Background
Endometriosis is a common gynecological condition that affects 6% to 11% of women of reproductive age and can cause dyspareunia, dysmenorrhea, and infertility . One treatment strategy is medical treatment with gonadotropin-releasing hormone analogues (GnRHas) to reduce pain due to endometriosis. One of the adverse effects of GnRHas is a decrease in bone mineral density.
In addition to evaluating the effect on pain, quality of life, most bothersome symptoms and patient satisfaction, the current review also evaluated the effect on bone mineral density and risk of adverse effects in women with endometriosis using GnRHa versus other treatment options.
Goals
To evaluate 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 in women with endometriosis.
Search methods
We searched the Cochrane Gynecology and Fertility Group (CGF) Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO and trials registers in May 2022 along with reference checking and contacting study authors and experts in the field to identify additional studies.
Selection criteria
We included randomized controlled trials (RCTs) that compared GnRHas with other hormonal treatment options, including analgesics, danazol, intrauterine progestins, oral or injectable progestins, gestrinone and also GnRHas compared with no treatment or placebo.
Trials comparing GnRHa versus GnRHa along with adjunctive therapy (hormonal or non-hormonal) or calcium-regulating agents were also included in this review.
Data collection and analysis
The standard methodology recommended by Cochrane was used. The primary outcomes are overall pain relief and objective measurement of bone mineral density. Secondary outcomes include adverse effects, quality of life, improvement in most bothersome symptoms, and patient satisfaction.
Due to the high risk of bias associated with some of the studies, primary analyzes of all review results were limited to studies with low risk of selection bias. A sensitivity analysis was then performed that included all studies.
Main results
72 studies with 7355 patients were included. The evidence was of 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
No studies were identified.
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), dysmenorrhea 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 of three months of treatment.
The effect for pelvic induration is not known based on results found after three months of treatment (RR 1.07, 95% CI 0.64 to 1.79; 1 RCT, n = 81, low-certainty evidence ). Furthermore, GnRHa treatment may be associated with a higher incidence of hot flashes at three months of treatment (RR 3.08, 95% CI 1.89 to 5.01, 1 RCT, n = 100, clear evidence low).
Trials comparing GnRHas versus danazol
For general pain, for women treated with GnRHas or danazol, a subdivision was made between pelvic tenderness, partially resolved and completely resolved. We are uncertain about the effect on overall pain relief when 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), dysmenorrhea (MD 0.10, very low certainty evidence), 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.
Trials comparing GnRHas versus analgesics
No studies were identified.
Trials comparing GnRHas versus intrauterine progestogens
No studies with low risk of bias were identified.
Trials comparing GnRHas versus GnRHas together with calcium-regulating agents
There may be a slight decrease in bone mineral density (BMD) after 12 months of treatment with GnRHa, compared to GnRHa together with calcium-regulating agents for the anteroposterior spine (MD -7.00, 95% CI -7 .53 to -6.47, 1 RCT, n = 41, very low certainty evidence) and lateral column (MD -12.40, 95% CI -13.31 to -11.49, 1 RCT, n = 41, very low certainty evidence).
Authors’ conclusions For overall pain relief, there may be a slight decrease in favor of GnRHa treatment compared to placebo or oral or injectable progestins. We are uncertain about the effect when GnRHa is compared with danazol, intrauterine progestins or gestrinone. For bone mineral density (BMD), there may be a slight decrease when women are treated with GnRHa, compared to gestrinone. There was a greater decrease in bone mineral density (BMD) in favor of GnRHa, compared to GnRHa together 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 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. |
Implications for practice
Women who have complaints of endometriosis can be treated in different ways. The current review suggests that, for overall pain relief, there may be a decline in favor of GnRHa treatment compared with placebo or oral or injectable progestins. We are not sure about the effects when GnRHa is compared with danazol, intrauterine progestins or gestrinone. Not all aspects of pain relief are looked at in all trials and generalizing about relief of specific aspects of pain can be difficult.
This review showed that there may be a slight decrease in BMD when women were treated with GnRHa, compared to gestrinone. There was also a greater decrease in bone mineral density (BMD) when women were treated with GnRHa alone, compared to GnRHa together with calcium-regulating agents. Therefore, there may be an increase in adverse effects when women are treated with GnRHas, compared to placebo or gestrinone. This should be considered in the decision-making process with the patient, as endometriosis is a common disease, with many different treatment options that must be individualized according to each patient’s wishes and stage of life.
Implications for research
Due to the limited number of low-risk studies and high heterogeneity in sensitivity analyses, further research is recommended on the effects of GnRHa and other hormonal treatment options on the reported outcomes. We recommend considering a large modern study with low risk of bias to validate the practice that has become common practice. Furthermore, it remains important to clearly describe the method in future articles, so that more articles can be labeled as low risk of bias in future reviews.
