Meta-Analysis
Gynecol Obstet Invest
DOI: 10.1159/000516517
Does Endometriosis Disturb Mental
Health and Quality of Life? A Systematic
Review and Meta-Analysis
Yuehan Wang Bo Li Yang Zhou Yizi Wang Xue Han Shitai Zhang
Zheng He Ling Ouyang
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
Keywords
Endometriosis · Depression · Anxiety · Mental health ·
Health-related quality of life
Abstract
Introduction: This study aimed to evaluate whether endo-
metriosis could disturb the mental health and health-related
quality of life (HRQoL) of patients and to provide a new pro-
spective for further treatment of endometriosis. Methods: A
comprehensive literature review was conducted among 4
international databases (PubMed, Embase, Web of Science,
and Cochrane Library) and 2 of the largest Chinese databas-
es (the China National Knowledge Infrastructure and Wang-
fang). The Newcastle-Ottawa Scale was used to assess the
quality of the included articles. Six effect sizes were synthe-
sized through a meta-analysis, and a subgroup analysis was
performed to identify potential moderating factors, includ-
ing types of control groups, methods of assessment, number
of study groups, and origin of the study. Potential publica-
tion bias was examined using a funnel plot. Results: This me-
ta-analysis pooled 44 articles from 4 continents and 13 coun-
tries and compared 6 types of main effect sizes (the odds
ratio [OR] for depression, the OR for anxiety, the standard-
ized mean difference [SMD] for depression, the SMD for anx-
karger@karger.com © 2021 S. Karger AG, Basel
www.karger.com/goi
Received: October 18, 2020
Accepted: April 4, 2021
Published online: August 5, 2021
iety, the SMD for the physical component summary [PCS]
and the SMD for the mental component summary [MCS]) be-
tween endometriosis patients and controls. Except for the
SMD for depression, all other effect sizes revealed statisti-
cally significant differences between the study group and
the controls. The main effect size outcomes of the subgroup
analysis were also similar. The type of control group (I2 = 35%
in non-endometriosis control groups for the SMD of anxiety;
I2 = 47% in non-endometriosis control groups for the MCS of
the 36-Item Short Form Health Survey) and the continent of
origin (I2 = 0% in studies from South America for the OR of
depression; I2 = 47% in studies from Europe for the SMD of
anxiety) may influence heterogeneity in this analysis. Addi-
tionally, depression and anxiety symptoms in patients
seemed to be more apparent compared with healthy con-
trols when the sample was smaller and when a questionnaire
was used. The publication bias of the articles was acceptable.
Conclusion: Endometriosis can disturb mental health (spe-
cifically depression and anxiety) and decrease both the men-
tal and physical HRQoL of patients. There may be some mod-
erating factors that we were unable to identify in the sub-
group analysis, but more research is necessary to develop
proper management and improve the prognosis of endome-
triosis patients. © 2021 S. Karger AG, Basel
130.209.6.61 - 8/12/2021 10:16:43 PM
Correspondence to:
Ling Ouyang, ouyang1964 @ 163.com
Glasgow Univ.Lib.
Downloaded by:
 Introduction
Endometriosis, a common gynaecological disease that
was first discovered by Sampson [1], affects nearly 10% of
reproductive-aged women. Endometriosis is character-
ized by normal endometrium-like lesions that implant
outside the uterus and displays 3 main pathological pat-
terns: peritoneal, ovarian, and deep infiltrating endome-
triosis [2]. Currently, the exact origin and mechanism of
endometriosis development remain unclear, but the
complex and heterogeneous presentations of the diseases
imply that multiple pathogenetic pathways may exist.
Furthermore, previous research has revealed that endo-
metriosis is the result of a combined contribution of ana-
tomical, hormonal, immunological, reactive, oestrogenic,
genetic, epigenetic, and environmental factors [3]. Gen-
erally, the pathological tissues may respond to oestrogen,
cause internal bleeding, and build scar tissue [4]. Patients
are often disturbed by symptoms including dysmenor-
rhoea, chronic pelvic pain, infertility, and dyspareunia.
Although a variety of medical and surgical methods can
be used, the disease persists for a long period of time [5].
Because of its specificity, endometriosis is more than a
disease. The long-term chronic course and the recurrence
of pelvic pain result in increased treatment costs as well
as increased work absenteeism and a loss in work produc-
tivity [6]. Simoens et al. [7] reported costs of approxi-
mately USD 2,000 per year for endometriosis treatment
and medical visits. Patients face dyspareunia, subfertility,
and infertility, which may impact sexual and intimate re-
lationships. In turn, this may harmfully influence the pa-
tients’ self-esteem and even cause problems in marital re-
lations. All of the complaints of endometriosis place large
psychological pressure on the patients, and when the
number of symptoms, their severity, or the persistence of
symptoms increase or become more severe after treat-
ment, psychological disturbances including depression
and anxiety may develop. Eventually, this may lead to the
further deterioration of the health-related quality of life
(HRQoL) of endometriosis patients.
Several studies have revealed that patients with endo-
metriosis have higher rates of depression and anxiety
than healthy people [8–10]. Endometriosis has also been
shown to impair physical and mental HRQoL compared
with healthy peers or patients with other gynaecological
diseases [11–13]. However, very few patients have re-
ceived psychological support as part of their treatment in
clinical practice until now. It is believed that the develop-
ment of complex novel interventions is best begun with a
review of the available evidence [14]. Therefore, the pres-
2 Gynecol Obstet Invest
DOI: 10.1159/000516517
ent meta-analysis aims to synthesize individual studies
that evaluated depression, anxiety, and HRQoL in endo-
metriosis patients compared with controls. It is hoped
that these findings will lay a foundation for further inter-
ventional research and provide a new prospective for fur-
ther endometriosis treatments.
Methods
Literature Search
A systematic search was conducted to identify published litera-
ture related to depression, anxiety, and HRQoL (measured with
the 36-Item Short Form Health Survey [SF-36]) in patients with
endometriosis. We searched 4 international databases: PubMed,
Embase, Cochrane Library, and Web of Science. Two of the largest
Chinese databases, the China National Knowledge Infrastructure
(CNKI) database and Wangfang database, were also included to
expand the data. The search identified studies published until May
2020. Both controlled vocabulary (e.g., Medical Subject Headings,
also known as MeSH terms) and random words were used. The
main concepts included “endometriosis,” “endometriomas,” “ad-
enomyosis,” “depression,” “anxiety,” “quality of life,” “HRQoL,”
and so on. All the related articles have been reviewed, and the
­reference lists of the relevant articles were also screened. Details
of the search strategy are provided in Appendix 1 in the online
supplementary material (for all online suppl. material, see
www.karger.com/doi/10.1159/000516517).
Study Selection
Reference manager (EndNote X9) was used to save the records
obtained from the databases. After removing the duplicates, 2 au-
thors (Y.H.W. and Y.Z.) screened the titles and abstracts indepen-
dently to identify related clinical studies. If the 2 authors held op-
posing views, another author (B.L.) made the final decision after
discussion, so that the reviewer bias and errors would be reduced.
We included all studies that met the following criteria: (1) the pa-
tients in the study group had been diagnosed with endometriosis;
(2) case-control studies were eligible and the control group was
patients with other gynaecological diseases, patients with symp-
toms related to endometriosis, or healthy peers; (3) depression
symptoms and anxiety symptoms were reported quantitatively or
qualitatively, but they were discussed independently; and (4) to
increase comparability, we only selected studies that used the SF-
36 to measure HRQoL. The following exclusion criteria were used:
(1) the studies did not have control groups; (2) the study group
included non-endometriosis patients; (3) the SF-36 was not used
to evaluate HRQoL; (4) the full text could not be obtained; (5) the
study reported outcomes in a bar chart or other diagrams without
exact data (emails were sent to the authors and were excluded if no
response was given within 2 weeks); (6) the articles used dupli-
cated data; (7) the articles were written in languages other than
English and Chinese; and (8) the articles assessed psychological
content but did not measure depression and anxiety.
Data Management and Quality Assessment
While reading the included articles, related data were extracted
and collected. The extracted data included the author and publica-
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Ouyang
Glasgow Univ.Lib.
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 Records identified Records identified
through CNKI through Wangfang
database searching database searching Records identified Records identified Records identified Records identified
n = 74 n = 137 through PubMed through Embase through Web of Science through Cochrane Library
database searching database searching database searching database searching
Records removed Records removed n = 1,082 n = 1,154 n = 1,862 n = 308
through title through title
and abstract and abstract
n = 170 n = 131
Records after Records removed based
duplicates removed on title and abstract
Records after n = 3,179 n = 3,008
duplicates romoved
n=8

Exclude articles:
Full-text screening No relevant comparison: n = 83
n = 176 Study group not endometriosis patients only: n = 4
Not written in English or Chinese: n = 3
Not use SF36 to evaluate HRQoL: n = 11
No full-text: n = 2
Duplicate data: n = 1
No exact data: n = 4
No depression and anxiety data: n = 24

Studies included in meta-analysis

n = 44

Studies related to depression Studies related to anxiety Studies related to HRQoL

n = 31 n = 22 n = 17

Fig. 1. The process of selecting studies.

tion year, the age range of the study/control groups, the type of
control, the depression/anxiety measurement methods, the quan-
titative/qualitative results of psychological symptoms, the mean ±
standard deviation of the SF-36, and the relevant findings of the
studies.
Although the quality assessment of observational studies is
controversial, the Newcastle-Ottawa Scale (NOS) was adapted to
assess the quality of the observational and non-randomized studies
[15]. We divided the articles into 3 grades according to the NOS.
High-quality studies received scores of 7 or higher, which means
they have a low risk of bias. Low-quality studies were classified
based on their scores for 3 criteria. Obtaining a score of 0–1 for
selection or a score of 0 for comparability or for the assessment of
outcomes, all indicate a high risk of bias. Studies that had scores
other than the above-described conditions had a moderate risk of
bias. Two of the authors (Y.H.W. and Y.Z.) scored the studies in-
dependently, and any disagreements were resolved through dis-
cussion with another author (B.L.).
Meta-Analysis
Assessment of Overall Effect Size
We used Review Manager 5.3 to analyse the overall effect. Be-
cause some of the depression and anxiety data were qualitative,
while others were quantitative, the odds ratio (OR) and standard-
ized mean difference (SMD) were both selected. The OR repre-
sented the effect size for qualitative data, while the SMD was used
for quantitative data. The original data in the 2 categories were
synthesized respectively. Only continuous data were selected for
quality-of-life data; thus, the SMD was used. In total, we evaluated
6 main effect sizes: the OR for depression, the OR for anxiety, the
SMD for depression, the SMD for anxiety, the SMD for the physi-
cal component summary (PCS), and the SMD for the mental com-
ponent summary (MCS). Pooled OR or SMD values and 95% con-
fidence intervals (CIs) were calculated using inverse variance
weighting methods, so that the larger and more precise estimates
were given relatively more weight. A random-effects model was
used because observational studies always have greater heteroge-
neity [16, 17].
Subgroup Analysis and Publication Bias
After synthesizing the original data, heterogeneity was assessed
with the I2 statistic. If I2 was <50%, the heterogeneity was accept-
able. If not, a subgroup analysis was conducted to explore potential
moderating factors. We included the continent of the study (Asia,
Europe, North America, and South America), the type of control
group (non-endometriosis controls vs. healthy controls), the sam-
ple size (more than the median vs. less than the median of the study
group), and the assessment method (only for depression and anx-
iety). Potential publication bias was also examined, although some
researchers argue that funnel plots are easily affected by subjective
judgement. We tend to believe that an asymmetric funnel can part-
ly prove the existence of publication bias.
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Endometriosis Could Cause Depression Gynecol Obstet Invest 3

and Anxiety and Decrease Quality of Life DOI: 10.1159/000516517
Glasgow Univ.Lib.
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 Results
Study Selection
We used a flow chart to describe the study selection
process. As shown in Figure 1, there were 174 possible
eligible articles in the CNKI and 137 articles in the Wang-
fang databases. Most of the records were removed after
scanning the title and abstract, and after removing dupli-
cates between the 2 databases, the full text of 8 articles was
reviewed. We also searched 4 international databases and
initially found 1,082 records in PubMed, 1,154 in Em-
base, 1,862 in Web of Science, and 308 in the Cochrane
Library. A total of 3,179 records were left after removing
the duplicates, and the researchers then passed judge-
ment based on the title and abstract. A total of 176 articles
were accepted to full-text reading, and 132 articles were
excluded according to the aforementioned criteria. Most
of the excluded articles were excluded because of the lack
of any relevant comparisons. Finally, 44 studies were in-
cluded in our meta-analysis [8–13, 18–55], with 31 of
them related to depression, 22 related to anxiety, and 17
studies related to HRQoL using the SF-36.
Characteristics of the Included Studies
Thirty-two of the included studies assessed depression
and anxiety. They were published between 1988 and 2020,
and 28 were published in this century. A total of 53.1% of
the studies originated in Europe, whereas the others orig-
inated in North America (31.3%), South America (9.4%),
and Asia (6.2%). All of the patients in these studies were
premenopausal adult women, and the age was matched
between the study groups and control groups. Only 5
studies had a longitudinal registry design; the majority
reported cross-sectional findings. There was a median of
112 subjects per study (range 36–7,178,460; total N =
8,170,235). Twenty-three studies used a questionnaire to
assess depression or anxiety in the participants whereas 6
studies were based on registered diagnoses (e.g., ICD
code and hospital record). Three studies relied on self-
reports, whereas 1 study conducted clinical interviews, as
shown in Table 1.
The SF-36 is a widely used scale for measuring HRQoL.
It has been validated among many general and disease-
specific populations, including patients with endometri-
osis [56]. In the SF-36, the PCS and MCS represent dif-
ferent aspects of HRQoL. The PCS is calculated using
general health, body pain, physical role limitations, and
physical functioning using original data. The MCS is cal-
culated using mental health, emotional role limitations,
social functioning, and vitality. For every scale, the scores
4 Gynecol Obstet Invest
DOI: 10.1159/000516517
range from 0 to 100, with a higher score indicating a bet-
ter quality of life. Of the 17 studies that reported HRQoL
using the SF-36, 14 were published in this decade, and the
other 3 were also published this century. A total of 64.7%
of the studies originated from Europe, while the others
were from Asia (17.6%), North America (5.9%), and
South America (11.8%). The median number of subjects
per study was 163 (range, 40–1,418; total N = 4,893). Two
studies included adolescent patients, whereas the remain-
der all included premenopausal adult women. Not all of
the included studies provided all the original data. There-
fore, we contacted the authors of those studies, but if they
did not provide the original data within 2 weeks, their
related data were not calculated. Table 2 shows the char-
acteristics of the studies that provided PCS or MCS data,
which were used to synthesize the main effect size.
Risk of Bias Assessment
Ratings of the quality of each study according to the
NOS criteria are presented in Table 3. According to the
NOS, the maximum score is 9, and higher scores indicate
better study quality. The average score of all studies was
above 5. Eighteen of the 44 studies were high quality, 1
was low quality, and the others were medium quality.
ORs of Depression and Anxiety in Endometriosis
Patients
The OR is an effect size that was used to compare the
prevalence rates of depression and anxiety between endo-
metriosis patients and those without endometriosis. The
depression group was composed of 18 studies that includ-
ed a total of 106,830 patients with endometriosis and
8,062,158 controls. As shown in Figure 2, endometriosis
patients had an obviously higher prevalence of depres-
sion compared with the control group (OR = 1.86, 95%
CI = 1.63–2.13, p = 0.000). However, the heterogeneity
analysis of the effect sizes of depression showed a high
amount of heterogeneity (p = 0.000, I2 = 84%).
Figure 3 shows the results for anxiety. Eleven studies
including a total of 25,436 endometriosis patients and
850,856 controls were analysed. The patients had a sig-
nificantly higher rate of anxiety than the controls (OR =
2.38, 95% CI = 1.06–5.37, p = 0.04). However, the hetero-
geneity was also high (p = 0.000, I2 = 98%). Therefore, a
subgroup analysis was necessary.
SMD of Depression and Anxiety in Endometriosis
Patients
The SMD was used to describe differences in continu-
ous data between endometriosis patients and controls.
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 Table 1. Characteristics of the included studies: depression and/or anxiety
Author Country Participants Type of control Mean age Age range Depression/ Depression/anxiety assessment Mean Prevalence of Relevant findings
(patients, n) anxiety method score ± SD depression/
(control, n) anxiety, %

Shatford et al. [18] Canada 23 Non-endometriosis – ≤37 Depression Questionnaire (BDI) 4.48±4.19 – No significant difference in depression scores between endometrio-
212 control 4.61±6.26 sis infertility patients and tubal original infertility controls

Canada 23 Non-endometriosis – ≤37 Anxiety Questionnaire (STAI) 33.00±9.15 – No significant difference in anxiety scores between endometriosis
212 control 33.93±10.79 infertility patients and tubal original infertility controls

Canada 23 Non-endometriosis – ≤37 Anxiety Questionnaire (STAI) 37.04±8.37 – No significant difference in anxiety scores between endometriosis
212 control 34.96±8.24 infertility patients and tubal original infertility controls

Walker et al. [19] USA 14 Non-endometriosis 31.9±5.2 – Depression Questionnaire (NIMH) – 14 No significant difference in the prevalence of depression between
55 control 28.8±6.5 22 endometriosis patients and non-endometriosis controls

Low et al. [20] England 40 Non-endometriosis 30±7.7 – Depression Questionnaire (BDI) 14.4±8.2 – No significant difference in depression scores between endometrio-
41 control 35.5±9.2 13.3±8.2 sis patients and non-endometriosis controls

England 40 Non-endometriosis 30±7.7 – Anxiety Questionnaire (STAI) 45.8±12.1 – Endometriosis patients had higher score in anxiety than non-endo-

Endometriosis Could Cause Depression

and Anxiety and Decrease Quality of Life
41 control 35.5±9.2 38.2±13.6 metriosis controls

England 40 Non-endometriosis 30±7.7 – Anxiety Questionnaire (STAI) 46.8±9.0 – Endometriosis patients had higher score in anxiety than non-endo-
41 control 35.5±9.2 42.3±8.7 metriosis controls

Waller et al. [21] England 31 Non-endometriosis 31.0±4.1 – Depression Questionnaire (BDI) 6.43±5.75 – No significant difference in depression scores between endometrio-
38 control 35.0±4.9 5.74±4.77 sis patients with infertility and sterilization controls

England 31 Non-endometriosis 31.0±4.1 – Depression Questionnaire (BDI) 6.43±5.75 – Endometriosis patients with infertility had significant higher score
30 control 30.6±7.6 11.17±7.63 in depression than pelvic pain controls

England 17 Non-endometriosis 30.9±7.5 – Depression Questionnaire (BDI) 11.18±6.62 – Endometriosis patients with other symptoms had significant higher
38 control 35.0±4.9 5.74±4.77 score in depression than sterilization controls

England 17 Non-endometriosis 30.9±7.5 – Depression Questionnaire (BDI) 11.18±6.62 – No significant difference in depression scores between endometrio-
30 control 30.6±7.6 11.17±7.63 sis patients with other symptoms and pelvic pain controls

England 31 Non-endometriosis 31.0±4.1 – Anxiety Questionnaire (Spielberger) 41.9±11.0 – No significant difference in anxiety scores between endometriosis
38 control 35.0±4.9 37.5±10.6 patients with infertility and sterilization controls

England 31 Non-endometriosis 31.0±4.1 – Anxiety Questionnaire 41.9±11.0 – No significant difference in anxiety scores between endometriosis
30 control 30.6±7.6 (Spielberger 42.1±10.2 patients with infertility and pelvic pain controls

England 17 Non-endometriosis 30.9±7.5 – Anxiety Questionnaire (Spielberger) 43.1±14.5 – No significant difference in anxiety scores between endometriosis
38 control 35.0±4.9 37.5±10.6 patients with other symptoms and sterilization controls

England 17 Non-endometriosis 30.9±7.5 – Anxiety Questionnaire (Spielberger) 43.1±14.5 – No significant difference in anxiety scores between endometriosis

Gynecol Obstet Invest

30 control 30.6±7.6 42.1±10.2 patients with other symptoms and pelvic pain controls

DOI: 10.1159/000516517
England 31 Non-endometriosis 31.0±4.1 – Anxiety Questionnaire (Spielberger) 40.8±10.6 – No significant difference in anxiety scores between endometriosis
38 control 35.0±4.9 38.5±10.0 patients with infertility and sterilization controls

England 31 Non-endometriosis 31.0±4.1 – Anxiety Questionnaire (Spielberger) 40.8±10.6 – No significant difference in anxiety scores between endometriosis
30 control 30.6±7.6 41.8±12.7 patients with infertility and pelvic pain controls

England 17 Non-endometriosis 30.9±7.5 – Anxiety Questionnaire (Spielberger) 40.9±11.1 – No significant difference in anxiety scores between endometriosis
38 control 35.0±4.9 38.5±10.0 patients with other symptoms and sterilization controls

England 17 Non-endometriosis 30.9±7.5 – Anxiety Questionnaire (Spielberger) 40.9±11.1 – No significant difference in anxiety scores between endometriosis
30 control 30.6±7.6 41.8±12.7 patients with other symptoms and pelvic pain controls

Peveler et al. [22] England 40 Non-endometriosis 32.2±6.3 – Depression Questionnaire (BSI) 0.84±0.67 – No significant difference in depression scores between endometrio-
51 control 30.6±7.7 0.75±0.83 sis patients and pain controls

England 40 Non-endometriosis 32.2±6.3 – Anxiety Questionnaire (BSI) 0.88±0.74 – No significant difference in anxiety scores between endometriosis
51 control 30.6±7.7 0.86±0.75 patients and pain controls

Cunha-Filho et al. Brazil 32 Non-endometriosis – – Depression Questionnaire (BDI) – 25 No significant difference in the prevalence of depression between
[23] 22 control 18.18 patients and non-endometriosis controls

Brazil 32 Non-endometriosis – – Anxiety Questionnaire (Hamilton – 78.13 No significant difference in the prevalence of anxiety between pa-
22 control Scale) 95.45 tients and non-endometriosis controls

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 6
Table 1 (continued)
Author Country Participants Type of control Mean age Age range Depression/ Depression/anxiety assessment Mean Prevalence of Relevant findings
(patients, n) anxiety method score ± SD depression/
(control, n) anxiety, %

Tietjen et al. [24] USA 34 Non-endometriosis 38.5±8 21–52 Depression Self-report – 56 No significant difference in the prevalence of depression between
125 control 37.6±11 18–62 48 patients and non-endometriosis controls

USA 34 Healthy control 38.5±8 21–52 Depression Self-report – 56 Endometriosis patients showed higher rate in depression than
104 40.6±12 22–67 15 healthy controls

USA 35 Non-endometriosis 38.5±8 21–52 Anxiety Self-report – 54 Endometriosis patients showed higher rate in anxiety than non-
123 control 37.6±11 18–62 35 endometriosis controls

USA 35 Healthy control 38.5±8 21–52 Anxiety Self-report – 54 Endometriosis patients showed higher rate in anxiety than healthy
100 40.6±12 22–67 9 controls

Mirkin et al. [25] USA 33,564 Healthy control – 18–55 Depression Registered diagnosis (ICD – 6.8 Endometriosis patients showed higher rate in depression than
7,144,896 18–55 codes) 3.9 general population

Siedentopf et al. [26] Germany 19 Non-endometriosis – 24–45 Depression Questionnaire (HADS) 10.5±4.52 – Endometriosis patients with an advanced stage (III∼IV) had signifi-
17 control 26–44 11.5±9.63 cant higher score in depression than non-endometriosis controls

Gynecol Obstet Invest

Germany 7 Non-endometriosis – 24–45 Depression Questionnaire (HADS) 22.5±12.96 – No significant difference in depression scores between patients

DOI: 10.1159/000516517
17 control 24–42 11.5±9.63 with I∼II stage and non-endometriosis controls

Taran et al. [28] USA 76 Non-endometriosis 41±6.4 – Depression Hospital record – 55.3 Endometriosis patients showed higher rate of depression than
152 control 44.4±4.8 26.3 leiomyoma controls

Karp et al. [29] USA 81 Non-endometriosis 31.2±0.8 17–45 Depression Questionnaire 27.1±2.1 – No significant difference in depression scores between patients
27 control 31.5±1.4 17–45 34.2±4.0 with symptoms and non-endometriosis controls

Issa et al. [34] England 20 Non-endometriosis – 19–48 Depression Questionnaire (HADS) 4.0±3.5 – No significant difference in depression scores between minimal to
20 control 23–46 3.0±4.0 mild endometriosis patients and sterilization controls

England 20 Non-endometriosis – 19–48 Depression Questionnaire (HADS) 4.0±3.5 – No significant difference in depression scores between minimal to
20 control 22–48 5.0±3.25 mild endometriosis patients with abdominal pain controls

England 20 Non-endometriosis – 22–47 Depression Questionnaire (HADS) 3.0±4.5 – No significant difference in depression scores between moderate to
20 control 23–46 3.0±4.0 severe endometriosis patients and sterilization controls

England 20 Non-endometriosis – 22–47 Depression Questionnaire (HADS) 3.0±4.5 – No significant difference in depression scores between moderate to
20 control 22–48 5.0±3.25 severe endometriosis patients and abdominal pain controls

England 20 Non-endometriosis – 19–48 Anxiety Questionnaire (HADS) 8.5±2.5 – Minimal to mild endometriosis patients had higher score in anxiety
20 control 23–46 6.0±4.0 than sterilization controls

England 20 Non-endometriosis – 19–48 Anxiety Questionnaire (HADS) 8.5±2.5 – No significant difference in anxiety scores between minimal to
20 control 22–48 8.0±3.5 mild endometriosis patients and abdominal pain controls

England 20 Non-endometriosis – 22–47 Anxiety Questionnaire (HADS) 7.5±3.5 – No significant difference in anxiety scores between moderate to
20 control 23–46 6.0±4.0 severe endometriosis patients and sterilization controls

England 20 Non-endometriosis – 22–47 Anxiety Questionnaire (HADS) 7.5±3.5 – No significant difference in anxiety scores between moderate to
20 control 22–48 8.0±3.5 severe endometriosis patients and abdominal pain controls

Ouyang
Kumar et al. [30] England 27 Non-endometriosis – 19–44 Depression Clinical interview – 14.81 Endometriosis patients showed higher rate in depression than
12 control 23–47 25 pelvic pain controls

Souza et al. [32] Brazil 32 Non-endometriosis 36.1±7.8 25–48 Depression Questionnaire (BDI) 15.6±8.2 – No significant difference in depression scores between endometrio-
25 control 40.6±8.6 25–48 17.5±6.1 sis patients without pain with other pelvic pain

Brazil 32 Non-endometriosis 36.1±7.8 25–48 Anxiety Questionnaire (Hamilton 26.6±10.3 – No significant difference in anxiety scores between endometriosis
25 control 40.6±8.6 25–48 Scale) 32.4±10.5 patients without pain with other pelvic pain

As-Sanie et al. [33] USA 17 Healthy control 26.1±1.5 18–52 Depression Questionnaire (CES-D) 12.5±7.2 – Endometriosis patients with pain had higher score in depression
17 25.9±1.6 18–52 2.4±2.8 than healthy controls

USA 15 Healthy control 36.8±2.2 18–52 Depression Questionnaire (CES-D) 4.8±6.5 – No significant difference in depression scores between endometrio-
14 36.2±2.6 18–52 1.0±2.2 sis patients without pain and healthy controls

USA 17 Healthy control 26.1±1.5 18–52 Anxiety Questionnaire (STPI) 18.3±4.5 – Endometriosis patients with pain had higher score in anxiety than
17 25.9±1.6 18–52 12.5±2.3 healthy controls

Wang/Li/Zhou/Wang/Han/Zhang/He/
USA 15 Healthy control 36.8±2.2 18–52 Anxiety Questionnaire (STPI) 15.0±4.0 – Endometriosis patients without pain had higher score in anxiety
14 36.2±2.6 18–52 12.3±2.3 than healthy controls

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 Table 1 (continued)
Author Country Participants Type of control Mean age Age range Depression/ Depression/anxiety assessment Mean Prevalence of Relevant findings
(patients, n) anxiety method score ± SD depression/
(control, n) anxiety, %

Hansen et al. [35] Denmark 487 Non-endometriosis – All age Depression Self-report – 19.9 Endometriosis patients showed higher rate in depression than
583 control 17.4 non-endometriosis controls

Cavaggioni et al. [37] Italy 33 Non-endometriosis 35±7.6 – Depression Questionnaire (SCL-90-R) – 39.39 Endometriosis patients showed higher rate of depression than
43 control 34.9±10.1 18.60 non-endometriosis controls

Italy 33 Non-endometriosis 35±7.6 – Anxiety Questionnaire (SCL-90-R) – 24.24 No significant difference in the prevalence of anxiety between pa-
43 control 34.9±10.1 13.95 tients and non-endometriosis controls

Laganà et al. [39] Italy 166 Non-endometriosis 36±6 – Depression Questionnaire (SDS) – 75.90 No significant difference in the prevalence of depression between
48 control 38.4±12.8 37.50 patients and non-endometriosis controls

Italy 166 Non-endometriosis 36±6 – Anxiety Questionnaire (SAS) – 89.76 Endometriosis patients showed higher rate of anxiety than non-
48 control 38.4±12.8 54.17 endometriosis controls

Facchin et al. [40] Italy 32 Healthy control 33.2±4.4 20–40 Depression Questionnaire (HADS) 3.84±2.93 – Endometriosis patients without pain had significant higher score in

Endometriosis Could Cause Depression

61 27.9±4.4 20–40 4.71±3.12 depression than healthy controls

and Anxiety and Decrease Quality of Life

Italy 78 Healthy control 32.7±5.5 20–40 Depression Questionnaire (HADS) 6.67±3.50 – Endometriosis patients with pain had significant higher score in
61 27.9±4.4 20–40 4.71±3.12 depression than healthy controls

Italy 32 Healthy control 33.2±4.4 20–40 Anxiety Questionnaire (HADS) 6.22±3.23 – Endometriosis patients without pain had significant higher score in
61 27.9±4.4 20–40 6.49±3.45 anxiety than healthy controls

Italy 78 Healthy control 32.7±5.5 20–40 Anxiety Questionnaire (HADS) 8.24±4.19 – Endometriosis patients without pain had significant higher score in
61 27.9±4.4 20–40 6.49±3.45 anxiety than healthy controls

Friedl et al. [41] Austria 62 Healthy control 33.4±5.41 – Depression Questionnaire (HADS) 3.42±3.779 – No significant difference in depression scores between endometrio-
61 29.6±7.3 4.15±4.274 sis patients without pain and healthy controls

Austria 62 Healthy control 33.4±5.41 – Anxiety Questionnaire (HADS) 5.85±4.548 – No significant difference in anxiety scores between endometriosis
61 29.6±7.3 5.67±3.124 patients without pain and healthy controls

Fuldeore et al. [42] England 37,570 Healthy control 36.4±6.6 18–45 Depression Registered diagnosis (ICD – 9.0 Endometriosis patients showed higher rate in depression than
37,570 36.4±6.6 18–45 codes) 6.1 healthy controls

Quiñones et al. [43] USA 29 Healthy control 29.1±1.2 15–49 Anxiety Questionnaire (STAI) – 57.1 Endometriosis patients showed higher rate of anxiety than healthy
36 31.7±2.4 15–49 8.3 controls

Rocha et al. [45] Brazil 24 Non-endometriosis 32.9±9.0 – Depression Questionnaire (HADS) 8.3±4.6 33.3 No significant difference in depression scores or rate in the χ2 test
16 control 32.7±7.8 10.8±6.7 31.2 among endometriosis patients, non-endometriosis controls, and
healthy controls

Gynecol Obstet Invest

Brazil 24 Healthy control 32.9±9.0 – Depression Questionnaire (HADS) 8.3±4.6 33.3
25 35.4±6.7 6.4±4.1 28

DOI: 10.1159/000516517
Brazil 24 Non-endometriosis 32.9±9.0 – Anxiety Questionnaire (HADS) 9.6±5.0 50 No significant difference in anxiety scores or rate in the χ2 test
16 control 32.7±7.8 10.1±6.9 31.2 among endometriosis patients, non-endometriosis controls, and
healthy controls
Brazil 24 Healthy control 32.9±9.0 – Anxiety Questionnaire (HADS) 9.6±5.0 50
25 35.4±6.7 6.4±4.1 24

Stratton et al. [46] USA 18 Non-endometriosis 32.1±8.0 18–50 Depression Questionnaire (Duke Health 32.4±16.9 – Endometriosis with pain patients had significant lower score in
11 control 35.9±9.3 18–50 Profile) 35.0±13.5 depression than patients without endometriosis but pain

USA 18 Healthy control 32.1±8.0 18–50 Depression Questionnaire (Duke Health 32.4±16.9 – Endometriosis patients had significant higher score in depression
20 35.4±8.8 18–50 Profile) 14.4±17.1 than healthy controls

USA 18 Non-endometriosis 32.1±8.0 18–50 Anxiety Questionnaire (Duke Health 36.6±17.7 – Endometriosis with pain patients had significant lower score in
11 control 35.9±9.3 18–50 Profile) 45.0±13.7 anxiety than patients without endometriosis but pain

USA 18 Healthy control 32.1±8.0 18–50 Anxiety Questionnaire (Duke Health 36.6±17.7 – Endometriosis patients had significant higher score in anxiety than
20 35.4±8.8 18–50 Profile) 19.9±21.0 healthy controls

7
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 8
Table 1 (continued)
Author Country Participants Type of control Mean age Age range Depression/ Depression/anxiety assessment Mean Prevalence of Relevant findings
(patients, n) anxiety method score ± SD depression/
(control, n) anxiety, %

As-Sanie et al. [47] America 17 Non-endometriosis – 18–52 Depression Questionnaire (STPI) 17.9±4.5 – No significant difference in STPI depression scores between pa-
6 control 18–52 14.0±4.1 tients with symptoms and non-endometriosis controls

USA 13 Non-endometriosis 36.6±8.7 18–52 Depression Questionnaire (STPI) 13.8±4.1 – No significant difference in STPI depression scores between pa-
6 control 24.2±4.6 18–52 14.0±4.1 tients without symptoms and non-endometriosis controls

USA 17 Non-endometriosis – 18–52 Anxiety Questionnaire (STPI) 18.3±4.5 – No significant difference in STPI anxiety scores between patients
6 control 18–52 16.3±3.9 with symptoms and non-endometriosis controls

USA 13 Non-endometriosis 36.6±8.7 18–52 Anxiety Questionnaire (STPI) 14.6±4.1 – No significant difference in STPI anxiety scores between patients
6 control 24.2±4.6 18–52 16.3±3.9 without symptoms and non-endometriosis controls

Chen et al. [48] China, Taiwan 10,439 Non-endometriosis 35.88±8.82 – Depression Registered diagnosis (ICD – 6.51 Endometriosis patients showed higher rate of depression than 1:1
10,439 control 35.88±8.82 codes) 4.42 matched non-endometriosis controls

China, Taiwan 10,439 Non-endometriosis 35.88±8.82 – Anxiety Registered diagnosis (ICD – 3.32 Endometriosis patients showed higher rate of anxiety than 1:1
10,439 control 35.88±8.82 codes) 2.29 matched non-endometriosis controls

Gynecol Obstet Invest

De Graaff et al. [50] The Netherlands 83 Non-endometriosis 34.3±4.5 18–42 Depression Questionnaire (HADS) 4±2.96 18.07 Endometriosis patients showed higher rate of depression than

DOI: 10.1159/000516517
40 control 32.4±6.5 18–42 1±1.48 7.5 non-endometriosis controls, including mild, moderate, and severe
depression

The Netherlands 83 Non-endometriosis 34.3±4.5 18–42 Anxiety Questionnaire (HADS) 7±5.19 44.58 Endometriosis patients showed higher rate of anxiety than non-
40 control 32.4±6.5 18–42 4±2.22 17.5 endometriosis controls, including mild, moderate, and severe anxi-
ety

Wu et al. [9] China, Taiwan 9,191 Healthy control – 18–49 Depression Registered diagnosis (ICD – 5.7 Endometriosis patients showed higher rate of depression than
27,573 18–49 codes) 3.4 healthy controls

Ramin-Wright et al. Switzerland and 514 Non-endometriosis 37.9±7.2 18–59 Depression Questionnaire (PHQ-9 score – 27.4 Higher prevalence of depression in endometriosis patients than
[52] Germany 491 control 37.6±8.9 18–59 ≥10) 10.8 non-endometriosis controls

Gallagher et al. [8] England 360 Non-endometriosis – 10–24 Depression Self-report – 16.4 Patients had higher rate in depression than non-endometriosis
207 control 10–24 9.7 controls

England 360 Non-endometriosis – 10–24 Anxiety Self-report – 25.6 Patients had higher rate in anxiety than non-endometriosis con-
207 control 10–24 9.7 trols

Grundström et al. Sweden 13 Non-endometriosis 22.6±6.3 19–40 Depression Questionnaire (HADS) 8.1±4.6 – No significant difference in HADS-d scores between patients and
[54] 24 control 26.6±5.7 17–39 7.7±4.2 non-endometriosis controls

Sweden 13 Non-endometriosis 22.6±6.3 19–40 Anxiety Questionnaire (HADS) 9.4±5.4 – No significant difference in HADS-s scores between patients and
24 control 26.6±5.7 17–39 10.1±3.7 non-endometriosis controls

Sweden 13 Healthy control 22.6±6.3 19–40 Depression Questionnaire (HADS) 8.1±4.6 – Patients get higher scores in HADS-d than non-endometriosis
55 30.2±5.6 18–40 2.3±2.4 controls

Sweden 13 Healthy control 22.6±6.3 19–40 Anxiety Questionnaire (HADS) 9.4±5.4 – Patients get higher scores in HADS-s than non-endometriosis
55 30.2±5.6 18–40 4.6±3.4 controls

Ouyang
Gao et al. [10] Sweden 14,114 Non-endometriosis – 26–43 Depression Registered diagnosis (ICD – 1.208 Women with a previous diagnosis of endometriosis showed higher
839,696 control 26–43 codes) 0.478 rate of depression than women without

Sweden 14,114 Non-endometriosis – 26–43 Anxiety Registered diagnosis (ICD – 1.732 Women with a previous diagnosis of endometriosis showed higher
839,696 control 26–43 codes) 0.685 rate of anxiety than women without

The characteristics of the included studies that assessed depression and/or anxiety were collected. The content covered are authors, country, number of participants, type of control, the age bracket of study/control groups, ways of measuring depression/anxiety,
level of depression/anxiety, and relevant findings of the studies. –, not available.

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Table 2. Characteristics of the included studies: SF-36

Author Country Participants Type of control Mean Age PCS MCS Relevant findings
(patients, n) age range (M ± SD) (M ± SD)
(control, n)

Siedentopf Germany 30 Non-endometriosis – 24–45 50.5±9.63 47.5±10.37 The quality of life was reduced in patients
et al. [26] 31 control 26–44 53.0±5.19 51.0±5.19 with endometriosis, particularly in patients
with severe endometriosis (stage III + IV)
Germany 8 Non-endometriosis – 24–45 50.7±5.93 43±14.81
31 control 24–42 53.0±5.19 51.0±5.19
As-Sanie USA 17 Healthy control 26.1±1.5 18–52 40.7±10.6 – PCS differences between endometriosis
et al. [33] 17 25.9±1.6 18–52 57.9±2.1 patients with pain and control were
statistically significant
USA 15 Healthy control 36.8±2.2 18–52 56.2±3.6 – PCS differences between endometriosis
14 36.2±2.6 18–52 57.6±2.1 patients without pain and control were not
statistically significant
Gallagher England 291 Healthy control – ≥7 43.9±10.1 43.8±12.1 Adolescents and young adults with
et al. [49] 143 ≥7 53.4±10.3 46.8±12.3 surgically confirmed endometriosis report
poorer QOL than their peers, both in PCS
and MCS
Gallagher England 360 Non-endometriosis – 10–24 43.7±11.2 43.5±12.2 Adolescents with endometriosis had
et al. [8] 207 control 10–24 53.9±7.8 46.4±11.1 significantly lower PCS and MCS scores
compared to controls, as well as lower scores
on all 8 subscales
van Aken The 30 Healthy control 34.2±7.09 ≥18 57.44±20.40 57.64±23.86 PCS and MCS differences between
et al. [51] Netherlands 29 35.19±6.3 ≥18 89.87±10.97 80.47±17.01 endometriosis patients and healthy controls
were statistically significant
Verket Norway 156–157 Healthy control 35.2±6.5 18–45 44.7±9.7 43.2±10.8 Compared to the control group, the
et al. [53] 153–156 32.6±6.5 18–45 56.0±07.4 48.9±9.8 endometriosis group had significantly
reduced mean scores for all SF-36 scales
Grundström Sweden 13 Non-endometriosis 22.6±6.3 19–40 39.4±7.7 29.4±13.1 PCS and MCS differences between
et al. [54] 24 control 26.6±5.7 17–39 41.2±9.3 26.3±11.4 endometriosis patients with pain and pain
controls were not statistically significant
Sweden 13 Healthy control 22.6±6.3 19–40 39.4±7.7 29.4±13.1 PCS and MCS differences between
55 30.2±5.6 18–40 55.5±3.6 48.8±8.7 endometriosis patients with pain and
healthy controls were statistical significant
Schneider England 32 Healthy control 20.4±2.2 18–25 50.3±11.09 50.2±16.64 In participants with and without
et al. [55] 172 22.5±1.8 18–25 57.0±6.69 47.0±40.15 endometriosis, all SF-36 subscale scores
were significantly lower in young adult
England 119 Healthy control 21.4±2.2 18–25 46.1±11.31 42.0±36.46 women (AYA) with dyspareunia than
115 22.6±1.7 18–25 55.3±32.28 44.2±31.73 without. For 6 subscales, the negative impact
was significantly stronger in AYA with
endometriosis than those without

The characteristics of the included studies that assessed quality of life by SF-36 were collected. The content covered are authors, country, number of par-
ticipants, type of control, the age bracket of study/control groups, M±SD of physical/mental component summary, and relevant findings of the studies. –,
not available; PCS, physical component summary; MCS, mental component summary; QOL, quality of life.

The SMD of depression was evaluated in 15 studies in-
cluding a total of 845 patients in the study group and
1,023 subjects in the control group. Depression symp-
toms did not differ significantly between the study group
and the control group (SMD = 0.19, 95% CI = −0.08 to
0.46, p = 0.16); however, the heterogeneity was not ac-
ceptable (p = 0.000, I2 = 85%) (Fig. 4).
As for the SMD of anxiety was evaluated in 14 stud-
ies including a total of 897 endometriosis patients and
1,351 controls. The study group had a mildly higher
anxiety score than the controls (SMD = 0.26, 95% CI =
0.12–0.40, p = 0.0004). However, the heterogeneity was
also larger than the upper limit of acceptability (p =
0.000, I2 = 55%). Therefore, a subgroup analysis was
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Endometriosis Could Cause Depression Gynecol Obstet Invest 9

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 Table 3. Quality of studies according to NOS

Studies Quality indicators from NOS

1 2 3 4 5A 5B 6 7 8 Total
score

Shatford et al. [18] Yes No Yes Yes Yes Yes No Yes Yes 7
Walker et al. [19] Yes No Yes Yes Yes Yes Yes Yes Yes 8
Low et al. [20] Yes No Yes Yes Yes Yes No Yes No 6
Waller et al. [21] Yes No Yes Yes Yes Yes Yes Yes Yes 8
Peveler et al. [22] Yes No Yes Yes Yes Yes No Yes No 6
Laursen et al. [11] Yes No Yes Yes Yes Yes No Yes Yes 7
Cunha-Filho et al. [23] Yes No Yes Yes Yes Yes No Yes No 6
Tietjen et al. [24] Yes No No Yes Yes Yes No Yes No 5
Mirkin et al. [25] No Yes Yes Yes Yes Yes Yes Yes Yes 8
Siedentopf et al. [26] Yes No Yes Yes Yes Yes No Yes Yes 7
Petrelluzzi et al. [27] Yes No No Yes Yes Yes No Yes Yes 6
Taran et al. [28] Yes No No Yes Yes Yes Yes Yes Yes 7
Karp et al. [29] Yes No Yes Yes Yes Yes No Yes No 6
Kumar et al. [30] Yes No Yes Yes Yes Yes Yes Yes No 7
Nnoaham et al. [31] Yes Yes No Yes Yes Yes No Yes Yes 7
Souza et al. [32] Yes No Yes Yes Yes Yes Yes Yes No 7
As-Sanie et al. [33] Yes No No Yes Yes Yes No Yes Yes 6
Issa et al. [34] Yes No Yes Yes Yes Yes No Yes Yes 7
Hansen et al. [35] Yes No Yes Yes No No Yes Yes No 5
Yang et al. [36] Yes No No Yes Yes Yes No Yes No 5
Cavaggioni et al. [37] Yes No Yes Yes Yes No No Yes Yes 6
Nunes et al. [38] Yes No No Yes Yes Yes No Yes Yes 6
Laganà et al. [39] Yes Yes Yes Yes Yes Yes Yes No Yes 8
Facchin et al. [40] Yes No No Yes Yes Yes No Yes Yes 6
Friedl et al. [41] Yes No No Yes Yes No No Yes No 4
Fuldeore et al. [42] No Yes No Yes Yes Yes No Yes Yes 6
Quiñones et al. [43] Yes No No Yes Yes No No Yes Yes 5
Xiaochun et al. [44] Yes No No Yes Yes Yes No Yes Yes 6
Rocha et al. [45] Yes No No Yes Yes Yes No Yes Yes 6
Stratton et al. [46] Yes No Yes Yes Yes Yes No Yes Yes 7
As-Sanie et al. [47] Yes No Yes Yes Yes Yes No Yes No 6
Chen et al. [48] No Yes Yes Yes Yes No No Yes No 5
Gallagher et al. [49] Yes No No Yes Yes Yes No Yes Yes 6
De Graaff et al. [50] Yes No Yes Yes Yes Yes No Yes Yes 7
van Aken et al. [12] Yes No No Yes Yes Yes No Yes Yes 6
van Aken et al. [51] Yes No Yes Yes Yes Yes No Yes Yes 7
Ramin-Wright et al. [52] Yes No Yes Yes Yes Yes No Yes Yes 7
Gallagher et al. [8] Yes No Yes Yes Yes Yes No Yes Yes 7
Verket et al. [53] Yes No No Yes Yes Yes No Yes No 5
Wu et al. [9] No Yes Yes Yes Yes No No Yes Yes 6
Grundström et al. [54] Yes No No Yes Yes Yes No Yes Yes 6
Huang and Qin [13] Yes No No Yes Yes Yes No Yes Yes 6
Gao et al. [10] No Yes Yes Yes Yes Yes No Yes Yes 7
Schneider et al. [55] Yes No No Yes Yes Yes No Yes Yes 6

The instrument relies on 3 criteria to evaluate observational studies: (1) selection of cases (1–4); (2) comparability of study
groups (5A and 5B); and (3) assessment of outcome or exposure (6–8). If a study met all the criteria, it got a score of 9. Quality of
the studies was assessed according to the scores. High-quality studies scored 7 points or more and means they have low risk of
bias. Decision of low-quality studies was according to the points of 3 criteria: obtaining a score of 0–1 point for selection or 0 for
comparability or for the assessment of outcomes, all indicate a high risk of bias. Studies that had scores other than the 2 conditions
stood for moderate risk of bias. 1, cases independently validated; 2, cases are representative of population; 3, community controls;
4, controls have no history of endometriosis; 5A, study controls for age/gender; 5B, study controls for additional factor(s); 6, as-
certainment of depression/anxiety by blinded structured interview or secure record; 7, same method of ascertainment used for
cases and controls; 8, non-response rate the same for cases and controls; NOS, Newcastle-Ottawa Scale.
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10 Gynecol Obstet Invest Wang/Li/Zhou/Wang/Han/Zhang/He/

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 Color version available online
Fig. 2. Forest plot of depression-OR. Endometriosis patients had an obviously higher prevalence of depression
as compared to the control group (OR = 1.86, 95% CI = [1.63–2.13], p = 0.000). The heterogeneity analysis of the
effect sizes of depression showed a high amount of heterogeneity (p = 0.000, I2 = 84%). OR, odds ratio; CI, con-
fidence interval.

Color version available online

Fig. 3. Forest plot of anxiety-OR. Patients had a significantly higher rate of anxiety than controls (OR = 2.38, 95%
CI = [1.06–5.37], p = 0.04). The heterogeneity of the effect sizes of anxiety was also high (p = 0.000, I2 = 98%).
OR, odds ratio; CI, confidence interval.
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Endometriosis Could Cause Depression Gynecol Obstet Invest 11

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 Color version available online
Fig. 4. Forest plot of depression-SMD). Depression symptoms were not significantly different compared with the
controls (SMD = 0.19, 95% CI = [−0.08 to 0.46], p = 0.16) and the heterogeneity could not be accepted (p = 0.000,
I2 = 85%). SMD, standardized mean difference; CI, confidence interval.

necessary to identify the potential moderating factors Subgroup Analysis

(Fig. 5).
SMD of HRQoL in Endometriosis Patients
As shown in Figures 6 and 7, both effect sizes differed
significantly between endometriosis patients and con-
trols. The patients had a worse quality of life than the
controls in both the physical and mental dimensions
(PCS: SMD = −1.05, 95% CI = −1.37 to −0.74, p = 0.000;
MCS: SMD = −0.44, 95% CI = −0.69 to −0.19, p = 0.0005).
However, there was some variability among the studies
(PCS: I2 = 88%; MCS: I2 = 81%). The data from the 8 sub-
scales of the SF-36 were also pooled, and the endome-
triosis patients had worse scores than the controls in ev-
ery dimension (differences between the 2 groups were
statistically significant). Details can be found in Appen-
dix 2.
ORs of Depression and Anxiety
Table 4 shows, when discussing the potential moderat-
ing factors of depression, the ORs ranged from 1.29 to
2.30 with no significant differences between the sub-
groups. When comparing the subgroups by continent,
the 33,704 endometriosis patients in North America had
a significantly higher rate of depression compared with
the 7,145,332 controls (OR = 2.30, 95% CI = 1.32–4.00, p
= 0.003). In the South America subgroup, I2 = 0%, which
indicates that heterogeneity was related to the country in
which the studies were conducted, and the studies in this
subgroup were homogeneous. Heterogeneity could not
be explained by other moderating variables except conti-
nent.
The OR for anxiety had a larger fluctuation (0.59–
6.63); however, no differences were found between the
subgroups. The ORs were significantly higher in the sub-
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12 Gynecol Obstet Invest Wang/Li/Zhou/Wang/Han/Zhang/He/

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 Color version available online
Fig. 5. Forest plot of anxiety-SMD: The study group had a mildly higher anxiety score than the controls (SMD =
0.26, 95% CI = [0.12–0.40], p = 0.0004). However, heterogeneity was larger than the upper limit (p = 0.000, I2 =
55%). SMD, standardized mean difference; CI, confidence interval.

Color version available online

Fig. 6. Forest plot of PCS-SMD. Patient had worse quality of life than the controls in physical dimensions
(SMD = −1.05, 95% CI = [−1.37, −0.74]). However, there was some variability among the studies (I2 = 88%). PCS,
physical component summary; SMD, standardized mean difference; CI, confidence interval.
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Endometriosis Could Cause Depression Gynecol Obstet Invest 13

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Fig. 7. Forest plot of MCS-SMD. Patient had worse quality of life than the controls in mental dimensions
(SMD = −0.44, 95% CI = [−0.69, −0.19], p = 0.0005). However, there was some variability among the studies
(MCS: I2 = 81%). MCS, mental component summary; SMD, standardized mean difference; CI, confidence inter-
val.
groups of healthy controls (OR = 5.48, 95% CI = 2.08–
14.47, p = 0.0006), self-report questionnaires (OR = 3.47,
95% CI = 2.17–5.54, p = 0.000), studies with sample sizes
less than the median (OR = 3.09, 95% CI = 1.35–7.07, p =
0.007), and studies in North America (OR = 6.63, 95%
CI = 1.85–23.70, p = 0.004), which indicates that in these
conditions, anxiety was much more obvious in endome-
triosis patients. The heterogeneity could not be explained
by any of the above-mentioned subgroups.
SMDs of Depression and Anxiety
In the synthesis of the SMDs of depression and anxi-
ety, all data were measured through questionnaires.
Therefore, in the subgroup of assessment methods, we
divided the studies into those that used the HADS ques-
tionnaires and those that had not. The SMD subgroup
values for depression ranged from −0.09 to 0.71. There
were some significant differences between subgroups,
such as in the type of control group (p = 0.02) and in the
study group size (p = 0.04). Furthermore, compared with
healthy controls (SMD = 0.71, 95% CI = 0.19–1.23, p =
0.008) or a small study group (SMD = 0.46, 95% CI =
0.10–0.82, p = 0.01), the SMD values were significantly
higher. No factors influencing heterogeneity were identi-
fied.
The SMD values for anxiety also had obvious fluctua-
tions from 0.01 to 0.62. When the control groups were
composed of healthy people, anxiety was much more sig-
nificant in the study group (SMD = 0.62, 95% CI = 0.26–
0.99, p = 0.008). When the subgroup analysis was con-
ducted according to the type of control group, the differ-
14 Gynecol Obstet Invest
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ences between subgroups were statistically significant.
Heterogeneity was found for the type of control group
(I2 = 35%) and in the country where the study was per-
formed (I2 = 40%); these values indicate that there was
low variability among these subgroup.
SMDs of PCS and MCS in the SF-36
The SMDs for the physical component of quality of life
ranged from −0.30 to −1.34, and the disturbance in the
PCS was larger when the control group was composed of
healthy peers (SMD = −1.34, 95% CI = −1.80 to −0.89,
p = 0.000) rather than other patients (SMD = −0.55, 95%
CI = −1.04 to −0.06, p = 0.03). The differences between
the 2 subgroups were significant (p = 0.02). Heterogeneity
was not found because none of the I2 values were <50%.
In the mental component of life quality, the influ-
ence on the MCS was more severe when fewer patients
were included (SMD = 0.62, 95% CI = 0.26–0.99, p =
0.008). However, the difference between subgroups was
not significant. Heterogeneity may occurred due to the
types of control groups because variability was lower in
the non-endometriosis group (I2 = 47%). A subgroup
analysis on the country of origin of those studies could
not be performed because all the studies were conduct-
ed in Europe.
Publication Bias
The funnel plots of the 6 main parts are shown in Fig-
ure 8. To some extent, publication bias is present because
the funnel plots for anxiety rate and the MCS are asym-
metric.
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Table 4. Subgroup analysis

Subgroups Studies, Participants Participants of OR/SMD 95% CI I2, % p value

n of study group, n control group, n

Depression (OR) 18 106,830 8,062,158 1.86 [1.63, 2.13] 84

Control group
Non-endometriosis control 14 26,403 851,929 1.93 [1.44, 2.60] 84
0.53
Healthy control 6 80,427 7,210,229 1.74 [1.51, 2.00] 86
Methods of assessment
Clinical diagnosis 7 7,066 286,321 1.82 [1.60, 2.08] 90.0
0.86
Self-report questionnaire 13 1,867 1,820 1.9 [1.21, 2.98] 79
Study group, n
Less than median 10 360 615 1.73 [1.04, 2.89] 58
0.84
More than median 10 106,470 8,061,543 1.83 [1.59, 2.10] 90.0
Continent of the study
Asia 2 1,203 38,012 1.67 [1.38, 2.02] 81
Europe 10 53,416 878,751 1.91 [1.39, 2.63] 89
North America 5 33,704 7,145,332 2.3 [1.32, 4.00] 76 0.54
South America 3 24 16 1.29 [0.61, 2.73] 0
Anxiety (OR) 11 25,436 850,856 2.38 [1.06, 5.37] 98
Control group
Non-endometriosis control 9 21,172 20,938 2.47 [1.64, 3.72] 78
0.14
Healthy control 4 150 222 5.48 [2.08, 14.47] 69
Methods of assessment
Clinical diagnosis 2 24,553 850,135 0.59 [0.10, 3.50] 100
0.06
Self-report questionnaire 11 883 721 3.47 [2.17, 5.54] 61
Study group, n
Less than median 7 212 365 3.09 [1.35, 7.07] 70.0
0.52
More than median 6 25,224 850,491 1.95 [0.63, 5.98] 99
Continent of the study
Asia 1 10,439 10,439 1.47 [1.24, 1.73] –
Europe 6 14,818 840,095 2.08 [0.46, 9.50] 98
North America 3 54 55 6.63 [1.85, 23.70] 79 0.14
South America 3 80 63 1.36 [0.32, 5.37] 63
Depression (SMD) 16 845 1,023 0.19 [−0.08, 0.46] 85
Control group
Non-endometriosis control 21 586 709 −0.01 [−0.31, 0.30] 83
0.02
Healthy control 8 259 314 0.71 [0.19, 1.23] 88
Methods of assessment
HADS 13 373 396 0.29 [−0.09, 0.66] 83
0.54
Non-HADS 16 472 627 0.12 [−0.26, 0.50] 87
Study group, n
Less than median 16 264 335 0.46 [0.10, 0.82] 76
0.04
More than median 13 581 688 −0.09 [−0.47, 0.30] 90.0
Continent of the study
Europe 18 563 644 0.22 [−0.06, 0.51] 81
North America 8 202 313 0.26 [−0.61, 1.13] 92
0.58
South America 3 80 66 −0.08 [−0.59, 0.43] 58
Anxiety (SMD) 14 897 1,351 0.26 [0.12, 0.40] 55
Control group
Non-endometriosis control 24 638 1,037 0.16 [0.02, 0.30] 35
0.05
Healthy control 8 259 314 0.62 [0.26, 0.99] 75
Methods of assessment
HADS 11 347 362 0.36 [0.11, 0.61] 57
0.33
Non-HADS 21 550 989 0.21 [0.03, 0.38] 53
Study group, n
Less than median 16 272 369 0.36 [0.09, 0.62] 59
0.31
More than median 16 624 982 0.2 [0.04, 0.36] 52
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Table 4 (continued)

Subgroups Studies, Participants Participants of OR/SMD 95% CI I2, % p value

n of study group, n control group, n

Continent of the study

Europe 21 673 787 0.27 [0.13, 0.41] 40.0
North America 8 144 498 0.36 [−0.08, 0.80] 71
0.73
South America 3 80 66 0.01 [−0.72, 0.75] 79
SF-36-PCS 7 1,084 991 −1.05 [−1.37, −0.74] 88
Control group
Non-endometriosis control 4 411 293 −0.55 [−1.04, −0.06] 75
0.02
Healthy control 8 673 698 −1.34 [−1.80, −0.89] 91
Study group, n
Less than median 7 126 201 −1.26 [−2.13, −0.40] 91
0.44
More than median 5 958 790 −0.91 [−1.19, 0.63] 85
Continent of the study
Europe 10 1,052 960 −1.02 [−1.35, −0.69] 89
North America 2 32 31 −1.31 [−3.02, 0.39] 89 0.74
SF-36-MCS 6 1,052 962 −0.44 [−0.69, −0.19] 81
Control group
Non-endometriosis control 4 411 293 −0.3 [−0.63, 0.03] 47
0.34
Healthy control 6 641 669 −0.54 [−0.92, −0.17] 88
Study group, n
Less than median 5 94 170 −0.84 [−1.53, −0.15] 83
0.1
More than median 5 958 792 −0.23 [−0.41, −0.05] 66

The first column lists the possible source of heterogeneity. p value means the comparison between subgroups. If p <0.05, difference
between the subgroups is significant. I2 stands for heterogeneity. I2 <50% in 1 subgroup means this subgroup is the source of heteroge-
neity. The number of studies per row is based on the independent group of endometriosis versus control group. However, some studies
included multiple control groups (e.g., disease and normal control). Thus, the total number of studies per subgroup of control group is
higher than the total number of the included studies in our meta-analysis. –, no report; OR, odds ratio; SMD, standardized mean differ-
ence; CI, confidence interval; PCS, physical component summary; MCS, mental component summary.

Discussion/Conclusion with endometriosis have higher psychological stress

This meta-analysis, which was based on structured
searches of 6 databases and defined inclusion and exclu-
sion criteria, finally identified 44 articles from 4 conti-
nents and 13 countries. Because there were several large
observation studies based on an entire country or region,
a very large number of subjects were included. Thus, it is
believed that the findings could deduce the existence of
disturbances in depression, anxiety, and injury related to
quality of life caused by endometriosis.
However, the psychological effects of endometriosis
may extend beyond depression and anxiety. Patients
with endometriosis seem to display more somatization
and sensitivity and more commonly experience fatigue
or insomnia [39, 52]. People with chronic diseases have
a higher occurrence of psychological disorders such as
depression, anxiety, and stress [57], and a similar pat-
tern appears in patients with endometriosis. A recent
meta-analysis provided strong evidence that women
levels [58]. Endometriosis may be the source of consid-
erable psychological disorders due to its chronic pain
and infertility [59, 60]. However, some animal models
revealed that stress is also related to the presentation
and progression of endometriosis [61, 62]. This begs the
question, is alleviating stress effective in improving en-
dometriosis? To some extent, it makes sense. A recent
prospective study found that endometriosis patients
who were using positive coping strategies adapted to
stress better and reported less depression and associat-
ed pelvic pain [63].
Although it is still in its infancy, this is not the only
study on psychological interventions for endometriosis.
Combined mindfulness, psychoeducation, and individu-
al psychotherapy based on cognitive behaviour therapy
have shown significant improvements in pain coping and
quality of life [64]. Progressive muscle relaxation was also
associated with significant reductions in psychological
distress and pain intensity [65]. These techniques are new
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16 Gynecol Obstet Invest Wang/Li/Zhou/Wang/Han/Zhang/He/

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 Color version available online
0 SE(log[OR]) 0 SE(log[OR])

0.2
0.5

0.4
1.0
0.6

1.5
0.8

OR OR
2.0 0.1
0.01 0.1 1 10 100 0.01 0.1 0 10 100
Anxiety rate Depression rate

0 SE(SMD) 0 SE(SMD)

0.1 0.1

0.2 0.2

0.3 0.3

0.4 0.4

SMD SMD
0.5 0.5
–2 –1 0 1 2 –2 –1 0 1 2
Anxiety MSD Depression MSD

0 SE(SMD) 0 SE(SMD)

0.1 0.1

0.2 0.2

0.3 0.3

0.4 0.4

SMD SMD
0.5 0.5
–4 –2 0 2 4 –2 –1 0 1 2
PCS MCS

Fig. 8. Funnel plots were used to assess the publication bias. To some extent, publication bias is existing because
funnel plots of anxiety rate and MCS are asymmetric. But it is acceptable in general. MCS, mental component
summary.
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Endometriosis Could Cause Depression Gynecol Obstet Invest 17

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approaches in endometriosis treatment that deserve more
attention in the future.
In addition to psychosocial interventions for endome-
triosis patients, the psychological effects of traditional
treatments also play an important role in women’s qual-
ity of life. Endometriosis treatment is complex, and ac-
cording to current guidelines, the main purpose of such
treatment should be pain control, improvement of qual-
ity of life, prevention of disease recurrence, fertility pres-
ervation, and the reduction of anatomical damage [66].
Hormonal treatment is a common therapy and most fre-
quently includes combined oral contraceptives, danazol,
gestrinone, medroxyprogesterone acetate, and gonado-
tropin-releasing hormone agonists; surgery is another
treatment option [67]. Although further research is nec-
essary, a few studies have reported the effects of common
treatments for endometriosis on quality of life and psy-
chological functioning. For example, gonadotropin-re-
leasing hormone agonists, which have been commonly
used as alternatives to gestagens and danazol to avoid the
high rate of side effects such as weight gain, acne, and
headache, are effective in reducing endometriosis symp-
toms; however, they are often associated with anxiety and
depression during treatment [67, 68]. Bergqvist and The-
orell found that nafarelin and medroxyprogesterone ac-
etate significantly reduced symptoms and improved fac-
tors related to quality of life such as sleep disturbances,
anxiety, and depression after treatment [69].
As for surgery, it is remains the primary treatment for
more severe forms of endometriosis, such as DIE [4]. To
date, there are few data available in the literature on qual-
ity of life and anxiety and depression levels after surgery
for endometriosis. A review by Deguara et al. [70] noted
that laparoscopic surgery is associated with improved
quality of life and emotional well-being compared with
medical therapies. These data suggest the importance of
psychological factors not only for the severity of symp-
toms but also for managing the disease and selecting the
most appropriate therapy. With the rapid development of
therapies, additional treatments for endometriosis can be
considered, such as phytotherapy, cabergoline, and some
novel drug delivery methods; however, the psychological
effects of these treatments still require long-term observa-
tion [71–73].
As a subject that only truly received recognition this
century, the interactions between endometriosis and
mental health and quality of life were previously based on
clinical manifestations and experiences until an increas-
ing number of doctors and researchers believed that en-
dometriosis was “more than a disease,” which prompted
18 Gynecol Obstet Invest
DOI: 10.1159/000516517
research on the topic. Aside from somatic discomfort,
they found that endometriosis also affects economical
pressure, career development, sexual relations, marital
status, and so on, because of its unique features, and these
effects may persist for a long time. Thus, in addition to
standard treatments, a comprehensive intervention will
be meaningful in the treatment of endometriosis. Our re-
search synthesizes former outcomes and provides direct
knowledge of evidence-based medicine. We hope that it
can serve as a foundation for further studies. We are look-
ing forward to further research and effective changes on
specialist consensus and guidelines in the near future.
Our meta-analysis has several limitations. First, some
research has noted that the mental health and quality of
life of endometriosis patients are influenced by many fac-
tors, such as infertility, chronic pelvic pain, and dyspareu-
nia; even the time of diagnosis and the patients’ charac-
teristics may play a role [54–58]. However, we did not
include these factors in our subgroup analyses because
many of the studies that we assessed did not pay attention
to these factors. Second, although a subgroup analysis was
performed and several moderating variables were found,
I2 was >50% in many cases. Third, most of the included
studies were cross-sectional, indicating that they only re-
flect the relationship of the variables at a specific moment.
The findings of the retrospective studies were based on
coded diagnoses or hospital records, making it easy to
wrongly estimate the exposure and outcomes. More lon-
gitudinal cohort studies are necessary in the future to bet-
ter explain whether the impact on mental health and
quality of life is lasting or temporary. Fourth, some stud-
ies had multiple control groups. For example, if a study
included a group with other gynaecological diseases and
another group of healthy controls, this study was includ-
ed twice in the meta-analysis. This may have overestimat-
ed the precision of the study. Fifth, the number of subjects
(approximately 1,000) was not very large, except for those
from the studies used to evaluate the ORs for depression
and anxiety, so the outcomes may be accidental findings.
Sixth, we only included articles published in English and
Chinese. Finally, although most of publication bias re-
sults were acceptable, the presence of this bias cannot be
ruled out.
We conclude that endometriosis appears to be associ-
ated with the mental health (i.e., depression and anxiety)
and HRQoL of patients since similar findings were found
in various subgroup analyses. However, the differences
were more obvious when patients with endometriosis
were compared with healthy individuals rather than with
other hospital-sourced controls. This phenomenon
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should receive more attention in future studies to prop-
erly develop the management of endometriosis patients
and improve their prognosis.
Funding Sources
This study was supported by the Program for Shenyang Science
Foundation (No. 19-112-4-020) and Natural Science Foundation
of Liaoning Province (No. JC2019012).

Statement of Ethics
Author Contributions
This systematic review is based on published research, which
complies with internationally accepted standards for research
Y.H.W.: data collection and management, data analysis, and
practice and reporting.
writing – original draft. B.L.: data collection and management.
Y.Z.: data collection and management. Y.W.: data analysis. X.H.:
project administration. S.Z.: writing – review and editing. Z.H.:
Conflict of Interest Statement writing – review and editing. L.O.: project administration.

The authors (Y.H.W., B.L., Y.Z., Y.W., X.H., S.Z., Z.H., and
L.O.) declare that they have no conflicts of interest.

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