ClinicalTrials.gov, a service of the US National Institutes of Health at http://clinicaltrials.gov/ct2/home; and the World Health Organization (WHO) International Trials Registry Platform search portal at http://www.who.int/trialsearch/Default.aspx.  

The search strategies are detailed in Appendix 1.

Data collection and analysis

Selection of studies

Two review authors (Ussanee Sangkomkamhang (US) and Malinee Laopaiboon (ML)) independently evaluated studies to assess eligibility. Discrepancies were resolved by discussion.

Data extraction and management

Two review authors (US, ML) independently extracted the data using forms designed according to Cochrane guidelines. We resolved discrepancies by discussion.

Assessment of risk of bias in included studies

Three review authors (US, Pisake Lumbiganon (PL), and ML) independently assessed risk of bias using the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion. We intended to extract the following data.

(1) Sequence generation:
  • low risk of bias (any truly random process, e.g. random number table, computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth, hospital or clinic record number); or

  • unclear risk of bias (insufficient information to allow judgment).

(2) Allocation concealment:
  • low risk of bias (e.g. telephone or central randomisation, consecutively numbered sealed opaque envelopes);

  • high risk of bias (e.g. open random allocation, unsealed or non-opaque envelopes, alternation, date of birth);

  • unclear risk of bias (insufficient information to allow judgment).

(3) Blinding:
  • low risk, high risk, or unclear risk of bias for participants;

  • low risk, high risk, or unclear risk of bias for personnel;

  • low risk, high risk, or unclear risk of bias for outcome assessors.

(4) Incomplete outcome data

We described for each included study and for each outcome or class of outcomes the completeness of the data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported; the numbers included in the analysis at each stage (compared with the total randomised participants); reasons for attrition or exclusion, where reported; and whether missing data were balanced across groups or were related to outcomes. We assessed methods as:

  • low risk of bias (20% or less missing data);

  • high risk of bias (more than 20% missing data);

  • unclear risk of bias.

We will discuss whether missing data greater than 20% might: (a) be reasonably expected (acknowledging that with long-term follow up complete data are difficult to attain), and (b) impact on outcomes.

(5) Selective outcome reporting

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:

  • low risk of bias (where it was clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review had been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes had been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest were reported incompletely and so could not be used; study fails to include results of a key outcome that would had been expected to have been reported);

  • unclear risk of bias.

(6) Other sources of bias

We described for each included study any important concerns we have about other possible sources of bias. We assessed whether each study was free of other problems that could put it at risk of bias:

  • low risk of bias;

  • high risk of bias;

  • unclear risk of bias.

Measures of treatment effect

For continuous data (for example menstrual blood loss, uterine volume), we used mean differences (MD) between treatment groups with 95% confidence intervals (CIs). For dichotomous data (for example uterine fibroid symptoms), we used relative risks (RR) with 95% CIs. We evaluated the following comparisons:

1. levonorgestrel-releasing IUS versus hysterectomy;

2. levonorgestrel-releasing IUS versus low dose combined oral contraceptive;

3. lynestrenol versus leuprorelin.

Unit of analysis issues

Our review involved outcome data only from RCTs that randomised individuals.

Dealing with missing data

We contacted the authors by email to obtain missing data. For each included trial, we recorded the proportion of participants who were missing from the final analysis. We used an intention to-treat analysis, where possible. We did not impute missing outcome data for any of the outcomes.

Assessment of heterogeneity

In this review we did not assess heterogeneity because data from only one study were available for each outcome. In the future, if we carry out meta-analysis, statistical heterogeneity will be assessed using the T², I², and Chi² statistics. We planned to investigate heterogeneity if I² was greater than 50% and either T² was greater than zero or there was a low P value (< 0.10) in the Chi² test.

Assessment of reporting biases

We ensured that our search was comprehensive and without any language restriction. In this review we could not assess publication bias using the funnel plot because there were not enough study data. In future updates, if the number of included trials is more than 10, potential publication bias will be assessed using a funnel plot or other corrective analytical methods (Egger 1997).

Data synthesis

As we only identified one study that contributed data to each analysis, it was not possible to perform meta-analysis. In future updates, if we include more studies, we plan to pool data in a meta-analysis using a fixed-effect model provided data are homogeneous (I² < 50%, consistency of forest plot, and P value of Chi² > 0.10) for:

• any dichotomous outcomes (e.g. uterine fibroids symptoms), relative risks (RR) with 95% CIs will be pooled;
• continuous outcomes (e.g. blood measures), the mean differences between the treatment arms at the end of follow up will be pooled if all trials measured the outcome on the same scale, otherwise the standardized mean differences will be pooled.

We planned to pool statistically heterogeneous results using a random-effects model. We will present pooled effect estimates with 95% CIs, and estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses, if data were available.

1. Location of uterine fibroids (subserous, intramural, and submucous).
2. Dose (low, medium, high based on data).

Sensitivity analysis

We did not carry out any sensitivity analyses. In future updates, we plan to perform sensitivity analyses by repeating the analyses in order to explore the influence of the following factors on effect size:

1. study quality, such as allocation concealment, blinding, and numbers lost to follow up;
2. any very long or large studies to establish how much they dominated the results;
3. use of different rating scales to assess symptom relief.

Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies.

Results of the search

The search of the MDSG Specialised Register (from inception to 17 August 2012) yielded 108 trials. The title and abstract screening of these references identified 20 trials as potentially eligible for this review. Full papers were retrieved and screened. Three studies (Inki 2002; Sayed 2011; Verspyck 2000) met the inclusion criteria and are described in the table Characteristics of included studies. We excluded 17 studies and the reasons are reported in the table Characteristics of excluded studies. Details of the screening and selection process are shown in Figure 1.

Figure 1.

Study flow diagram.

Included studies

For more information about the included studies, see Characteristics of included studies.

Design and setting

All included studies were RCTs. These studies were undertaken in Finland, France, and Egypt. Two studies (Inki 2002; Verspyck 2000) were described as multicentre studies.

Participants

Three studies included a total of 187 women, 90 women in the intervention groups and 97 in the control groups, with the following characteristics.

Two studies (Inki 2002; Sayed 2011) included 73 and 58 women, respectively, who had fibroids with heavy menstruation or menorrhagia. Verspyck 2000 included 56 women with fibroids that indicated the need for surgery. Uterine fibroids were diagnosed by ultrasonography.

Interventions

Two studies assessed a levonorgestrel-releasing intrauterine device (LNG-IUS) compared with hysterectomy (Inki 2002) and low dose combined oral contraceptive (COC) (Sayed 2011). Verspyck 2000 compared preoperative lynestrenol with a gonadotropin-releasing hormone (GnRH) agonist (leuprorelin).

Outcomes

Outcome measures included an improvement in uterine fibroid-related symptoms, such as heavy menstrual blood loss and pelvic pain (Sayed 2011; Verspyck 2000), uterine and fibroid volume (Inki 2002).

Excluded studies

We excluded 17 studies from this review. In four studies the interventions were not progestogen only (Caird 1997; Carr 1993; Friedman 1988; Scialli 1995). Seven studies were non-randomised trials (Chwalisz 2005; Koh 2007; Magalhaes 2010; Rodriguez 2010; Siddiqui 2008; Soysal 2005; Yoshida 2010). Four studies had inappropriate comparator interventions (Chwalisz 2007; Levens 2008; West 1992; Wilkens 2008). Two studies were conducted on non-eligible participants (Chan 2007; Palomba 2002). For more information see Characteristics of excluded studies.

Risk of bias in included studies

Results of individual domains of the risk of bias assessments for the included studies are presented in Figure 2 and summarized in Figure 3.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Two studies were at low risk of selection bias, related to adequate sequence generation for randomisation (Sayed 2011) and allocation concealment (Inki 2002). In the other study (Verspyck 2000) no sequence generation and allocation concealment were reported and the study was rated as 'unclear risk'.

Blinding

Three studies (Inki 2002; Sayed 2011; Verspyck 2000) did not blind the interventions to clinicians, participants, and outcome assessors because the interventions were different and patients would know which group they were in. However, as we did not consider that blinding status could affect findings we assessed them to be at low risk of performance bias and detection bias.

Incomplete outcome data

The rate of losses to follow up varied from 9.3% to 27.6%.

Selective reporting

We did not have the protocols for the included studies, therefore we assessed their risk of bias for selective reporting as unclear.

Other potential sources of bias

None identified

Effects of interventions

See: Summary of findings for the main comparison Levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC) for uterine fibroids; Summary of findings 2 Lynestrenol versus leuprorelin (leuprolide) for uterine fibroids

Three included studies, involving 187 women, reported three comparisons.

1. Levonorgestrel-releasing intrauterine device (LNG-IUS) versus hysterectomy

(Inki 2002)

Primary outcomes

1.1 Improvement in uterine fibroid-related symptoms: no data were available.

1.2 Reduction in fibroid size: we were unable to estimate mean differences between groups because in the patients with a hysterectomy the fibroids were removed.

Secondary outcomes

1.3 Quality of life: no data were available.

1.4 Recurrence rate with the possibility of necessitating further additional therapy: no data were available.

1.5 Adverse events: no data were available.

1.6 Cost effectiveness: no data were available.

2. LNG-IUS versus low dose combined oral contraceptive (COC)

(Sayed 2011)

Primary outcomes

2.1 There was a statistically significant reduction of menstrual blood loss (MBL) at the end of 12 months in women receiving a LNG-IUS compared to COC, determined by using the alkaline hematin test (MD 77.5%, 95% CI 71.3% to 83.67%, 58 women) and a pictorial assessment chart (PBAC) (MD 34.5%, 95% CI 14.9% to 54.1%, 58 women) (Analysis 1.1). Haemoglobin levels at 12 months after treatment with the LNG-IUS were significant higher than with the COC (MD 1.50, 95% CI 0.93 to 2.07 g/dl, 58 women) (Analysis 1.3).

2.2 There was no significant difference in the reduction of uterine fibroid size between the two groups (MD 1.90 cm, 95% CI -8.04 to 11.84 cm, 58 women) (Analysis 1.2).

Secondary outcomes

2.3 Quality of life: no data were available.

2.4 Recurrence rate with the possibility of necessitating additional therapy: no data were available.

2.5 Adverse events: rate of LNG-IUS expulsion was 0.1%.

2.6 Cost effectiveness: no data were available.

3. Lynestrenol versus leuprorelin

(Verspyck 2000)

3.1 There was no significant difference in fibroid-related symptoms (pelvic pain) between the lynestrenol and leuprorelin groups, with a risk ratio (RR) of 1.20 (95% CI 0.56 to 2.56, 55 women) at 28 days and 1.48 (95% CI 0.59 to 3.71, 49 women) at 16 weeks (Analysis 2.3). Non-pelvic pain-related fibroid symptoms were also not significantly different between the two groups at 28 days (RR 1.32, 95% CI 0.68 to 2.56, 54 women) and 16 weeks (RR 2.41, 95% CI 0.90 to 6.49, 49 women) (Analysis 2.4). Haemoglobin levels at 16 weeks after treatment were also not significantly different between the two groups (MD 0.18, 95% CI 0.01 to 0.35 g/dl, 45 women) (Analysis 2.2).

3.2 There was a statistically significant reduction in mean uterine fibroid size at 16 weeks in the leuprorelin group compared to lynestrenol (MD -15.93 mm, 95% CI -18.02 to -13.84 mm, 46 women) (Analysis 2.1).

Secondary outcomes

3.3 Quality of life: no data were available.

3.4 Recurrence rate with the possibility of necessitating additional therapy: no data were available.

3.5 There were no significant differences between lynestrenol and leuprorelin for adverse events: headache (RR 0.26, 95% CI 0.06 to 1.07, 56 women), nausea (RR 2.87, 95% CI 0.57 to 14.38, 56 women), and weight gain (RR 2.15, 95% CI 0.39 to 11.88, 56 women) (Analysis 2.5).

3.6 Cost effectiveness: no data were available.

Discussion

Summary of main results

This review found three eligible studies. These studies had different interventions and outcome measures. When compared with low dose COC, the LNG-IUS significantly reduced menstrual blood loss (MBL) (as assessed by a PBAC or the alkaline hematin test) related to uterine fibroids at 12 months. However, there were methodological limitations and small sample sizes. We were unable to estimate the effects of the LNG-IUS compared with hysterectomy in terms of reduction of uterine fibroid size.

There was no evidence that at a 16 week preoperative period oral progestogens (lynestrenol) had a beneficial effect on uterine fibroid size or improvement in fibroid-related symptoms.

According to the GRADE system as used by the review authors, the quality of the evidence was rated as low.

Overall completeness and applicability of evidence

Three studies were identified. Only one study (Sayed 2011) was conducted in a low-middle income country (Egypt) while the others were from high income countries (Finland and France). The primary objective of one included study (Inki 2002) was to assess the incidence of ovarian cyst formation, which was not relevant to this review. However, a subgroup of participants who had uterine fibroids was relevant to this review and was therefore included. The review findings of the LNG-IUS were therefore based on evidence from only one study (Sayed 2011). One other study (Verspyck 2000) was conducted during the preoperative period. The interventions were different in the included studies and thus we were unable to combine the data. The overall completeness of evidence in this review is therefore limited.

Quality of the evidence

The quality of the available evidence was judged to be low. Two included studies (Sayed 2011; Verspyck 2000) had a high risk of bias in incomplete outcome data (high losses to follow up). AIl included studies also had small sample sizes. Therefore, the findings should be interpreted with caution.

Potential biases in the review process

We followed the methods set out in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). A comprehensive search was performed, all studies were examined, and the data were independently extracted by at least two review authors. We restricted the included studies to RCTs as they provide the strongest level of evidence. Therefore, we have attempted to reduce bias in the review process.

Agreements and disagreements with other studies or reviews

A systematic review of LNG-IUS contraception in women with uterine fibroids reported that LNG-IUS use can reduce MBL and increase serum levels of haemoglobin, the haematocrit, and ferritin compared to the copper intrauterine device (Zapata 2010). Another review also supported the evidence on the effectiveness of the LNG-IUS for women with uterine fibroids and menorrhagia. They found that MBL was reduced in LNG-IUS users but the uterine fibroid size did not reduce (Kaunitz 2007). We did not identify any other review on progestogens in treating premenopausal women with uterine fibroids.

Authors' conclusions

Implications for practice

There is no evidence to support the effectiveness of progestogens on uterine fibroids. There is some evidence of benefit of the progestogen-releasing intrauterine system (LNG-IUS) in premenopausal women with uterine fibroids. The LNG-IUS results in a significant reduction in menstrual blood loss compared to low dose combined oral contraceptive but the uterine fibroids did not shrink. However, there were methodological limitations and small sample sizes. Therefore, there is insufficient evidence to support the use of progestogens or progestogen-releasing intrauterine systems for uterine fibroids.

Implications for research

Future high-quality, adequate sample size RCTs are needed to evaluate the effectiveness of progestogens and the progestin-releasing intrauterine system.

Acknowledgements

The authors wish to thank the Cochrane Menstrual Disorders and Subfertility Group.

Data and analyses

Download statistical data

Comparison 1. Levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Menstrual blood loss (MBL) reduction at 12 months1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 MBL reduction by the alkaline hematin test1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 MBL reduction by a pictorial assessment chart (PBAC)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Reduction in fibroid size at 12 months1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3 Hemoglobin level at 12 months158Mean Difference (IV, Fixed, 95% CI)1.5 [0.93, 2.07]
3.1 Hemoglobin level at 12 months158Mean Difference (IV, Fixed, 95% CI)1.5 [0.93, 2.07]
Analysis 1.1.

Comparison 1 Levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC), Outcome 1 Menstrual blood loss (MBL) reduction at 12 months.

Analysis 1.2.

Comparison 1 Levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC), Outcome 2 Reduction in fibroid size at 12 months.

Analysis 1.3.

Comparison 1 Levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC), Outcome 3 Hemoglobin level at 12 months.

Comparison 2. Lynestrenol versus leuprorelin (leuprolide)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean decrease of fibroid size at 16 weeks146Mean Difference (IV, Fixed, 95% CI)-15.93 [-18.02, -13.84]
2 Hemoglobin level at 16 weeks145Mean Difference (IV, Fixed, 95% CI)0.18 [0.01, 0.35]
3 Pelvic pain1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 At baseline156Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.67, 2.21]
3.2 At 28 days155Risk Ratio (M-H, Fixed, 95% CI)1.2 [0.56, 2.56]
3.3 At 16 weeks149Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.59, 3.71]
4 Other fibroid symptoms (non pelvic pain)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 At baseline156Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.60, 1.23]
4.2 At 28 days154Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.68, 2.56]
4.3 At 16 weeks149Risk Ratio (M-H, Fixed, 95% CI)2.41 [0.90, 6.49]
5 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Headache156Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.06, 1.07]
5.2 Nausea156Risk Ratio (M-H, Fixed, 95% CI)2.87 [0.57, 14.38]
5.3 Weight gain156Risk Ratio (M-H, Fixed, 95% CI)2.15 [0.39, 11.88]
Analysis 2.1.

Comparison 2 Lynestrenol versus leuprorelin (leuprolide), Outcome 1 Mean decrease of fibroid size at 16 weeks.

Analysis 2.2.

Comparison 2 Lynestrenol versus leuprorelin (leuprolide), Outcome 2 Hemoglobin level at 16 weeks.

Analysis 2.3.

Comparison 2 Lynestrenol versus leuprorelin (leuprolide), Outcome 3 Pelvic pain.

Analysis 2.4.

Comparison 2 Lynestrenol versus leuprorelin (leuprolide), Outcome 4 Other fibroid symptoms (non pelvic pain).

Analysis 2.5.

Comparison 2 Lynestrenol versus leuprorelin (leuprolide), Outcome 5 Adverse events.

Appendices

Appendix 1. Search strategies

Menstrual Disorders and Subfertility Group database search string revised 29 November 2011

Keywords CONTAINS "uterine fibroids"or"uterine leiomyomas"or"uterine myoma"or "uterine myomas"or"myoma"or "myomas"or "myomata"or"Leiomyoma"or"leiomyomata"or "fibroids"or "myomatous uterus" or Title CONTAINS "uterine fibroids"or"uterine leiomyomas"or"uterine myoma"or "uterine myomas"or"myoma"or "myomas"or "myomata"or"Leiomyoma"or"leiomyomata"or "fibroids"or "myomatous uterus"

AND

Keywords CONTAINS "progestagen"or"progesteron"or "Progesterone"or "progesterone capsule"or "progesterone, micronized" or"progestin" or"progestin implant" or"progestins"or "progestogen" or"progestogens" or"Medroxyprogesterone Acetate" or"medroxyprogesterone" or"Depoprovera"or "depot medroxyprogesterone" or"depot medroxyprogesterone acetate" or"levonorgestrel intrauterine system" or "levonorgestrel-releasing intrauterine device"or "levonorgestrel-releasing intrauterine system"or "Levonorgestrel-Therapeutic-Use" or"LNG-IUS" or"Mirena" or Title CONTAINS"progestagen"or"progesteron"or "Progesterone" or "progestin" or"progestins"or "progestogen" or"Medroxyprogesterone Acetate" or"medroxyprogesterone" or"Depoprovera"or "depot medroxyprogesterone" or "levonorgestrel intrauterine system" or "levonorgestrel-releasing intrauterine device"or "levonorgestrel-releasing intrauterine system"or "Levonorgestrel-Therapeutic-Use" or"LNG-IUS" or"Mirena"

Database: PsycINFO

1     Leiomyoma$.tw. (9)

2     fibromyoma$.tw. (1)

3     myoma$.tw. (16)

4     fibroid$.tw. (28)

5     or/1-4 (52)

6     exp progesterone/ (1548)

7     medroxyprogesterone.tw. (203)

8     progesterone.tw. (2766)

9     progest?gen$.tw. (124)

10     progestin$.tw. (416)

11     levonorgestrel-releasing intrauterine.tw. (6)

12     DPMA.tw. (5)

13     LNG-IUS.tw. (7)

14     hormone-releasing intrauterine system$.tw. (0)

15     IUS.tw. (46)

16     mirena.tw. (0)

17     or/6-16 (3313)

18     5 and 17 (1)

Database: EBM Reviews - Cochrane Central Register of Controlled Trials

1     exp Leiomyoma/ (308)

2     Leiomyoma$.tw. (172)

3     fibromyoma$.tw. (11)

4     myoma$.tw. (180)

5     fibroid$.tw. (181)

6     or/1-5 (504)

7     exp progesterone/ or exp medroxyprogesterone acetate/ (1447)

8     progesterone.tw. (2046)

9     medroxyprogesterone.tw. (1205)

10     progest?gen$.tw. (681)

11     progestin$.tw. (795)

12     levonorgestrel-releasing intrauterine.tw. (74)

13     DPMA.tw. (0)

14     LNG-IUS.tw. (44)

15     hormone-releasing intrauterine system$.tw. (0)

16     IUS.tw. (61)

17     mirena.tw. (19)

18     or/7-17 (4554)

19     6 and 18 (57)

Database: EMBASE

1     exp leiomyoma/ (11250)

2     Leiomyoma$.tw. (9553)

3     fibromyoma$.tw. (495)

4     myoma$.tw. (4331)

5     fibroid$.tw. (3515)

6     or/1-5 (20317)

7     exp progeria/ or exp progesterone/ or exp gestagen/ (117344)

8     medroxyprogesterone acetate.m_titl. (1662)

9     exp medroxyprogesterone acetate/ or exp injectable contraceptive agent/ (12831)

10     progesterone.tw. (58247)

11     medroxyprogesterone.tw. (4914)

12     progest?gen$.tw. (6072)

13     progestin$.tw. (8942)

14     levonorgestrel-releasing intrauterine.tw. (409)

15     DPMA.tw. (87)

16     LNG-IUS.tw. (298)

17     hormone-releasing intrauterine system$.tw. (10)

18     IUS.tw. (554)

19     mirena.tw. (737)

20     exp levonorgestrel/ (6848)

21     or/7-20 (139929)

22     6 and 21 (1249)

23     Clinical Trial/ (785091)

24     Randomized Controlled Trial/ (265639)

25     exp randomization/ (50957)

26     Single Blind Procedure/ (12580)

27     Double Blind Procedure/ (94812)

28     Crossover Procedure/ (28096)

29     Placebo/ (162102)

30     Randomi?ed controlled trial$.tw. (52824)

31     Rct.tw. (5593)

32     random allocation.tw. (960)

33     randomly allocated.tw. (13863)

34     allocated randomly.tw. (1624)

35     (allocated adj2 random).tw. (670)

36     Single blind$.tw. (9916)

37     Double blind$.tw. (108670)

38     ((treble or triple) adj blind$).tw. (208)

39     placebo$.tw. (144876)

40     prospective study/ (150428)

41     or/23-40 (1056160)

42     case study/ (9738)

43     case report.tw. (188909)

44     abstract report/ or letter/ (747109)

45     or/42-44 (942300)

46     41 not 45 (1024962)

47     22 and 46 (252)

48     (2009$ or 2010$).em. (1597240)

49     47 and 48 (35) 

***************************

Database: Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®

1     exp Leiomyoma/ (14708)

2     Leiomyoma$.tw. (8751)

3     fibromyoma$.tw. (573)

4     myoma$.tw. (3807)

5     fibroid$.tw. (2975)

6     or/1-5 (19278)

7     exp progesterone/ or exp medroxyprogesterone acetate/ (59283)

8     progesterone.tw. (59358)

9     medroxyprogesterone.tw. (4820)

10     progest?gen$.tw. (6016)

11     progestin$.tw. (8943)

12     levonorgestrel-releasing intrauterine.tw. (362)

13     DPMA.tw. (78)

14     LNG-IUS.tw. (256)

15     hormone-releasing intrauterine system$.tw. (9)

16     IUS.tw. (451)

17     mirena.tw. (146)

18     or/7-17 (94441)

19     6 and 18 (841)

20     randomized controlled trial.pt. (296179)

21     controlled clinical trial.pt. (82073)

22     randomized.ab. (210847)

23     placebo.tw. (127697)

24     clinical trials as topic.sh. (149957)

25     randomly.ab. (155889)

26     trial.ti. (90677)

27     (crossover or cross-over or cross over).tw. (48873)

28     or/20-27 (720486)

29     exp animals/ not humans.sh. (3512000)

30     28 not 29 (666592)

31     19 and 30 (73)

Contributions of authors

Ussanee S Sangkomkamhang (US) and Malinee Laopaiboon (ML) drafted the review, and Pisake Lumbiganon (PL), Ben Willem J Mol (BWJ Mol) revised and approved the draft version of the review. All authors approved the final version of the manuscript.

Declarations of interest

None known

Sources of support

Internal sources

  • Khon Kaen Hospital, Khon Kaen, Ministry of Public Health, Thailand.

  • Khon Kaen University, Faculty of Medicine, Khon Kaen, Thailand.

  • Khon Kaen University, Faculty of Public Health, Khon Kaen, Thailand.

External sources

  • Thai Cochrane Network, Thailand.

  • Thailand Research Fund (Senior Research Scholar), Thailand.

Differences between protocol and review

  • The methods have been updated following the standards set out in the most recent Cochrane Handbook (Higgins 2011).

  • The objective was modified to be consistent with the review title.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Inki 2002

Methods

Location: five university hospitals in Finland.

Randomised controlled trial: using numbered, opaque, sealed envelopes to receive either LNG-IUS (n = 119) or hysterectomy (n = 117).

Participants

Number of women randomised: 236 (only 73 having uterine fibroids examined by ultrasound).

Inclusion criteria                                           

Women referred for menorrhagia with mean age 43 years (range 35–49 years), all had regular menstrual cycles, had completed family size.                                                     

Exclusion criteria

Women with large enough fibroids to cause bowel or urinary symptoms, with submucous fibroids, lack of indication for hysterectomy, metrorrhagia as a main complaint, previous treatment failure with LNG-IUS, severe depression, history of malignancies, uterine malformation, or with ovarian cysts exceeding 55 mm in diameter, or with adnexal tumors regardless of the size.

Interventions

LNG-IUS (n = 38)

LNG-IUS (Mirena, Leiras, Turku, Finland) was inserted during the randomisation visit in 38 randomised women.

Hysterectomy (n = 35)

Hysterectomy was performed in 35 women.

Outcomes

- Presence and location of any uterine fibroids exceeding 20 mm in diameter measured in two dimensions.

The outcome was measured by using transvaginal ultrasound examinations at baseline, at 6-month and at 12-month follow-up visits by eight experienced gynecologists. The examinations were performed using real-time linear array ultrasound machines equipped with a high frequency (5.0–7.5 MHz) endovaginal convex probe (Toshiba SSA 270 sonolayer, Tokyo, Japan).

Notes

There were only 73 randomised women of this trial that satisfied this review inclusion criteria, having uterine fibroids examined by ultrasound. Diameter of fibroid is only the outcome that was reported in the trial.

There was 46% of fibroids patients initially randomised into the LNG-IUS group and actually had subsequently hysterectomy (data not shown).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information available.
Allocation concealment (selection bias)Low riskQuote "Patients were randomized using numbered, opaque, sealed envelopes to receive either LNG-IUS (n = 119) or hysterectomy (n = 117)."
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt was not possible to blind LNG-IUS and hysterectomy from the gynecologists.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

In LNG-IUS group: Quote "At the 6-month follow-up visit, uterine fibroids were found in 19 out of 98 patients (19.4%), and at the 12-month follow-up in 16 out of 82 (19.5%)".

There was no report in hysterectomy group.

Selective reporting (reporting bias)Unclear riskNo information available.
Other biasUnclear riskNo other obvious biases.

Sayed 2011

Methods

Location: Faculty of Medicine of Assiut University in Egypt.

Randomised controlled trial: using numbered, opaque, sealed envelopes to receive either LNG-IUS (n = 29) or combined oral contraceptive (n = 29).

Participants

Number of women randomised: 58 having uterine fibroids examined by ultrasound.

Inclusion criteria                                           

Women were 20-50 years with heavy menstrual bleeding,requested contraception, had a regular cycle, and make follow up possible. Uterine fibroid was identified on pelvic ultrasound.                                                    

Exclusion criteria:

pregnancy,

history of ectopic pregnancy,

puerperal sepsis,

pelvic inflammatory disease,

evidence of defective coagulation,

abnormalities on ultrasound; including submucous fibroids of any size distorting the cavity of the uterus or intramural or subserous fibroids > 5 cm in diameter

history of malignancy,

evidence of hyperplasia in the endometrial biopsy,

incidental adnexal abnormality on ultrasound,

previous endometrial ablation or resection,

uninvestigated postcoital bleeding,

untreated abnormal cervical cytology results,

contraindication to combined oral contraceptive (COCs).

Interventions

LNG-IUS (n = 29)

LNG-IUS (Mirena; Bayer Schering Pharma, Bayer Healthcare, Berlin, Germany) was inserted during the randomisation visit in 29 randomised women.

Low dose COC (n = 29)

Twelve monthly low dose COC ( Microvlar [Bayer Schering Pharma]) was performed in 29 women. The pills contained 30 μg of ethinyl estradiol and 150 μg of levonorgestrel.

Both groups used same sanitary pads (Always Ultra; Proctor & Gamble, Cairo, Egypt).

Outcomes

A primary outcome was reduction of menstrual blood loss (MBL).

MBL was measured by using a pictorial blood assessment chart (PBAC) at baseline, 6 months, and 12 months.

A direct measurement of MBL was also performed by the alkaline hematin method at baseline and at 12 months.

Secondary outcomes were:

  • haemoglobin and ferritin levels;

  • health-related quality of life;

  • treatment failure (at 12 months e.g. LNG-IUS expulsion, removal of the device, persistent bleeding treated by hysterectomy).

NotesThe size of the fibroids was categorized as less than 3 cm and 3 cm or greater.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe randomisation was conducted using a computer-generated table of random numbers.
Allocation concealment (selection bias)Unclear riskSealed envelope (not described whether it was opaque or not).
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt was not possible to blind LNG-IUS and low dose COC from the participants and investigators.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information available.
Incomplete outcome data (attrition bias)
All outcomes
High riskAt the end of the study 6 cases (20.7%) were lost to follow up in LNG-IUS and 8 cases (27.6%) were lost to follow up in COC.
Selective reporting (reporting bias)Unclear riskNo information available.
Other biasUnclear riskNo information available.

Verspyck 2000

Methods

Location: ten hospitals in France.

Multicentre randomised controlled trial: predefined randomisation list with balanced after every four patients was performed for each centre to receive either lynestrenol or leuprorelin before surgery.

Participants

Number of women randomised: 56 having uterine fibroids examined by ultrasonography were recruited over three years.

Inclusion criteria                                           

Women with symptomatic uterine fibroids indicating surgery and mean age was 41.3 (SD 1.02) years. Uterine fibroid was identified on pelvic ultrasound with one or more fibroids at least 5 cm in diameter or a submucous fibroid. They were not amenorrhoeic and had not received progestin or GnRH agonist therapy in the last 6 months.                                                   

Exclusion criteria:

calcified fibroid,

cause acute compressive complications,

administration of another hormone therapy (except for insulin).

Interventions

Lynestrenol (n = 23)

Preoperative 16-week treatment of oral dose of lynestrenol 5 mg two tabs per day (5th to the 25th menstrual cycle), prior to surgery. Failure to take more than eight tablets in succession also resulted in withdrawal from the study.

Leuprorelin (n = 33)

Preoperative 16-week treatment of subcutaneous injection of leuprorelin 3.75 mg sustained release every 28 days, prior to surgery. The first injection was administered on the first day of the menstrual cycle. A deviation of no more than 1 week in the administration schedule was allowed.

Outcomes

A primary outcome was reduction of fibroid(s) diameter by using pelvic ultrasonography (evaluated at baseline and then after 16 weeks of therapy).

Secondary outcomes were:

  • fibroid symptoms (pelvic pain, non pelvic pain; vaginal bleeding, pressure effect);

  • hormone and serum parameters (estradiol, progesterone, and LH), haemoglobin and ferritin levels (evaluated at baseline and then after 4 weeks and 16 weeks of treatment);

  • serum haemoglobin and haematocrit (evaluated at baseline and then in the pre- and postoperative periods (48 hrs postoperatively));

  • adverse events.

Various laboratory findings were not centralised.

NotesBaseline participants for each group were 22 women in lynestrenol and 32 women in leuprorelin.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information available.
Allocation concealment (selection bias)Unclear riskPredefined randomisation list with balanced after every four patients was mentioned. But no information of concealment was available.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt was not possible to blind oral route of lynestrenol and a subcutaneous injection of leuprorelin from the participants and investigators.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information available.
Incomplete outcome data (attrition bias)
All outcomes
High riskAt the end of the study 5 cases (22.7%) were lost to follow up in lynestrenol and 3 cases (9.3%) were lost to follow up in leuprorelin.
Selective reporting (reporting bias)Unclear riskNo information available.
Other biasUnclear riskNo information available.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Caird 1997The interventions were not progestogen only. Study of oral progestin (MPA) combine with GnRH agonist (Zoladex).
Carr 1993The interventions were not progestogen only. Study of oral progestin (MPA) combine with GnRH agonist (leuprolide).
Chan 2007Study of prophylactic levonorgestrel intrauterine system in tamoxifen-treated women.
Chwalisz 2005Study of the progesterone receptor modulator in treatment of uterine fibroids. This was not RCT.
Chwalisz 2007Study of the progesterone receptor modulator (asoprisnil) on uterine fibroid volume and clinical symptoms.
Friedman 1988The interventions were not progestogen only. Study of oral progestin (MPA) combine with GnRH agonist (leuprolide).
Koh 2007Study of levonorgestrel-releasing intrauterine system on menorrhagia. This was not RCT.
Levens 2008Study of the progesterone receptor modulator (CDB-2914) on uterine fibroid volume and clinical symptoms.
Magalhaes 2010A prospective cohort study of levonorgestrel intrauterine system on uterine fibroid volume.
Palomba 2002Study of the different doses of progestin in postmenopausal women with uterine fibroids.
Rodriguez 2010Study of intrauterine progestins, progesterone antagonists, and receptor modulators in gynecologic applications. This was not RCT study.
Scialli 1995Not only progestin intervention. Study of oral progestin (MPA) compare to placebo subsequent after GnRH agonist (leuprolide acetate).
Siddiqui 2008Study of levonorgestrel intrauterine system (Mirena). This was a review article.
Soysal 2005Study of levonorgestrel-releasing intrauterine device compared to thermal balloon ablation in uterine fibroid-related menorrhagia. This was not an RCT.
West 1992Study of medroxyprogesterone acetate combine with luteinizing hormone-releasing hormone (LHRH) agonist in uterine fibroids.
Wilkens 2008Study of the progesterone receptor modulator on clinical symptoms in patients with uterine fibroid.
Yoshida 2010Study of cell-type specific actions of progesterone receptor modulators in the regulation of uterine leiomyoma growth. This was not an RCT.