Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: cytokine/interleukin-6/liver dysfunction/ovarian hyperstimulation syndrome/vascular endothelial growth factor
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Recent observations provide evidence for hepatic disturbance in the most severe form of OHSS (Sueldo et al., 1988; Younis et al., 1988
; Balasch et al., 1990
; Ryley et al., 1990
; Nawroth et al., 1996
; Shimono et al., 1998
; Tortoriello et al., 1998
). Abnormal liver function tests (LFT) were recorded in 37.5% (3/8) patients with severe OHSS in a European series (Forman et al., 1990
). The mechanism of elevated LFT in severe OHSS remains unclear. The proposed mechanisms include increased circulating sex steroid concentrations (Younis et al., 1988
; Balasch et al., 1990
), hepatocellular damage from the increased vascular permeability that characterizes severe OHSS (Wakim and Fox, 1996
), and consequences of hepatic ischaemia/reperfusion (Simpson et al., 1997
) as a result of circulatory dysfunction in severe OHSS (Balasch et al., 1998
).
Pro-inflammatory cytokines [e.g. interleukin (IL)-6, IL-8, and tumour necrosis factor- (TNF-
)] and vascular endothelial growth factor (VEGF) have been implicated as mediators in the pathogenesis of capillary leakage in OHSS (Friedlander et al., 1993
; McClure et al., 1994
; Abramov et al., 1996
). Pro-inflammatory cytokines have also been reported to be involved in the acute phase response to hepatic injury (Moshage, 1997
). Furthermore, serum VEGF has been reported to be involved in hypoxia-related angiogenesis occurring in various liver diseases (Akiyoshi et al., 1998
). Therefore, it was postulated that pro-inflammatory cytokines and VEGF might be involved in the pathogenesis of liver dysfunction in severe OHSS. If factor(s) that cause liver dysfunction in severe OHSS also lead to a hostile environment for implantation, reduced pregnancy rates should be observed in women with abnormal LFT.
The current study was designated to examine whether differences in serum pro-inflammatory cytokine and VEGF concentrations, as well as the clinical pregnancy rate, could be observed in women with severe OHSS in those who did and did not have liver dysfunction.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The ovarian stimulation protocols were performed as previously described (Chen et al., 1997).
Monitoring and management of the patients during hospitalization
Monitoring of the patients included daily measurement of body weight, abdominal girth, fluid intake and urine output, and periodic ultrasound assessment as well as routine blood parameter measurements (complete blood counts, electrolytes, liver and renal function tests) at intervals of 35 days. Additional blood was drawn for oestradiol, progesterone, and cytokine assays. The blood samples were centrifuged for 10 min at 400 g, and the serum was stored immediately at 70°C before assay for cytokines and steroids. Abdominal paracentesis for tense ascites and thoracentesis for massive pleural effusion were performed as needed (Chen et al., 1998).
To describe the clinical course of OHSS, all measurements were normalized to the day of pre-ovulatory human chorionic gonadotrophin (HCG) administration (day 0). Furthermore, to correlate the concentrations of various cytokines and abnormal LFT with changes in symptoms or disease severity, the hospital stay was divided from the day of admission day to the day of spontaneous diuresis into three periods. The day of spontaneous diuresis was defined as the day that fluid balance shifted from a positive fluid balance to a negative fluid balance during the resolution stage of OHSS. This day was identified by reviewing the medical records of fluid intake and output throughout the course of hospitalization. The period from the day of spontaneous diuresis to the day of discharge was termed period 4.
The four periods were taken to represent different time phases of the course of OHSS. While periods 1 and 2 represented the active phase of disease, periods 3 and 4 represented the resolution phase and clinical convalescence of OHSS. There were 17, 13, nine and 15 serum samples respectively in the four periods of OHSS in the normal LFT group and 17, 12, 11 and 13, respectively in the abnormal LFT group. Data within each period were pooled for statistical analyses.
Cytokines and hormone assays
Concentrations of cytokines (IL-6, IL-8 and TNF-) and VEGF were measured by solid-phase enzyme-linked immunosorbent assay using commercially available kits (Quantikine; R&D System, Inc., Minneapolis, MN, USA). The sensitivity of these cytokine assays was 1 pg/ml for IL-6, 5 pg/ml for TNF-
and VEGF, and 10 pg/ml for IL-8. All samples were run in duplicate and were assayed at the same time to avoid inter-assay variations and possible alterations due to freezing and thawing.
Serum oestradiol and progesterone concentrations were assayed using a chemiluminescent immunoassay (Immulite; Diagnostic Products Corporation, Los Angeles, CA, USA). The intra-assay and inter-assay coefficients of variation for oestradiol at a concentration of 480 pg/ml were 6.3 and 6.4% respectively, and 10.5 and 8.1% for progesterone at a concentration of 7.2 ng/ml.
Statistical analysis
Results are expressed as means ± SD. Statistical analyses were performed using Student's t-test, Fisher's exact test, the MannWhitney test and KruskalWallis test as appropriate. Correlation analysis was carried out using Spearman correlation coefficients. Statistical significance was defined as a value of P < 0.05. Statistical analysis was performed with the Statistical Package for the Social Sciences (version 9.0, SPSS Inc., Chicago, IL, USA).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Figure 2 shows changes in serum cytokine concentrations during the four periods of severe OHSS in the normal and abnormal LFT groups. Concentrations of IL-6 in period 1 (active phase) of OHSS were significantly higher in the abnormal LFT group [19.7 ± 15.7 (mean ± SD) versus 8.1 ± 7.0 pg/ml, respectively; P = 0.01 by the MannWhitney test].
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The clinical significance of elevated LFT in severe OHSS has not yet been thoroughly investigated. Conceivably, factor(s) that cause liver dysfunction in severe OHSS may also provoke a hostile environment that leads to implantation failure. Clinical pregnancy rates in women with severe OHSS after IVF have recently been reported to be 73.2% in a multicentre study (Abramov et al., 1998). Workers in a European series (Forman et al., 1990
) observed liver dysfunction in three of eight (37.5%) patients with severe OHSS. The pregnancy in one of them ended in intrauterine death 60 days after oocyte retrieval, but the outcome in the other two patients with liver dysfunction was not mentioned. Instead, they showed the pregnancy outcome in these eight OHSS patients including five live births (62.5%), two miscarriages (25%), and one conception failure (12.5%). In the present study, it was found that the clinical pregnancy rate was significantly lower in the abnormal LFT group (46.7%) than in the normal LFT group (85.7%), suggesting that an abnormal LFT is associated with a lower clinical pregnancy rate.
Table III summarizes the pregnancy outcome of reported cases of abnormal LFT with OHSS. One-third of patients (3/9) did not conceive, one-third experienced early miscarriage, and only one-third of patients had an uneventful pregnancy course. Patients with severe OHSS are exposed to a variety of insults that potentially affect early pregnancy. Haemodynamic instability, hypoxaemia, and liver and renal dysfunction are potential offensive mechanisms (Abramov et al., 1998
). Further, patients with severe OHSS are exposed to extremely high endogenous oestrogen concentrations, in addition to cytokines (Abramov et al., 1996
) and possibly the reninangiotensin system (Navot et al., 1987
), the effects of which on an early pregnancy are unknown. Whether the presence of an abnormal LFT in severe OHSS is associated with a higher miscarriage rate and a diminished pregnancy potential remains to be elucidated.
|
In conclusion, the results of this study suggest that IL-6 cytokine system may play a role in the pathogenesis of liver dysfunction. Clinicians should be aware of the presence of liver dysfunction in severe OHSS. The possible role of abnormal LFT as a prognostic marker for adverse pregnancy outcome in OHSS awaits further clarification.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Abramov, Y., Schenker, J.G., Lewin, A. et al. (1996) Plasma inflammatory cytokines correlate to the ovarian hyperstimulation syndrome. Hum. Reprod., 11, 13811386.
Akiyoshi, F., Sata, M., Suzuki, H. et al. (1998) Serum vascular endothelial growth factor levels in various liver diseases. Dig. Dis. Sci., 43, 4145.[ISI][Medline]
Balasch, J., Carmona, F., Llach, J. et al. (1990) Acute prerenal failure and liver dysfunction in a patient with severe ovarian hyperstimulation syndrome. Hum. Reprod., 5, 348351.[Abstract]
Balasch, J., Fábregues, F. and Arroyo, V. (1998) Peripheral arterial vasodilation hypothesis: a new insight into the pathogenesis of ovarian hyperstimulation syndrome. Hum. Reprod., 13, 27182730.
Chen, C.D., Wu, M.Y., Yang, J.H. et al. (1997) Intravenous albumin does not prevent the development of severe ovarian hyperstimulation syndrome. Fertil. Steril., 68, 287291.[ISI][Medline]
Chen, C.D., Yang, J.H., Chao, K.H. et al. (1998) Effects of repeated abdominal paracentesis on uterine and intraovarian haemodynamics and pregnancy outcome in severe ovarian hyperstimulation syndrome. Hum. Reprod., 13, 20772081.[Abstract]
Forman, R.G., Frydman, R., Egan, D. et al. (1990) Severe ovarian hyperstimulation syndrome using agonists of gonadotrophin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil. Steril., 53, 502509.[ISI][Medline]
Friedlander, M.A., Loret de Mola, J.R. and Goldfarb, J.M. (1993) Elevated levels of interleukin-6 in ascites and serum from women with ovarian hyperstimulation syndrome. Fertil. Steril., 60, 826833.[ISI][Medline]
Martin, C., Saux, P., Mege, J.L. et al. (1994) Prognostic values of serum cytokines in septic shock. Intensive Care Med., 20, 272277.[ISI][Medline]
McClure, N., Healy, D.L., Rogers, P.A.W. et al. (1994) Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet, 344, 235236.[ISI][Medline]
Moshage, H. (1997) Cytokines and the hepatic acute phase response. J. Pathol., 181, 257266.[ISI][Medline]
Navot, D., Margalioth, E.J., Laufer, N. et al. (1987) Direct correlation between plasma renin activity and severity of the ovarian hyperstimulation syndrome. Fertil. Steril., 48, 5761.[ISI][Medline]
Nawroth, F., Heinrich, J., Bruns, U. et al. (1996) Severe ovarian hyperstimulation syndrome and icterus. Hum. Reprod., 11, 24412442.[Abstract]
Polishuk, W.Z. and Schenker, J.G. (1969) Ovarian overstimulation syndrome. Fertil. Steril., 20, 443450.[ISI][Medline]
Ryley, N.G., Forman, R., Barlow, D. et al. (1990) Liver abnormality in ovarian hyperstimulation syndrome. Hum. Reprod., 5, 938943.[Abstract]
Schenker, J.G. and Weinstein, D. (1978) Ovarian hyperstimulation syndrome: a current survey. Fertil. Steril., 30, 255268.[ISI][Medline]
Sheron, N., Bird, G., Goka, J. et al. (1991) Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis. Clin. Exp. Immunol., 84, 449453.[ISI][Medline]
Shimono, J., Tsuji, H., Azuma, K. et al. (1998) A rare case of hepatic injury associated with ovarian hyperstimulation syndrome. Am. J. Gastroenterol., 93, 123124.[ISI][Medline]
Simpson, K.J., Lukacs, N.W., Colletti, L. et al. (1997) Cytokines and the liver. J. Hepatol., 27, 11201132.[ISI][Medline]
Sueldo, C.E., Price, H.M., Bachenberg, K. et al. (1988) Liver dysfunction in ovarian hyperstimulation syndrome: a case report. J. Reprod. Med., 33, 387390.[ISI][Medline]
Tortoriello, D.V., McGovern, P.G., Colon, J.M. et al. (1998) Critical ovarian hyperstimulation syndrome in a `coasted' in-vitro fertilization patient. Hum. Reprod., 13, 30053008.[Abstract]
Wakim, A.N. and Fox, S.D. (1996) Elevated liver function tests in a case of moderate ovarian hyperstimulation syndrome. Hum. Reprod., 11, 588589.[Abstract]
Wang, P., Ba, Z.F. and Chaudry, I.H. (1997) Mechanism of hepatocellular dysfunction during early sepsis: key role of increased gene expression and release of pro-inflammatory cytokines tumor necrosis factor and interleukin-6. Arch. Surg., 132, 364370.[Abstract]
Wigmore, S.J., Walsh, T.S., Lee, A. et al. (1998) Pro-inflammatory cytokine release and mediation of the acute phase protein response in fulminant hepatic failure. Intensive Care Med., 24, 224229.[ISI][Medline]
Younis, J.S., Zeevi, D., Rabinowitz, R. et al. (1988) Transient liver function tests abnormalities in ovarian hyperstimulation syndrome. Fertil. Steril., 50, 176178.[ISI][Medline]
Submitted on May 24, 1999; accepted on October 8, 1999.