Preoperative medical therapy before surgery for uterine fibroids.

Background: Uterine fibroids occur in up to 40% of women over 35 years of age. Up to 50% of uterine fibroids cause symptoms that warrant treatment: anaemia caused by heavy menstrual bleeding, pelvic pain, dysmenorrhoea, infertility and poor quality of life. Surgery is the first choice of treatment, but medical therapies have been used prior to surgery to improve outcomes. Gonadotropin-hormone-releasing analogues (GnRHa) induce a low-oestrogen state that shrinks fibroids, but they have unacceptable side effects if used long-term. Other potential hormonal treatments include progestins and selective progesterone-receptor modulators (SPRMs). This updates a Cochrane review published in 2017.

Objectives: To assess the benefits and risks of medical treatments prior to surgery for uterine fibroids.

Search methods: We searched the Cochrane Gynaecology and Fertility Group Specialized Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL on 8 August 2024. We also searched trials registers (ClinicalTrials.gov; WHO ICTRP), theses and dissertations, and grey literature, as well as handsearching reference lists of retrieved articles and contacting pharmaceutical companies.

Selection criteria: We included randomised controlled trials of premenopausal women receiving medical therapy before myomectomy, hysterectomy or hysteroscopic resection for uterine fibroids versus placebo, no pretreatment or another medical therapy.

Data collection and analysis: We used standard Cochrane methods. We assessed the certainty of the evidence using GRADE.

Main results: We included 41 RCTs, which involved 3982 women. Thirty-six studies evaluated GnRHa: the comparators were no pretreatment (19 studies), placebo (9 studies), or other medical pretreatments (progestin, SPRMs, selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor antagonists) (8 studies). Five studies evaluated SPRMs versus placebo. Most results provided low-certainty evidence due to poor reporting of randomisation procedures, lack of blinding, imprecision and inconsistency. Some outcomes were not measured or did not have usable data. The use of ulipristal acetate (an SPRM) is suspended at this time (March 2025) because of an association with cases of liver failure. GnRHa versus placebo or no pretreatment before surgery for uterine fibroids GnRHa pretreatment may reduce uterine volume (mean difference (MD) -175.34 mL, 95% confidence interval (CI) -219.04 to -131.65; 13 studies, 858 participants; I² = 67%; low-certainty evidence) and fibroid volume (MD range 5.7 mL to 155.4 mL; 5 studies to heterogeneous to pool, 427 participants; low-certainty evidence), and probably increases preoperative haemoglobin (MD 0.88 g/dL, 95% CI 0.68 to 1.08; 10 studies, 834 participants; I² = 0%; moderate-certainty evidence). However, there is probably a greater likelihood of adverse events with GnRHa (odds ratio (OR) 2.78, 95% CI 1.77 to 4.36; 5 studies, 755 participants; I² = 28%; moderate-certainty evidence). No usable data were available for preoperative bleeding. Hysterectomy Duration of hysterectomy may be reduced amongst women who receive GnRHa treatment (-10.11 minutes, 95% CI -16.96 to -3.25; 6 studies, 617 participants; I² = 57%; low-certainty evidence). Results are uncertain for intraoperative blood loss (4 heterogeneous studies, 258 participants; MD range 25 mL to 148 mL, in favour of GnRHa; very low-certainty evidence). There are probably fewer blood transfusions with GnRHa (OR 0.54, 95% CI 0.29 to 1.01; 6 studies, 601 participants; I² = 0%; moderate-certainty evidence) and less postoperative morbidity (OR 0.54, 95% CI 0.32 to 0.91; 7 studies, 772 participants; I² = 28%; moderate-certainty evidence). Myomectomy There is uncertainty about the effects of GnRHa pretreatment on surgery duration (7 heterogeneous studies, 443 participants) (very low-certainty evidence) and intraoperative blood loss during myomectomy (11 studies too heterogenous to pool, 549 participants; very low-certainty evidence). GnRHa may make little to no difference to blood transfusions (OR 0.85, 95% CI 0.26 to 2.75; 4 studies, 121 participants; I² = 0%; low-certainty evidence) or postoperative morbidity (OR 1.07, 95% CI 0.43 to 2.64; I² = 0%; 5 studies, 190 participants; low-certainty evidence). Hysteroscopic resection GnRHa treatment before hysteroscopic resection of uterine myomas may result in little to no difference in surgery duration (2 studies,123 participants; low-certainty evidence). One study reported no cases of postoperative morbidity in either group (84 participants; low-certainty evidence). GnRHa versus other medical therapies before surgery - preoperative outcomes GnRHa may be associated with a greater reduction in uterine volume than other medical therapies (-47% compared to -20% and -22% with 5 mg and 10 mg ulipristal acetate, respectively; low-certainty evidence). There may be little to no difference in bleeding reduction (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.30 to 1.68; 1 study, 199 participants; low-certainty evidence), and there is probably little to no difference in preoperative haemoglobin (MD -0.02, 95% CI -0.41 to 0.37; 242 participants; moderate-certainty evidence). We are uncertain whether there is any difference in fibroid volume between GnRHa and cabergoline (MD 12.71 mL, 95% CI -5.92 to 31.34; 2 studies, 110 participants; I² = 0%; low-certainty evidence). Adverse events such as hot flushes may be more likely with GnRHa (OR 2.83, 95% CI 1.68 to 4.77; 6 studies, 507 participants; I² = 59%; low-certainty evidence). SPRMs versus placebo before surgery - preoperative outcomes SPRMs (mifepristone, CDB-2914, ulipristal acetate and asoprisnil) before surgery probably reduce uterine volume (2 heterogenous studies, 275 participants; moderate-certainty evidence) and may reduce fibroid volume (5 heterogeneous studies, 451 participants; low-certainty evidence). SPRMs probably increase preoperative haemoglobin (MD 0.93 g/dL, 95% CI 0.52 to 1.34; 2 studies, 173 participants; I² = 0%; moderate-certainty evidence), and they may reduce bleeding before surgery (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.26 to 112.38; 1 study, 143 participants; asoprisnil: MD -166.9 mL; 95% CI -277.60 to -56.20; 1 study, 22 participants; low-certainty evidence). Results were very imprecise for adverse events (low-certainty evidence).

Authors' conclusions: Pretreatment with gonadotropin-hormone-releasing analogues may reduce uterine and fibroid volume and probably increases preoperative haemoglobin levels, but probably also increases the number of adverse events. Blood transfusions and operation time during hysterectomy may be reduced, with fewer women experiencing postoperative morbidity. SPRMs, such as ulipristal acetate, seem to offer similar advantages: they probably reduce uterine volume and increase haemoglobin level before surgery, and may reduce fibroid volume and fibroid-related bleeding. However, replication of these studies is advised as the certainty of the evidence is moderate to low.