Re: Elevated ghrelin levels in the peritoneal fluid of patients with endometriosis: associations with vascular endothelial growth factor (VEGF) and inflammatory cytokines

15 02 2010

To the Editor:

We read the article by Dziunycz et al. (1) with great interest. The aims of the study were to evaluate ghrelin concentrations in the peritoneal fluid of women with endometriosis and of control women without pelvic pathology and its associations with the levels of proinflammatory cytokines and vascular endothelial growth factor (VEGF). Ghrelin concentrations were increased in peritoneal fluid of women with endometriosis compared with controls. Peritoneal ghrelin levels in patients with endometriosis were positively associated with VEGF, but there was no correlation between interleukin (IL) 1β, IL-6, or tumor necrosis factor (TNF).

Studies have demonstrated that peritoneal endometriosis, ovarian endometriosis, and deep endometriotic (adenomyotic) nodules of the rectovaginal septum are three distinct entities (2,3). It has been reported that deep endometriosis and cystic ovarian endometriosis have escaped from the predominant influence of peritoneal fluid (4). Superficial pelvic endometriosis is hormonally influenced mainly by the peritoneal fluid microenvironment, whereas deep endometriosis is mainly influenced by plasma hormone concentrations (4). Leptin that is an adipocyte derived protein belonging to the class of helical cytokines and ghrelin antagonizer was found to be increased in peritoneal but not in ovarian endometriosis (5).

In this study, peritoneal ghrelin levels were higher in moderate/severe endometriosis compared with minimal/mild disease, but it was not statistically significant. Ghrelin concentrations in patients with peritoneal lesions were lower than in patients with ovarian and both ovarian and peritoneal type of lesions, however, this difference was not also statistically significant in this study. Minimal/mild (I/II) grade of the disease was diagnosed in 14 patients, and moderate/severe (III/IV) grade was found in 32 cases and there was only 20 women without endometriosis.

They also compared peritoneal endometriosis with ovarian endometriosis; however, there were only thirteen patients with peritoneal and seven patients with ovarian endometriosis. The study would be better if the number of these subgroups were larger and equal; the results might be different statistically.

Correlations between ghrelin concentrations and inflammatory cytokines and VEGF were assessed by Spearman’s rank test. It is better to evaluate these associations with Pearson’s correlation analysis, because all these variables are parametric and Spearman’s rank test is used for nonparametric tests.

Peritoneal TNF is also evaluated in patients with endometriosis. Was it TNF α or β? We think it would be better to identify its subtype to the readers.

Fatma Ferda Verit, M.D.
Department of Obstetrics and Gynecology
Harran University, Faculty of Medicine
Sanliurfa, Turkey

Selcuk Ayas, M.D.
Department of Obstetrics and Gynecology
Zeynep Kamil Women and Children’s Hospital
Istanbul, Turkey

References
1. Dziunycz P, Milewski Ł, Radomski D, Barcz E, Kamiński P, Roszkowski PI, Malejczyk J. Elevated ghrelin levels in the peritoneal fluid of patients with endometriosis: associations with vascular endothelial growth factor (VEGF) and inflammatory cytokines. Fertil Steril 2009;92:1844-9.

2. Donnez J, Nisolle M, Smoes P, Gillet N, Beguin S, Casanas-Roux F. Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities. Fertil Steril 1996;66: 362–8.

3. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997;68:585–96.

4. Koninckx PR, Oosterlynck D, D’Hooghe T, Meuleman C. Deeply infiltrating endometriosis is a disease whereas mild endometriosis could be considered a non-disease. Ann N Y Acad Sci 1994;734:333-41.

5. De Placido G, Alviggi C, Carravetta C, Pisaturo ML, Sanna V, Wilding M, Lord GM, Matarese G. The peritoneal fluid concentration of leptin is increased in women with peritoneal but not ovarian endometriosis. Hum Reprod 2001;16:1251-4.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.02.028

The Authors Respond:

We would like to express our thanks to Drs. Verit and Ayas for their interest on our paper on elevated ghrelin in endometriosis (1).

We do agree with their suggestion based on original hypothesis of Nisolle and Donnez (2) that endometriosis is a complex disorder and some peritoneal, ovarian, or deep lesions may be considered as entities of different origin. In our study we classified our patients according to revised American Fertility Society (rAFS) criteria (3) which are based on both localization and extension of the disease. A majority of patients enrolled in our study (56.5%) had both peritoneal and ovarian lesions. Therefore, our study suggests that elevated ghrelin is rather related to general extension of the disease and not localization and particular type of the lesions. Accordingly, lower ghrelin levels in peritoneal endometriosis group when compared to peritoneal/ovarian lesions would rather reflect fact that they belong to minimal/mild grade of the disease. This assumption may be further confirmed by our unpublished observation that the levels of ghrelin in the peritoneal fluid significantly correlates with rAFS points.

We do agree that if the numbers of patients in different subgroups were larger it would be possible to reach higher statistical significance. Indeed, the number of patients in our study was limited due to the very strict inclusion criteria such as normal BMI and follicular phase of the menstrual cycle. Furthermore, the statistical significance was strongly affected by high intragroup variability (standard deviation) of ghrelin levels that may be partially due to unrevealed genetic heterogeneity of the patients’ population (4).

We cannot agree that application of Pearson correlation analysis would be more adequate in the case of our study. As mentioned above, the levels of ghrelin and all tested cytokines were highly variable and as such do not display normal distribution. Therefore, in our study we used non-parametric tests such as Mann-Whitney U-test and Spearman’s rank-order correlation test.

Basing on current cytokine nomenclature, the term TNF corresponds to former TNF-α. Accordingly, the name TNF-β which was used to describe lymphotoxin is now replaced by LT-α.

Jacek Malejczyk M.D., Ph.D.
Department of Histology and Embryology
Center for Biostrucure Research
Medical University of Warsaw
Warsaw, Poland

Ewa Barcz, M.D., Ph.D.
I Department of Obstetrics and Gynecology
Medical University of Warsaw
Warsaw, Poland

References
1. Dziunycz P, Milewski Ł, Radomski D, Barcz E, Kamiński P, Roszkowski PI, Malejczyk J. Elevated ghrelin levels in the peritoneal fluid of patients with endometriosis: associations with vascular endothelial growth factor (VEGF) and inflammatory cytokines. Fertil Steril 2009;92:1844-9.

2. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997;68:585-96.

3. American Fertility Society. Revised American Fertility Society classification of endometriosis. Fertil Steril 1985;43:351-2.

4. Tempfer CB, Simoni M, Destenaves B, Fauser BCJM. Functional genetic polymorphisms and female reproductive disorders: Part II – endometriosis. Hum Reprod Update 2009;15:97-118.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.02.027

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