What are the benefits and risks of gonadotrophin-releasing hormone analogues (GnRHas) for pain associated with endometriosis?
Key messages
GnRHas offer more pain reduction compared to placebo or progestogens. However, the largest decrease in bone mineral density (BMD) was found when using GnRHas, compared to a different hormone called gestrinone and GnRHas together with calcium-regulating agents (acting on bone).
Most adverse effects were hot flushes for patients treated with GnRHas or gestrinone (hormone) and weight gain when treated with danazol (hormone).
Further, well-designed research is needed to provide better understanding of the benefits and risks of using GnRHas and other hormonal treatment options for pain associated with endometriosis.
What is endometriosis?
Endometriosis is a common condition, affecting women of childbearing age, and is usually due to the presence of endometrial-like tissue in places other than the uterus. The most reported symptoms are pain and infertility.
What are GnRHas?
GnRHas are a group of drugs often used to treat endometriosis. GnRHas are a synthetic form of the hormone gonadorelin, released by the hypothalamus in the brain. They stimulate the pituitary gland in the brain to produce luteinising hormone (LH) and follicle-stimulating hormone (FSH), both reproductive hormones. These reproductive hormones further stimulate the production of progesterone and oestrogen in the ovaries, the hormones that control your menstrual cycle.
However, continued use of GnRHas results in a suppression of ovarian function and therefore reduces oestrogen and progesterone levels. This will in turn result in a decrease of endometrial tissue and therefore reduce complaints of endometriosis.
Because GnRHas temporarily stop the production of reproductive hormones, they mimic symptoms of menopause, including a decrease in bone mineral density (the amount of calcium and other minerals present in your bones).
What did we want to find out?
In the current review, we looked at women with endometriosis, who were treated with GnRHas, and compared this treatment with other forms of hormonal treatment.
We wanted to find out if GnRHas were better than any other hormonal treatment to improve pain and to see their effect on bone mineral density.
Additionally, we wanted to find out if GnRHas were associated with an improved quality of life and also unveil any unwanted effects.
What did we do?
The review involved searching for studies that investigated the effect of GnRHas compared with placebo (dummy treatment) and other hormonal treatment in women with endometriosis. We compared and 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 72 trials that involved 7355 women with endometriosis.
- A difference in overall pain, reported as pain reduction was seen in favour of GnRHas compared to placebo. We also saw that women treated with GnRHas had less pelvic pain reduction and an increase in endometriotic lesions after six months of treatment, compared to danazol.
- After six months of treatment, there was a greater decrease of pain for women treated with GnRHas compared to gestrinone.
- No difference was seen in pain scores between women treated with GnRHas compared to other hormonal treatment options.
- Most adverse effects were seen in women treated with GnRHas compared to placebo (hot flushes), with danazol (weight gain) and gestrinone (hot flushes).
- A greater decrease in bone mineral density was found in GnRHas compared to gestrinone and GnRHas in conjunction with calcium-regulating agents.
- For the other comparisons examined in the current review, we are uncertain of the effect between the examined groups. It should be noted, however, that the evidence was often of (very) low quality in the analyses undertaken for the other comparisons.
What are the limitations of the evidence?
The included studies were of low quality mainly due to poor reporting of study methods and the inaccuracy with which the results were reported.
How up-to-date is this evidence?
The evidence is up-to-date to May 2022.
For relief of overall pain, there may be a slight decrease in favour of treatment with GnRHas compared to placebo or oral or injectable progestogens. We are uncertain about the effect when comparing GnRHas with danazol, intra-uterine progestogens or gestrinone. For BMD, there may be a slight decrease when women are treated with GnRHas, compared to gestrinone. There was a bigger decrease of BMD in favour of GnRHas, compared to GnRHas in conjunction with calcium-regulating agents. However, there may be a slight increase in adverse effects when women are treated with GnRHas, compared to placebo or gestrinone.
Due to a very low to low certainty of the evidence, a wide range of outcome measures and a wide range of outcome measurement instruments, the results should be interpreted with caution.
Endometriosis is a common gynaecological condition affecting 6 to 11% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is medical therapy with gonadotrophin-releasing hormone analogues (GnRHas) to reduce pain due to endometriosis. One of the adverse effects of GnRHas is a decreased bone mineral density. In addition to assessing the effect on pain, quality of life, most troublesome symptom and patients' satisfaction, the current review also evaluated the effect on bone mineral density and risk of adverse effects in women with endometriosis who use GnRHas versus other treatment options.
To assess the effectiveness and safety of GnRH analogues (GnRHas) in the treatment of painful symptoms associated with endometriosis and to determine the effects of GnRHas on bone mineral density of women with endometriosis.
We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and the trial registries in May 2022 together with reference checking and contact with study authors and experts in the field to identify additional studies.
We included randomised controlled trials (RCTs) which compared GnRHas with other hormonal treatment options, including analgesics, danazol, intra-uterine progestogens, oral or injectable progestogens, gestrinone and also GnRHas compared with no treatment or placebo. Trials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) or calcium-regulation agents were also included in this review.
We used standard methodology as recommended by Cochrane. Primary outcomes are relief of overall pain and the objective measurement of bone mineral density. Secondary outcomes include adverse effects, quality of life, improvement in the most troublesome symptoms and patient satisfaction.
Due to high risk of bias associated with some of the studies, primary analyses of all review outcomes were restricted to studies at low risk of selection bias. Sensitivity analysis including all studies was then performed.
Seventy-two studies involving 7355 patients were included. The evidence was very low to low quality: the main limitations of all studies were serious risk of bias due to poor reporting of study methods, and serious imprecision.
Trials comparing GnRHas versus no treatment
We did not identify any studies.
Trials comparing GnRHas versus placebo
There may be a decrease in overall pain, reported as pelvic pain scores (RR 2.14; 95% CI 1.41 to 3.24, 1 RCT, n = 87, low-certainty evidence), dysmenorrhoea scores (RR 2.25; 95% CI 1.59 to 3.16, 1 RCT, n = 85, low-certainty evidence), dyspareunia scores (RR 2.21; 95% CI 1.39 to 3.54, 1 RCT, n = 59, low-certainty evidence), and pelvic tenderness scores (RR 2.28; 95% CI 1.48 to 3.50, 1 RCT, n = 85, low-certainty evidence) after three months of treatment. We are uncertain of the effect for pelvic induration, based on the results found after three months of treatment (RR 1.07; 95% CI 0.64 to 1.79, 1 RCT, n = 81, low-certainty evidence). Besides, treatment with GnRHas may be associated with a greater incidence of hot flushes at three months of treatment (RR 3.08; 95% CI 1.89 to 5.01, 1 RCT, n = 100, low-certainty evidence).
Trials comparing GnRHas versus danazol
For overall pain, for women treated with either GnRHas or danazol, a subdivision was made between pelvic tenderness, partly resolved and completely resolved. We are uncertain about the effect on relief of overall pain, when a subdivision was made for overall pain (MD -0.30; 95% CI -1.66 to 1.06, 1 RCT, n = 41, very low-certainty evidence), pelvic pain (MD 0.20; 95% CI -0.26 to 0.66, 1 RCT, n = 41, very low-certainty evidence), dysmenorrhoea (MD 0.10; 95% CI -0.49 to 0.69, 1 RCT, n = 41, very low-certainty evidence), dyspareunia (MD -0.20; 95% CI -0.77 to 0.37, 1 RCT, n = 41, very low-certainty evidence), pelvic induration (MD -0.10; 95% CI -0.59 to 0.39, 1 RCT, n = 41, very low-certainty evidence), and pelvic tenderness (MD -0.20; 95% CI -0.78 to 0.38, 1 RCT, n = 41, very low-certainty evidence) after three months of treatment. For pelvic pain (MD 0.50; 95% CI 0.10 to 0.90, 1 RCT, n = 41, very low-certainty evidence) and pelvic induration (MD 0.70; 95% CI 0.21 to 1.19, 1 RCT, n = 41, very low-certainty evidence), the complaints may decrease slightly after treatment with GnRHas, compared to danazol, for six months of treatment.
Trials comparing GnRHas versus analgesics
We did not identify any studies.
Trials comparing GnRHas versus intra-uterine progestogens
We did not identify any low risk of bias studies.
Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents
There may be a slight decrease in bone mineral density (BMD) after 12 months treatment with GnRHas, compared to GnRHas in conjunction with calcium-regulating agents for anterior-posterior spine (MD -7.00; 95% CI -7.53 to -6.47, 1 RCT, n = 41, very low-certainty evidence) and lateral spine (MD -12.40; 95% CI -13.31 to -11.49, 1 RCT, n = 41, very low-certainty evidence).