Selective oestrogen receptor modulators (SERMs) for endometriosis

Abstract

Background: 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.

Objectives: To evaluate the effectiveness and safety of selective oestrogen receptor modulators (SERMs) in the management of endometriosis.

Search methods: 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.

Selection criteria: We included randomised controlled trials (RCTs) comparing selective oestrogen receptor modulators (SERMs) with placebo, no treatment, other medical treatment, or surgery for endometriosis.

Data collection and analysis: 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.

Main results: 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. AUTHORS' CONCLUSIONS: 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.

1

Study flow diagram.

2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

1.1. Analysis

Comparison 1: Raloxifene versus placebo, Outcome 1: Adverse events

1.2. Analysis

Comparison 1: Raloxifene versus placebo, Outcome 2: Quality of life ‐ Mental health

1.3. Analysis

Comparison 1: Raloxifene versus placebo, Outcome 3: Recurrence rate of endometriosis ‐ Biopsy proven