Hum. Reprod. Advance Access originally published online on February 17, 2006
Human Reproduction 2006 21(6):1539-1544; doi:10.1093/humrep/del021
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Perifollicular vascularity in poor ovarian responders during IVF
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, People’s Republic of China
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, The University of Hong Kong, 6/F, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, People’s Republic of China. E-mail: nghye{at}hkucc.hku.hk
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Abstract |
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BACKGROUND: Normal ovarian responders who have follicles with good vascularity shown by power Doppler scanning are associated with a better pregnancy rate following IVF treatment. This study evaluated the significance of perifollicular vascularity and follicular fluid hormonal profile in poor responders who developed
3 dominant follicles. METHODS: Before oocyte retrieval, they underwent power Doppler examination for perifollicular vascularity. Patients who had all follicles with low-grade vascularity were classified as Group A, whereas those with at least one follicle with high-grade vascularity were Group B. Their follicular fluid concentrations of estradiol (E2), progesterone, HCG, vascular endothelial growth factor (VEGF) and inhibin B were measured. RESULTS: A total of 58 consecutive patients were recruited: 38 in Group A and 20 in Group B. Implantation rate, clinical pregnancy rate and follicular fluid hormonal concentrations were comparable for Groups A and B. Multiple pregnancy and live birth rates appeared higher, whereas miscarriage rate were lower in Group B than Group A, but these differences did not reach statistical significance. CONCLUSION: There were no significant differences in the implantation, clinical pregnancy and live birth rates among poor responders with and without high-grade perifollicular vascularity.
Key words: follicular fluid/perifollicular vascularity/poor ovarian response
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Introduction |
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Multiple embryos are usually replaced in IVF treatment to compensate for their low implantation potential, despite advances in ovarian stimulation, gamete handling, assisted fertilization and embryo culture. Development of multiple follicles in response to gonadotrophin stimulation is, therefore, considered as the key factor leading to successful outcome. Cycles with poor ovarian response are usually cancelled, because they are associated with low pregnancy rates (Keay et al., 1997
). On the contrary, Lashen et al. (1999) showed that the pregnancy rate of 124 patients who had normal Day 3 FSH concentration and produced <5 follicles during IVF treatment was comparable with the overall rate during the study period. Biljan et al. (2000) also found that the implantation and pregnancy rates of IVF treatment in women developing 3 follicles were similar to those with >3 follicles if they were less than 40 years old. These findings indicate that a reasonable success rate can be achieved in a selected group of poor responders following IVF treatment.
Blood flow is increased around developing follicles during the follicular phase in ovarian stimulation (Balakier and Stronell, 1994). Colour Doppler indices of follicular blood flow are correlated with oocyte recovery (Nargund et al., 1996; Oyesanya et al., 1996), fertilization rate (Nargund et al., 1996), developmental potential of the oocyte (Van Blerkom et al., 1997; Huey et al., 1999) and pregnancy rate (Coulam et al., 1999) of IVF treatment. Power Doppler imaging is more sensitive than colour Doppler imaging at detecting low velocity flow and hence improves the visualization of small vessels (Guerriero et al., 1999). Patients who have follicles with good vascularity shown by power Doppler scanning are associated with better pregnancy rates following IVF (Chui et al., 1997; Bhal et al., 1999) and stimulated intrauterine insemination cycles (Bhal et al., 2001). The pregnancy rate was only 7.3% (3/41) per cycle in those having all follicles with low-grade vascularity (Bhal et al., 2001). Therefore, assessment of perifollicular vascularity in poor responders may be useful in selecting a subgroup of patients with better outcomes. Those patients with poorer outcomes could perhaps be advised against transvaginal ultrasound-guided oocyte retrieval (TUGOR).
We aimed to evaluate implantation, clinical pregnancy and live birth rates of poor responders without high-grade perifollicular vascularity assessed by power Doppler ultrasound. Their treatment outcomes and follicular fluid hormonal concentrations were compared with those with high-grade vascularity. The hypothesis of this study was that the absence of high-grade perifollicular vascularity was associated with lower implantation, clinical pregnancy and live birth rates in poor responders, which were defined as those who developed 3 dominant follicles of 
16 mm in diameter after ovarian stimulation.
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Materials and methods |
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Infertile patients undergoing the first IVF cycle at Department of Obstetrics and Gynaecology in The University of Hong Kong were recruited if they developed
3 dominant follicles of 16 mm in diameter after ovarian stimulation. Serum estradiol (E2) concentration on the day of HCG was not used as one of selection criteria. Indications for conventional IVF treatment included tubal, male, endometriosis, unexplained and mixed factors. ICSI was performed for couples with severe semen abnormalities where <100 000 motile spermatozoa were recovered after sperm preparation. In case of obstructive or non-obstructive azoospermia, surgically retrieved spermatozoa from epididymis or testis, respectively, were used for ICSI. Basal serum FSH concentration was checked on Days 2–3 of the cycle within 2–3 months of commencing treatment. Every patient gave their written consent before participating in the study, which was approved by the Ethics Committee of the Faculty of Medicine, The University of Hong Kong. They were evaluated only once during the study period and did not receive any monetary compensation for their participation in the study.
The details of the long protocol of ovarian stimulation regimen, gamete handling, standard insemination and ICSI were as previously described (Ng et al., 2000). In short, they were pretreated with Buserelin (Suprecur, Hoechst, Frankfurt, Germany) nasal spray, 150 µg, four times a day from the mid-luteal phase of the cycle preceding the treatment cycle. HMG (Pergonal, Serono, Geneva, Switzerland) was started at 300 IU for the first 2 days followed by 150 IU daily afterwards. Patients usually received a higher dosage of HMG (600 IU for the first 2 days followed by 300 IU daily afterwards) if they were >40 years or Day 2 FSH was >10 IU/l. The ovarian response was monitored by serial transvaginal scanning after 7 days of stimulation, and the HMG dosage would be increased in patients receiving the lower dosage protocol if there was no follicle 10 mm after 7 days of stimulation. During the study period, TUGOR was performed even when there was only one dominant follicle. HCG (Profasi, Serono, Geneva, Switzerland) of 10,000 IU was given intramuscularly to trigger final maturation of oocytes. E2 was checked on the day of HCG.
All Doppler ultrasound examinations were carried out by an experienced operator (E.H.Y.N) using a 6.5 MHz vaginal probe (Aloka, Model SSD-5500; Aloka, Tokyo, Japan) with the same ultrasound setting at around 9 a.m. in poor responders after emptying the bladder, on the day of TUGOR before the procedure. The vascularity of each follicle was subjectively graded using power Doppler imaging, according to the grading system by Chui et al. (1997), i.e. Grade 1: <25% of the circumference; Grade 2: 26–50%; Grade 3: 51–75% and Grade 4: >75%. Grades 1 and 2 were considered as low-grade vascularity, whereas Grades 3 and 4 were high grade. Flow velocity waveforms were then obtained from the ascending main branch of the uterine artery on the right and left side of the cervix in a longitudinal plane before it entered the uterus. The ‘gate’ of the Doppler was positioned when the vessel with good colour signals was identified on the screen. The pulsatility index (PI) and resistance index (RI) of the uterine arteries were calculated electronically when three similar, consecutive waveforms of good quality were obtained. As no significant differences in the Doppler velocimetry indices between the left and right side of uterine vessels were obtained, the data were combined, and the average value of both vessels was used. The intra-observer coefficient of variation (CV) is 9.6% for PI and 4.1% for RI.
TUGOR was scheduled 36 h after the HCG injection and was performed using a 16 gauge double-channel needle (Cook® IVF, Cook, Australia) under ultrasound guidance with a 5 MHz vaginal probe fitted with a needle guide. The double-channel needle allowed aspiration and flushing of follicles >10 mm on both sides. The follicle with the highest grade perifollicular vascularity was first aspirated. Follicular fluid of the first follicle uncontaminated with blood was collected and frozen at –20°C until the measurement of E2, progesterone, HCG, vascular endothelial growth factor (VEGF) and inhibin B. Blood was taken for serum HCG after TUGOR. Patients were advised to have two embryos replaced into the uterine cavity 48 h after TUGOR but replacing three embryos was allowed. Excess good quality embryos were frozen. Luteal phase was supported by two doses of HCG. A urine pregnancy test was done 16 days after embryo transfer. If it was positive, ultrasound examination was performed 10–14 days later to confirm intrauterine pregnancy and to determine the number of gestational sacs present.
FSH, E2, progesterone and HCG concentrations were measured using commercially available kits (Automated Chemiluminescence System, Bay Corporation, Tarrytown, NY, USA). The inter- and intra-assay CVs for FSH were 2.8% and 1.7%, respectively. The intra- and inter-assay CVs for E2 were 8.1% and 8.7%, respectively. The intra- and inter-assay CVs for progesterone were 5.0% and 7.8%, respectively. The intra- and inter-assay CVs for HCG were 1.8% and 4.9%, respectively. Follicular fluid VEGF165 concentration was measured by a quantitative sandwich enzyme immunoassay technique (Quantikine®, R & D Systems, Oxon, UK). The minimum detectable VEGF concentration by the assay was 9.0 pg/ml. The inter-assay CVs were 8.8%, 7.0%, and 6.2% at the concentrations of 65, 250, and 1,003 pg/ml, respectively, whereas the intra-assay CVs were 6.7%, 4.5%, and 5.1% at the concentrations of 54, 235, and 910 pg/ml, respectively. Follicular fluid inhibin B was measured by a two-site enzyme-linked immunoassay (Serotec, Kidlington, Oxford, UK), and the inter- and intra-assay CVs were <7%.
Statistical analysis
Patients who had all follicles with low-grade vascularity were classified as Group A, whereas those with at least one follicle with high-grade vascularity were Group B. Retrieval rate was defined as the proportion of punctured follicles that contained an oocyte and fertilization rate was the proportion of oocytes resulting in two pronuclei formation. Only clinical pregnancies defined by the presence of one or more gestation sacs or the histological confirmation of gestational product in miscarriages were considered. Implantation rate was the proportion of embryos transferred resulting in an intrauterine gestational sac. Miscarriage was the loss of an intrauterine pregnancy before 24 completed weeks of gestation.
The primary outcome measures were implantation, clinical pregnancy and live birth rates. Secondary outcome measures included follicular fluid to serum HCG ratio and follicular fluid concentrations of E2, progesterone, VEGF and inhibin B. Continuous variables were not normally distributed and were given as median (range), unless indicated. Statistical tests were carried out by Mann–Whitney U tests, chi-square tests and Fisher’s exact tests, whenever these were appropriate. Multiple logistic regression analysis was applied to determine the best predictive variables for clinical pregnancy and live birth. The correlation was assessed by using the Spearman rank method. Statistical analysis was performed using the Statistical Program for Social Sciences (SPSS Inc., Version 12.0, Chicago, IL, USA). The two-tailed value of P < 0.05 was considered statistically significant.
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Results |
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A total of 58 consecutive patients were recruited from January 2000 to December 2002: 38 in Group A and 20 in Group B. Age of women, body mass index, the proportion with primary infertility, the duration of infertility, basal serum FSH concentration, causes of infertility and the proportion having ICSI were comparable for Groups A and B (Table I). Patients in Groups A required significantly higher HMG dosage than those in Group B (P < 0.05). Groups A and B had similar HMG duration, number of follicles, serum E2 on the day of HCG, uterine PI, uterine RI, number of oocytes obtained, number of oocytes fertilized and number of embryos frozen, as well as the retrieval and fertilization rates (Table II).
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No egg was obtained in two (2/38; 5.3%) patients in Group A, whereas TUGOR was successful in all cycles in Group B (P = 0.548; Fisher’s exact tests). Failed fertilization was encountered in another two cycles in Group A and one cycle in Group B. Similar number of embryos was replaced in Groups A and B, giving rise to similar clinical pregnancy and implantation rates (Table III). Multiple pregnancy and live birth rates appeared higher and miscarriage rate lower in Group B than Group A, but the difference did not reach statistical significance. None of the patients in Group B had three follicles with high-grade vascularity, whereas 12 (60.0%) and 8 (40.0%) patients had one and two follicles with high-grade vascularity, respectively. There were no significant differences in the clinical pregnancy and live birth rates between patients having one and two follicles with high-grade vascularity (Figure 1) although those having one follicle with high-grade vascularity appeared to have higher rates.
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When age of women, basal serum FSH concentration, serum E2 concentration, number of embryos replaced, the absence or presence of high-grade vascularity and the number follicles with high-grade vascularity were entered in a conditional forward fashion in the multiple logistic regression analysis, only the age of women significantly reduced the chance of a clinical pregnancy with an odds ratio of 0.80 [95% confidence interval (CI) = 0.65–0.99; P = 0.037]. Similarly, the age of women was the only predictive factor for a live birth in the multiple logistic regression analysis with an odds ratio of 0.79 (95% CI = 0.63–0.99; P = 0.046).
Follicular fluid was collected in 35 patients in Group A and in 17 patients in Group B. The follicular fluid to serum HCG ratio and follicular fluid concentrations of E2, progesterone, VEGF and inhibin B was similar between Groups A and B (Table IV). Follicular fluid VEGF concentration was positively correlated with follicular fluid progesterone concentration (r = 0.358; P = 0.009) and negatively correlated with follicular fluid to serum HCG ratio (r = –0.372; P = 0.007).
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Discussion |
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To the best of knowledge, this is the first study in the literature evaluating the significance of perifollicular vascularity in poor responders during IVF treatment with regard to implantation, clinical pregnancy and live birth rates. The overall clinical pregnancy and live birth rates were 24.1% (14/58) and 15.5% (9/58). There was no significant difference in the clinical pregnancy rate among poor responders with and without high-grade perifollicular vascularity. Implantation and live birth rates seemed to be lower in patients without high-grade perifollicular vascularity than those with high-grade vascularity, but the difference did not reach statistical significance. The follicular fluid to serum HCG ratio and follicular fluid concentrations of E2, progesterone, VEGF and inhibin B was also comparable for the two groups.
To avoid confounding variables, our patients were in their first IVF cycle and received a standard long protocol of pituitary down-regulation. Follicular fluid hormonal concentrations may be different between long and short protocols of pituitary down-regulation (Bo-Abbas et al., 2001). We defined poor responders as patients who developed 3 dominant follicles of 16 mm in diameter after ovarian stimulation. There is still no universally accepted definition for poor responders. The number of developed follicles and/or number of oocyte aspirated are two of the most important criteria for defining ovarian response (Tarlatzis et al., 2003). Various threshold values have been used in the literature, ranging from <3 to <5 for dominant follicles on the day of HCG (Serafini et al., 1988; Jenkins et al., 1991; Land et al., 1996; Fridstrom et al., 1997; Raga et al., 1999) or for retrieved oocytes (Chong et al., 1986; Rombauts et al., 1998; Surrey et al., 1998). A maximum E2 concentration of <300–500 pg/ml has been used to define poor responders (Garcia et al., 1983; Brzyski et al., 1988; Raga et al., 1999). However, the measurement of E2 is assay dependent and subject to large inter-laboratory variations. Some patients in this study had unexpectedly high serum E2 concentration on the day of HCG as they had at most three dominant follicles. This may be explained by the prolongation of the ovarian stimulation in these patients to achieve three dominant follicles.
Poor responders were reported in 9–24% of stimulated cycles (Keay et al., 1997). The management of poor ovarian responders has been extensively reviewed (Keay et al., 1997; Karande and Gleicher, 1999; Fasouliotis et al., 2000; Surrey and Schoolcraft, 2000; Mahutte and Arici, 2002; Tarlatzis et al., 2003) but remains a great challenge in assisted reproduction. Different stimulation regimens have been tried in poor responders with an attempt to improve the ovarian response or pregnancy rate, but their efficacy remains unproven or appears very limited (Fasouliotis et al., 2000; Surrey and Schoolcraft, 2000). Although a better ovarian response may not be achieved in the next cycle, patients who develop <3 dominant follicles are generally advised against TUGOR in many IVF programs. The concerns of the continuation of treatment are the known risk of retrieving no oocytes with the associated economic and psychological consequences and poor pregnancy rate. These cycles are then cancelled or converted to intrauterine insemination, which is not indicated in many patients with tubo-peritoneal factors and is associated with low success rates in poor responders (Abusheikha et al., 2001). The continuation of IVF treatment may be a better alternative in these poor responders than cycle cancellation or intrauterine insemination in view of similar pregnancy rate in both poor and normal responders (Lashen et al., 1999; Biljan et al., 2000). Our results revealed that clinical pregnancy and live birth rates were 24.1% and 15.5%, respectively.
Poor responders with and without high-grade perifollicular vascularity were comparable with regard to age of women, basal serum FSH concentration, ovarian response and uterine Doppler flow indices although patients with high-grade perifollicular vascularity required significantly lesser amount of HMG. The two groups had similar retrieval and fertilization rates. No significant difference was demonstrated in the percentage of no oocytes aspirated among poor responders without high-grade vascularity (2/38, 5.3%) and those with high-grade vascularity (0%). Our results were different from others (Nargund et al., 1996; Oyesanya et al., 1996; Bhal et al., 1999), who found lower retrieval or fertilization rates in follicles without high-grade vascularity. There were no significant differences in the implantation, clinical pregnancy and live birth rate among poor responders with and without high-grade perifollicular vascularity. The outcomes were again comparable for patients with one and two follicles with high-grade vascularity. The age of women was the only predictive factor in the multiple logistic regression analysis. The absence or the presence of high-grade vascularity nor the number follicles with high-grade vascularity was predictive of the successful outcomes. Therefore, it is worthwhile to proceed to TUGOR in those poor responders having all follicles with low-grade vascularity.
Patients without high-grade perifollicular vascularity seemed to have lesser multiple pregnancies and more miscarriages than those with high-grade perifollicular vascularity, but the number of subjects was too small to draw a firm conclusion. Follicular hypoxia reflected by impaired perifollicular vascularity can lead to reduced levels of metabolism and lower intracellular pH, which in turn could influence the organization and stability of the meiotic metaphase spindle (Van Blerkom et al., 1997). This may possibly explain a higher miscarriage in patients without high-grade perifollicular vascularity.
One of the limitations of this study is the small sample size, which may lead to non-significant findings. However, the sample size required would be 720 embryos or 498 patients in each arm to give a test of significance of 0.05 and a power of 0.8 (Sigmastat, Jandel Scientific, San Rafael, CA, USA) to demonstrate significant difference in implantation or live birth rates. The intra-observer vascularity variation was not assessed in this study because of difficulty in identifying the exact position of the follicles on scanning, but the inter-observer variation was found to be low (Bhal et al., 1999). We did not measure the Doppler flow indices of intra-ovarian vessels as they were not predictive of pregnancy (Chui et al., 1997). Our results contradicted with that of Bhal et al. (1999). They studied perifollicular vascularity of normal responders following different stimulation protocols (ultrashort, short and long) and transferred embryos based on both morphological grading of embryos and perifollicular vascularity. It was shown that follicles with high-grade vascularity were associated with higher oocyte retrieval, fertilization and pregnancy rates in IVF treatment. Although perifollicular vascularity may provide another means to select embryos for transfer with highest implantation potential, the moderate predictive power (sensitivity and specificity of 60–70%) may limit its clinical applicability (Huey et al., 1999). In this study, only morphological grading was employed to select good quality embryos for transfer, and the embryologists were blind to the results of follicular vascularity assessment.
Follicular fluid concentrations of various hormones have been extensively studied as follicular fluid represents a functional compartment that integrates endocrine, immunological and mitogenic signalling of an ovarian follicle. VEGF is a diffusible endothelia cell mitogen with potent angiogenic properties (Ferrara and Henzel, 1989; Gospodarowicz et al., 1989) and is one of the key factors regulating angiogenesis in the ovary during the cyclic growth of ovarian follicles and corpus luteum development (Abulafia and Sherer, 2000; Geva and Jaffe, 2000). We did not demonstrate any difference in follicular fluid VEGF concentration among poor responders with and without high-grade vascularity. Therefore, the difference in perifollicular vascularity could not be explained by follicular fluid VEGF concentration. Other angiogenic factors such as nitric oxide may be involved in the regulation of angiogenesis but were not measured in this study. Follicular fluid concentrations of E2, progesterone and inhibin B were similar for patients with and without high-grade perifollicular vascularity although follicular fluid inhibin B has been shown to be a useful marker of follicular development and embryo quality (Chang et al., 2002). We did not attempt to compare follicular fluid hormonal concentrations among pregnant and non-pregnant patients, because follicular fluid was obtained from the first follicle only.
Ovarian blood flow was not measured in this study as two-dimensional Doppler ultrasonography was limited by the subjective selection of the plane of measurement, low sensitivity, angle-dependency and susceptibility to aliasing (Rubin et al., 1994). Follicular fluid to serum HCG ratio was used as a reflection of gonadotrophin diffusion, which gave an indirect assessment of ovarian blood flow (Nagata et al., 1998). Follicular fluid VEGF concentration was negatively correlated with follicular fluid to serum HCG ratio. That means a lower follicular fluid to serum HCG ratio will increase follicular fluid VEGF production, probably as a result of reduced ovarian blood flow. Progesterone may play a role in determining VEGF concentration in the follicular fluid (Moncayo et al., 1998). This explains a positive correlation between follicular fluid VEGF and progesterone concentrations. There was no correlation of follicular fluid VEGF concentration with age of patients, basal FSH concentration, HMG dosage and ovarian response. This finding is in contrast with normal responders who showed a correlation of follicular fluid VEGF concentration with age of patients (Friedman et al., 1997; Manau et al., 2000), the amount of gonadotrophin used (Manau et al., 2000; Benifla et al., 2001) and the number of follicles and oocytes (Ocal et al., 2004).
In conclusion, our results indicated that clinical pregnancy and live birth rates were 24.1% and 15.5%, respectively, in poor responders who developed 3 dominant follicles during ovarian stimulation for IVF treatment. There were no significant differences in the implantation, clinical pregnancy and live birth rate among poor responders with and without high-grade perifollicular vascularity.
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Acknowledgements |
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This study was supported by grants from the Committee on Research and Conference Grants, The University of Hong Kong.
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Submitted on August 29, 2005; resubmitted on December 10, 2005; accepted on January 11, 2006.
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