Department of Obstetrics and Gynecology, Rabin Medical Center, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Rabin Medical Center, Petah Tiqva 49 100, Israel. e-mail: orvieto{at}clalit.org.il
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Abstract |
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Key words: BMI/C-reactive protein/follicular fluid/ovulation induction/sex steroids
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Introduction |
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C-reactive protein (CRP) is a biological marker of systemic inflammation, produced by the liver. It was recently demonstrated to have strong prognostic value for cardiovascular events (Ridker et al., 2002). CRP levels have no diurnal variation, are stable over long periods (Meier Ewert et al., 2001
) and increase after estrogen administration (Kluft et al., 2002
). The aim of the present prospective study was to longitudinally investigate serum and follicular fluid CRP levels during different time points of COH, and to determine whether they correlate with serum sex steroid levels or other COH variables.
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Patients and methods |
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For the purposes of the study, in addition to the routine monitoring during the COH cycle, blood samples were drawn to determine the hormonal profile (E2, progesterone and HCG) and serum CRP levels at three time points: (i) the day on which adequate suppression was obtained (Day-S); (ii) the day of or prior to HCG administration (Day-HCG); and (iii) the day of (and before) oocyte pick-up (Day-OPU). For serum CRP determination, blood samples were centrifuged for 10 min at 1000 g, and the plasma was stored in aliqouts at 20°C until assayed.
Serum and follicular fluid concentrations of CRP were determined with a high-sensitivity immunoturbidimetric assay (Roche Diagnostics Corporation, Indianapolis, IN, USA) using an automated clinical chemistry analyser. The intra-assay and interassay coefficients of variation were 1.0% and 2.9%, respectively. Blanks and controls were included in all experiments.
Informed consent was obtained from all patients before participation in the study, and the study was approved by the Clinical Research Committee.
The results are expressed as means ± SD. The statistical analysis was performed with paired Students t-test and correlation analysis. P-values of 0.05 were considered significant.
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Results |
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Mean serum E2, progesterone and CRP levels on Day-S, Day-HCG and Day-OPU, and follicular fluid CRP level on Day-OPU, are presented in Table I. As expected, serum E2 and progesterone levels were significantly higher on Day-OPU than Day-S (P < 0.01 for both). The serum E2 level was significantly higher on Day-HCG than Day-OPU (P < 0.01), whereas serum progesterone was significantly lower (P < 0.01).
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Discussion |
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To the best of our knowledge, the present study is the first to provide information on CRP levels during COH. We observed a 60% increase in CRP levels from Day-S to Day-HCG, which is in accordance with the positive effect of E2 level on CRP level (Kluft et al., 2002; Tchernof et al., 2002
). The increase in CRP is known to be coincident with an increase in other acute-phase proteins (fibrinogen, ceruloplasmin, von Willebrand factor originating from the liver and vessel walls) (Kluft et al., 2002
). This observation is also in agreement with our previous in vitro study (Orvieto et al., 2003
) on cytokine production by peripheral lymphocytes of patients undergoing COH, wherein whole-blood culture interleukin-2 was found to be significantly increased during COH until peak E2. Moreover, the significant (30%) increase in CRP level on Day-OPU compared with Day-HCG, despite the decrease in E2 level, substantiates our previous studies, which showed that neutrophil and endothelial activations, as reflected by the observed increase in L-selectin and E-selectin levels, respectively, are significantly stimulated by HCG administration (Orvieto et al., 2000
; 2001
). Furthermore, CRP levels on Day-OPU rise significantly above the cutoff value of 0.5 mg/dl, which indicates the presence of an inflammatory process (Thomas, 1992
).
The present finding of an observed increase in serum CRP, which reflects a state of systemic inflammatory response, may further substantiate the role of systemic inflammation in the pathophysiology of OHSS. It is in line with the suggestion of our group in an earlier work that hyperstimulated human ovaries may contain an as yet undetermined factor that might cause OHSS (Orvieto et al., 1995). Moreover, the absence of a correlation between CRP and E2 levels supports our previous conclusion that the occurrence of different, unrelated ovarian responses to COH could account for both the ovarian enlargement and excessive steroidogenesis, and the release of the intermediate factor, causing an increase in capillary permeability (Orvieto, 2003
).
Additional studies are required to elucidate the role of COH in systemic inflammatory response and its relation to the pathophysiology of OHSS. These may ultimately lead to new strategies in the prevention and treatment of complications of COH.
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References |
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Kluft C, Leuven JA, Helmerhorst FM and Krans HM (2002) Pro-inflammatory effects of oestrogens during use of oral contraceptives and hormone replacement treatment. Vascul Pharmacol 39,149154.[CrossRef][ISI][Medline]
Meier Ewert HK, Ridker PM, Rifai N, Price N, Dinges DF and Mullington JM (2001) Absence of diurnal variation of C-reactive protein levels in healthy human subjects. Clin Chem 47,426430.
Orvieto R (2003) Prediction of ovarian hyperstimulation syndrome: challenging the estradiol mythos. Hum Reprod 18,665667.
Orvieto R, Voliovitch I, Fishman P and Ben-Rafael Z (1995) Interleukin-2 and ovarian hyperstimulation syndrome a pilot study. Hum Reprod 10,2427.[Abstract]
Orvieto R, Schwartz A, Bar Hava I, Abir R, Ashkenazi J, La Marca A and Ben Rafael Z (2000) Controlled ovarian hyperstimulation a state of endothelial activation. Am J Reprod Immunol 44,257260.[CrossRef][ISI][Medline]
Orvieto R, Ben-Rafael Z, Schwartz A, Abir R, Fisch B, La Marca A and Bar Hava I (2001) Soluble L-selectin levels during controlled ovarian hyperstimulation. Gynecol Endocrinol 15,2933.[ISI]
Orvieto R, Elites T, Abir R, Bar J, Yoeli R, Feldberg D and Fisch B (2003) Interleukin-2 production in whole blood cell cultures of women undergoing controlled ovarian hyperstimulation for assisted reproductive technology cycles. Am J Reprod Immunol 50,220223.[CrossRef][ISI][Medline]
Ridker PM, Rifai N, Rose L, Buring JE and Cook NR (2002) Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 347,15571565.
Tchernof A, Nolan A, Sites CK, Ades PA and Poehlman ET (2002) Weight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation 105,564569.
Thomas L (1992) Labor und Diagnose, 4th edn. Die Medizinische Verlagsgesellschaft, Marburg, Germany, p. 781.
Submitted on August 7, 2003; resubmitted on September 30, 2003; accepted on October 27, 2003.