Selective estrogen receptor modulators (SERMs) for endometriosis

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the effectiveness and safety of SERMs for the management of endometriosis.


Description of the condition

Endometriosis is a common, estrogen-dependent, chronic recurrent disease characterized by the presence of endometrial tissue outside the uterine cavity. It is found mainly on the pelvic peritoneum but may also be found on the ovaries, recto-vaginal septum, and occasionally in the pericardium, pleura and urinary tract (Child 2001; Schweppe 2001; Valle 2003). The cause of endometriosis is unknown. The leading theory of causation is retrograde menstruation, which postulates that intraperitoneal spilling of endometrial cells leads to cells that adhere to the peritoneal surface and implant there (D'Hooghe 2002). Early menarche and late menopause increase the risk of endometriosis (Farquhar 2000).

The main symptoms are dysmenorrhoea, infertility and pelvic pain. In women without symptoms the prevalence of endometriosis ranges from 2% to 22% (Farquhar 2000), while in women with dysmenorrhoea the range is 40% to 60% (Farquhar 2007). In women with infertility it ranges from 20% to 30% (Dunselman 2014). Endometriosis can result in substantial morbidity, including dyspareunia, intermenstrual bleeding and menorrhagia, and pelvic pain of varying severity and in differing locations (Galle 1989). It is associated with a huge social and economical burden (Bianconi 2007; Jones 2002; Marques 2004).

Description of the intervention

There is no gold standard treatment for women with endometriosis.

The standard diagnosis of endometriosis is made through laparoscopy or laparotomy, and at the same time the surgeon may remove the lesion, but sometimes surgical treatment does not confer greater pain relief than medical treatment (Winkel 2000). Ectopic endometriotic cysts are treated by surgery.

Conventional medical treatment focuses on relieving symptoms and limiting the growth of the endometriotic lesions. The most widely used drugs are oral contraceptives (OCs), oral danazol, gonadotropin-releasing hormone (GnRH) agonists (by injection or nasal spray), and progestins given orally or by intramuscular or subcutaneous depot injection (Crosignani 2006; Schroder 2004). Medical treatments including anti-tumour necrosis factor (TNF)-alpha drugs, danazol, GnRHa, OCs, pentoxifylline and progestagens have been evaluated for their efficacy and safety. GnRHas are thought to be the most effective drug for endometriosis but they can cause loss of bone density, hot flushes, vaginal dryness, decreased libido, irregular vaginal bleeding and thrombosis. These substantial side effects limit their long term application.

Many newer treatment options have emerged. These include aromatase inhibitors, progesterone receptor modulators and selective estrogen-receptor modulators (SERMs) (Crosignani 2006).

SERMs can be divided into three categories. First are the triphenylethylene derivatives like tamoxifen, used to treat breast cancer but with their application limited due to endometrial stimulation; second are non-steroidal compounds like raloxifene, a benzothiophene derivative; and third are the steroidal compounds. Different types of SERMs may play different roles when acting on different tissues, which makes them interesting agents for further study of endometriosis (Dutertre 2000).

In recent years the SERM raloxifene has been used to treat endometriosis (Stratton 2008) but its efficacy and safety have not been systematically reviewed. Raloxifene has been used to treat osteoporosis since 1999. It influences estrogen levels, has beneficial estrogen agonist effects on bone density and can reduce the incidence of atherosclerosis, but stimulates neither the endometrium nor the breasts in postmenopausal women (Eng -Wong 2004; Francucci 2005; Scott 1990; Silfen 1999; Thiebaud 2001). This suggests that raloxifene may be an effective treatment for endometriosis. However it has been associated with adverse effects including increased risk of thromboembolism, vaginal dryness, generalized rash and abdominal cramps.

How the intervention might work

Endometriosis is an estrogen-dependent disease, and estrogen is an important factor in its development (Simsa 2007). SERMs have estrogen-antagonistic effects on the uterine endometrium (Delmas 1997). They interact with estrogen receptors (ERs) and block the hormonal signalling pathway (Simsa 2007), leading to a reduction in estrogen activity.

Why it is important to do this review

Endometriosis strongly affects women's lives. There are some systematic reviews on the conservative treatment of endometriosis that did not determine which is the best treatment for endometriosis. There have been many clinical studies of various SERMs for endometriosis (Altintas 2010; Pierzynski 2006; Stratton 2008) however poor design has been a common problem with these studies and systematic evaluation of their reported benefits and risks is required.


To determine the effectiveness and safety of SERMs for the management of endometriosis.


Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) of the use of selective estrogen-receptor modulators (SERMs) in the treatment of endometriosis will be included. Crossover trials will be eligible, but only data from the first phase will be included in meta-analyses, as the crossover is not a valid design in this context. Quasi-randomised and non-randomised studies (case control studies, cohort studies) will be excluded.

Types of participants

Women of reproductive age (usually up to 50 years of age) with visually diagnosed or biopsy-proven endometriosis by laparoscopy, or on the basis of international guidelines (Dunselman 2014; RCOG 2006) used to diagnose endometriosis will be included. Women who have endometriosis clinically but with no visual or laparoscopic confirmation will be excluded.

Types of interventions

Trials comparing SERMs via any route versus any other active intervention (for example danazol, GnRHa), placebo or no treatment will be eligible for inclusion.

Any dosage or duration of treatment will be included. Available SERMs include: raloxifene, arzoxifene, levormeloxifene, ospemifene, lasofoxifene, bazedoxifene, centchroman, arzoxifene, tamoxifen, toremifene, droloxifene, idoxifene.

Types of outcome measures

Primary outcomes

We will consider the outcome measures at the end of the treatment and, when possible, at 3, 6, 9, 12, 18 months following completion of treatment.

1. Relief of pelvic pain, on a visual analogue scale (VAS) (0 (no pain) to 10 (worst pain imaginable) or subjective improvement.

  • The painful symptoms may take the form of dysmenorrhoea, dyspareunia (pain during or after sexual intercourse) or pelvic or lower abdominal pain. Some women also present with cyclical pain at other sites, relating to endometriosis at extra-pelvic sites. In this review we discuss pelvic pain. Measures of subjective pain relief will be assessed. These include VAS or any other recognised scoring system or qualitative measures such as cured, better, same, or worse.

2. Adverse events resulting from treatment with SERMs (hot flushes, endometrial cancer, vaginal bleeding, thrombosis) either during or following treatment.

Secondary outcomes

3. Quality of life (by quality of life scores)

4. Recurrence rate (symptoms or biopsy-proven)

5. Fertility outcomes (only in women wishing to conceive)

  • Live birth

  • clinical pregnancy

  • Fertility-related adverse events (miscarriage, multiple birth)

6. Economic outcomes (costs, time taken for the treatment)

Search methods for identification of studies

All published and unpublished RCTs of SERMs versus other interventions will be sought using the following search strategy, without language restriction and in consultation with the Menstrual Disorders and Subfertility Group Trials Search Co-ordinator. Relevant trials will be identified from both electronic databases and other resources.

Electronic searches

The following electronic databases, trial registers and web sites will be searched from inception to the present.

  • Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials.

  • Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library.

  • English language electronic databases: MEDLINE, EMBASE, PsycINFO and CINAHL.

  • Chinese language electronic databases: Chinese Biomedical Literature Database (CBM) and Chinese Medical Current Contents (CMCC); using the corresponding Chinese terms for: “endometriosis” AND “SERMs”, “ERs”,“Raloxifene”, etc.

  • Current Controlled Trials (;

  • (;

  • World Health Organization International Trials Registry Platform search portal (;

  • Citation indexes (;

  • Conference abstracts in the Web of Knowledge (;

  • LILACS (Latin American and Caribbean Health Science Literature) (;

  • PubMed (;

  • OpenGrey database (; and

  • Google for grey literature.

The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying RCTs, which appears in the searching chapter of the Cochrane Handbook for Systematic Reviews of Interventions. The EMBASE search will be combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (

Searching other resources

We will also do the following:

(1) search the references lists of all included studies and relevant reviews to identify further relevant articles;

(2) contact authors and experts in the field for potential studies;

(3) handsearch the following Chinese journals:

  • Chinese Journal of Obstetrics and Gynecology (from 1953 to present),

  • Chinese Journal of Practical Gynecology and Obstetrics (from 1985 to present),

  • Journal of Practical Obstetrics and Gynecology (from 1985 to present),

  • Maternal and Child Health Care of China (from 1986 to present).

See Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5 for the search strategies.

Data collection and analysis

We will perform statistical analysis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Review Manager 5.2 will be used to analyse the data.

Selection of studies

Two review authors will independently examine the full text articles for compliance with the inclusion criteria and will select studies eligible for inclusion in the review. The full text will be retrieved when the information given in the titles, abstracts and keywords suggests that the study uses SERMs as an intervention; the participants have endometriosis; the study has a prospective design and a control group. The authors will correspond with study investigators, if required, to clarify study eligibility (for example with respect to participant eligibility and allocation method). Disagreements as to study eligibility will be resolved by consensus or by discussion with a third author.

The study selection process will be documented with a PRISMA flow-chart.

Data extraction and management

Data will be extracted from the eligible studies using a special data extraction form. Two review authors (Chen YL and Wan Q) will independently extract the data, and any disagreement between review authors will be resolved by discussion with a third review author (Zheng A). The main trial report will be used as the reference and additional details will be obtained from secondary reports, where studies have multiple publications. We will correspond with study investigators for further data on methods and/or results, as required.

Assessment of risk of bias in included studies

The included studies will be assessed for risk of bias using the Cochrane risk of bias assessment tool ( to assess: selection bias (random sequence generation, allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other biases. Two authors will assess risk of bias with any disagreements resolved by consensus or by discussion with a third author (Zheng A). We will correspond with the trialists to identify any within-trial selective reporting. We will seek published protocols and compare the outcomes between the protocol and the final published study. The risk of bias table will be included in the table 'Characteristics of included studies'. All judgements will be fully described. The conclusions will be presented in the 'Risk of bias' table and will be incorporated into the interpretation of review findings by means of sensitivity analyses.

Measures of treatment effect

For dichotomous data (for example recurrence and adverse events) we will record the number of participants experiencing the event in each group of the trial. Odds ratios (ORs) with 95% confidence intervals (CI) will be used to report dichotomous data. For continuous outcomes (for example pain scores) we will extract the final value and standard deviation of the outcome of interest, and the number of women assessed at the endpoint in each treatment arm and at the end of follow-up. Mean differences (MD) with 95% CIs will be used to report continuous data. In the case of outcomes with continuous data in different scales, we will use the standardized mean difference (SMD) with 95% CI. Where data to calculate ORs or MDs are not reported, we will utilise the most detailed numerical data available that may facilitate similar analyses of included studies (for example test statistics, P values) or report the results in narrative form only.

Unit of analysis issues

The primary analysis will be per woman randomised. Fertility outcomes will only be measured among women seeking pregnancy. For certain fertility outcomes (for example miscarriage or multiple birth) the per pregnancy data will be used.

Dealing with missing data

We will try to obtain missing data from the original investigators through email or telephone. The data will be analysed on an intention-to-treat basis as far as possible (the analysis should include all the randomised participants in the groups to which they were originally randomly assigned). Where missing data are unobtainable, imputation of individual values will be undertaken for the primary outcomes only. If studies report sufficient detail to calculate mean differences but provide no information on the associated standard deviations (SDs), the outcome will be assumed to have an SD equal to the highest SD from other studies within the same analysis. For other outcomes, only the available data will be analysed.

Assessment of heterogeneity

We will check the included trials to see if the participants, interventions and outcomes in the included studies are similar enough to consider pooling in a meta-analysis. If so, then the rest of the section will refer to statistical heterogeneity after pooling. Tests for heterogeneity will be carried out using the Chi2 test, with significance set at P < 0.1. The I2 statistic will be used to estimate the total variation across studies due to heterogeneity, where > 50% is high-level heterogeneity (Higgins 2011. An I2 value of over 50% will be taken to indicate substantial heterogeneity and we will investigate this using the sensitivity and subgroup analyses described below. When heterogeneity was not significant (P > 0.1, I2 < 50%) among subgroups, a fixed-effect model will be used. Where heterogeneity is significant (P < 0.1, I2 > 50%) a random-effects model will be used.

Assessment of reporting biases

We will aim to minimise publication bias and other reporting biases by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. Potential publication bias will be assessed using a funnel plot or other corrective analytical methods if there are 10 or more studies in an analysis (Egger 1997). Study reporting bias will be detected by seeking published protocols and comparing the outcomes between the protocol and the final published study.

Data synthesis

If sufficient clinically similar studies are available, the data will be pooled in meta-analyses. For continuous outcomes (pain relief measures) the MD between the treatment arms at the end of follow-up will be determined if all trials measured the outcome on the same scale, otherwise the SMD will be calculated. An increase in the odds of a particular outcome will be displayed to the right of the centre line. While the precise scaling of diary data may vary when using a VAS score, the trials can use the mean VAS score or report a reduction in the VAS score (with a 50% reduction being considered clinically significant). Different comparisons will be analysed separately:

  • all SERMs versus placebo or no treatment;

  • all SERMs versus alternative active therapy, stratified by all SERMs versus medical treatment and versus surgery.

Subgroup analysis and investigation of heterogeneity

Where data are available, we intend to explore the following potential sources of heterogeneity using subgroup analyses:

  • individual types of SERMs versus placebo, no treatment, or each alternative active therapy;

  • duration of treatment (three months, three to six months, six to 12 months, at least 12 months).

  • When substantial heterogeneity is present, we will explore possible explanations including individual study risk of bias, dose of SERM.

Sensitivity analysis

We will consider sensitivity analyses for the primary outcomes to determine whether the conclusions are sensitive to arbitrary decisions made regarding the eligibility and analysis. These analyses will include consideration of whether conclusions would have differed if:

  • studies that had a high risk of bias were excluded

  • studies that used different rating scales to assess symptom relief such as unpublished rating scales or scales with no established reliability or validity were excluded.

Summary of findings table

We will prepare a summary of findings table using GRADEPro or Guideline Development Tool software. This table will evaluate the overall quality of the body of evidence for the primary review outcomes (relief of pelvic pain and adverse events following SERM treatment) using the GRADE criteria (study limitations (that is risk of bias), consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate or low) will be justified, documented and incorporated into reporting of results for each outcome.


We would like to thank the people that contributed to this protocol. We thank Helen Nagels, Marian Showell, Li Wang (teacher in the Chinese-Evidence Base Center) and the editorial board of the Cochrane Menstrual Disorders and Subfertility Group (MDSG) for their significant assistance in developing this protocol. We thank Marian Showell for designing the search strings for us.


Appendix 1. MDSG search string

Keywords CONTAINS "Endometriosis"or "endometriosis-outcome"or"endometriosis scores"or "Endometriosis-Symptoms"or "endometriotic cysts"or "endometrioma" or Title CONTAINS  "Endometriosis"or "endometriosis-outcome"or"endometriosis scores"or "Endometriosis-Symptoms"or "endometriotic cysts"or "endometrioma"


Keywords CONTAINS "SERM" or"selective estrogen receptor modulator" or"*Raloxifene" or"Tamoxifen"or "toremifen" or"toremifene"or "Evista" or Title CONTAINS  "SERM" or"selective estrogen receptor modulator" or"*Raloxifene" or"Tamoxifen"or "toremifen" or"toremifene"or "Evista"

Appendix 2. CENTRAL search strategy

1 exp selective estrogen receptor modulators/ or exp raloxifene/ or exp tamoxifen/ or exp toremifene/
2 selective oestrogen receptor modulator$.tw.
3 selective estrogen receptor modulator$.tw.
4 SERM$.tw.
8 Evista$.tw.
9 Nolvadex$.tw.
10 Fareston$.tw.
11 or/1-10
12 exp Endometriosis/
13 Endometrio$.tw.
14 or/12-13
15 11 and 14

Appendix 3. MEDLINE search strategy

1 exp selective estrogen receptor modulators/ or exp raloxifene/ or exp tamoxifen/ or exp toremifene/
2 selective oestrogen receptor modulator$.tw.
3 selective estrogen receptor modulator$.tw.
4 SERM$.tw.
8 Evista$.tw.
9 Nolvadex$.tw.
10 Fareston$.tw.
11 or/1-10
12 exp Endometriosis/
13 Endometrio$.tw.
14 or/12-13
15 11 and 14
16 randomized controlled
17 controlled clinical
18 randomized.ab.
20 clinical trials as
21 randomly.ab.
22 trial.ti.
23 (crossover or cross-over or cross over).tw.
24 or/16-23
25 exp animals/ not
26 24 not 25
27 15 and 26

Appendix 4. EMBASE search strategy

1 exp selective estrogen receptor modulator/
2 exp raloxifene/
3 exp tamoxifen citrate/ or exp tamoxifen/
4 exp toremifene/
5 selective oestrogen receptor modulator$.tw.
6 selective estrogen receptor modulator$.tw.
7 SERM$.tw.
11 Evista$.tw.
12 Nolvadex$.tw.
13 Fareston$.tw.
14 or/1-13
15 exp endometriosis/
16 Endometrio$.tw.
17 or/15-16
18 14 and 17
19 Clinical Trial/
20 Randomized Controlled Trial/
21 exp randomization/
22 Single Blind Procedure/
23 Double Blind Procedure/
24 Crossover Procedure/
25 Placebo/
26 Randomi?ed controlled trial$.tw.
28 random
29 randomly
30 allocated
31 (allocated adj2 random).tw.
32 Single blind$.tw.
33 Double blind$.tw.
34 ((treble or triple) adj blind$).tw.
35 placebo$.tw.
36 prospective study/
37 or/19-36
38 case study/
39 case
40 abstract report/ or letter/
41 or/38-40
42 37 not 41
43 18 and 42

Appendix 5. PsycINFO search strategy

1 selective oestrogen receptor modulator$.tw.
2 selective estrogen receptor modulator$.tw.
3 SERM$.tw.
7 Evista$.tw.
8 Nolvadex$.tw.
9 Fareston$.tw.
10 or/1-9
11 exp Gynecological Disorders/
12 Endometrio$.tw.
13 11 or 12
14 10 and 13

Contributions of authors

Yali Chen: selection of trials for inclusion or exclusion; extraction of data; drafting of protocol and review; search for trials; data entry into RevMan.
Qi Wan: selection of trials for inclusion or exclusion; obtaining copies of trial reports; extraction of data; assessment of risks of bias.
Ai Zheng: all correspondence; drafting of protocol and review; interpretation of results.

Declarations of interest

The authors have no commercial interests to disclose.

Sources of support

Internal sources

  • Dept of Obstetrics and Gynaecology, University of Auckland, New Zealand.

  • Dept of Obstetrics & Gynaecology, Sichuan University, Chengdu, China.

External sources

  • None, Not specified.