Key messages
- Gonadotropin-releasing hormone analogues (GnRHa) are medications that may be able to reduce womb and fibroid size and increase haemoglobin (a protein that helps transport oxygen in red blood cells) levels before surgery to treat uterine fibroids (non-cancerous growths in the womb). Pretreatment with GnRHa may also reduce the time taken to undergo the operation, the need for blood transfusion, and some complications that can occur during or after surgery.
- Women taking GnRHa before surgery are more likely to experience unwanted side effects such as hot flushes.
- Further research is needed.
What are fibroids?
Fibroids are smooth muscle tumours (non-cancerous growths) found in a woman's uterus (womb) that can make it difficult to become pregnant. They cause pain in the stomach area and heavy bleeding when a woman has her period. Fibroids can make it more likely for a woman to lose her baby through miscarriage.
How are fibroids treated?
Fibroids are often treated by surgery. Some medications, particularly gonadotropin-releasing hormone analogues (GnRHa), might reduce the size of the womb and fibroid(s), making surgery easier, and they might also control heavy bleeding. However, they cannot be used for longer than six months because they may cause bone loss. Other medications that might have similar short-term effects include progestins, dopamine agonists, selective progesterone receptor modulators (SPRMS), oestrogen receptor antagonists and selective oestrogen receptor modulators (SERMS). However, these medications tend to be expensive.
What did we want to find out?
We wanted to find out whether pretreatment with the above-mentioned medications was helpful for:
- reducing heavy blood loss;
- making surgery easier by shrinking the size of the womb and the fibroid growths;
- reducing the time taken to do the operation, number of blood transfusions, amount of bleeding during the operation and complications after the operation.
We also wanted to find out if any of the medications caused unwanted effects.
What did we do?
We searched for studies that looked at medications used before a fibroid operation, either compared with each other or compared with placebo (fake treatment) or no treatment. We summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 41 studies, which included 3982 premenopausal women who were waiting for an operation to remove fibroids that were causing symptoms. Many of the women were anaemic (had low levels of red blood cells or haemoglobin, which affects the oxygen-carrying capacity of the blood). The operations were hysterectomy (uterus removal), myomectomy (removal of the fibroids from the uterus wall) or hysteroscopic resection (removal of fibroids from the uterine cavity).
The studies tested three comparisons: GnRHa versus no treatment or placebo; GnRHa versus other medical therapies; and selective progesterone receptor modulators (SPRMs) versus placebo.
Some of the studies were supported by the companies that made the medications being tested.
Main results
GnRHa versus placebo or no pretreatment
Gonadotropin-releasing hormone analogues (GnRHa) may reduce womb size and fibroid size before surgery. There was no useful information about their effect on bleeding before surgery. GnRHa probably increase haemoglobin levels. However, women taking GnRHa are more likely to experience hot flushes.
Hysterectomy
The time taken to perform a hysterectomy may be less for women who have pretreatment with GnRHa drugs. Their effect on other outcomes measured in the hysterectomy studies is very uncertain: blood loss during the operation, blood transfusions, and complications after the operation.
Myomectomy
The results of these outcomes measured in the myomectomy studies are very uncertain: the length of the operation, blood loss during the operation, blood transfusions, and complications after the operation.
Hysteroscopic resection
GnRHa treatment before hysteroscopic resection for uterine fibroids may make little or no difference to how long the operation takes. One study measured complications after the operation; none were reported. Blood loss and blood transfusions were not measured for hysteroscopic resection.
GnRHa versus other medical therapies
Before surgery
GnRHa pretreatment may reduce womb size before surgery compared to other medical therapies. GnRHa pretreatment may make little or no difference to bleeding or fibroid size. It probably does not affect haemoglobin levels. However, GnRHa may result in more unwanted effects such as hot flushes.
SPRMs versus placebo
Before surgery
Compared to placebo medication, SPRMs (such as mifepristone, CDB-2914, ulipristal acetate and asoprisnil) before surgery probably reduce womb size and increase haemoglobin levels. They may reduce fibroid size and bleeding. Results were imprecise for unwanted effects.
What are the limitations of the evidence?
Our certainty in the evidence for most outcomes is low or very low, due to poor reporting in the studies and lack of outcome assessor 'blinding' (i.e. the people measuring the outcomes knew who was in each group, which could have influenced their findings). In addition, results varied across studies, and some results were based on only one study.
How up-to-date is this evidence?
This review updates one published in 2017 and is up to date to August 2024.
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.
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.
To assess the benefits and risks of medical treatments prior to surgery for uterine fibroids.
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.
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.
We used standard Cochrane methods. We assessed the certainty of the evidence using GRADE.
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).