The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a dramatic complicationof ovulation induction. In its most severe form, OHSS is characterizedby massive cystic enlargement of the ovaries associated withthird space fluid shift, resulting in the formation of ascitesand pleural effusion. Ascites develops because of increasedperitoneal capillary permeability. In this study we examinedthe role of vascular endothelial growth factor (VEGF) and interleukinsin the pathogenesis of increased capillary permeability. VEGFis a member of the family of heparin binding proteins that actdirectly on endothelial cells to induce proliferation and angiogenesis.VEGF mRNA and protein are expressed by human ovarian granulosaand theca cells late in follicular development and subsequentto ovulation by granulosa and theca cells. Therefore, VEGF isideally positioned to provoke the increased permeability oftheca blood vessels that occurs shortly before ovulation. Hybridizationstudies in the rat and primate ovary have demonstrated VEGFmRNA expression predominantly after the luteinizing hormone(LH) surge known to be essential for OHSS. The gonadotrophin-releasinghormone antagonist results in a decreased mRNA expression, implyingsuch expression is dependent on LH. The expression of VEGF mRNAhas been recently shown to be enhanced by human chorionic gonadotrophin(HCG) in a dose- and time-dependent fashion. These studies confirmthe timely association between VEGF and HCG that has been clinicallyknown for many years to be integral in the development of OHSS.VEGF concentrations in serum, peritoneal fluid and follicularfluid of patients at risk for OHSS have been shown to be significantlyrelated to the development of the syndrome. Furthermore, thekinetics of VEGF in the plasma of patients who actually developsevere OHSS are closely correlated with the clinical courseof the syndrome and with certain biological characteristicsof OHSS and of capillary leakage, such as leukocytosis and increasedhaematocrit. Studies on ascitic fluid from patients with severeOHSS have proved that VEGF is the major capillary permeabilityagent. Incubation with VEGF antiserum decreased the vascularpermeability activity by 70%. Interleukin-2 (IL-2) is the firstof a series of lymphocytotrophic hormones to be recognized aspivotal for the regulation of immune response. However, harddata to confirm its central role in the pathogenesis of OHSSare still lacking, despite the fact that some preliminary studiessuggest a positive association between the pooled follicularfluid IL-2 concentration and the development of OHSS. IL-6 isa mediator of the acute phase response to injury, a systemicreaction characterized by leukocytosis, increased vascular permeabilityand increased synthesis of acute phase proteins by the liver.Significantly higher serum and ascites IL-6 concentrations wereseen in OHSS patients. The immunohistochemical localizationpattern suggested that IL-6 is LH or HCG dependent. However,the use of IL-6 as a predictor for the occurrence of OHSS hasnot been successful. The kinetics of IL-6 in patients with severeOHSS are correlated with the clinical symptoms and the biochemicalparameters known to be associated with the severity of the syndrome,suggesting a possible role for IL-6. Further molecular biologystudies similar to those performed on EGF are needed to confirmif this interleukin is central in the cascade of events. IL-8is a chemoattractant, activating cytokine and a potent angiogenicagent. The peritoneal fluid levels is increased in patientswith severe OHSS; its concentration in peritoneal fluid is increasedin patients with severe OHSS. The place of this interleukinin the cascade of events is as yet undetermined and furtherstudies are needed. In conclusion, molecular biology and clinicalstudies strongly suggest that VEGF is the principal mediatorby which HCG might increase capillary permeability in OHSS.     

Relationships of serum pro-inflammatory cytokines and vascular endothelial growth factor with liver dysfunction in severe ovarian hyperstimulation syndrome

The aims of this study were to determine if differences in serum pro-inflammatory cytokines, vascular endothelial growth factor (VEGF) and clinical pregnancy rate, could be observed in women with severe ovarian hyperstimulation syndrome (OHSS) in those who did and did not have liver dysfunction. Twenty-nine in-vitro fertilization patients with severe OHSS were included. The patients were divided into the normal liver function tests (LFT) group (n = 14) and the abnormal LFT group (n = 15) according to the LFT on day of admission. Periodic measurements of serum interleukin (IL)-6, IL-8, tumour necrosis factor-alpha (TNF-alpha), VEGF, oestradiol, progesterone concentrations, and LFT were performed during hospitalization. Concentrations of IL-6 in the active phase of OHSS were significantly higher in the abnormal LFT group than in the normal LFT group (19.7 +/- 15.7 versus 8.1 +/- 7.0 pg/ml, respectively). The severity of liver dysfunction was not correlated with concentrations of oestradiol, progesterone, haematocrit, white blood cell counts, or any studied cytokine. The clinical pregnancy rate was significantly lower in the abnormal LFT group (46.7%) than in the normal LFT group (85.7%). These results suggest that IL-6 cytokine system may play a role in the pathogenesis of liver dysfunction in severe OHSS. Abnormal LFT were associated with lower clinical pregnancy rates.     

Human albumin enhances expression of vascular endothelial growth factor in cultured human luteinizing granulosa cells: importance in ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is a severe complication of ovarian stimulation for assisted reproductive techniques. Clinical manifestations are massive extravascular fluid accumulation and haemoconcentration. Vascular endothelial growth factor (VEGF) has been demonstrated to mediate the development of OHSS. Intravenous albumin at the time of oocyte aspiration has been suggested as an effective prophylactic treatment against the occurrence of severe OHSS. Here it is reported that in cultured human luteinizing granulosa cells, VEGF mRNA expression was enhanced by human albumin and maximum expression was observed in cultured granulosa cells obtained from patients with serum oestradiol concentrations >2000 pg/ml on the day of human chorionic gonadotrophin injection (P < 0. 05).     

Circulating levels of free and total vascular endothelial growth factor (VEGF)-A, soluble VEGF receptors-1 and -2, and angiogenin during ovarian stimulation in non-human primates and women

BACKGROUND: In a prospective study we measured circulating levels of vasoactive factors and their soluble receptors in women undergoing controlled ovarian stimulation (COS) for IVF who were at risk for ovarian hyperstimulation syndrome (OHSS), and compared them to those in a primate model, the rhesus monkey. METHODS: A total of 23 women were enrolled in the study and serum vascular endothelial growth factor (VEGF)-A (free and total), soluble (s)VEGF-R1 and -R2, and angiogenin levels were compared in pregnant and non-pregnant women, and in monkeys, during follicular stimulation, the luteal phase and early pregnancy. RESULTS: VEGF levels were similar during the period of follicular stimulation in pregnant and non-pregnant women, but a significant rise in both free and total VEGF occurred in pregnant women during the luteal phase (P < 0.05). The level of sVEGF-R1 (but not -R2) increased (P < 0.05) following implantation, and the rise in sVEGF-R1 corresponded to an abrupt fall in free (but not total) VEGF. In contrast, total VEGF levels remained similar to those observed on the day of hCG injection. Angiogenin levels tended to decline during follicular stimulation, then increased marginally during the luteal phase and were unchanged in early pregnancy. In contrast to women, free VEGF levels were non-detectable and total levels remained constant through the natural menstrual cycle and COS protocols in monkeys. CONCLUSIONS: The levels of circulating angiogenic factors and soluble receptors demonstrate significant changes during COS cycles and early pregnancy in women. Thus, the systemic effect of these agents is influenced by ligand-receptor protein-binding interactions, and these relationships may exhibit dynamic changes during COS cycles and early pregnancy, and could contribute to the development of OHSS.     

Value of serum and follicular fluid cytokine profile in the prediction of moderate to severe ovarian hyperstimulation syndrome

The aim of this study was to examine the role of serum and follicular fluid pro-inflammatory cytokines and vascular endothelial growth factor (VEGF) in the prediction of ovarian hyperstimulation syndrome (OHSS). A total of 156 consecutive women undergoing in-vitro fertilization were recruited. The study group comprised 12 women who subsequently developed moderate (n = 7) or severe (n = 5) OHSS. The two control groups were comprised of a randomized selection of 12 high-risk and 12 low-risk women in whom OHSS did not develop. Serum was collected on days of human chorionic gonadotrophin, oocyte retrieval, and embryo transfer. Serum and follicular fluid concentrations of interleukin (IL)-6, IL-8, tumour necrosis factor-alpha (TNF-alpha), and VEGF were measured. Follicular fluid IL-6 concentrations at the time of oocyte retrieval and serum IL-8 concentrations at the time of embryo transfer were significantly higher in the OHSS compared to the two control groups (P = 0.026 and P = 0.017 respectively). Serum concentrations of TNF-alpha and VEGF showed no statistically significant difference between the OHSS group and the controls at any studied time point. This study suggests that follicular fluid IL-6 concentrations at the time of oocyte retrieval and serum IL-8 concentrations on the day of embryo transfer may serve as early predictors for this syndrome.     

Prevention of severe ovarian hyperstimulation syndrome in IVF with or without ICSI and embryo transfer: a modified 'coasting' strategy based on ultrasound for identification of high-risk patients

Ovarian hyperstimulation syndrome (OHSS) can be a severe and potentially life-threatening complication of ovarian stimulation for IVF. Coasting or withholding gonadotrophin stimulation relies on frequent estimation of serum oestradiol to identify patients at risk. A modified coasting protocol was developed in which identification of patients at risk of severe OHSS was based on ultrasound monitoring. Serum oestradiol concentrations were measured only in patients with >20 follicles on ultrasound (high risk). If serum oestradiol concentrations were <3000 pmol/l, the gonadotrophin dose was maintained; if concentrations were >/=3000 pmol/l but <13200 pmol/l and >/=25% of the follicles had a diameter of >/=13 mm, the gonadotrophin dose was halved; and if serum oestradiol concentrations were >/=13 200 pmol/l and >/=25% of the follicles had a diameter of >/=15 mm, patients were coasted. In the latter group, human chorionic gonadotrophin (HCG) 10000 IU was administered when at least three follicles had a diameter of >/=18 mm and serum oestradiol concentrations were <10000 pmol/l. Over a 10 month period, serum oestradiol concentrations were measured in 123 out of 580 cycles (24%) and in 50 cycles, gonadotrophins were withheld. Overall, moderate OHSS occurred in three patients (0.7%) and severe OHSS in one patient (0.2%). The pregnancy rates in the cycles where the gonadotrophin dose was reduced or withheld were 39.6 and 40% per cycle respectively; corresponding implantation rates were 30.7 and 25.6%. It is concluded that the modified coasting strategy is associated with a low risk of moderate and severe OHSS to a minimum without compromising pregnancy rates. Identification of patients at risk by ultrasound reduces the number of serum oestradiol measurements and thus inconvenience to patients as well as costs and workload.     

Soluble vascular endothelial-cadherin levels correlate with clinical and biological aspects of severe ovarian hyperstimulation syndrome

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovarian stimulation, and the pathophysiological mechanisms that trigger the syndrome remain unknown. HCG increases serum vascular endothelial growth factor (VEGF) concentrations, and VEGF modulates transendothelial permeability via endothelial adherens junctions, a downstream target for VEGF signalling. We examined whether women with severe OHSS have altered serum levels of soluble vascular endothelial (sVE)-cadherin. METHODS: We conducted a prospective, case-control study of 28 women with severe OHSS and 34 women undergoing controlled ovarian hyperstimulation (COH) for IVF without developing OHSS. We collected serum samples from both groups on the day of ovum retrieval (Day 0), and on Days 3, 6, 9 and 15. Samples were assayed for sVE-cadherin by enzyme-linked immunosorbent assay. RESULTS: Women with severe OHSS had significantly higher levels of sVE-cadherin than patients without OHSS (P = 0.001). sVE-cadherin serum levels decreased with clinical improvement; however, they did not reach normal levels in the resolution phase. A positive correlation was demonstrated between sVE-cadherin and serum estradiol levels at the time of HCG administration (r = 0.621; P < 0.001). Serum sVE-cadherin levels were more closely chronologically correlated with corpus luteum function than with biological and clinical aspects of severe OHSS. CONCLUSIONS: sVE-cadherin may be involved in the pathogenesis of severe OHSS and may possibly serve as an indicator of corpus luteum function after COH.     

Increased erythrocyte aggregation in ovarian hyperstimulation syndrome: a possible contributing factor in the pathophysiology of this disease

BACKGROUND: Many theories regarding the pathophysiology leading to ovarian hyperstimulation syndrome (OHSS) have been proposed and tested. Increased erythrocyte aggregation is associated with capillary slow flow and tissue hypoxaemia. We performed this study in order to assess the degree of erythrocyte aggregation in the peripheral blood of individuals with OHSS and undergoing controlled ovarian stimulation (COH). METHODS: Twenty women with severe OHSS, 20 women undergoing COH under IVF protocol, and 20 healthy matched controls were recruited for this prospective study. Blood samples were drawn for determination of erythrocyte aggregation as well as haematological indices. The percentage of slide covered by the cells ('erythrocyte percentage': EP) was determined using a simple slide test and image analysis. Lower EP values correspond to higher degrees of aggregation. RESULTS: The respective measures of EP were 59.2 +/- 3.0, 42.0 +/- 3.0 and 35.0 +/- 2.4% micro m for the controls, women with COH and OHSS (P < 0.01 between controls and the two stimulation groups). CONCLUSIONS: The degree of erythrocyte aggregation is enhanced in the peripheral venous blood of patients with both COH and OHSS. This finding, known to cause capillary leak, may contribute to the pathophysiology of the OHSS.     

Endocrinology and paracrinology: Urinary vascular endothelial growth factor concentrations in women undergoing gonadotrophin treatment

A recently identified cytokine, vascular endothelial growthfactor (VEGF, vascular permeability factor) has been implicatedin ovarian hyperstimulation syndrome in women undergoing assistedreproduction. We postulate that circulating and urinary VEGFvalues increase following gonadotrophin stimulation, in parallelwith the increased ovarian vascularity. A VEGF radioimmunoassaywas developed using iodinated VEGF as tracer, a goat anti-VEGFserum as antiserum and recombinant human VEGF as standard. Thespecificity of the assay was confirmed by comparing the reversephase high-performance liquid chromatography (HPLC) patternof VEGF immunoactivity in urine and urine spiked with recombinantVEGF. Urine was concentrated 5-fold prior to measurement bythe radioimmunoassay. VEGF: creatinine ratios in early morningurine samples were used to monitor daily urinary VEGF concentrationsbased on its high correlation (r = 0.77, P < 0.001) withVEGF concentrations in 24 h urine collections. No diurnal variationin VEGF: creatinine ratios was detected. VEGF: creatinine ratioswere determined daily from nine women undergoing gonadotrophin-releasinghormone (GnRH) agonist/gonadotrophin treatment. In a further16 women, early morning urine samples were collected in theperi-ovulatory period. A significant increase (P < 0.005,n = 25) was observed in VEGF: creatinine ratios following humanchorionic gonadotrophin (HCG) administration. VEGF: creatinineratios correlated poorly (r < 0.34) with plasma oestradiol,follicle number and size. It is concluded that urinary VEGF/creatinineratios increase following HCG stimulation.     

Early unilateral follicular aspiration compared with coasting for the prevention of severe ovarian hyperstimulation syndrome: a prospective randomized study.

Thirty women undergoing in-vitro fertilization or intracytoplasmic sperm injection considered to be at high risk of ovarian hyperstimulation syndrome (OHSS) were randomly allocated to have early unilateral follicular aspiration (EUFA) (group 1) or coasting (group 2) when the serum oestradiol concentration was >6000 pg/ml and there were more than 15 follicles each of >/=18 mm diameter in each ovary. EUFA was performed in group 1 at 10-12 h after the human chorionic gonadotrophin (HCG) trigger injection and human menopausal gonadotrophin (HMG) were withheld for 4.9 +/- 1.6 days until serum oestradiol concentrations fell below 3000 pg/ml when HCG was administered. The mean total dose and duration of administration of HMG were similar in groups 1 and 2 (48.3 +/- 17.4 and 50.2 +/- 16.5 ampoules; 13.7 +/- 2.2 and 14.1 +/- 3.2 days respectively). The mean serum oestradiol concentrations (9911 pg/ml versus 10 055 pg/ml) and number of follicles (43.3 versus 41.4) seen in both ovaries on the day of HCG administration in group 1 and on the day coasting was commenced in group 2 were also similar. After coasting, the mean serum oestradiol concentration on the day of HCG administration in group 2 was lower than in group 1 (1410 pg/ml versus 9911 pg/ml; P < 0.001). The mean serum progesterone concentrations on the day of HCG administration in both groups were similar, and fell in all women in group 2. The mean number of oocytes retrieved and percentage of oocytes retrieved per follicle punctured was significantly higher in group 1 (15.4 +/- 2.1 versus 9.6 +/- 3.2, P < 0.001; 91.4 +/- 4.4% versus 28.3 +/- 3.7%, P < 0.001 respectively). The fertilization and embryo cleavage rates were similar in both groups. Clinical pregnancy was diagnosed in 6/15 (40%) patients in group 1 and in 5/15 (33%) patients in group 2, while four women in group 1 and three in group 2 developed severe OHSS.     

Relationship of ovarian stimulation response with vascular endothelial growth factor and degree of granulosa cell apoptosis

BACKGROUND: The aim of this study was to evaluate the concentration of vascular endothelial growth factor (VEGF) in follicular fluid and in granulosa cell cultures in relation to the degree of apoptosis in granulosa cells from patients with different types of ovarian response to controlled ovarian hyperstimulation. METHODS: We studied 30 women who underwent controlled ovarian hyperstimulation and oocyte retrieval. Group A comprised patients with 1-4 follicles (n = 10), group B patients with 5-14 follicles (n = 10) and group C patients with >15 follicles (n = 10). RESULTS: Mean (+/-SD) VEGF concentrations in follicular fluid were 1232 +/- 209, 813 +/- 198 and 396 +/- 103 pg/ml for groups A, B and C respectively (P > 0.01). Concentrations of VEGF in granulosa cell supernatant were 684 +/- 316, 1101 +/- 295 and 1596 +/- 227 pg/ml respectively (P < 0.05). Percentages of apoptotic cells in granulosa cells culture was 55.02 +/- 7.5, 23.98 +/- 4.4 and 14.2 +/- 2.3% respectively (A versus B, P < 0.01, A versus C, P < 0.006, B versus C, NS). CONCLUSIONS: Our findings showed that in patients with decreased ovarian response to controlled ovarian hyperstimulation, follicular fluid VEGF concentration is elevated, the concentration from granulosa cells culture supernatant is decreased and the percentage of apoptotic granulosa cells is increased, while opposite findings occurred in patients with normal or hyper-responses.     

Hormonal profiles and follicular growth in cycles with imminent ovarian hyperstimulation

Ovarian hyperstimulation syndrome is a common and serious complication of human menopausal gonadotrophin/human chorionic gonadotrophin treatment. We evaluated the changes in the pituitary and ovarian hormone profiles and ultrasonographic follicular regression in 12 patients in whom human menopausal gonadotrophin was discontinued due to 'imminent' ovarian hyperstimulation. Following discontinuation, three distinct periods were observed: (i) days 1-2, the levels of oestradiol, testosterone and prolactin, and the total number of follicles continued to rise; (ii) days 3-6, the levels of oestradiol, testosterone and prolactin declined sharply and the total number of follicles was reduced significantly, while the large and medium sized follicles continued to increase. Levels of follicle-stimulating hormone and luteinizing hormone gradually declined to reach their lowest levels by days 5-6 and then increased. (iii) Thereafter the number of follicles and steroid output declined to early follicular phase levels. We conclude that discontinuation of human menopausal gonadotrophin and withholding human chorionic gonadotrophin in cycles with laboratory signs of 'imminent' ovarian hyperstimulation syndrome, allows regression of the ovarian ultrasonographic finding and prevents the development of clinical symptoms. However, if rescue of the cycle is attempted, human chorionic gonadotrophin should be given during the first 4 days after discontinuation of stimulation.     

Characteristics of populations of granulosa cells from individual follicles in women undergoing 'coasting' during controlled ovarian stimulation (COS) for IVF

BACKGROUND: The aim of this study was to evaluate the functional characteristics of granulosa cell populations of individual follicles of women undergoing controlled ovarian stimulation (COS) for IVF/ICSI in whom gonadotrophin had been withheld ('coasted') for the prevention of OHSS. METHODS: Follicular fluid and granulosa cells were isolated from 224 individual follicles in 41 women who had been coasted and from 257 individual follicles in 50 women who had a 'normal' response to COS. Cells were cultured at 10,000 cells per well, to evaluate progesterone secretion. Follicular fluid was assayed for progesterone and estradiol (E2). RESULTS: No significant differences were observed between the two groups with respect to granulosa cell number or follicular fluid progesterone and E2 and follicle size, the retrieval of an oocyte and the subsequent fertilization of the oocyte. However, the granulosa cells derived from the coasted group showed a higher rate of progesterone secretion per cell at 72 h which was sustained for longer. Differences were also seen at 72 and 120 h of culture with a loss of correlation between progesterone secretion and follicle diameter in the coasted group. CONCLUSIONS: Our findings suggest that coasting has an effect on the functional capacity of the granulosa cells and the duration of their function. It is likely that in women at risk of OHSS who are not coasted, the granulosa cells have the capacity to produce significantly more chemical mediators per cell and for a more prolonged period of time.     

High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by 'prolonged coasting' of very hyperstimulated patients: a multicentre study

In a multicentre trial, 65 in-vitro fertilization (IVF)-embryo transfer cycles were severely hyperstimulated. Instead of cancelling the cycle, gonadotrophins were withheld for a 'coasting period' until serum oestradiol concentrations had dropped below 10,000 pmol/l (mean 4.3 days), and then human chorionic gonadotrophin was administered. Four cycles were cancelled and there were 61 oocyte aspirations. A total of 103 fresh embryos was transferred to 53 patients, resulting in a pregnancy rate of 42% per started cycle (51% per embryo transfer), with an implantation rate of 31%. Only one patient developed severe ovarian hyperstimulation syndrome (OHSS). Four patients developed moderate OHSS. In all, two patients were hospitalized for OHSS. In order to optimize the coasting procedure, it seems important that each IVF centre identifies its appropriate cut-off limits for serum oestradiol concentrations and follicle size for initiating and ending of the coasting period. Correctly handled, it seems to be a major advance in the search for improved stimulation policies for high-responders.     

Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups.

In a retrospective analysis of 637 cycles of ovarian stimulation and transvaginal follicular aspiration for various assisted reproductive technologies, severe ovarian hyperstimulation syndrome (SOH) occurred in six (0.94%) cycles. The patients at a high risk of developing SOH in cycles of assisted reproduction were those who had excessive serum oestradiol levels on the day of human chorionic gonadotrophin (HCG) administration (oestradiol greater than 6000 pg/ml; 38% SOH) and a high number of oocytes obtained (greater than 30 oocytes; 23% SOH). In those patients with both oestradiol greater than 6000 pg/ml on the day of HCG administration and greater than 30 eggs retrieved, the chance of developing SOH was 80%. The higher the serum oestradiol levels and the more eggs retrieved, the higher the pregnancy rates observed. High oestradiol level did not appear to have a detrimental effect on pregnancy rates and outcome. Furthermore, our results are not consistent with suggestions that the addition of gonadotrophin-releasing hormone agonist to ovarian stimulation protocols, follicular aspiration and/or luteal support with progesterone may reduce the incidence of ovarian hyperstimulation syndrome.     

Induction of pre-ovulatory luteinizing hormone surge by gonadotrophin-releasing hormone agonist for women at risk for developing the ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a major risk inpatients undergoing ovulation induction protocols. Withholdinginjection of human chorionic gonadotrophin (HCG) may preventthe development of OHSS, but can also result in failure to ovulateand conceive. We have used a gonadotrophin-releasing hormoneagonist (GnRHa) as an alternative to HCG in women not undergoingin-vitro fertilization in an attempt to prevent OHSS. The studyincluded 12 cycles in 12 women scheduled for ovulation inductionwith human menopausal gonadotrophin (HMG) who were at risk ofdeveloping OHSS (oestradiol>3500 pg/ml, number of follicles>20).GnRHa was injected to induce the pre-ovulatory, luteinizinghormone surge which triggers follicular maturation. Progesteronewas administered for luteal support. Six pregnancies were achieved,and none of the 12 women developed OHSS. Since the pregnancyrate in this study was acceptable, we can recommend the useof GnRHa instead of HCG in any case at risk of developing OHSS     

Endocrinology: von Willebrand factor: an endothelial marker to monitor in-vitro fertilization patients with ovarian hyperstimulation syndrome

A retrospective study was conducted to evaluate the possiblerole of endothelial and extracellular factors in the pathophysiologyof ovarian hyperstimulation syndrome (OHSS). Plasma changesin von Willebrand—Jürgen factor were correlated withthe clinical condition of hyperstimulated patients, since therise of capillary permeability is the central event in all subsequentmorbidity. The corresponding oestradiol levels and ultrasoundparameters were assessed. In-vitro fertilization patients designatedas ‘high responders’ and with oestradiol values>2500 pg/ml and >8 pre-ovulatory follicles at the timeof human chorionic gonadotrophin (HCG) injection were assessed.Among 62 patients, 37 fulfilled these criteria and 18 developedOHSS, indicating the low predictive ability of ultrasound andoestradiol values alone. The remaining 19 patients served ascontrol group. von Willebrand factor-associated antigen in plasmawas measured using enzyme-linked immunosorbent assay and ristocetinco-factor activity by an aggregatometric test. Basal valuesof the two groups of patients did not differ but there werelarge inter-individual variations. A slight increase occurredin the control group until the day of HCG although individualcycles showed ‘no change of pattern’ or a ‘decreasingtendency’ from the start. Some patients allocated to thenon-hyperstimulated type showed a steep increase of values followedby a decline. A consistent increase in the OHSS group lastedafter embryo transfer even to the late corpus luteum phase.These subtle changes of capillary permeability or damage alwayspreceded the clinical signs, such as ascites, haemoconcentration,hypoproteinaemia and pleural effusion. Mean values differedin the two groups from the day preceding ovum retrieval. Thistest may therefore provide an additional ‘prognostic marker’for early recognition and monitoring of OHSS.     

Criteria of a successful coasting protocol for the prevention of severe ovarian hyperstimulation syndrome

BACKGROUND: The aim of this study is to report a large series of patients (n = 1223) at risk of developing ovarian hyperstimulation syndrome (OHSS) who underwent coasting. METHODS: Coasting started when the leading follicle reached 16 mm and continued until the estradiol (E2) level fell to 3000 pg/ml. RESULTS: The E2 level at the start of coasting was (mean +/ SD) 6408 +/- 446 and it fell to 2755 +/- 650 on the day of HCG injection, after (mean +/- SD) 2.89 +/- 0.94 days. The results were analysed according to the duration of coasting (< or = 3 days, group I: n = 983; >3 days, group II: n = 240). The number of oocytes retrieved was (mean SD) 16.45 +/- 6.25 and 14.93 +/- 6.01 in groups I and II respectively (P < 0.05). The fertilization rates were 63 and 65% in groups I and II respectively (P > 0.05). The implantation and clinical pregnancy rates were 26 and 52% in group I compared to 18 and 36% in group II respectively (P < 0.05). Severe OHSS occurred in 16 cases, which represented 0.13% of all stimulated cycles, and 1.3% of patients who were at risk of developing OHSS. CONCLUSIONS: Our protocol of coasting was an effective measure in the prevention of OHSS, without jeopardizing the ICSI outcome. Coasting for >3 days is associated with a moderate decrease in the pregnancy rate.     

Vascular endothelial growth factor levels in serum and plasma from patients undergoing controlled ovarian hyperstimulation for IVF

BACKGROUND: Vascular endothelial growth factor (VEGF) has been investigated as a marker of ovarian response to controlled ovarian hyperstimulation and as a predictor of ovarian hyperstimulation syndrome (OHSS) in IVF cycles. In most studies, serum has been used for circulating VEGF concentration measurement, but it has been suggested that plasma is the preferred medium to measure VEGF levels because of the potential contribution of VEGF released from platelets during blood clotting. This study investigated VEGF concentrations in paired serum and plasma samples from patients undergoing controlled ovarian hyperstimulation for IVF. METHODS: Serum and plasma VEGF levels, as well as the number of platelets, were measured in 30 IVF patients who comprised three study groups delineated according to the estradiol (E(2)) serum concentration reached on the day of HCG administration: 10 patients having low E(2) serum levels (<1500 pg/ml, group L), 10 patients having intermediate E(2) serum levels (1500-3000 pg/ml, group I) and 10 patients having high E(2) serum levels (>3000 pg/ml, group H). RESULTS: There was a statistically significant correlation between plasma and serum VEGF levels (rho = 0.61; P < 0.005) for the entire population studied, although serum values were higher by a factor of approximately 6-fold. No significant correlation was found between peripheral blood VEGF concentrations and serum E(2) or follicle number on HCG day or the number of oocytes collected. Similarly, paired serum and plasma VEGF measurements did not correlate with platelet count. CONCLUSIONS: Serum and plasma VEGF concentrations are strongly correlated in paired samples from infertile patients undergoing controlled ovarian hyperstimulation. However, neither serum nor plasma VEGF levels were correlated with parameters associated with ovarian follicular activity. Peripheral blood VEGF levels were not correlated with platelet count.     

Metabolic characteristics of women who developed ovarian hyperstimulation syndrome

BACKGROUND: The aim of this study was to investigate whether a higher incidence of hyperinsulinism is found in women who have suffered from ovarian hyperstimulation syndrome (OHSS) as compared with other IVF patients. Additionally, we also assessed whether any abnormalities in the haemostatic system were more frequent in women with a past history of OHSS. METHODS: A pilot study was carried out involving OHSS patients and matched IVF patients. Homeostasis model assessment (HOMA) of insulin sensitivity was calculated. The main outcome measures were: insulin sensitivity, coagulation anomalies, factor V Leiden mutations, methylene tetrahydrofolate reductase (MTHFR) polymorphism and prothrombin gene mutation, protein C and protein S deficiency. RESULTS: No increased incidence in hyperinsulism nor in abnormalities of the haemostatic system were observed. CONCLUSIONS: This pilot study does not provide evidence for an increased prevalence of hyperinsulinism among women who have developed OHSS in the past.