Serum kisspeptin levels in deep-infiltrating, ovarian, and superficial endometriosis: A prospective observational study

Mesut Önal, Pervin Karli, P Karlı, Karli P, Ayşe Zehra Özdemir, Ayşe Özdemir, Özdemir AZ, Adem Kocaman, Kocaman A, Yunus KATIRCI, Gülnur Çoban, Gülen Kübra Nakişli, Nakişli GK, Yeşim Civil, Civil Y, Bahattin Avcı, Bahattin Avci, Avci B
Medicine · 2022 · vol. 101(45) , pp. e31529 · doi:10.1097/md.0000000000031529 · PMID:36397399 · PMC9666188 · W4309266440
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This study found that serum kisspeptin levels were higher in women with endometriosis compared to controls, but did not differ between superficial and deep infiltrating types, suggesting kisspeptins' role in endometriosis pathogenesis.

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This prospective observational study (2020–2021) measured serum Ca125 and kisspeptin in 40 women with endometrioma and compared them with 40 age-matched controls without endometrioma or symptoms, using ELISA assays after diagnostic laparoscopy confirmed endometriosis status; exclusion criteria included prior endometrial cyst surgery and cancer history. Women with endometriosis showed significantly different Ca125 and kisspeptin levels versus controls, with Ca125 higher in deep infiltrating endometriosis (DIE) than in superficial endometriosis (SE) and controls, while kisspeptin levels were similarly elevated in both SE and DIE relative to controls; CA125 and kisspeptin were not correlated within SE, DIE, or controls. The paper’s key limitation is its small sample size and restriction to women with endometrioma plus reliance on single baseline serum measurements rather than longitudinal dynamics. This paper is centrally about endometriosis — it evaluates whether serum kisspeptin relates to endometriosis presence and invasion depth (SE vs DIE) in women with surgically confirmed disease.

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Abstract

The diagnosis of endometriosis may delay for many years due to non-deterministic symptoms and avoiding surgical interventions. Kisspeptins are hormones that interact with endometrial tissue to limit invasions during placentation and various cancers and are suggested to be also associated with endometriosis. This study evaluated if serum kisspeptin levels are associated with the invasion depth in endometriosis. Forty patients between 18 and 45 years of age and admitted to a tertiary-care Obstetrics and Gynecology Department between 2020 and 2021 with a diagnosis of endometriosis, and 40 patients without endometrioma were included in the study. Demographic, obstetric, clinical, and biochemical characteristics were evaluated in patients with superficial (SE) and deep infiltrating (DIE) endometriosis and healthy controls. Twenty patients (50%) had SE, 14 (35%) had DIE, and 22 (55%) had endometrioma in the patient group. Fertility rates were higher among controls, but similar between patients with SE and DIE. CA125 levels were significantly higher in the DIE group. SE and DIE groups had similar kisspeptin values, significantly higher than controls. CA125 and kisspeptin levels were not correlated in study groups. Serum kisspeptin levels were significantly different between endometriosis patients and healthy controls. However, kisspeptin levels were unable to differentiate endometriosis severity. Our results suggest that kisspeptins might play a role in the pathogenesis of endometriosis, which needs further assessment in more comprehensive studies.
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Intro

Endometriosis is a benign condition characterized by the ectopic localization of the endometrial glandular and stromal structures out of the uterine cavity, with a prevalence of 10-15% among women at reproductive ages. [ 1 – 5 ] However, specific populations have significantly higher prevalence, such as 40% in adolescents with genital system abnormalities, 50% in infertile women, and 70% in patients with pelvic pain. [ 6 – 11 ] Although the exact path of progression is still unknown, several mechanisms are suggested to develop ectopic implants, including Mullerian residuals, lymphatic or vascular invasion, and coelomic metaplasia. [ 1 ] But, the most widely accepted is Sampson’s retrograde menstruation theory, which suggests the endometrial cell backflow in fallopian tubes and implantation to the peritoneal cavity. [ 12 ] Pelvic endometriosis lesions are classified as superficial-peritoneal, ovarian (endometrioma), or deep infiltrating based on the localization and invasion depth. [ 13 – 16 ] Matrix metalloproteinases (MMP) 2 and 9 facilitate cell migration and invasion by degrading the extracellular matrix and may play a role in the pathogenesis of endometriosis. [ 17 – 27 ] Although endometriosis is a benign disorder, it also has characteristics similar to malignities like adhesion, invasion, and localization on ectopic tissues. [ 28 – 30 ] Kisspeptins are peptides encoded by the KISS1 gene localized on 1q32 that was first described as a metastasis suppressor gene in human malign melanoma cell cultures, thus also called metastin . [ 31 – 34 ] Kisspeptins are also known as neuropeptide hormones of the RF-amid family that interact with MMP in endometrial tissue to form focal adhesions to limit the tissue, limit trophoblast invasion during placentation, and suppress metastasis in various cancers (malign melanoma, choriocarcinoma, and bladder, gastric, esophagus, pancreas, endometrium cancers). [ 21 , 32 , 33 , 35 – 40 ] Kisspeptins also regulate the hypothalamic-hypophysial-gonadal axis and acknowledge as neuropeptides that are effective during puberty and have reproductive roles. [ 41 – 44 ] Endometriosis changes kisspeptin and magnesium metabolism. Local role of kisspeptin signaling in the control of follicular dynamics and ovulation has been identified in accelerated ovarian aging in endometriosis. Magnesium and kisspeptin are successfully used as dietary supplements for treatment of endometriosis. Endometriosis changes kisspeptin and magnesium metabolism. [ 45 , 46 ] Local role of kisspeptin signaling in the control of follicular dynamics and ovulation has been identified in accelerated ovarian aging in endometriosis. Magnesium and kisspeptin are successfully used as dietary supplements for treatment of endometriosis. [ 45 ] The diagnosis of endometriosis is generally delayed about 7 to 12 years due to inconclusive symptoms and risks associated with surgical diagnosis. [ 47 – 49 ] Nonsurgical diagnosis of endometriosis may include a combination of clinical and radiological assessments that might be supported by microRNA markers. [ 50 – 54 ] Currently, there is no pathognomonic laboratory test for endometriosis. Although the serum Ca125 levels increase in endometriosis (>35 U/mL), it has no role in primary diagnosis and does not inform about the invasion depth. Given the probable association of kisspeptin with the pathogenesis of endometriosis, this study hypothesized and evaluated whether it might also be associated with the invasion depth in endometriosis.

Author

Conceptualization: Mesut Önal, Yunus Katirci, Gülnur Çoban. Data curation: Mesut Önal, Yunus Katirci, Gülnur Çoban. Funding acquisition: Pervin Karli. Methodology: Adem Kocaman, Pervin Karli, Bahattin Avci. Project administration: Adem Kocaman, Gülen Kübra Nakişli. Resources: Adem Kocaman. Supervision: Yeşim Civil. Validation: Yeşim Civil, Ayşe Zehra Özdemir. Visualization: Gülen Kübra Nakişli. Writing – original draft: Mesut Önal, Ayşe Zehra Özdemir. Writing – review & editing: Mesut Önal, Adem Kocaman.

Methods

This prospective observational study was conducted at the Ondokuz Mayis University Faculty of Medicine between 2020 and 2021 and approved by the local ethics committee of Ondokuz Mayis University with the approval number of 2021/66. As a result of power analysis, forty women aged 18 to 45 years and diagnosed with endometrioma formed the patient group. Forty women in the same age range without endometrioma and any symptoms were included in the control group. Patients who had undergone endometrial cyst surgery or had a history of cancer were not included in the study. In the control group, patients underwent diagnostic L/S for infertility, and the presence or absence of endometriosis was confirmed surgically in all participants. All participants provided informed consent at recruitment before collecting blood samples to analyze serum Ca125 and kisspeptin levels. Ca125 and kisspeptin levels were analyzed biochemically by Elisa method. In addition, the demographic, obstetric, clinical, and biochemical characteristics were evaluated in patients with superficial endometriosis (SE) and deep infiltrating endometriosis (DIE) and healthy controls. Descriptive statistics were presented using frequency and percent for categorical data, median, interquartile range (25th–75th percentiles— inter-quartile range), and minimum and maximum values for non-normally distributed continuous variables. Comparisons between independent groups were performed using the Chi-square test for categorical variables and the Kruskal–Wallis non-parametric analysis of variances test for continuous variables. Post hoc pairwise comparisons for interpreting statistically significant results in overall comparisons were made using the Mann–Whitney U test. All statistical analyses were considered significant at a type-I error level of 5% ( P  < .05), and post hoc pairwise comparisons were evaluated using Bonferroni correction. SPSS 25 (IBM Inc., Armonk, NY) was used for statistical analyses.

Results

Twenty patients (50%) had SE, 14 (35%) had DIE, and 22 (55%) had endometrioma in the patient group. Median ages ( P  = .12) and body-mass indexes ( P  = .64) were similar. Obstetric characteristics revealed that the fertility rates were significantly different between groups ( P  = .002), but the gravida was similar ( P  = .11). The proportion of fertile patients was significantly higher among controls but similar between patients with SE and DIE. Clinical characteristics regarding dysmenorrhea ( P  = .29), dyspareunia ( P  = .067), and chronic pelvic pain ( P  = .29) were similar, but CA125 ( P  < .001) and kisspeptin ( P  < .001) levels were significantly different between groups. Accordingly, CA125 levels were significantly higher in the DIE group but similar between SE and control groups. For kisspeptin levels, SE and DIE groups had similar values, significantly higher than controls. Demographic, obstetric, and clinical characteristics and laboratory analyses are summarized in Table 1 . Basal demographic and clinical characteristics of patients. IQR = inter-quartile range. Correlations between CA125 and kisspeptin levels were presented in scatterplot graphs in Figure 1 . Analyses revealed that CA125 and kisspeptin levels were not correlated in SE ( R  = 0.27; P  = .25), DIE ( R  = −0.11; P  = .71), and control ( R  = 0.056; P  = .73) groups. Correlations between CA125 and kisspeptin levels in study groups.

Discussion

The pathophysiology of endometriosis is still not known precisely despite rigorous research, and the treatment is symptomatic rather than curative. [ 55 ] Although Sampson’s retrograde menstruation theory is widely accepted, other factors like genetic susceptibility, environmental factors, and changes in immune and endocrine functions are suggested to play a role in the pathogenesis. [ 30 , 56 ] The eutopic endometrium of women with and without endometriosis are histologically similar but different at the cellular and molecular levels, including abnormal expression of tissue MMPs, several cytokines, growth factors, steroid receptors, 17-β-hydroxysteroid dehydrogenase deficiency, resistance to the protective effect of progesterone, and decreased apoptosis. [ 57 ] Moreover, an association between endometriosis and clear cell and endometrioid ovarian cancers was also shown by previous epidemiological studies. [ 29 ] Nevertheless, there is no pathognomic laboratory finding for endometriosis. Several urinary and endometrial biomarkers are evaluated for noninvasive diagnosis of endometriosis, but none are found to have clinical utility. [ 58 – 62 ] The CA125 is the most studied marker and has shown to be correlated with endometriosis (>35 U/mL), but its sensitivity is low in mild endometriosis (sensitivity 28%, specificity 90%), and functions better in the diagnosis of grade 3 to 4 endometriosis, thus not routinely assessed for the primary diagnosis. [ 1 , 13 , 61 , 63 – 66 ] Some other biomarkers studied were CA19-9 which has shown to be correlated with the endometriosis severity, [ 67 – 69 ] serum placental protein 14 (PP14–glycodelin-A), interleukin-6, and tumor necrosis factor-α, which have limited diagnostic accuracy. [ 1 , 70 – 72 ] In addition, serum hepatocyte growth factor and CA19-9 expressions were correlated with patient age, prognosis, number of nodules, and infiltration depth and were found to be higher in grade III-IV patients than in grade I-II cases. [ 73 ] Another biomarker associated with ovarian endometriosis and enlargement of ovarian cysts is an estrogen-related receptor-α, which is suggested to be used to monitor the disease progression non-invasively. [ 74 ] Studies are ongoing to identify potential biomarkers to evaluate and monitor the disease progression. [ 75 – 79 ] Endometriosis shares many features of cancer, particularly migration and invasion; on the contrary, kisspeptins have antimetastatic characteristics in various cancer types. [ 33 , 80 ] In addition, the KISS1R mRNA levels were previously found to be statistically significantly higher in the cumulus cells of endometriosis patients compared to healthy oocyte donors. Thus, KISS1R expression was suggested as a potential factor that might have a role in endometriosis and associated infertility and can be used as a biomarker for diagnosing endometriosis. [ 81 ] Previous studies also revealed that kisspeptin expression varies in the glandular or stromal endometrial components in endometriosis. [ 80 , 82 , 83 ] The kisspeptin levels were lower in the eutopic endometrial glandular epithelium but similar in the stromal endometrium of women with endometriosis when compared to women without endometriosis. [ 80 ] Another study also reported that KISS1 expression was similar in stromal components from endometriosis lesions, eutopic endometrium, and healthy controls, but the expression was significantly lower in eutopic glandular endometrium than in ectopic lesions. [ 84 ] Since KISS1 is known to suppress metastasis, low levels in eutopic endometrium may permit migration to ectopic localization, suggesting a potential role of KISS1 in endometriosis, which also supports Sampson’s theory. A previous study reported that the expression of kisspeptin was significantly lower in DIE than in SE, which may explain that lower kisspeptin expression might be associated with invasion depth given the antimetastatic feature of the kisspeptin. [ 80 ] Another study showed that peripheral blood kisspeptin levels were significantly higher, but endometrial KISS1/KISS1R expressions were lower in endometriosis patients than in controls. In addition, the KISS1 expression and receptor KISS1R were significantly increased in endometrioid heterotopic regions on the pelvic peritoneum compared to normal peritoneal fragments. Also, the KISS1R receptor expression fields in the endometrioid heterotopic areas were significantly larger than the eutopic endometrium of endometriosis patients and the endometrium of the women in the control group. [ 85 ] Contrary to these findings, another study reported that KISS1 expression was not observed in any of the eutopic and ectopic endometrium samples from endometriosis patients, and almost none of the endometrial tissues of the control group, [ 86 ] which were then presumed to be associated with the methods as well as the limited number of the samples analyzed. [ 84 ] The tissue studies evaluating the kisspeptin and its receptor levels in deep, superficial, and ovarian endometriosis patients reported that deep lesions had lower levels of KISS1, thus, suggesting that kisspeptin might contribute to implant invasiveness. [ 83 ] When compared to SE, lower KISS1 levels were found in both glandular and stromal endometrium in deep and ovarian endometriosis, whereas lower KISS1R levels were observed in the glandular component of ovarian endometriosis. Additionally, comparisons of KISS1 and KISS1R between eutopic endometrium of endometriosis patients and normal endometrium of control patients revealed that endometriosis patients had decreased levels, which are concordant with previous studies. [ 83 , 84 ] This study found that the serum kisspeptin levels were significantly different between endometriosis patients and healthy controls. The increased levels among endometriosis patients were in accordance with the serum findings of Aylamazyan et al. [ 85 ] Nevertheless, our primary aim, determining the endometriosis severity using serum kisspeptin levels, seems not possible based on these results. Although endometriosis patients and the control group differ regarding kisspeptin levels, superficial and deep endometriosis patients were not significantly different. To the best of our knowledge, there is no study on the kisspeptin and CA125 association in endometriosis in the literature. Our study is the first that reported on this association, but no further assessments are available due to the lack of simultaneous evaluation of tissue kisspeptin expression. Previous studies reported that serum levels of CA125 were associated with endometriosis severity, but our results were contrary. This might be partly associated with the patient characteristics, but we considered that kisspeptin and CA125 levels were not superior to each other in determining endometriosis severity. The body mass index is strongly negatively correlated with the severity of endometriosis. [ 87 , 88 ] We have not evaluated the influence of BMI on Serum Kisspeptin Levels and we acknowledge this as a limitation of the study. Kisspeptins are thought to have a role in the pathogenesis of endometriosis. Nevertheless, further studies are needed for utilizing KISS1 as a marker for a neater understanding of the pathogenesis of the endometriosis, potentially targeted therapies, and identifying early and minimal invasive disease.

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Condition tags

endometriosisdie_deep_infiltratingendometrioma

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

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