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Editorial |
The Egyptian In Vitro Fertilization Center, Maadi, Cairo 12411, Egypt
Address all correspondence and requests for reprints to: M. A. Aboulghar, Professor, Cairo University, The Egyptian In Vitro Fertilization Center, No. 3, St. 161 Hadaek El Maadi, Cairo 12411, Egypt. E-mail: ghar{at}link.net.
The paper by Alvarez et al. (1) in this issue evaluated the role of dopamine agonist cabergoline in prevention of ovarian hyperstimulation syndrome (OHSS) for patients undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF).
This editorial covers the following items:
OHSS is the most serious complication of ovulation induction. In severe forms, the syndrome is characterized by ovarian enlargement, ascites, hydrothorax, electrolyte imbalance, hypovolemia, and oliguria (2). Vascular complications are the most serious complications. They include cerebrovascular thrombosis and arterial thrombosis (3). Respiratory complications include pleural effusion and adult respiratory distress syndrome (4). Renal failure and liver dysfunction were also reported. The condition could be lethal, and mortalities have been reported in rare cases (2).
During the past decade, there was an explosion in the number of COH cycles worldwide, both for IVF/intra-cytoplasmic sperm injection and ovulation induction for ovulatory infertility. In the last report of the American Society for Reproductive Medicine in 2001, 10,8130 cycles of assisted reproductive technology were started in the United States (5), and the last report of European Society of Human Reproduction and Embryology showed that 324,238 cycles of assisted reproductive technology were performed during the year 2002 in Europe (6).
This tremendous increase in the number of cycles worldwide was associated with a global increase in the number of complications of COH and, in particular, OHSS.
A search of PubMed revealed 685 publications cited on OHSS, which emphasized the seriousness of the syndrome and its importance. So far, treatment of established cases of OHSS has been symptomatic and mostly expectant apart from paracentesis of ascetic or pleural fluid with replacement of the depleted albumin and correction of the electrolyte imbalance.
The great part of research in this area during the past decade has been directed toward the pathogenesis of OHSS, hoping that this can lead to an effective preventive measure, hence the importance of the manuscript by Alvarez et al. (1).
Pathogenesis
In OHSS the ovaries are the site of significant stromal edema with bilateral cystic ovarian enlargement. The ascetic fluid accumulation was suggested to be due to increased capillary permeability, which results in fluid shift from intravascular to extravascular compartment (7).
The exact etiology of OHSS is not clear, and several biochemical markers were considered to be possible mediators. Rather recently, there has been an accumulation of evidence showing that VEGF is responsible for the development of the syndrome.
VEGF is a member of a family of heparin-binding proteins that acts directly on endothelial cells to induce proliferation and angiogenesis (8).
McClure et al. (9) pioneered investigations of the role of VEGF as a capillary permeability agent in the pathogenesis of OHSS.
Albert et al. (10) summarized the reasons that affirm the role of VEGF as a potential mediator in the development of OHSS. First, VEGF and its isoforms have vasoactive properties (11). Second, VEGF has been identified in follicular fluid. Third, mRNA transcripts and proteins have been detected in granulosa luteal cells (12). Finally, VEGF is increased in the serum and peritoneal fluid of women who develop OHSS compared with controls (13). Aboulghar et al. (13) verified an increase in total follicular production of VEGF that accounted for elevated serum levels of VEGF, which was associated with the development of OHSS.
Gómez et al. (14) reported that VEGF receptor activation induces vascular permeability in hyperstimulated rats, and this effect is prevented by receptor blockade.
In vivo, VEGF is a powerful mediator of vascular permeability; it is also strongly implicated in the initiation and development of angiogenesis in the developing embryo and in adult tissue undergoing profound angiogenesis, such as cycling endometrium and the luteinizing follicle. It also plays an important role in the growth and maintenance of ovarian follicles and corpus luteum by mediating angiogenesis (10).
Rationale of the Study
The study by Alvarez et al. (1) is based on the strong available evidence that VEGF is involved in the pathogenesis of OHSS. It is logical that the authors tried to study a pharmacological agent that antagonizes VEGF.
Recently, Sarkar et al. (15) demonstrated that vascular permeability factor (VPF)/VEGF-induced phosphorylation of VEGF receptor 2, focal adhesion kinase, and MAPK in the endothelial cells is strikingly increased in both dopamine-depleted and dopamine D (3) receptor knockout mice compared with normal controls, thereby indicating that endogenous dopamine regulates three critical signaling cascades required for the in vivo endothelial functions of VPF/VEGF. Kosaka et al. (16) found that circulating immune cells are involved in the pathogenesis of OHSS via VEGF production.
The study by Albert et al. (10) showed that estradiol (E2) does not increase vascular permeability, human chorionic gonadotropin (hCG) acts through VEGF, and blocking VEGF action is a valid alternative to overcome the changes induced in the endothelium by hCG.
Basu et al. (17) reported that at nontoxic levels, the neurotransmitter dopamine strongly and selectively inhibits the vascular permeability and angiogenic activities of VPF/VEGF. These results reveal a link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors, already in clinical use, might have value in antiangiogenesis therapy.
In rats, both a specific antagonist and monoclonal anti-body agonist VEGF are able to prevent the gonadotropin-induced OHSS (17). A previous study showed that dopamine treatment of OHSS may induce prompt resolution of OHSS in humans (18).
Cabergoline was administered to 20 women at risk for OHSS on an outpatient basis starting the evening after ovum pickup. They observed no OHSS in the treated group (19). The authors believed that cabergoline may be more effective in prevention of OHSS if administrated immediately after pickup.
The safety of the long-term use of cabergoline was well documented, and it was shown that cabergoline does not increase the miscarriage rate or rate of congenital anomalies when administrated during pregnancy (20, 21)
Several recent publications showed that coasting is an effective method for prevention of OHSS, and it is possible that coasting alters the capacity of the granulosa cells to produce VEGF (22).
Prevention of OHSS
Several methods were tried to prevent OHSS, however, the syndrome is unlikely to be eliminated completely by dose individualization because of the narrow margin between the dose needed for multifollicular development and the dose that induces hyperresponse (23).
In high-risk patients for OHSS as diagnosed by high E2 levels and the large number of follicles in each ovary, particularly if most of them are small to medium sized, several options were tried to prevent OHSS. Withholding hCG and continuation of GnRH analog is still being used to guarantee avoiding OHSS. However, it is done at the expense of canceling the cycle. Intravenous albumin and cryopreservation of all embryos for transfer in later cycle were not effective in prevention of OHSS (23).
Coasting is withholding FSH and delaying hCG until serum E2 decreases to a safe level (24). It is currently the most commonly used method for prevention of OHSS, and it reduced markedly the incidence of OHSS; however, prolonged coasting was associated with lower pregnancy rates (22).
Coasting possibly works through the loss of FSH effect on granulosa cells until it undergoes apoptosis (25). It is believed that this may result in reduction of chemical mediators (VEGF) that trigger ovulation.
It seems logical that if we can antagonize or stop the production of VEGF, we may be able to prevent OHSS or at least reduce its severity, and this is the basis of the study by Alvarez et al. (1).
Comment on Paper
The study by Alvarez et al. (1) is the first well-designed randomized double-blind study that investigated the role of cabergoline on the prevention of OHSS. The current study showed that cabergoline significantly lowered hematocrit, hemoglobin, and ascites on d 4 and 6 after treatment compared with placebo.
However, the study showed only significant reduction in the incidence of moderate OHSS in the cabergoline arm. No difference was noticed in the incidence of severe OHSS.
Diagnosis of severe OHSS in the study was based on changes in the hematocrit, hemoglobin, and liver dysfunction. These biochemical markers, upon which the diagnosis of severe OHSS was made, did not reflect relevant clinical significance.
The study was designed to detect differences in the rate of moderate OHSS between cabergoline and placebo arms assuming that the incidence of moderate OHSS would be 15–20%. However, the results of the study showed that the incidence of severe OHSS according to authors’ criteria was 14.9%. None of the patients who were diagnosed with severe OHSS had severe ascites, or even clinically detected ascites or hydrothorax, were admitted to the hospital, or had paracentesis performed.
Although cabergoline was affective in prevention of moderate OHSS, it did not affect the E2 level. It was previously observed that coasting was associated with a decrease of the E2 level, and hCG was only given when E2 decreases to a safe level. It seems that cabergoline works through a different mechanism.
Magnetic resonance studies were used by the authors in severe OHSS, and showed an increase in vascular permeability and extracellular leakage of fluid 5 d after hCG injection. This was significantly prevented by cabergoline.
A randomized study comparing cabergoline and coasting, which is the most widely used method for prevention of OHSS, would evaluate the future role of cabergoline in clinical practice. Researchers could also try to start cabergoline a few days earlier.
Choosing patients at very high risk for OHSS may also be more suitable to evaluate the real value of cabergoline in prevention of severe OHSS.
Footnotes
Abbreviations: COH, Controlled ovarian hyperstimulation; E2, estradiol; hCG, human chorionic gonadotropin; IVF, in vitro fertilization; OHSS, ovarian hyperstimulation syndrome; VEGF, vascular endothelial growth factor; VPF, vascular permeability factor.
Received June 5, 2007.
Accepted June 12, 2007.
References
, interleukin-6, soluble interleukin-6 receptor and vascular endothelial growth factor in serum and ascitic fluid of patients with severe ovarian hyperstimulation syndrome. Eur J Obstet Gynecol Reprod Biol 87:81–85[CrossRef][Medline]
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