Intervention Review

You have free access to this content

Progestogens or progestogen-releasing intrauterine systems for uterine fibroids

  1. Ussanee S Sangkomkamhang1,*,
  2. Pisake Lumbiganon2,
  3. Malinee Laopaiboon3,
  4. Ben Willem J Mol4

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 17 AUG 2012

DOI: 10.1002/14651858.CD008994.pub2


How to Cite

Sangkomkamhang US, Lumbiganon P, Laopaiboon M, Mol BWJ. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD008994. DOI: 10.1002/14651858.CD008994.pub2.

Author Information

  1. 1

    Khon Kaen Hospital, Department of Obstetrics and Gynaecology, Khon Kaen, Thailand

  2. 2

    Khon Kaen University, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen, Thailand

  3. 3

    Khon Kaen University, Department of Biostatistics and Demography, Faculty of Public Health, Khon Kaen, Thailand

  4. 4

    Academic Medical Centre, University of Amsterdam, Obstetrics and Gynaecology, Amsterdam, Netherlands

*Ussanee S Sangkomkamhang, Department of Obstetrics and Gynaecology, Khon Kaen Hospital, Srichan Road, Maung, Khon Kaen, 40000, Thailand. swadpanich@hotmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Inki 2002

MethodsLocation: five university hospitals in Finland.

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


ParticipantsNumber 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.


InterventionsLNG-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).


NotesThere 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 riskIn 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

MethodsLocation: 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).


ParticipantsNumber 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).


InterventionsLNG-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).


OutcomesA 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

MethodsLocation: 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.


ParticipantsNumber 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).


InterventionsLynestrenol (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.


OutcomesA 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.

 
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 months1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 MBL reduction by the alkaline hematin test
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 MBL reduction by a pictorial assessment chart (PBAC)
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Reduction in fibroid size at 12 months1Mean 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 months
158Mean Difference (IV, Fixed, 95% CI)1.5 [0.93, 2.07]

 
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 pain1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 At baseline
156Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.67, 2.21]

    3.2 At 28 days
155Risk Ratio (M-H, Fixed, 95% CI)1.2 [0.56, 2.56]

    3.3 At 16 weeks
149Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.59, 3.71]

 4 Other fibroid symptoms (non pelvic pain)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 At baseline
156Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.60, 1.23]

    4.2 At 28 days
154Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.68, 2.56]

    4.3 At 16 weeks
149Risk Ratio (M-H, Fixed, 95% CI)2.41 [0.90, 6.49]

 5 Adverse events1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Headache
156Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.06, 1.07]

    5.2 Nausea
156Risk Ratio (M-H, Fixed, 95% CI)2.87 [0.57, 14.38]

    5.3 Weight gain
156Risk Ratio (M-H, Fixed, 95% CI)2.15 [0.39, 11.88]

 
Summary of findings for the main comparison. Levonorgestrel-releasing intrauterine system (LNG-IUS) versus low dose combined oral contraceptive (COC) for uterine fibroids

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low1,2

*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.

 1 There was a small sample sizes and high loss of follow-up rate.
2 Total population size was less than 400.
 
Summary of findings 2. Lynestrenol versus leuprorelin (leuprolide) for uterine fibroids

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low1,2

*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.

 1 High loss of follow up rate
2 Total number of events is less than 300