Progestogens or progestogen-releasing intrauterine systems for uterine fibroids (other than preoperative medical therapy)

Review question

Are progestogens or progestogen-releasing intrauterine systems (LNG-IUS) effective treatments for premenopausal women with uterine fibroids who are not preparing for surgery?

Background

Uterine fibroids are non-cancerous tumours in the uterus, common in women who are premenopausal. Most fibroids do not cause symptoms, but some women experience significant symptoms. Common symptoms include abnormal uterine bleeding (heavier, or longer than usual menstrual bleeding), pelvic pressure (urinary frequency, constipation), and pelvic pain. Treatment for fibroids includes medical treatment, surgery, or both. Medical treatments are considered the first-line treatment, to preserve fertility, and avoid or delay surgery. Surgery may remove the fibroid, or the whole uterus, depending on the situation. Progestogens (medications similar to the natural hormone, progesterone) can be taken orally, or administered by injection. Depot medroxyprogesterone acetate (DMPA) is a synthetic progesterone hormone, given by intramuscular injection, which may prevent the growth of uterine fibroids. The progestogen-releasing (levonorgestrel) intrauterine system (LNG-IUS) is a device placed inside the uterus, which releases progesterone and suppresses the endometrium, or uterine lining, to reduce menstrual blood flow.

Study characteristics

We included four randomised controlled trials, with a total of 221 women with uterine fibroids; 161 women were randomised to compare LNG-IUS to other medical treatment (low dose combined oral contraceptive (COC) or oral progestogen (norethisterone acetate (NETA)), and 60 women were randomised to compare oral progestogen to goserelin acetate (injected medication that suppresses the hormone oestrogen). The studies reported on uterine fibroid-related symptoms, such as menstrual blood loss, and fibroid size. The evidence is current to July 2020.

Key results

Very low-quality evidence suggests that we are uncertain whether using a LNG-IUS reduces abnormal uterine bleeding, or increases haemoglobin levels more than taking COC or NETA, in premenopausal women with uterine fibroids. We are also uncertain whether oral progestogen reduces abnormal uterine bleeding more than goserelin acetate. Women who had a LNG-IUS, were more likely to report more spotting than those taking NETA. Evidence on fibroid size and adverse events for progestogens was poorly reported and inconclusive.

Quality of the evidence

The evidence was of very low-quality. The main limitations of the evidence were poor reporting of study methods (high or unclear risk of bias), lack of precise findings, and small numbers of studies and participants.

Authors' conclusions: 

Because of very low-quality evidence, we are uncertain whether the LNG-IUS reduces abnormal uterine bleeding or increases haemoglobin levels in premenopausal women with uterine fibroids, compared to COC or norethisterone acetate. There was insufficient evidence to determine whether the LNG-IUS reduces the size of uterine fibroids compared to COC. We are uncertain whether oral progestogens reduce abnormal uterine bleeding as effectively as goserelin acetate, but women reported fewer adverse events, such as hot flashes.

Read the full abstract...
Background: 

Uterine fibroids can cause heavy menstrual bleeding. Medical treatments are considered to preserve fertility. It is unclear whether progestogens or progestogen-releasing intrauterine systems can reduce fibroid-related symptoms. This is the first update of a Cochrane Review published in 2013.

Objectives: 

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

Search strategy: 

We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and PsycINFO databases to July 2020. We also searched trials registers for ongoing and registered trials, and checked references of relevant 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: 

Two authors independently extracted data, assessed risk of bias, and assessed the quality of the evidence using the GRADE approach.

Main results: 

This updated review included four studies with 221 women with uterine fibroids. The evidence was very low quality, downgraded for serious risk of bias, due to poor reporting of study methods, and serious imprecision.

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

There was no information on the outcomes of interest, including adverse events.

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

At 12 months, we are uncertain whether LNG-IUS reduced the percentage of abnormal uterine bleeding, measured with the alkaline hematin test (mean difference (MD) 77.50%, 95% confidence interval (CI) 70.44 to 84.56; 1 RCT, 44 women; very low-quality evidence), or the pictorial blood assessment chart (PBAC; MD 34.50%, 95% CI 11.59 to 57.41; 1 RCT, 44 women; very low-quality evidence); increased haemoglobin levels (MD 1.50 g/dL, 95% CI 0.85 to 2.15; 1 RCT, 44 women; very low-quality evidence), or reduced fibroid size more than COC (MD 1.90%, 95% CI -12.24 to 16.04; 1 RCT, 44 women; very low-quality evidence). The study did not measure adverse events.

LNG-IUS versus oral progestogen (norethisterone acetate (NETA))

Compared to NETA, we are uncertain whether LNG-IUS reduced abnormal uterine bleeding more from baseline to six months (visual bleeding score; MD 23.75 points, 95% CI 1.26 to 46.24; 1 RCT, 45 women; very low-quality evidence); increased the percentage of change in haemoglobin from baseline to three months (MD 4.53%, 95% CI 1.46 to 7.60; 1 RCT, 48 women; very low-quality evidence), or from baseline to six months (MD 10.14%, 95% CI 5.57 to 14.71; 1 RCT, 45 women; very low-quality evidence). The study did not measure fibroid size. Spotting (adverse event) was more likely to be reported by women with the LNG-IUS (64.3%) than by those taking NETA (30%; 1 RCT, 45 women; very low-quality evidence).

Oral progestogen (dienogest, desogestrel) versus goserelin acetate

Compared to goserelin acetate, we are uncertain whether abnormal uterine bleeding was reduced at 12 weeks with dienogest (PBAC; MD 216.00 points, 95% CI 149.35 to 282.65; 1 RCT, 14 women; very low-quality evidence) or desogestrel (PBAC; MD 78.00 points, 95% CI 28.94 to 127.06; 1 RCT, 16 women; very low-quality evidence). Vasomotor symptoms (adverse events, e.g. hot flashes) are only associated with goserelin acetate (55%), not with dienogest (1 RCT, 14 women; very low-quality evidence) or with desogestrel (1 RCT, 16 women; very low-quality evidence). The study did not report fibroid size.

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