**3.2. Markers of inflammation and peritoneal irritation**

EP can lead to inflammation and peritoneal irritation and the following biomarkers have been investigated as an potential biomarkers of the same process.

**1.** Circulating cytokines

**3.** Mucin-1 (Muc-1)

60 Contemporary Gynecologic Practice

**4.** Adrenomedullin

marker for EP. **5.** Activin B

ising marker for EP diagnostic triage.

**3. Markers related to tubal implantation**

investigated as biomarkers for diagnosing EP.

**1.** Creatine Kinase (CK)

**3.1. Markers of compromised tubal musculature markers**

Muc-1 is a glycoprotein expressed by endometrium and fallopian tube epithelium involved in implantation [96]. Muc-1 expression was observed to be lower in luminal epithelial of tubes with ectopic pregnancies [97]. Similar findings were observed by Reefaat et al [98]. However, the role of serum Muc-1 as a diagnostic modality has not been studied in much detail.

Adrenomedullin is a peptide hormone belonging to calcitonin/calcitonin gene related peptide, and is thought be involved in endometrial angiogenesis. Liao et al found plasma and oviductal tissue adrenomedullin to be lower in EP and suggested that this decreases ciliary beating and muscle contraction leading to retained embryo and its implantation in the oviduct [99]. Similar findings were observed in nasal epithelium in patients of tEP by the same group [100]. Further studies are required to explore the possible role of serum adrenomedullin as a diagnostic

Activins, dimeric proteins of transforming growth factor-beta (TGF-b), have recently been found in gonadal fluid with growth factor like actions [101]. It is produced by many organs including pituitary gland, gonads, placenta etc. It has been shown to promote decidualization of the endometrium during pregnancy [102]. Consequently low serum activin levels have been associated with ectopic pregnancy. Although recent studies have mainly focussed the role of serum activin A as a potential marker of ectopic pregnancy, limited literature is available regarding the role of activin B in-spite of the experimental evidence of differential effect of activin B on decidua. In our population, we observed that the concentration of activin B in maternal serum to be significantly lower in patients with tEP compared to those with normal IUP [Unpublished data]. Similar results were observed by Horne et al, who found decreased expression of activin B in endometrium along with decreased serum levels of activin B with normal levels of progesterone in 11 women with tEP [103]. Activin B is a new, though prom‐

These markers reflect the disruption of the integrity of the tubal circular smooth muscle layer, which can happen in an ectopic implantation. These markers of muscle damage have been

Creatine Kinase is the enzyme released from damaged muscles, which is currently used in the diagnosis of myocardial infarction. Lavie et al found serum CK levels to be significantly higher in patients with tEP as compared to those with missed abortion or normal IUP [104]. Similar Several cytokines as marker of peritoneal inflammation has been reported including IL-2R, IL-6, IL-8, IL-10, IL-11, IL-15 and TNF-α. Soriano et al observed increased concentration of IL-6, IL-8 and TNF-α in patients with EP compared with normal and abnormal IUP. IL-8 at a cutoff of >40 pg/ml was shown to have a sensitivity and specificity of 82.4% and 81.8 % respectively in diagnosing EP [115]. Experience in our population regarding IL-6 & IL-8 levels, we observed that the level of IL-6 shows a significant increase in the women with tubal ectopic pregnancy in comparison to intrauterine abortion and normal pregnancy. It was also seen that IL-8 levels decrease significantly in the tubal ectopic pregnancy cases and in intrauterine abortion patient when compared to the normal pregnancy group. ROC analysis revealed that at the cut-off of 26.48pg/ml of IL-6 level predict the probability of tubal ectopic pregnancy with 53.57% sensitivity, 80%specificity [Unpublished paper]. Similar observations were made by Rausch et al, who observed lower values of IL-8 and TNF-α in women with EP, whereas no significant difference was observed in the IL-6 levels between EP and viable IUP [28]. No difference has been observed in the levels of IL-10 and IL-11between EP and viable IUP [90]. IL-15 has also been studied as it is expressed by human placental tissue culture and it is maximally expressed during the implantation period in the deciduas. Daponte et al reported that IL-15 concentra‐ tions were significantly higher in women with EP compared to patients with IUP, and found IL-15 to have high diagnostic accuracy for the discrimination of a viable IUP from an EP with an area under the curve of 0.818 [116].
