Review question
Cochrane Review authors reviewed the evidence on efficacy and safety of drugs called selective oestrogen receptor modulators (SERMs) for women with biopsy-proven endometriosis.
Background
Endometriosis is a disease that affects 1 in 10 women of reproductive age. Endometriosis can cause abdominal and menstrual pain and infertility. Spreading and activity of the disease are dependent on the hormone oestrogen. Medical treatment consists of pain medication to relieve symptoms, oral contraceptive pills to suppress the menstrual cycle, or other hormonal treatments such as progestogen medication or hormonal intrauterine devices. SERMs aim to block the effects of oestrogen and could offer promise as medical treatment for endometriosis. We compared the effects and safety of SERMs versus placebo or other treatment for endometriosis.
Study characteristics
Only one randomised controlled trial was included in this review. This study compared the SERM 'raloxifene' versus placebo in 93 women who had undergone complete surgical excision of all endometriosis lesions. Evidence is current to 28 May 2020.
Key results
The included study did not report the primary outcome of pain relief. Adverse events such as pelvic pain, ovarian cyst, headache, migraine, and depression did not differ between study groups. We are uncertain whether raloxifene improves adverse outcomes when compared with placebo (1 study, 93 women; very low-quality evidence). We are uncertain whether raloxifene improves the recurrence rate of endometriosis, as proven by biopsy, when compared to placebo (1 study, 93 women; very low-quality evidence). This suggests that if 28% of women taking placebo have biopsy-proven recurrence of endometriosis pelvic pain, between 19% and 62% of those taking raloxifene will do so. These outcomes are limited, as not all women had an actual second laparoscopy to take biopsy samples. However, study authors reported that women in the raloxifene group were likely to experience return of pain sooner than women in the placebo group. The included study reported that quality of life measurements did not differ between raloxifene and placebo groups, except in the domain of mental health. By 12 months, mental health quality of life scores favoured placebo treatment (mean difference 11.1, 95% confidence interval (CI) 0.01 to 21.19). There were no usable data on fertility nor on economic outcomes.
Based on the single study included in this review, reviewers found no evidence of a beneficial effect of SERMs as treatment for pain relief in surgically treated endometriosis. On the contrary, the study was prematurely stopped because women who used SERMs experienced a return of pain sooner than women who used placebo.
Quality of the evidence
Evidence was of very low quality. The main limitations were inclusion of only one study with a small number of participants and lack of both primary and secondary outcome data.
Based on a single, small RCT and incomplete data, we are uncertain of the effects of SERMs on pain relief in surgically treated patients with endometriosis. The included study was stopped prematurely because of higher pain scores among women who took SERMs when compared to scores among those receiving placebo. Further research is needed to fully evaluate the role of SERMs in endometriosis.
Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. This chronic and recurring condition occurs in women of reproductive age. It is a common cause of pain or infertility and can cause non-specific symptoms such as lower back pain, dyspareunia (pain during or after intercourse), and dysmenorrhoea (menstrual pain). Endometriosis is an oestrogen-dependent disease. Medical treatment aims to relieve symptoms and shrink lesions by suppressing the normal menstrual cycle. In this review, we consider medication specifically aiming to modulate oestrogen receptors as an alternative method of treatment.
To evaluate the effectiveness and safety of selective oestrogen receptor modulators (SERMs) in the management of endometriosis.
We searched for trials in the following databases (from their inception to 28 May 2020): Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies (CRS Online), MEDLINE, Embase, CINAHL, PsycINFO, and registers of ongoing trials. In addition, we searched all reference lists of included trials, and we contacted experts in the field, in an attempt to locate trials.
We included randomised controlled trials (RCTs) comparing selective oestrogen receptor modulators (SERMs) with placebo, no treatment, other medical treatment, or surgery for endometriosis.
We used standard methodological procedures recommended by Cochrane. Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted data using data extraction forms. We used risk ratios (RRs) with 95% confidence intervals (CIs) for reporting dichotomous data. Primary review outcomes were relief of pelvic pain and adverse events. Secondary outcomes included quality of life, recurrence rate, and economic and fertility outcomes.
We included only one RCT, which included 93 women, comparing the SERM raloxifene with placebo in biopsy-proven endometriosis. All women first underwent complete surgical excision of all lesions. Evidence was of very low quality: the main limitation was imprecision - with very sparse data from only one small study, which included only women after surgical treatment.
Relief of pelvic pain
The included study did not specifically measure the primary outcome of pain relief. Study authors reported that time to return of pelvic pain (defined as two months of pain equal to or more severe than pain at study entry) was more rapid in the raloxifene group (P = 0.03).
Adverse events
The included study reported adverse events such as pelvic pain, ovarian cyst, headache, migraine, and depression. We are uncertain whether raloxifene improves the incidence of pelvic pain (RR 1.25, 95% CI 0.63 to 2.45), ovarian cysts (RR 1.57, 95% CI 0.55 to 4.43), headache (RR 1.09, 95% CI 0.49 to 2.43), migraine (RR 0.73, 95% CI 0.28 to 1.95), depression (RR 1.96, 95% CI 0.63 to 6.06), or other adverse events (RR 0.08, 95% CI 0.00 to 1.30) (all: 1 study, n = 93; very low-quality evidence).
Quality of life
The study described a statistically significant difference in mental health quality of life (QoL) by 12 months, in favour of placebo treatment (mean difference 11.1, 95% CI 0.01 to 21.19). Other QoL data did not differ between groups but were not reported in detail.
Recurrence rate, fertility, and economic outcomes
We are uncertain whether raloxifene improves the recurrence rate of endometriosis, proven by biopsy, when compared to placebo (RR 1.20, 95% CI 0.66 to 2.21; 1 study, n = 93; very low-quality evidence). This suggests that if 28% of women taking placebo have biopsy-proven recurrence of endometriosis, between 19% and 62% of those taking raloxifene will do so. These outcomes are prone to bias, as not all women had an actual second laparoscopy. Recurrence based on symptoms (non-menstrual pain, dysmenorrhoea, or dyspareunia) was described; in these cases, symptoms improved after use of raloxifene as well as after use of placebo.
The included study did not report data on economic outcomes. No comparative data were available on pregnancy, as the study included only women who agreed to postpone pregnancy until after the study endpoint; the few pregnancies that did occur were uneventful but were regarded as an adverse event.