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Hum Reprod Update. 2010 Nov-Dec; 16(6): 651–674.
Published online May 12, 2010. doi:  10.1093/humupd/dmq009
PMCID: PMC2953938

Peripheral biomarkers of endometriosis: a systematic review

Abstract

BACKGROUND

Endometriosis is estimated to affect 1 in 10 women during the reproductive years. There is often delay in making the diagnosis, mainly due to the non-specific nature of the associated symptoms and the need to verify the disease surgically. A biomarker that is simple to measure could help clinicians to diagnose (or at least exclude) endometriosis; it might also allow the effects of treatment to be monitored. If effective, such a marker or panel of markers could prevent unnecessary diagnostic procedures and/or recognize treatment failure at an early stage.

METHODS

We used QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria to perform a systematic review of the literature over the last 25 years to assess critically the clinical value of all proposed biomarkers for endometriosis in serum, plasma and urine.

RESULTS

We identified over 100 putative biomarkers in publications that met the selection criteria. We were unable to identify a single biomarker or panel of biomarkers that have unequivocally been shown to be clinically useful.

CONCLUSIONS

Peripheral biomarkers show promise as diagnostic aids, but further research is necessary before they can be recommended in routine clinical care. Panels of markers may allow increased sensitivity and specificity of any diagnostic test.

Keywords: endometriosis, infertility, laparoscopy

Introduction

Endometriosis, the presence of endometrial-like tissue outside the uterus, is a disease associated with pelvic pain and infertility. It affects approximately 10% of women of reproductive age (Giudice and Kao, 2004), although its prevalence in women with chronic pelvic pain is much higher, and infertility has been reported in 30–50% of endometriosis patients (Practice committee of the American Society for Reproductive Medicine, 2004). As such, it has significant socio-economic implications for individuals and society as a whole (Simoens et al., 2007).

The symptoms are often non-specific as they may mimic those associated with other chronic pain disorders, such as irritable bowel syndrome and pelvic inflammatory disease. In addition, in the overwhelming majority of cases a surgical procedure is required to make a definitive diagnosis. As a result, women can suffer for 8–12 years before obtaining a diagnosis and receiving appropriate treatment (Hadfield et al., 1996). Therefore, the ability to diagnose patients more easily, using less invasive means (e.g. a biomarker), would be of great value, particularly if the same biomarker could be used to monitor treatment efficacy. A biomarker is defined as ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention’ (Biomarkers Definitions Working Group, 2001). Hence, if reliable, such a biomarker, or a panel of biomarkers, could be an effective tool to diagnose endometriosis without the need of surgery.

To date, biomarker discovery in this field has utilized hypothesis-free approaches, e.g. differential expression in eutopic endometrium and endometriotic lesions from the same patients, or a more hypothesis-driven approach assessing candidate biomarkers in urine and/or blood samples. The majority of the latter studies have focused on single markers, and many results have been inconsistent and, at times, contradictory. Several narrative reviews have been published, but most authors have failed to use methods that are now recommended for systematic reviews of diagnostic tests (Levine et al., 1994; Stroup et al., 2000).

Our primary aim, therefore, was to conduct a systematic review of the literature from the last 25 years to assess critically the clinical value of all proposed biomarkers for endometriosis in serum, plasma and urine. Although recent research has highlighted endometrial biopsy as a potential diagnostic tool (Al-Jefout et al., 2009; Bokor et al., 2009), the role of endometrial samples, endometrial fluid aspirates and menstrual effluent as biomarkers will be considered separately in a companion review article because of the overwhelmingly large amount of data.

Methods

A primary computerized search was performed in PubMed, MEDLINE, EMBASE, and CINAHL of publications from January 1984 to August 2009. We searched using the following MeSH or keyword terms: endometriosis and urine or plasma or serum or tissue or endometrium or endometrial or blood or cell or saliva or menstrua* or sputum and biological markers and diagnosis or mass screening. We then searched in the bibliography of the retrieved articles and reviews and included any additional relevant articles. Only English language publications were included. The potentially relevant studies were retrieved, reviewed and categorized by two authors. Studies were evaluated according to specific criteria (Table I).

Table I
Inclusion and exclusion criteria for studies.

Two authors assessed the methodological quality of the studies and extracted relevant data such as sample size, biomarkers evaluated, tissue sampled, visual/histological confirmation of disease state, and whether or not confounding factors were controlled for by matching or adjustment. Where available, we extracted statistical data from the original papers or calculated missing measures using the data provided. The quality of individual studies was judged using a modified version of the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria (Whiting et al., 2003) (Table II).

Table II
Modified QUADAS criteria used for assessing studies.

Results

The primary computerized search produced 11 122 results, of which 10 950 were eliminated after screening their titles and abstracts (Fig. 1). If the abstract did not clearly indicate whether a study met the initial inclusion criteria, the entire article was assessed. The remaining 172 articles were considered relevant and the full papers were obtained, as well as an additional 17 papers identified from their reference lists. From this pool of 189 papers, 27 studies were excluded because, on more detailed assessment, they did not meet the selection criteria. One further study was excluded as the full text was unavailable, leaving 161 studies that were included in the final review (Fig. 1).

Figure 1
Flow diagram depicting selection of articles for review.

Table III shows the modified QUADAS criteria, biomarkers assessed and number of subjects and controls included in each study. Study sample size ranged from 8 (Panidis et al., 1988) to 775 (Kitawaki et al., 2005). None of the identified studies fulfilled all methodological criteria. The most common flaws were lack of blinding of investigators to disease state, poorly defined patient and control selection criteria, and lack of adjustment for menstrual cycle or stage of disease.

Table III
Modified QUADAS scoring for studies and main biomarkers assessed.

Cytokines

Many authors have sought to identify elevated or decreased levels of a variety of cytokines in women with endometriosis, partly to provide insights into the pathogenesis of disease and partly to assess their use as putative biomarkers. The most studied cytokines have been interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNFα), but the results from these (and other studies) have sometimes been conflicting.

Interleukin 6

IL-6 is a pro-inflammatory cytokine involved in the activation of T cells; it also promotes the differentiation of B cells (Kishimoto et al., 1995). Six studies have indicated a link between raised serum levels of IL-6 and endometriosis (Pellicer et al., 1998; Bedaiwy et al., 2002; Darai et al., 2003; Iwabe et al., 2003; Martinez et al., 2007; Othman et al., 2008), but other studies have shown no link (Somigliana et al., 2004; Kalu et al., 2007; Jee et al., 2008; Seeber et al., 2008).

The accuracy of the test for diagnostic purposes varied in the six positive studies. Martinez et al. (2007) found elevated levels of serum IL-6, but only in women with Stages I–II disease yielding a sensitivity of 75% and specificity of 83.3% for disease of this severity, using a threshold of 25.75 pg/ml. A separate study used a much lower threshold point of 1.3 pg/ml: it yielded a sensitivity of 81%, with a specificity of only 51% to diagnose all women regardless of stage (Othman et al., 2008).

Various differences between these studies may account for their very different findings. For example, some studies compare only women with ovarian cysts (endometriomas versus other benign cysts) (Jee et al., 2008). Others use different control groups: healthy, fertile controls or women with infertility other than that attributed to endometriosis (Kalu et al., 2007; Martinez et al., 2007). Furthermore, results may have been affected because of different assay sensitivities (Iwabe et al., 2003; Kalu et al., 2007). Finally, the stage of disease may considerably alter the cytokine levels: one study that showed no change in IL-6 levels between endometriosis patients and controls excluded women with Stage I disease from the analysis (Seeber et al., 2008). This resulted in the majority of women in their study being at Stages III–IV, which may therefore have affected their overall results.

Interleukin 8

IL-8 is a monocyte/macrophage-derived chemokine, capable of attracting and activating neutrophils (Baggiolini and Clark-Lewis, 1992). One paper found no difference in serum IL-8 levels in women with endometriosis compared with controls, and another reached the same conclusion for women with endometriomas (Gazvani et al., 1998; Darai et al., 2003). Kalu et al. (2007) reported a non-significant trend towards increased serum IL-8 levels in women with endometriosis . In another study, the serum levels were below the detection threshold of the test used (Othman et al., 2008).

Two studies have shown elevated IL-8 levels. The first demonstrated significantly higher levels in women with endometriosis versus controls (Pizzo et al., 2002). Interestingly, levels were higher in Stages I–II than in Stage III disease. Similarly, the second paper found increased IL-8 levels in women with endometriomas (Ohata et al., 2008).

Tumour necrosis factor-alpha

TNFα, a cytokine with pro-inflammatory and pro-angiogenic roles (Yan et al., 2006), appears in a variety of studies as a putative biomarker. Seven studies demonstrated an increase in TNFα levels in women with endometriosis (Markham and I., 1997a,b; Matalliotakis et al., 1997; Pizzo et al., 2002; Darai et al., 2003; Xavier et al., 2006; Cho et al., 2007), but four studies showed no such difference (Vercellini et al., 1993; Kalu et al., 2007; Othman et al., 2008; Seeber et al., 2008).

Two papers from the same group have shown elevated levels of serum TNFα in women with endometriosis compared with controls (Markham and I., 1997a,b). The first study also assessed TNFα levels in women with adhesions or a past history of endometriosis. These were not found to be significantly different to women with current endometriosis, raising concerns over the specificity of TNFα as a diagnostic test. The second (smaller) study showed that the elevated level was only significant in the group with an AFS (American Fertility Society) score of 11–20.

Matalliotakis et al. (1997) showed that serum TNFα levels were elevated in women with endometriosis compared with healthy controls and that levels were reduced by treatment with danazol for 6 months. Three months after discontinuation of treatment, TNFα levels were no longer significantly lower than pretreatment levels. A more recent study found a similar serum TNFα increase in endometriosis, but no increase in urinary TNFα levels (Cho et al., 2007). Analysis of subgroups showed no difference in serum levels between controls and women with Stages I–II disease, but showed a significant increase in women with Stages III–IV endometriosis. One further paper demonstrated an apparent association of increasing TNFα levels and worsening stage of disease (Pizzo et al., 2002). Infertility could be a confounding factor when assessing TNFα levels, as women with endometriosis had equivalent levels to those with idiopathic infertility, both of which were higher than in controls (Bedaiwy et al., 2002).

Two papers identified raised serum TNFα levels in women with endometriomas. The first study found significantly higher TNFα concentrations in women with endometriomas than in those with benign cysts, but no difference compared with levels in women with malignant cysts (Darai et al., 2003). The second paper reported higher levels in women with endometriomas compared with healthy controls (Xavier et al., 2006).

Vercellini et al. (1993) found no difference in serum TNFα levels between women with and without endometriosis, although the levels were below the detection limits of their assay in >80% of subjects. However, other groups have also reported no significant change in TNFα levels (Kalu et al., 2007; Seeber et al., 2008), even after stratifying women into two groups based on stage of disease (Othman et al., 2008).

Finally, one study measured levels of soluble TNF receptor in women with endometriosis and found a significant elevation in these levels during the follicular phase of the cycle (Steff et al., 2004b).

Monocyte chemotactic protein 1

It is known that macrophages play a role in endometriosis, and numbers of peritoneal macrophages are often increased in women with the disease compared with controls (Olive et al., 1985). One study found significant monocyte chemotactic protein 1 (MCP-1) increases but only during the luteal phase (Akoum et al., 1996): a threshold of 100 pg/ml gave a sensitivity of only 65% with 61% specificity. Disease stage may also affect the diagnostic value of this cytokine, although one study has shown higher levels in early disease stages (Pizzo et al., 2002) and another demonstrated higher values in more severe stages (Gmyrek et al., 2005).

Othman et al. (2008) studied MCP-1 as part of a panel of potential biomarkers. Although MCP-1 levels were higher in women with disease, IL-6 was a better discriminator; the use of MCP-1 and IL-6 together did not improve sensitivity or specificity. Two further studies did find MCP-1 to be of use in a panel (Agic et al., 2008; Seeber et al., 2008). The first used MCP-1 with cancer antigen 125 (CA125) and cognate chemokine receptor 1 (CCR1) mRNA levels (Agic et al., 2008). The second generated a sensitive and specific biomarker panel using MCP-1 in combination with leptin and CA125 (Seeber et al., 2008).

Interferon gamma

Despite the pro-inflammatory nature of interferon gamma (IFNγ), most studies have failed to find a correlation between peripheral blood levels and endometriosis. Two studies failed to demonstrate any change in serum IFNγ levels in women with endometriosis, using ELISA (Wu et al., 1998; Hassa et al., 2009). One paper identified increased IFNγ levels in affected women versus controls, but noted that IL-6 was a better discriminator (Othman et al., 2008); another study attempted to assess IFNγ but levels were below the detection threshold for the assay used (Seeber et al., 2008).

A recent study looked at levels of CXCL10, also known as IFNγ-inducible protein-10, which is involved in TH1-type immune responses (Galleri et al., 2009). Reduced serum levels were found in women with endometriosis compared with healthy controls.

Other cytokines

One study found elevated levels of IL-1α and IL-1 receptor antagonist, and decreased levels of IL-1 soluble receptor type II, in the serum of women with endometriosis (Kondera-Anasz et al., 2005). These differences showed an association with stage of disease.

Levels of IL-1β in infertile women with endometriosis have been found to be equivalent to those in women with tubal factor infertility (Pellicer et al., 1998). This finding is supported by more recent studies (Bedaiwy et al., 2002; Kalu et al., 2007).

No difference in serum IL-2, -4 or -10 levels has been found (Hassa et al., 2009). One further paper found IL-2 levels to be undetectable with their assay (Othman et al., 2008).

In some studies, IL-12 and -18 have been found to be elevated in peritoneal fluid of women with endometriosis (Arici et al., 2003; Gallinelli et al., 2004). However, no change in serum IL-18 levels has been identified (Fairbanks et al., 2009). Overall, IL-12 levels were no different in women with endometriosis, although levels were higher in women with Stages III–IV than Stages I–II disease (Fairbanks et al., 2009). Another study failed to find a correlation between IL-12 levels and endometriosis (Bedaiwy et al., 2002).

Serum IL-13 levels have not been found to alter with endometriosis (Bedaiwy et al., 2002). IL-15 levels were assessed in one study, but levels were below the detection threshold for the assay used (Othman et al., 2008).

IL-16 is known to be involved in regulation of the TH1/2 balance (Center et al., 1997), but no association has been found between serum levels and endometriosis (Zhang et al., 2005). Increased levels of serum TGFβ have been reported in women with endometriosis (Pizzo et al., 2002). Furthermore, the concentration appeared to correlate with stage of disease, such that the highest levels were found in women with more severe disease.

Levels of RANTES (regulated on activation normal T cell expressed and secreted) have been measured without finding any significant differences (Markham and I., 1997b). This result was supported by a separate study (Kalu et al., 2007).

Serum levels of macrophage migration inhibitory factor (MIF) have also been studied (Morin et al., 2005; Seeber et al., 2008). Levels were significantly higher in women with endometriosis, especially in women with more advanced disease stages, in one report (Morin et al., 2005). However, the second paper was unable to identify a difference in this cytokine between women with and without the disease (Seeber et al., 2008).

Intracellular cytokines

Some studies have looked at intracellular levels of cytokines in various cell populations to try to identify differences between women with and without endometriosis. One study looked at intracellular staining of a variety of cytokines (TNFα, IFNγ, IL-2, -4, -6, -10 and -12) and found increased expression of TNFα and IL-6 in peripheral T cells of women with endometriosis. (Szyllo et al., 2003). A similar study looked at a panel of cytokines (TNFα, IFNγ, IL-8, IL-6, IL-10 and MCP-1) and assessed their intracellular expression after stimulating different cell types (Gmyrek et al., 2008). The authors found that cytokine levels were similar in women with and without disease. The only statistically significant differences were in women with advanced disease who showed a reduction in IFNγ levels in CD3+CD8 cells, and an increase in MCP-1 levels in CD14+ cells.

Other studies have used RT–PCR and western blotting to identify intracellular mRNA and protein concentrations. Two studies showed increased IL-4 mRNA and protein in peripheral blood mononuclear cells of women with endometriosis, but no change in IL-2 (Hsu et al., 1997; Antsiferova et al., 2005). However, the first of these studies showed an increase in IL-10 mRNA and protein, whereas the second identified unchanged IL-10 levels in women with endometriosis. Finally, one study has found equivalent IFNγ mRNA levels in peripheral mononuclear cells of women with and without disease (Hsu et al., 1997).

Two studies reported mRNA levels of CCR1 (a RANTES receptor) in peripheral blood leucocytes of women with endometriosis (Agic et al., 2007; Agic et al., 2008). The first used CCR1 mRNA levels alone as a diagnostic test and found good sensitivity and specificity (90% and 74%, respectively) (Agic et al., 2007). The second combined CCR1 mRNA levels with MCP-1 and CA125 measurements to try to increase the test's diagnostic accuracy (Agic et al., 2008). Sensitivity and specificity were improved to 92% and 82%, respectively, by using this biomarker panel.

Antibodies

A great deal of interest has focused on circulating antibodies that may be a marker of endometriosis or involved in disease pathogenesis, especially because the interaction of the immune system with the endometrium is thought to have a major influence on how, and if, the disease develops.

Total immunoglobulin

Two studies have assessed total immunoglobulin levels in women with and without endometriosis, but found them unaffected by disease (El-Roeiy et al., 1988; Confino et al., 1990). However, El-Roeiy and colleagues did identify a positive correlation between increasing disease stage and IgG and IgM levels; they also noted a significant reduction in all immunoglobulin subtypes studied (IgG, IgM and IgA) after treatment with danazol for 6 months. A separate study found reduced IgA levels throughout the cycle, and reduced IgG in the follicular phase, but no significant change in IgM levels (Meek et al., 1988).

Anti-endometrial antibodies

Studies aimed at identifying circulating antibodies directed against endometrial antigens commenced in the early 1980s with the work of Methur (Methur et al., 1982). Later, Wild and Shivers (1985) analysed peripheral blood from women with infertility and found antibodies to be more common in women with, than in those without, endometriosis. Similar results were found by later studies (Badawy et al., 1990; Garza et al., 1991; Wild et al., 1991b; Hatayama et al., 1996; Meek et al., 1988; Bohler et al., 2007). One study reported a sensitivity of 86% and specificity of 76% for the diagnosis of endometriosis in women with infertility or other gynaecological pathology (Wild et al., 1991a). When compared with CA125, the diagnostic accuracy of endometrial antibody testing appeared favourable with a sensitivity of 83% and specificity of 79% versus 27 and 83%, respectively, for CA 125 (Wild et al., 1991b). Another study showed the presence of anti-endometrial antibodies in the serum of women with and without endometriosis, but demonstrated reactivity to different antigens in each group (Rajkumar et al., 1992).

It appears that IgG shows the strongest correlation with disease (Mathur et al., 1990; Odukoya et al., 1995a). One study identified anti-endometrial IgG antibodies in 56% of endometriosis patients, but only 5% of healthy control women (Odukoya et al., 1996). Another study demonstrated the presence of anti-endometrial IgG antibodies in 33% of women with endometriosis and anti-endometrial IgM antibodies in 27% (Gajbhiye et al., 2008).

The potential value of anti-endometrial antibodies as a diagnostic test has been revisited recently in a prospective multi-centre study (Randall et al., 2007). The authors tested for anti-endometrial antibodies using indirect immunofluorescence in a large group of women who consulted a medical practitioner for infertility, chronic pelvic pain or dysmenorrhoea: the sensitivity and specificity were both 87%.

Autoantibodies may also be affected by treatment: levels of nine types of autoantibody were reduced by 6 months treatment with danazol (El-Roeiy et al., 1988).

Specific antibodies

Other researchers have tried to determine the exact nature of autoantibodies in endometriosis. One early study looked for antibodies against progestagen-associated endometrial protein (PEP) and endometrial glycoproteins, but was unable to identify these autoantibodies in either patients or controls (Joshi et al., 1986).

Some studies have looked at antibodies directed against carbonic anhydrase. The first of these demonstrated the presence of antibodies against human carbonic anhydrase in women with endometriosis (Kiechle et al., 1994). A further study showed significantly higher levels of anti-carbonic anhydrase I antibodies in women with all disease stages compared with controls (D'Cruz et al., 1996). Antibodies against carbonic anhydrase II were also detected, but these were only significantly elevated in women with Stage II disease. However, the absolute numbers of women with strongly positive sera were relatively low in the endometriosis group. This study also measured levels of other common autoantibodies, including antinuclear, anti-DNA and anti-RNA protein antibodies (extractable nuclear antigens and anti-Ro). Several women with positive anti-carbonic anhydrase antibodies had significant titres of anti-Ro or ENA, but no analysis was done to indicate whether these may also be relevant tests for women with endometriosis.

Pillai et al. (1996) used western blotting and sequencing to identify transferrin, collagen, albumin, IgG and α2-Heremans Schmidt glycoprotein (α2-HS glycoprotein) as potential autoantigens in endometriosis. Antibodies to collagen, albumin and IgG were infrequent, but 89% of endometriosis patients had antibodies against transferrin (versus 28% of controls); 86% of patients had antibodies to α2-HS glycoprotein (versus 38% of controls). These figures correspond to sensitivities of 89% and 86% and specificities of 72% and 63%, respectively, for transferrin and α2-HS glycoprotein antibodies. The same group followed this up with a larger study using ELISA detection of antibodies, and again found significantly elevated antibody levels against these two antigens (Mathur et al., 1998). The sensitivity and specificity for both tests was 95% or greater.

Another group has assessed autoantibodies directed against markers of oxidative stress (Shanti et al., 1999). Their study identified significantly increased levels of three autoantibodies against lipid peroxide modified rabbit serum albumin, copper oxidized low-density lipoprotein and malondialdehyde-modified low-density lipoprotein in women with endometriosis.

Anti-laminin-1 antibodies have previously been found to be associated with recurrent miscarriage (Inagaki et al., 2001). Levels were increased in infertile women compared with fertile controls and were found to be significantly associated with endometriosis (Inagaki et al., 2003).

Anti-cardiolipin antibodies have also been measured (Kilpatrick et al., 1991; Abrao et al., 1997). One study showed no significant difference in levels between women with and without endometriosis, regardless of stage or fertility status (Kilpatrick et al., 1991). However, a second study found IgM anti-cardiolipin at significantly increased titres in women with endometriosis, but there was no difference in IgG levels (Abrao et al., 1997).

In summary, some autoantibodies appear promising candidates as biomarkers for endometriosis. However, further work is required to elucidate which antigens are triggers for some of these autoantibodies, to refine laboratory testing for the disease.

Cell populations

One of the mechanisms that is probably involved in the development of endometriotic lesions is the interaction between sloughed endometrial tissue and the immune system. Consequently, various populations of immune cells have been studied to gain insights into the disease pathogenesis, and test their utility as biomarkers.

T cells

T lymphocytes are critical players in cell-mediated, adaptive immune responses, and their levels and markers have been subject to scrutiny in women with endometriosis. One of the earliest studies demonstrated increased numbers of both T and B lymphocytes, as well as an increase in the CD4:CD8 ratio in women with endometriosis (Badawy et al., 1987). A later study failed to verify this change in lymphocyte numbers, but did show alterations in specific subsets of T cells, with increased numbers of suppressor (CD8+, CD11b+) and activated (CD3+, HLA-DR+) T cells and reduced numbers of cytotoxic T cells (CD8+, CD11b) (Iwasaki et al., 1993). These studies used very different methods to assess cell numbers (rosette formation with sheep erythrocytes versus flow cytometry), which probably accounts for their different findings. Other studies using flow cytometry techniques have also failed to identify differences in T cell numbers (using anti-CD3 antibodies) or major subsets (CD4+ or CD8+) (Garzetti et al., 1993; Oosterlynck et al., 1994; Ho et al., 1995; Maeda et al., 2002b; Zhang et al., 2006a; Gmyrek et al., 2008; Hassa et al., 2009). One of these studies in fact found a decrease in the activated T cell subset in women with the disease (CD25+CD3+ cells) (Ho et al., 1995).

One study has assessed changes in lymphocyte subsets following surgery (Kikuchi et al., 1993). There was a significant increase in peripheral blood levels of suppressor (CD8+CD11+), suppressor inducer (CD4+4B4) and helper T cells (CD4+2H4+) 1 month after a wide range of operations (ovarian cystectomy to total abdominal hysterectomy), but lymphocyte subsets did not change in a control group having surgery for leiomyomas.

CD4+CD25+ T cells were first identified in 1995 as a cell population capable of reducing the occurrence of autoimmunity (Sakaguchi et al., 1995). No differences in the proportion of these cells have been found in women with endometriosis (Górski et al., 2007). However, this study did show a reduction in the percentage of CD8+ cells and a subsequent increase in the CD4+:CD8+ ratio. These findings were confirmed in a separate study (Szyllo et al., 2003).

Finally, Gagne et al. (2003b) have cautioned against using data that have not been adjusted for important confounders, such as age, use of oral contraceptives and history of acute infection. Their study identified a significant decrease in both total T cell levels and a population of activated T cells (CD3+HLA-DR+), but these changes were not seen after adjusting for confounders.

B cells

The possible role of autoantibodies in endometriosis suggests that B cell populations may be important in the development of disease. However, several studies have failed to identify a difference in B cell levels when comparing healthy women to those with endometriosis (Iwasaki et al., 1993; Oosterlynck et al., 1994; Ho et al., 1995; Maeda et al., 2002a; Zhang et al., 2006a). One study in fact found a small but significant reduction in peripheral B cell numbers in women with the disease (Szyllo et al., 2003).

It is possible that subsets of B cells may be altered in women with endometriosis. One study has looked at levels of B-1 cells, a group of B cells involved in the production of autoantibodies, which express CD5 (Chishima et al., 2000). There was no overall difference in B-1 cell levels; however, when the women with endometriosis were subdivided into those with and without antinuclear autoantibodies (ANA), they found significantly increased B-1 cell levels in women who were ANA positive. Another study identified decreased numbers of CD20+, CD20+HLA-DR+ (activated B cells) and CD20+CD44high+ cells in women with endometriosis, even after adjusting for important confounders (Gagne et al., 2003b). However, this finding was not supported by a more recent study, which found equivalent numbers of total B cells, B-1 cells and CD20+HLA-DR+ B cells in women with and without endometriosis (Antsiferova et al., 2005).

Natural killer cells

Natural killer (NK) cells have been a focus of intense research in endometriosis. For example, studies have looked at cytotoxicity by measuring the lytic effects on target cells, but whether there is any correlation with disease stage remains controversial (Oosterlynck et al., 1991; Garzetti et al., 1993; Ho et al., 1995).

Several studies have failed to identify different levels of NK cells in peripheral blood (Garzetti et al., 1993; Iwasaki et al., 1993; Oosterlynck et al., 1994; Ho et al., 1995; Gagne et al., 2003b; Zhang et al., 2006a; Hassa et al., 2009). However, we identified two studies that have reported a difference in NK cell numbers. The first showed a reduction only in the CD57+CD16+ subset of moderately differentiated NK cells (Kikuchi et al., 1993). There was also a significant increase in this subset of NK cells 1 month after surgery for endometriosis. The second study identified a small reduction in the percentage of NK cells in peripheral blood of women with endometriosis (Szyllo et al., 2003).

Expression of a killer inhibitory receptor (KIR), known as KIR2DL1, on NK cells has been found to be increased in women with endometriosis, perhaps accounting for their decreased activity against target cells (Maeda et al., 2002a). No difference in the expression of KIR2DL2 was identified. The same group confirmed this finding in further studies, when they also found that the elevated levels persisted for at least 1 month after laparoscopic surgery or after 12 weeks of GnRH analogue treatment (Maeda et al., 2002b; Maeda et al., 2004). Similar findings were reported later confirming increased expression of CD158a (a form of KIR) on peripheral blood NK cells (Zhang et al., 2006a).

Macrophages/monocytes

No changes in peripheral CD14+ macrophage numbers have been identified in women with endometriosis (Oosterlynck et al., 1994). Similarly, Zhang et al. (2006a) reported similar macrophage numbers in women with and without disease and found no differences in the expression of HLA-ABC, -DR or a variety of other co-stimulatory molecules (CD40, CD54, CD58, CD80, CD86). A more recent study also found no difference in the expression levels of various markers on the macrophage surface (CD14, ICAM-1 and HLA-DR) as measured by relative fluorescence intensity (Izumiya et al., 2003). One study did find a significant increase in the CD14+CD44high+ leucocyte subset (Gagne et al., 2003b). CD44 is an adhesion molecule involved in cell homing to sites of inflammation (Jalkanen et al., 1986), so this may reflect the pro-inflammatory nature of endometriosis.

Functional studies on monocytes have also been conducted. One study used chemiluminescence to assess the generation of reactive oxygen species by macrophages (Zeller et al., 1987). The authors showed no difference in resting monocyte activity, but saw increased activity in response to various stimuli (e.g. serum-opsonized zymosan), in monocytes from women with endometriosis.

Polymorphonuclear neutrophils

One study showed no change in absolute numbers of polymorphonuclear neutrophils (PMN), but did reveal a small but significant reduction in chemotactic index (i.e. PMN from women with endometriosis showed reduced chemotaxis in response to a stimulus than those from control women) (Garzetti et al., 1998). More recently, the ratio of neutrophils:lymphocytes (NLR) has been suggested as a diagnostic test (Cho et al., 2008). This study identified an increase in total white blood cell levels, and a particular increase in neutrophil levels in endometriosis. The NLR gave a sensitivity and specificity of 60%. Furthermore, combining NLR and CA125 levels gave improved sensitivity over either test alone, but with slightly reduced specificity compared with CA125 alone. This recent study demonstrates the continued interest and effort placed into identifying possible cell-type alterations in endometriosis, which itself reflects the widespread view that immunological alterations lie at the heart of this disease.

Other immunology

One early study identified significant increases in levels of C3c and C4, but no difference in Factor B or properdin (components of the alternative complement pathway) in women with endometriosis (Badawy et al., 1984). Elevated levels of C3c and C4 were also found in a more recent study, along with an increase in SC5b-9—the membrane attack complex (Kabut et al., 2007). One study has reported lower levels of C3 and C4 in women with endometriosis, during the follicular phase (Meek et al., 1988). A further study looked at levels of C3a, a proteolytic fragment of the complement pathway that induces inflammatory reactions, but found levels to be similar in infertile women with and without endometriosis (Fassbender et al., 2009).

Significant reductions in peripheral mononuclear cell β-endorphin levels have been noted in women with endometriosis, particularly in the luteal phase (Vercellini et al., 1992). However, the finding only applied to symptomatic women with endometriosis when compared with symptomatic controls; healthy controls and asymptomatic women with endometriosis had equivalent levels.

Levels of soluble CD4 have been found to be increased in endometriosis, but levels of soluble CD8 appear to be unchanged by the disease (Matalliotakis et al., 1997).

Three studies have looked at levels of CD23, an IgE receptor that also exists in a soluble form (Gordon, 1991). All have shown raised levels of soluble CD23 in peripheral blood of women with endometriosis (Odukoya et al., 1995b; Odukoya et al., 1996; Matalliotakis et al., 2000b). Two of these studies also revealed a reduction in CD23 levels during treatment (Odukoya et al., 1995b; Matalliotakis et al., 2000b).

Levels of CD163, a macrophage scavenger receptor that also exists in a soluble form, were similar in women with endometriosis and healthy controls (Jee et al., 2008).

Three studies have investigated soluble HLA in endometriosis. The first of these showed that, overall, there was no association between endometriosis and serum soluble HLA-1 concentrations, although women with Stages I–II disease had significantly higher levels than those with Stages III–IV (De Placido et al., 1998). The second study found that levels of soluble HLA class I and II were significantly lower in women with endometriosis than control women (Matalliotakis et al., 2001b). One explanation for the contradictory findings is that different controls were used in these studies: women with various gynaecological complaints, including infertility, Müllerian malformations and those attending for tubal ligation were used in the first and infertile women only in the second. However, a more recent study has also demonstrated reduced HLA class I and II levels in serum of women with endometriosis, using slightly larger numbers of women, suggesting that there may be a true difference (Matalliotakis et al., 2003) (38 women with endometriosis, 30 controls with pelvic pain but no disease).

One group has measured levels of secretory leucocyte protease inhibitor in the serum of women with and without endometriosis, but there was no significant difference in levels (Suzumori et al., 1999).

Glycoproteins

Many authors have assessed levels of a variety of serum glycoproteins as potential diagnostic tools. The majority of these studies have looked at glycoproteins which have been assessed in the past as ‘tumour markers’ because of their association with malignant disease.

Cancer antigen 125

The most consistently studied glycoprotein in endometriosis has been CA125. A very comprehensive meta-analysis was published over 10 years ago, which found that CA125 may be of more benefit in diagnosing Stages III–IV, than Stages I–II, disease (Mol et al., 1998). Hence, studies published before 1998 were not included in our review.

Studies published since continue to demonstrate a correlation between raised CA125 levels and endometriosis (Abrao et al., 1999; Somigliana et al., 2004; Agic et al., 2008; Seeber et al., 2008), and some imply a correlation with stage of disease (Chen et al., 1998; Amaral et al., 2006; Martinez et al., 2007; Rosa e Silva et al., 2007). One study has indicated that CA125 may be more accurate at diagnosing women with later stages of disease, in concordance with the review by Mol (Maiorana et al., 2007).

One interesting study looked at fluctuations in CA125 levels across the menstrual cycle, and whether alterations in this flux could be used as a possible diagnostic tool (Kafali et al., 2004). Infertile women without endometriosis tended to have slight elevations in serum CA125 levels during menstruation; however, the magnitude of this increase was much greater in women with endometriosis. A sensitivity of 93% and specificity of 92% for the diagnosis of endometriosis was achieved, using a threshold of an 83% increase in CA125 during menses. The use of cycle fluctuations in CA125 has not yet been assessed in women without infertility.

A difficulty that has been noted in the past with CA125 is that levels tend to be higher in women with endometriomas: the accuracy CA125 certainly seems significantly better for women with, compared with those without, endometriomas (sensitivity 79% versus 44% with 30 IU/ml threshold) (Kitawaki et al., 2005). CA125 may also be helpful in the detection of unusual presentations of endometriosis: for example, measuring CA125 levels in women presenting with recurrent pneumothorax may identify thoracic endometriosis (Bagan et al., 2008).

The type of assay used to detect CA125 may also affect its clinical performance. One method known as CA125II (O'Brien et al., 1991), which uses a combination of two monoclonal antibodies that bind at different sites, could not distinguish women with Stages I–II disease from those without, although it did identify women with Stages III–IV endometriosis (Abrao et al., 1997).

Some studies have assessed the value of CA125 measurements during treatment. Chen et al. (1998) found that CA125 levels fell significantly after 3 months treatment with danazol. Ten women in this study underwent a ‘second-look’ laparoscopy while on treatment with danazol; however, despite having normal CA125 measurements, all of the women still had laparoscopic evidence of disease (albeit at a lesser stage than pre-treatment). A further study looked at the effect of leuprolide acetate and danazol on CA125 levels (Matalliotakis et al., 2004). Reduced levels were seen during treatment with both drugs. Three months after treatment, levels tended to rise again, but were still significantly reduced compared with pre-treatment levels in the danazol group.

CA19-9

In the first study to assess CA19-9, Panidis et al. (1988) reported that baseline levels of CA19-9 were elevated above the usual normal range (<37 IU/ml) in five of eight women with endometriosis, although no control group was studied. Levels were found to drop significantly during treatment with danazol. A similar study was conducted in 1998, which again demonstrated elevated baseline CA19-9 levels and a significant decrease during treatment with danazol (Matalliotakis et al., 1998). Levels rose 3 months after treatment was completed, but remained significantly lower than baseline due perhaps, the authors postulated, to disease recurrence. Other studies have failed to find an association between raised CA19-9 levels and endometriosis (Abrao et al., 1999; Somigliana et al., 2004).

Several studies have attempted to compare CA19-9 and CA125 measurements. Harada et al. (2002) found that CA19-9 had similar specificity but reduced sensitivity compared with CA125. The authors did note that CA125 levels tend to be increased in women with adenomyosis, whereas CA19-9 levels were often normal in these women. In a more recent study, CA125 and CA19-9 had similar sensitivities and specificities (86–89% and 61–52%, respectively) (Kurdoglu et al., 2009).

Xavier et al. (2005) have highlighted the importance of choosing the correct threshold for a putative biomarker. These authors calculated cut-off values using ROC curves (a comparison of sensitivity against false-positive rate) to identify the level at which most women were correctly diagnosed: 22.6 IU/ml for CA125 and 5.4 IU/ml for CA19-9—much lower levels than those often reported in the literature. At these thresholds, the sensitivity and specificity of both CA125 and CA19-9 were greatly improved.

CA15-3

We identified three papers that considered CA15-3 levels in endometriosis. The first reported elevated levels, compared with the ‘normal’ range, in six of eight women with endometriosis (Panidis et al., 1988). Levels fell during treatment with danazol and were significantly reduced from baseline 3 months after treatment ended. The lack of control group means that sensitivity/specificity could not be calculated.

Two further papers found no association between CA15-3 and endometriosis (Muscatello et al., 1992; Abrao et al., 1999). Hence, it seems unlikely that CA15-3 has potential as a diagnostic test.

CA-72

CA-72 (also known as TAG72) has been studied in two papers, neither of which found any association with endometriosis (Muscatello et al., 1992; Molo et al., 1994).

Other glycoproteins

As autoantibodies to transferrin and α2-HS glycoprotein have been identified in women with endometriosis (see Antibodies section), one group investigated serum levels of these glycoproteins and found significantly reduced levels of serum transferrin and increased levels of α2-HS glycoprotein in women with endometriosis (Mathur et al., 1999).

Serum levels of alpha-fetoprotein (AFP) have been measured in endometriosis, but not shown to be different in women with and without disease (Abrao et al., 1999; Philippoussis et al., 2004). Carcinoembryonic antigen (CEA) and beta-2 microglobulin levels were also measured in one of these studies, but the findings were similarly unhelpful (Abrao et al., 1999).

Haptoglobin has been identified as a secretory product of endometriotic lesions (Sharpe-Timms et al., 1998a) leading to the study of haptoglobin-β (Hpβ) chain isoforms (Ferrero et al., 2005). Serum HpβE levels were significantly higher in women with endometriosis than controls, during the follicular phase of the cycle, although levels of the other isoforms were unchanged.

Follistatin is a glycoprotein involved in the inhibition of activin (de Winter et al., 1996). One study has shown significant increases in serum follistatin levels in women with endometriosis and endometriomas compared with controls (Florio et al., 2009). Follistatin had superior specificity and sensitivity than CA125 levels.

Gremlin-1 is a secreted glycoprotein that has previously been found to be up-regulated in the endometrial stromal cells of women with endometriosis (Sha et al., 2007). One study has found increased Gremlin-1 levels in the serum of women with endometriosis, but the difference was only significant during the proliferative phase of the cycle (Sha et al., 2009).

Cell adhesion

A variety of factors involved in cell adhesion have been studied in endometriosis. These may have important roles in cell–cell interaction or other accessory roles.

Intracellular adhesion molecule-1

The first studies to assess this protein found conflicting results. One showed a significant increase in soluble intracellular adhesion molecule-1 (ICAM-1) levels in plasma of women with endometriosis (Wu et al., 1998), whereas the other showed no change (De Placido et al., 1998). However, these differences may have been stage dependent: the first study mainly recruited women with Stages I–II disease, whereas the second mainly looked at women with Stages III–IV. Increased levels of ICAM-1 with Stages I–II disease have also been reported more recently (Matalliotakis et al., 2001b). In this study, levels tended to rise further during treatment (danazol or leuprolide acetate) and were still significantly higher than baseline 3 months after treatment stopped. Only one study reported an increase in serum ICAM-1 levels in women with Stages III–IV disease (Daniel et al., 2000). Another paper showed a significant increase in levels in women with deep pelvic endometriosis only (Somigliana et al., 2002).

Conversely, a reduction in serum ICAM-1 levels in women with Stages III–IV endometriosis has also been shown (Barrier and Sharpe-Timms, 2002). Hence, it is possible that levels increase during the early stages of the disease, but decrease at more advanced stages. However, the importance of confounders has been highlighted (Steff et al., 2004a). These authors identified a reduction in ICAM-1 levels in women with Stages III–IV disease, but this was not apparent after adjusting for the surgical indication or for infertility.

Other

Soluble E-cadherin levels in endometriosis have been found to be elevated in women with endometriosis, but no association with stage of disease was noted (Fu and Lang, 2002).

One study has measured levels of osteopontin, a glycoprotein involved in interactions between integrins, known to be expressed in the endometrium (Cho et al., 2009). Plasma levels were elevated in women with endometriosis throughout the cycle, although they did not correlate with disease stage. The authors calculated a sensitivity of 93% and specificity of 72% for the test.

Raised serum levels of soluble VCAM-1 were identified in one study (Barrier and Sharpe-Timms, 2002), consistent with another study that showed a trend which did not reach statistical significance (Daniel et al., 2000). P-selectin and E-selectin levels were unchanged in women with endometriosis in these two studies (Daniel et al., 2000; Barrier and Sharpe-Timms, 2002).

Growth factors

One study has showed a significant increase in insulin-like growth factor-I (IGF-I) levels in Stages III–IV, but not Stages I–II, disease (Gurgan et al., 1999), whereas another showed no significant difference from control patients (Steff et al., 2004b). Levels of IGF-II have not been found to be altered in the disease (Gurgan et al., 1999).

IGFBP3 is a protein that regulates the transport of IGF and influences the growth of endometrial cells (Koutsilieris et al., 1995). However, two studies have demonstrated no significant difference in serum IGFBP3 levels between women with and without endometriosis (Gurgan et al., 1999; Philippoussis et al., 2004).

Levels of granulocyte macrophage colony-stimulating factor (GM-CSF), a growth factor that stimulates stem cells to produce granulocytes and monocytes, were unchanged in women with endometriosis compared with controls (Othman et al., 2008).

Proteomics

In the area of biomarker discovery, proteomic techniques are proving particularly powerful tools to identify protein ‘fingerprints’ in blood or tissues that may be markers of disease. From patterns of expression, individual peptides or proteins that are present or absent (or up- or down-regulated) in various disease states can be identified and assessed as possible biomarkers. Alternatively, the actual protein/peptide pattern itself can be used as a distinctive marker of disease presence.

The search for differential serum protein expression in endometriosis commenced more than 20 years ago (Joshi et al., 1986): however, gel electrophoresis could not distinguish serum from women with and without disease in this study. More recently, Zhang et al. (2006b) have identified 13 differentially expressed proteins in sera of women with endometriosis, using two-dimensional gel electrophoresis. Some of these proteins were characterized by searching a computerized database using molecular weight and isoelectric points, but some remain elusive.

A variety of groups are now attempting to identify specific peptide and protein patterns to diagnose endometriosis, mainly using mass spectrometry. Different serum protein peaks have been identified using this technique (Liu et al., 2007). Twenty protein peaks were found to be different between women with and without the disease; three of these were used to generate a diagnostic model with 88% sensitivity and 86% specificity.

Another group used a similar technique and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to identify 288 differently expressed peaks (Wang et al., 2007). A further study by the same group showed that a distinctive pattern of five protein peaks gave a sensitivity of 92% and a specificity of 90.0% (Wang et al., 2008).

A third group, using the same technique, reported a sensitivity of 87% and specificity of 97% for their diagnostic algorithm, which was based on just two protein peaks (Jing et al., 2008). This study also found that one of these two peaks was significantly altered 1 month after surgery, suggesting that it may be a possible marker of disease stage or activity.

Three further studies were published last year, all evaluating mass spectrometry of serum proteins in endometriosis, but these have generally shown less diagnostic accuracy then the initial studies. One identified 24 differently expressed protein peaks, and generated a diagnostic model with 92% sensitivity, but only 75% specificity (Zhang et al., 2009). A further study looked only at women with symptoms consistent with endometriosis (e.g. pelvic pain, infertility) and used two different analytic methods to distinguish endometriosis from non-endometriosis subjects (Wolfler et al., 2009). However, these two methods only gave a sensitivity of 78–81% and specificity of 59–50%. The final study we identified used only proteins of small molecular mass, and identified six discriminatory peaks (Seeber et al., 2009). This model correctly diagnosed 66% of the women with endometriosis and 45% of those without the disease.

Proteomic technologies are providing innovative ways to identify biomarkers of disease and may be of use in identifying diseases by their protein fingerprints. However, the time and cost associated with these technologies currently prohibit their widespread use.

Hormones

Prolactin

An association between galactorrhoea and endometriosis was first identified over 30 years ago (Hirchowitz et al., 1978), which led to further investigation of the role of prolactin (PRL) in endometriosis. Although one study indicated a higher basal prolactin level in women with endometriosis (Acien et al., 1989), others have failed to confirm this finding (Arumugam, 1991; Panidis et al., 1992; Matalliotakis et al., 1996). Timing of sampling is particularly important for prolactin, as levels have a diurnal pattern. One study showed that the 8 am decline in prolactin levels (seen in healthy women) failed to occur in women with endometriosis (Radwanska et al., 1987).

Two more recent studies have revisited this issue. The first assessed prolactin levels in fertile controls, as well as fertile and infertile women with Stages I–II endometriosis (Cunha-Filho et al., 2001). Significantly higher prolactin levels were found in women with endometriosis, compared with controls: 30% of the women with endometriosis-associated infertility had hyperprolactinaemia (>20 ng/ml), but none of the controls or fertile women with endometriosis. The second study showed significantly higher prolactin levels in infertile women with all stages of endometriosis compared with fertile controls (Lima et al., 2006).

Three studies have assessed the response of serum prolactin levels to a challenge with thyrotropin releasing hormone (TRH), and particularly the effect of treatment on this (Acien et al., 1989; Panidis et al., 1992; Matalliotakis et al., 1996). The first of these studies found that the prolactin response, following a challenge with TRH and luteinising hormone (LH) releasing hormone, was greater in women with endometriosis than controls (Acien et al., 1989). Responses were significantly reduced following 6 months treatment with danazol. A similar study was carried out that showed a significantly reduced prolactin response during treatment with danazol (Panidis et al., 1992). The final study confirmed these findings but also showed that, conversely, the levels of thyroid stimulating hormone (TSH) in response to a TRH challenge were increased in women on danazol treatment compared with pretreatment (Matalliotakis et al., 1996).

Pituitary hormones

One study found LH levels to be significantly increased in women with endometriomas compared with healthy controls, but equivalent to levels in women with other ovarian cysts (Adamyan et al., 1993). Significant elevations in LH levels in women with endometriosis have also been reported, throughout the cycle (Illera et al., 2001). Conversely, a second study showed no association between LH levels and endometriosis, when measured in the early follicular phase (Cunha-Filho et al., 2001). This study also measured TSH and follicle stimulating hormone, but found no association with endometriosis.

Steroids

Six studies were identified that measured serum steroid hormone levels. No significant change in progesterone levels has been identified in women with endometriosis (Fazleabas et al., 1987; Adamyan et al., 1993; Matsuzaki et al., 2006; Szymanowski, 2007). One study has also found no change in estradiol levels, but elevated testosterone levels in women with an endometrioma (Adamyan et al., 1993). However, a more recent study did indicate that infertile women with endometriosis had lower early follicular estradiol levels than fertile controls (Cunha-Filho et al., 2001). The final study looked at cortisol levels and found them to be increased in women with Stages III–IV disease, but not at earlier stages (Lima et al., 2006).

Other

The most common other hormone to be assessed has been leptin. The first study found serum leptin levels to be significantly higher in patients with endometriosis than in controls (Matarese et al., 2000). A similar finding was reported in a more recent paper, which used leptin levels as part of a biomarker panel to diagnose endometriosis (Seeber et al., 2008). However, three other studies have concluded that serum leptin is unchanged in endometriosis (Vigano et al., 2002; Wu et al., 2003; Gungor et al., 2009). One further study found baseline serum leptin levels to be no different in women with endometriosis, but did demonstrate an increase in levels during treatment with danazol or leuprolide acetate, suggesting that this may be a means of monitoring treatment (Matalliotakis et al., 2000a).

Finally, one study has measured levels of serum adiponectin and found them to be significantly lower in women with endometriosis than in controls (Takemura et al., 2005).

Angiogenesis

Several studies have sought to identify a link between endometriosis and pro-angiogenic factors in serum or urine—principally vascular endothelial growth factor (VEGF)—which may have use as biomarkers. However, no significant difference in VEGF levels was seen when comparing women with endometriosis-associated infertility to those with tubal factor infertility (Pellicer et al., 1998). Similarly, no difference in serum VEGF levels was found by four further studies (Gagne et al., 2003a; Bourlev et al., 2006b; Pupo-Nogueira et al., 2007; Othman et al., 2008).

One study has demonstrated elevated VEGF levels during the secretory phase in women with endometriomas (Xavier et al., 2006). A second study found a similar increase in VEGF levels in women with all types of endometriosis (Matalliotakis et al., 2003). There were no obvious methodological differences between this study and the others, therefore the reason for this discrepancy is unclear.

Increased levels of serum angiogenin (a polypeptide that stimulates angiogenesis) have been identified in women with endometriosis; however, this difference was only seen during the follicular phase of the cycle (Steff et al., 2004b).

Some studies have also analysed pro-angiogenic factors in urine as possible biomarkers. No association between urinary VEGF and endometriosis has been found (Potlog-Nahari et al., 2004). Raised urinary soluble Flt-1 levels (a VEGF receptor) have been noted in endometriosis patients, although there was no overall difference in serum levels (Cho et al., 2007). Interestingly, significantly higher urine and serum sFlt-1 levels were identified in women with earlier stage disease.

One study has found levels of fibroblast growth factor-2 (FGF-2) to be increased throughout the cycle in women with endometriosis (Bourlev et al., 2006a).

No significant difference in levels of soluble epidermal growth factor (EGF) receptor has been found between women with and without endometriosis (Matalliotakis et al., 2003). Serum levels of EGF itself have also been assessed and were not found to correlate with the disease (Philippoussis et al., 2004).

One paper measured levels of platelet-derived growth factor (PDGF) in women with endometriosis, but found similar levels to those in infertile controls (Kalu et al., 2007).

Two studies have looked at levels of hepatocyte growth factor (HGF), a protein with important roles as a mitogen and chemoattractant for endothelial cells (Bussolino et al., 1992). Serum HGF levels were initially found to be elevated in women with endometriosis (Zong et al., 2003). Levels did not change throughout the cycle, but did correlate with disease stage (levels in Stages I–II were lower than in Stages III–IV disease). However, this finding was not confirmed by a smaller, second study, which showed no correlation with incidence or stage of disease (Khan et al., 2006).

Apoptosis

Cells expressing Fas undergo apoptosis on interaction with other cells expressing Fas ligand (for review see Nagata and Goldstein, 1995). However, it also exists in a soluble form, due to cleavage from the cell surface by matrix metalloproteinases (Kayagaki et al., 1995; Powell et al., 1999). Women with Stages I–II disease had equivalent levels of soluble Fas ligand (sFasL) in serum compared with controls, but levels were significantly increased in women with Stages III–IV disease (Garcia-Velasco et al., 2002). A second study also identified significantly higher levels of sFasL in women with endometriosis, compared with both fertile and infertile controls (Linghu et al., 2004). This study also considered Fas levels, which did not differ between the subject groups. Equivalent serum Fas levels were also found in another study (Kalu et al., 2007).

Other

Three studies have measured levels of C-reactive protein (CRP), an acute phase protein used widely to monitor inflammatory and infectious processes. The first of these showed that CRP appeared to be increased in women with endometriosis, but more markedly in those with more advanced disease (Abrao et al., 1997). However, a more recent study was unable to identify an increase in CRP level with the disease (Xavier et al., 2006). CRP results were below the sensitivity threshold of the test used in the final study (Matarese et al., 2000).

Urocortin is a peptide belonging to the corticotrophin releasing hormone family, known to be expressed in the endometrium (Florio et al., 2002). Serum levels of urocortin were found to be significantly higher in women with endometriomas than in women with other benign ovarian cysts, giving a sensitivity of 88% and specificity of 90% (Florio et al., 2007).

One study has assessed antioxidant and cholesterol levels (Verit et al., 2008). Women with endometriosis showed significant reductions in serum paroxonase-1 (PON-1) and high-density lipoprotein levels, as well as increased levels of total cholesterol, triglycerides, low-density lipoprotein and lipid peroxidises. PON-1 yielded a sensitivity of 98% and specificity of 83%. Other markers of oxidative stress were measured in a recent study, which found elevated levels of heat shock protein 70B′ (HSP70b′), a stress-induced protein involved in cell protection, in endometriosis, but no change in HSP70, ischaemia modified albumin (IMA) or thioredoxin (TRX) (Lambrinoudaki et al., 2009).

Levels of circulating free DNA appear to be elevated in women with endometriosis, with a sensitivity of 70% and specificity of 87% (Zachariah et al., 2009).

One study has measured serum levels of vitamin D binding protein, but did not demonstrate significant differences compared with controls (Borkowski et al., 2008).

In one study, no differences in the levels of PEP could be identified between women with and without endometriosis (Joshi et al., 1986). Levels of endometrial protein PP14 (related to PEP) have also been assessed, and were found to be increased in all women with endometriosis, but particularly so in more advanced stages (Telimaa et al., 1989). Treatment (either surgical, danazol or medroxyprogesteronee acetate) reduced PP14 levels.

Tumour-associated trypsin inhibitor (TATI) is a polypeptide known to be associated with gynaecological neoplasms (Huhtala et al., 1983). One study has shown that levels are elevated in endometriosis, although only significantly so in women with Stage II disease or greater (Medl et al., 1997). The test gave poor sensitivity (34%) but reasonable specificity (85%). Levels of TATI were also elevated in women taking a GnRH analogue after surgery, although they fell when treatment was discontinued.

Levels of the proto-oncogene c-erbB-2 were not found to differ between women with and without the disease (Philippoussis et al., 2004).

Levels of serum amyloid A (an acute phase protein) were increased in women with Stages III–IV disease during menses, but not in those with earlier stages (Abrao et al., 1997).

A reduction in serum tissue inhibitor of metalloproteinase-1 (TIMP-1) levels has been shown in women with endometriosis (Sharpe-Timms et al., 1998b). This appeared to be the case throughout the proliferative and secretory phases. Furthermore, levels of TIMP-1 were shown to rise significantly after 6 months GnRH analogue treatment.

Finally, elevated levels of serum matrix metalloproteinase-2 (MMP-2) have been found in women with endometriosis, throughout the cycle (Huang et al., 2004) (Fig. 2).

Figure 2
Spider diagram depicting putative biomarkers.

Discussion

Establishing a correct diagnosis of endometriosis is often problematic, because the presenting symptoms can be non-specific and associated with a number of different conditions (Giudice and Kao, 2004). Imaging methods such as transvaginal ultrasound and magnetic resonance imaging may help to identify ovarian endometriomas or a rectovaginal endometriotic nodule, but they have no value in diagnosing peritoneal endometriosis (Moore et al., 2002; Kennedy et al., 2005). Consequently, it is recommended that pelvic endometriosis should be diagnosed surgically (Kennedy et al., 2005).

An accurate blood or urine test could avoid the need for an invasive procedure (Brosens et al., 2003a, b), or at the very least could enable symptomatic women to be screened. It has previously been suggested that a biomarker may be of most clinical use in specific subgroups of women with endometriosis (D'Hooghe et al., 2006). For example, women with symptoms consistent with Stages I–II disease may benefit from laparoscopic treatment if endometriosis is present. However, for those women with the same symptoms but no endometriosis, the risks of laparoscopy may outweigh the benefits. As such, this may be the group of women in whom a biomarker test might be most useful.

Another role for a biomarker would be to identify early signs of therapeutic efficacy, other than symptom relief itself, which is so difficult to measure. Such a molecule would be vitally important for novel drug design and early clinical studies. In addition, as recurrence rates of up to 50% after 5 years have been reported (Guo, 2009), it would be desirable if a biomarker or a panel of biomarkers could predict the likelihood of disease recurrence. This could lead to different therapeutic approaches depending on the outcome of the test.

We therefore chose to conduct a systematic review of the literature to determine which biomarkers have been proposed over the last 25 years as potential diagnostic tests. The search identified over 100 possible biomarkers that have been investigated; however, none of these have been clearly shown to be of clinical use. Some have undoubtedly shown promise as diagnostic tools, but further research needs to be conducted to establish their true value in clinical practice.

We find the lack of high-quality studies investigating large numbers of well-phenotyped patients surprising, given the obvious clinical need. Symptoms suggestive of the disease are common in the general population and it is currently difficult to establish a firm diagnosis. All these factors contribute to the well-recognized delay in diagnosis of 8–12 years (Hadfield et al., 1996) and further exacerbate the effects on quality of life and work productivity.

Although the diagnostic value of many of these biomarkers in endometriosis remains unclear, some appear to be more reliable in other conditions. For example, IGF has been used as a urine marker to diagnose urothelial carcinoma of the bladder (Watson et al., 2008). MIF has been used in urine to screen for acute pyelonephritis in children with urinary tract infections (Otukesh et al., 2009). Anti-cardiolipin antibodies and VEGF have both been implicated in systemic lupus erythematosus (Tanaseanu et al., 2007). CA125 has been used as both a diagnostic and surrogate marker in epithelial ovarian cancer, and CA 19-9 is highly sensitive in detecting mucinous ovarian cancer, a tumour type that does not express high levels of CA125 (Gadducci et al., 2004). Urocortin is a valuable biomarker in cardiac failure, with elevated levels correlating with the degree of cardiac dysfunction (Wright et al., 2009). These examples should convince gynaecologists, patients and industry that the search for a biomarker in endometriosis is worth pursuing.

Problems with the studies identified in this review include the wide range of assay methods, recruitment strategies and study designs employed; failing to correct for the phase of the menstrual cycle, and the use of different types of patients as controls. These factors have undoubtedly contributed to some of the conflicting results we report above. For example, three of the nine papers investigating IL-6 failed to adjust for the phase of the menstrual cycle, despite evidence that levels are known to change throughout the cycle (Angstwurm et al., 1997).

The numbers of patients recruited vary widely, and studies clearly differ in their scope—some studies seek to demonstrate a proof of concept (that a difference in a biomarker may be seen) and others aim to prove the clinical usefulness of a particular marker/panel of markers. Direct comparison of studies would therefore be unjust. In addition, few of the studies reported power calculations to guide recruitment figures, and this should be considered when planning high-quality biomarker research in the future.

Selection of an appropriate control group is often a challenge. Screening tests for disease can be employed in one of two ways—either applied to the entire population (e.g. cervical screening programme) or offered to women at increased risk of having disease, due to their clinical presentation. As the benefits of treating women with asymptomatic endometriosis are unclear, it is likely that any biomarker would be used only to investigate women with symptoms suggestive of endometriosis. Consequently, to show true promise as an aid to diagnosis, a prospective biomarker needs to distinguish women with endometriosis from unaffected women with a similar presentation (e.g. dysmenorrhoea, pelvic pain or subfertility). This has not been the case in all of the studies included in this review. For example, one study of MCP-1 levels found increased levels in infertile women with endometriosis compared with women with leiomyomas or fertile controls, but no significant difference compared with women with unexplained infertility (Gmyrek et al., 2005). This may be partly due to the small numbers in the infertile control group, but the possibility that infertility itself may affect biomarker levels cannot be ignored. Similarly, studies investigating women with endometriomas may need to consider using women with other benign ovarian cysts as a control group, rather than those with no disease.

The type of endometriosis may also impact on biomarker levels, i.e. women with peritoneal disease may have different markers to those with rectovaginal endometriosis or endometriomas. This does not necessarily mean that a biomarker is not of use, but interpretation of the result may have to take other clinical findings into account. For example, no difference in IL-8 levels was found between women with endometriosis and those with other benign gynaecological disease (Gazvani et al., 1998). However, a more recent study did find significantly elevated serum IL-8 levels in women with an endometrioma compared with women with other ovarian cysts (Ohata et al., 2008).

The one biomarker that has been used in clinical practice over the last 20 years is CA125. However, in a meta-analysis published in 1998, Mol et al. (1998) showed convincingly that the biomarker's performance in diagnosing endometriosis was low, even though it showed some promise in detecting more severe disease. Since their meta-analysis was published, we identified 15 further studies reporting a correlation between endometriosis and CA125. More recent studies tend to assess the use of CA125 in monitoring treatment (Chen et al., 1998; Matalliotakis et al., 2004). Although these studies suggest CA125 levels fall during treatment, they have not shown a correlation with disease response. Owing to the ethical constraints on performing second-look laparoscopies in these studies (and the impracticalities in a modern clinical setting), it may be useful to include some form of health-related questionnaire such as the Endometriosis Health Profile-30 (Jones et al., 2001), to try to gain more information about disease activity.

In our analysis, we took into consideration the strong possibility of reporting bias. There is statistical evidence to suggest that the data available are heavily skewed as a result of investigators' failure to present negative data for publication and the disinclination of journals to publish negative data (Dwan et al., 2008). It is common knowledge that negative data are often either not submitted to scientific journals or not accepted by the reviewers or editors. However, if a study is well designed then negative data can be extremely informative and should, in our opinion, be published. In fact, as patients consent to collect and use their samples to help increase knowledge of the disease and/or find new diagnostic tools, it is ethically highly questionable when negative data are not published.

It is worth noting that surgery often plays a vital role in the treatment of endometriosis. Furthermore, it may also be of importance in the management of other conditions which present in a similar manner (e.g. tubal infertility). The use of a biomarker may well be tempered in these circumstances, but it may still help to reduce the need for diagnostic surgery in some women, enable monitoring of the disease progression by non-surgical methods, and potentially allow for better pre-operative assessment of women with endometriosis.

Finally, the majority of the studies included in our review focused on assessing the diagnostic performance of single biomarkers. Realistically, however, a reliable diagnostic tool for endometriosis is likely to consist of a panel of biomarkers, not a single molecule, as has been the case for example with screening for Down's syndrome (Pihl et al., 2008). Ultimately, with more studies investigating the use of technologies such as genomics, proteomics and metabolomics, it can be expected that a panel of molecules or a typical profile of gene or protein expression will in the future help to distinguish between patients with and without disease. In combination with imaging techniques, such a panel of biomarkers may indicate which women need a laparoscopy and eliminate countless unnecessary operations. Future, larger well-designed studies together with increased knowledge of the pathogenesis of endometriosis are essential to improve overall health-related quality of life for patients suffering from this debilitating disease.

Funding

Supported by an MRC New Investigator Award (G0601458 to C.B.) and the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health's NIHR Biomedical Research Centres scheme. K.M. was funded by a MRC Doctoral Training Account (DTA).

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