Review question
We investigated if giving drugs before surgery for uterine fibroids improves outcomes.
Background
Uterine fibroids are smooth muscle tumours of the uterus (womb) that can cause fertility problems, heavy menstrual bleeding, repeated pregnancy loss and pelvic pain. Fibroids are usually treated by surgery. Some drugs, particularly gonadotropin-releasing hormone analogues (GnRHa), have been used to temporarily control bleeding and reduce fibroid and uterine size before surgery. They are unsuitable for long-term use because they may cause bone loss. Other drugs, including progestins, dopamine agonists, selective progesterone receptor modulators (SPRMs), oestrogen receptor antagonists and selective oestrogen receptor modulators (SERMs), may also provide benefits used short-term. However, such therapies tend to be expensive.
Search date
We searched for evidence to June 2017.
Study characteristics
We included 38 studies that involved 3623 women with fibroids that caused symptoms and who were scheduled for surgery to remove the fibroids. Surgeries were either hysterectomy (uterus removal) or myomectomy or resection (removal of fibroids from the uterus wall). Many women were anaemic (had low red blood cell or haemoglobin levels).
The studies compared GnRHa with no treatment or sham treatment, GnRHa with other medical treatments, and SPRMs with sham treatment.
Study funding sources
Fourteen studies were either wholly or partially funded by pharmaceutical companies; three were funded by institutions or hospitals; the source of funding was unclear for 21 trials. It was not possible to determine whether funding source influenced results.
Key results
GnRHa increased haemoglobin levels before surgery and decreased uterine and fibroid size, compared with no treatment or placebo. Blood loss, need for blood transfusion, operation time during hysterectomy and postoperative complications were reduced. However, women were more likely to experience hot flushes during treatment. An SPRM drug (ulipristal acetate) had similar benefits, particularly reduced bleeding. Future research should focus on cost-effectiveness and distinguish between groups of women with fibroids who would most benefit.
Quality of the evidence
The overall quality of evidence for most outcomes was low or very low, meaning there is substantial uncertainty about findings. Quality limitations included lack of reporting of randomisation methods and allocation concealment, lack of blinding (which means that knowledge of treatment could have influenced the findings) and variation in findings among studies. Some findings were imprecise because they were based on only one study.
A rationale for the use of preoperative medical therapy before surgery for fibroids is to make surgery easier. There is clear evidence that preoperative GnRHa reduces uterine and fibroid volume, and increases preoperative haemoglobin levels, although GnRHa increases the incidence of hot flushes. During hysterectomy, blood loss, operation time and complication rates were also reduced. Evidence suggests that ulipristal acetate may offer similar advantages (reduced fibroid volume and fibroid-related bleeding and increased haemoglobin levels) although replication of these studies is advised before firm conclusions can be made. Future research should focus on cost-effectiveness and distinguish between groups of women with fibroids who would most benefit.
Uterine fibroids occur in up to 40% of women aged over 35 years. Some are asymptomatic, but up to 50% cause symptoms that warrant therapy. Symptoms include anaemia caused by heavy menstrual bleeding, pelvic pain, dysmenorrhoea, infertility and low quality of life. Surgery is the first choice of treatment. In recent years, medical therapies have been used before surgery to improve intraoperative and postoperative outcomes. However, such therapies tend to be expensive.
Fibroid growth is stimulated by oestrogen. Gonadotropin-hormone releasing analogues (GnRHa) induce a state of hypo-oestrogenism that shrinks fibroids , but has unacceptable side effects if used long-term. Other potential hormonal treatments, include progestins and selective progesterone-receptor modulators (SPRMs).
This is an update of a Cochrane Review published in 2000 and 2001; the scope has been broadened to include all preoperative medical treatments.
To assess the effectiveness and safety of medical treatments prior to surgery for uterine fibroids.
We searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL in June 2017. We also searched trials registers (ClinicalTrials.com; WHO ICTRP), theses and dissertations and the grey literature, handsearched reference lists of retrieved articles and contacted pharmaceutical companies for additional trials.
We included randomised comparisons of medical therapy versus placebo, no treatment, or other medical therapy before surgery, myomectomy, hysterectomy or endometrial resection, for uterine fibroids.
We used standard methodological procedures expected by The Cochrane Collaboration.
We included a total of 38 RCTs (3623 women); 19 studies compared GnRHa to no pretreatment (n = 19), placebo (n = 8), other medical pretreatments (progestin, SPRMs, selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor antagonists) (n = 7), and four compared SPRMs with placebo. Most results provided low-quality evidence due to limitations in study design (poor reporting of randomisation procedures, lack of blinding), imprecision and inconsistency.
GnRHa versus no treatment or placebo
GnRHa treatments were associated with reductions in both uterine (MD -175 mL, 95% CI -219.0 to -131.7; 13 studies; 858 participants; I² = 67%; low-quality evidence) and fibroid volume (heterogeneous studies, MD 5.7 mL to 155.4 mL), and increased preoperative haemoglobin (MD 0.88 g/dL, 95% CI 0.7 to 1.1; 10 studies; 834 participants; I² = 0%; moderate-quality evidence), at the expense of a greater likelihood of adverse events, particularly hot flushes (OR 7.68, 95% CI 4.6 to 13.0; 6 studies; 877 participants; I² = 46%; moderate-quality evidence).
Duration of hysterectomy surgery was reduced among women who received GnRHa treatment (-9.59 minutes, 95% CI 15.9 to -3.28; 6 studies; 617 participants; I² = 57%; low-quality evidence) and there was less blood loss (heterogeneous studies, MD 25 mL to 148 mL), fewer blood transfusions (OR 0.54, 95% CI 0.3 to 1.0; 6 studies; 601 participants; I² = 0%; moderate-quality evidence), and fewer postoperative complications (OR 0.54, 95% CI 0.3 to 0.9; 7 studies; 772 participants; I² = 28%; low-quality evidence).
GnRHa appeared to reduce intraoperative blood loss during myomectomy (MD 22 mL to 157 mL). There was no clear evidence of a difference among groups for other primary outcomes after myomectomy: duration of surgery (studies too heterogeneous for pooling), blood transfusions (OR 0.85, 95% CI 0.3 to 2.8; 4 studies; 121 participants; I² = 0%; low-quality evidence) or postoperative complications (OR 1.07, 95% CI 0.43 to 2.64; I² = 0%; 5 studies; 190 participants; low-quality evidence). No suitable data were available for analysis of preoperative bleeding.
GnRHa versus other medical therapies
GnRHa was associated with a greater reduction in uterine volume (-47% with GnRHa compared to -20% and -22% with 5 mg and 10 mg ulipristal acetate) but was more likely to cause hot flushes (OR 12.3, 95% CI 4.04 to 37.48; 5 studies; 183 participants; I² = 61%; low-quality evidence) compared with ulipristal acetate. There was no clear evidence of a difference in bleeding reduction (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.3 to 1.7; 1 study; 199 participants; moderate-quality evidence; ulipristal acetate 10 mg: OR 0.39, 95% CI 0.1 to 1.1; 1 study; 203 participants; moderate-quality evidence) or haemoglobin levels (MD -0.2, 95% CI -0.6 to 0.2; 188 participants; moderate-quality evidence).
There was no clear evidence of a difference in fibroid volume between GnRHa and cabergoline (MD 12.71 mL, 95% CI -5.9 to 31.3; 2 studies; 110 participants; I² = 0%; low-quality evidence).
The included studies did not report usable data for any other primary outcomes.
SPRMs versus placebo
SPRMs (mifepristone, CDB-2914, ulipristal acetate and asoprisnil) were associated with greater reductions in uterine or fibroid volume than placebo (studies too heterogeneous to pool) and increased preoperative haemoglobin levels (MD 0.93 g/dL, 0.5 to 1.4; 2 studies; 173 participants; I² = 0%; high-quality evidence). Ulipristal acetate and asoprisnil were also associated with greater reductions in bleeding before surgery (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.3 to 112.4; 1 study; 143 participants; low-quality evidence; ulipristal acetate 10 mg: OR 78.83, 95% CI 24.0 to 258.7; 1 study; 146 participants; low-quality evidence; asoprisnil: MD -166.9 mL; 95% CI -277.6 to -56.2; 1 study; 22 participants; low-quality evidence). There was no evidence of differences in preoperative complications. No other primary outcomes were measured.