Hum. Reprod. Advance Access originally published online on December 19, 2006
Human Reproduction 2007 22(4):1095-1099; doi:10.1093/humrep/del472
The 3D vascular status of the follicle after HCG administration is qualitatively rather than quantitatively associated with its reproductive competence
1 Department of Obstetrics and Gynecology and Reproductive Medicine 2 Department of Biology and Genetics of Reproduction, INSERM Unit 782, Clamart, Université Paris XI, Le Kremlin-Bicêtre, France
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology and Reproductive Medicine, Hôpital Antoine Béclère, 157, rue de la Porte de Trivaux, 92141 Clamart, France. E-mail: renato.fanchin{at}abc.aphp.fr
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Abstract |
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BACKGROUND: The objective of this study was to determine whether the vascular status of a single pre-ovulatory follicle is associated quantitatively and/or qualitatively with its reproductive competence.
METHODS: We studied 61 monofollicular IVF-embryo transfer cycles. Just before single oocyte retrieval, follicle vascularization was detected by transvaginal power-Doppler, 3-dimensionally reconstructed, and analysed quantitatively by coloured/gray voxel ratio [vascularization index (VI)] and qualitatively by blood cell displacement [flow index (FI)] calculation. Cycles were sorted in two sets of two groups: low VI (
8%, n = 44) and high VI (>8%, n = 17); low FI (30, n = 22) and high FI (>30, n = 39).
RESULTS: Patients' characteristics, fertilization rates, and embryo morphology were comparable in all groups. In contrast, clinical pregnancy rates/oocyte retrieval (4% versus 33%, P < 0.009) and implantation rates (11% versus 50%, P < 0.04) were markedly poorer in the low as compared to the high FI groups, respectively, but remained similar between the low and the high VI groups (22% versus 23% and 38% versus 44%, respectively).
CONCLUSIONS: A qualitative (FI) rather than quantitative (VI) relationship exists between vascular status and functional quality of the follicle after HCG administration.
Key words: blood flow/embryo implantation/follicular vascularization/power Doppler
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Introduction |
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During the menstrual cycle, LH-driven luteinization is marked by a profound increase in the vascularization of the pre-ovulatory follicle (Bourne et al., 1991
; Collins et al., 1991; Campbell et al., 1993; Janson, 1975; Neulen et al., 1995; Brannstrom et al., 1998; Wulff et al., 2001; Phan et al., 2006). Throughout this process, some granulosa cell-derived products are likely to promote (vascular endothelial growth factor, fibroblast growth factor and angiopoietins) (Gruemmer et al., 2005) or inhibit (acid hyaluronic and 2-methoxyestradiol) (Hazzard et al., 1999; Koga et al., 2000) blood vessel outgrowth from the thecal vascular plexus towards the inner compartments of the corpus luteum. This suggests that granulosa cells play an important role in the recruitment of blood vessels into the early corpus luteum (Redmer et al., 1991; Zheng et al., 1993; Redmer and Reynolds, 1996), which implies that luteinized follicle vascularization, granulosa cell activity and possibly oocyte competence may be interrelated events (Picton et al., 1998). In addition, it is possible that the vascularization status of ovarian follicles influences their reproductive competence by regulating oxygen supply to the oocytes (Gaulden, 1992; Van Blerkom et al., 1997).
During the last 15 years, numerous studies using bi-dimensional Doppler technologies attempted to non-invasively confirm the possible relationship between vascularization and reproductive competence of ovarian follicles. Most of them concurred to show a positive association between follicle vascularization and ovarian responsiveness to controlled ovarian stimulation (Zaidi et al., 1996; Bassil et al., 1997; Engmann et al., 1999), oocyte retrieval rate (Nargund et al., 1996a,b; Oyesanya et al., 1996; Engmann et al., 1999) or embryo morphology (Nargund et al., 1996a,b; Van Blerkom et al., 1997; Huey et al., 1999).
Moreover, the issue of whether follicular vascularization is associated (Nargund et al., 1996a,b; Chui et al., 1997; Bhal et al., 1999; Coulam et al., 1999; Engmann et al., 1999) or not (Tekay et al., 1995; Kan et al., 2006; Palomba et al., 2006; Ng et al., 2006) with embryo implantation remains controversial. The lack of concordance among published data may be, at least in part, attributed to methodological limitations such as subjectivity and insufficiency of measurements, lack of direct traceability between follicle vascularization and the fate of oocyte and embryos, and disregard of blood flow dynamics in favour of merely quantitative information.
Hence, in the present study, we used an original model that allows the precise tracking of the oocyte–embryo fate to verify whether a quantitative and/or qualitative relationship exists between the vascular status of the luteinized dominant follicle, objectively assessed in the whole follicle wall, and its reproductive competence.
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Materials and methods |
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Patients
We prospectively studied 61 infertile women, 24–40 years of age, undergoing 61 consecutive IVF-embryo transfer (IVF-ET) in mono-dominant follicle cycles from July 2005 to December 2005. All women met the following inclusion criteria: (i) both ovaries present and devoid of morphological abnormalities; (ii) regular menstrual cycles between 25 and 35 days; (iii) no current or past diseases affecting the ovaries or gonadotrophin or sex steroid secretion, clearance or excretion; (iv) no clinical signs of hyperandrogenism; (v) body mass indexes (BMIs) ranging from 18 to 25 kg m–2; (vi) no current hormone therapy; (vii) adequate visualization of both ovaries in transvaginal ultrasound scans; and (viii) no smoking. Aetiologies of infertility were sperm abnormalities (45.9%), tubal abnormalities (24.6%), unexplained infertility (24.6%) and endometriosis (4.9%). An informed consent was obtained from all patients and this investigation received the approval of our internal Institutional Review Board.
IVF-ET protocol
On cycle day 3, women underwent blood samplings by venipuncture at approximately 9 AM for serum estradiol (E2), progesterone and LH measurements. Later in the morning, the number and the sizes of early antral follicles were assessed by ultrasound equipped with a tissue harmonic imaging system (Thomas and Rubin, 1998). From cycle day 8 onward, the selection of the dominant follicle was monitored by ultrasound. When its mean diameter exceeded 12 mm, to prevent the risk of premature LH peak and to control further follicular maturation, women were administered s.c. 0.5 mg of a GnRH antagonist (cetrorelix acetate; Cetrotide 0.25 mg, Serono Pharmaceuticals, Boulogne, France) and 150 IU of HMG (Menopur, Ferring Pharmaceuticals, Gentilly, France) daily until the day of HCG (Gonadotrophine Chorionique "Endo", Organon Pharmaceuticals, Saint-Denis, France) administration. Women received a 5000-IU HCG injection i.m. when the dominant follicle diameter exceeded 16 mm.
The oocyte was retrieved approximately 34 h after HCG administration. Under transvaginal ultrasound guidance, the follicular fluid from the single pre-ovulatory follicle was aspirated using a 10-ml syringe. The aspiration needle was kept steady inside the follicle until the oocyte was found and isolated. In case of negative oocyte recovery, sequential follicular flushings were performed using 10-ml syringes filled with 3 ml of a balanced salt solution (Tyrode's salt solution, Eurobio Pharmaceuticals, Courtaboeuf, France). Oocyte retrieval failure was defined by a negative oocyte recovery after three consecutive follicular flushings. Top quality embryo was defined on Day 2 as those having no multinucleated blastomeres, four or five blastomeres and <20% anucleated fragments (Van Royen et al., 1999). Embryo transfer was performed 2 days after oocyte retrieval. Luteal phase was supported with micronized progesterone (Estima Gé, Effik Pharmaceuticals, Bièvres, France, 600 mg day–1) administered daily by vaginal route starting on the evening of ET.
Follicular vascularization assessment
Just before oocyte retrieval at approximately 9:30 AM, vascularization status of the pre-ovulatory follicle was assessed by transvaginal power Doppler using a 3.7–9.3 MHz ultrasound probe (RIC5-9H, General Electric Medical Systems, Paris, France) equipped with a 146°-angle rotating head that allowed data acquisition for further 3-dimensional (3D) reconstruction. Patients were first examined with a B-mode ultrasound to identify the maximal follicular diameter and to rule out the interference of extra-ovarian organs that could hinder adequate image quality. Data acquisition was then performed according to similar, pre-established 3D power Doppler settings: (i) high tissue harmonic frequency; (ii) colour gain at –4; (iii) zoom at 1.3 fold; (iv) wall motion filter at 2 and (v) pulse repetition frequency at 0.6 kHz. To reduce acquisition time, the swept volume was reduced to an angle of 60°, in which the total follicle was included.
Afterwards, the pre-ovulatory follicle was entirely 3D-reconstructed offline using a virtual organ computer aided analysis (VOCAL) technology (General Electric Medical Systems, Paris, France). For this, the region of interest (ROI) in the 3D volume, which corresponded to the outer follicle borders, was manually and progressively (every 15°) set. Subsequently, follicle vascularization was assessed quantitatively and qualitatively in the ROI. For quantitative assessment, we used the vascularization index (VI) that is calculated by the colour voxels/(total voxels–background voxels) ratio. The VI reflects the number of vessels in the follicle as a percentage of the total 3D volume. For the qualitative assessment, we used the flow index (FI), a parameter that assesses blood cell displacement and reflects the mean intensity of colour voxels in a scale going from 0 (minimum intensity) to 100 (maximum intensity) (Pairleitner et al., 1999). All ultrasound scans and vascularization analysis were performed by a single operator (D.H.M.L.), who was unaware of oocyte retrieval outcome and IVF-ET results. Intraobserver reproducibility of VI and FI, measurements, assessed by the intraclass correlation coefficients (ICCs), were 0.89 and 0.82 for VI and FI, respectively, thereby confirming data from other investigators (Jarvela et al., 2003; Merce et al., 2005). In addition, an accessory parameter of follicle vascularization (vascularization–flow index) that expresses a combination of quantitative and qualitative information on the follicular vascular status was also investigated.
Definition of follicle vascularization groups
Cycles were sorted into two sets of two groups according to VI (quantitative index) and FI (qualitative index) values, based on the best likelihood ratio provided by receiver operating characteristic (ROC) analysis. Therefore, the low VI group included cycles in which VI values remained 8% (n = 44) and the high VI group included those in which they were >8% (n = 17), whereas the low FI group comprised cycles in which FI values were 30 (n = 22) and the high FI group included those in which FI remained >30 (n = 39).
Hormonal measurements
Serum E2 and progesterone levels were determined by an automated multi-analysis system using a chemiluminescence technique (Advia-Centaur, Bayer Diagnostics, Puteaux, France). For E2, lower detection limit was 15 pg ml–1, linearity up to 1000 pg ml–1, and intra- and inter-assay coefficients of variation (CVs) were 8% and 9%, respectively. For progesterone, lower detection limit was 0.1 ng ml–1, linearity up to 60 ng ml–1, and intra- and inter-assay CVs were 8% and 9%, respectively. Serum LH levels were measured by an immunometric technique using an Amerlite kit (Ortho Clinical Diagnostics, Strasbourg, France). Lower limit of detection was 0.1 mIU ml–1 and intra- and inter-assay CVs were 5% and 7%, respectively, for LH.
Statistical analysis
The measures of central tendency and variability were, respectively, the mean and SEM when data distribution was normal, and the median and the ranges when normality could not be ascertained. Normality distribution of the data was assessed with the Kolmogorov–Smirnov test. Unpaired data were compared with the unpaired Student's t-test or the Mann–Whitney test, when appropriate. Relationship between two continuous variables was assessed by correlation when they were independent from each other and by simple regression when there was a dependency relationship. The Spearman's test was used to determine if coefficients of correlation (r) were significantly different from zero. The chi-square and Fisher's exact test were used to compare categorical variables. As mentioned before, the reproducibility of measurements was evaluated by the ICC. To characterize the predictability of follicle vascularization, we employed relative risk (RR) and its 95% confidence intervals (CIs) calculation as well as logistic regression analysis (to exclude explicative variables) and ROC analysis. The present study was powered to detect anticipated differences of 25% in embryo implantation rates at >80% power at 0.05 significance level. A P-value of <0.05 indicated statistically significant differences.
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Patients' characteristics and cycle monitoring data
Patients' characteristics and cycle monitoring data in the low and high VI and FI groups are detailed in Table I. As shown, ages of patients, BMI values, menstrual cycle lengths, antral follicle counts on Day 3 were comparable within each set of follicle vascularization groups. Aetiologies of infertility were also similar in both sets of follicle vascularization groups. Similarly, the day of HCG administration and pre-ovulatory follicle size, endometrial thickness and serum E2, progesterone and LH levels of the day of HCG were not statistically different between low and high VI cycles and low and high FI cycles.
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Overall, in the 61 IVF-ET cycles studied, mean VI values were at 7.8 ± 0.6% and varied from 0.7% to 32.3% whereas mean FI values were 33.4 ± 0.8 and varied from 17.4 to 48.7. We observed a positive correlation between VI and FI values (r = 0.48; P <0.0001). In line with data described in Table I, continuous statistical analysis failed to show any significant relationship between VI or FI values and patients' characteristics or cycle monitoring data.
Embryology and IVF-ET outcome data
Embryology data and IVF-ET outcome data are summarized in Table II. Both sets of groups remained similar with regard to positive oocyte retrieval rate, fertilization rates and prevalence of top quality embryos. Yet, whereas clinical pregnancy (gestational sac observed at ultrasound scans at around 7 weeks of amenorrhoea) rates/oocyte retrieval and the implantation rates (total number of gestational sacs x 100/total number of embryos transferred) were similar in the low and the high VI groups, they were higher in the high FI as compared to the low FI groups (P = 0.009).
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In line with this, logistic regression analysis indicated that only FI values (P <0.01; 95% CIs, 1.02–1.31) were predictive of clinical pregnancy, in contrast with patient's ages (P = 0.47; 0.75–1.14), BMIs (P = 0.55; 0.66–1.24), the day of HCG administration (P = 0.54; 0.80–1.50), serum E2, progesterone and LH levels on the day of HCG administration (P = 0.29; 0.98–1.00; P = 0.25; 0.18–605.90 and P = 0.33; 0.64–1.15, respectively), follicular size on the day of HCG administration (P = 0.56; 0.36–1.72), and VI values (P = 0.84; 0.68–1.02).
Also, VI could not adequately discriminate the likelihood of a clinical pregnancy as the area under the ROC curve was 0.56 (P = 0.45; 95% CIs, 0.39–0.74). Conversely, FI values showed good predictability as the area under the ROC curve was 0.71 (P <0.01; 95% CIs, 0.57–0.85). Indeed, the best likelihood ratio for FI was 6.8 with a rounded cutoff value of 30 which corresponds to a sensitivity of 48.9 (95% CIs, 34.1–63.9%) and a specificity of 92.9 (95% CIs, 66.1–99.8%).
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Discussion |
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The present study aimed at evaluating the possible relationship between vascularization of the pre-ovulatory follicle and its reproductive competence. For this, its design required the following methodological characteristics. First, we included IVF-ET candidates undergoing single pre-ovulatory follicle cycles to properly track the link between the originating follicle and oocyte/embryo outcome. Second, we elected to assess, by a single operator, vascularization on the entire follicle using automated 3D reconstruction and sensitive power Doppler technology, in an improved methodology as compared to previous studies, which were limited to the assessment of random vessels around the follicle (Tekay et al., 1995
; Nargund et al., 1996a; Chui et al., 1997; Palomba et al., 2006). Third, we employed an expert computerized system (VOCAL) that allows the distinct analysis of quantitative and qualitative aspects (Pairleitner et al., 1999) of follicle vascularization. Even when the RR for FI are high, 7.3 for clinical pregnancy (P < 0.001) and 4.5 for implantation rate (P < 0.04), a larger study must confirm these data. The results of our investigation indicated that the vascular status of the pre-ovulatory follicle is qualitatively (FI) but not quantitatively (VI) related to the implantation outcome of the corresponding embryo.
The mechanisms underlying this relationship remain unclear. Despite the fact that VI and FI values were significantly correlated, it is conceivable that HCG-driven angiogenesis is not systematically associated with an increase of the blood flow through the follicular wall, as far as it may be reflected by FI values. According to this hypothesis, it is the blood flow dynamics rather than the vascularized extension of the follicle wall that plays a determining role in the reproductive competence of the follicle. Indeed, functional defects of follicle perfusion have been shown to alter the organization and stability of the metaphase spindle through the reduction of the oxygen supply to the oocytes (Gaulden, 1992; Van Blerkom et al., 1997), a phenomenon that possibly exerts a detrimental role in the embryo aptitude to implantation. Furthermore, growing evidence indicates that, in pre-ovulatory follicles, the oocyte directly activates several physiological processes that occur in its surrounding granulosa cells, including plasminogen activator production (Canipari et al., 1995), and LH receptor (Joyce et al., 1999), kit ligand (Joyce et al., 1999) and anti-Mullerian hormone (Salmon et al., 2004) gene expression. Therefore, by extrapolation, we hypothesize that poor quality oocytes are unable to drive some functional vascular modifications that the pre-ovulatory follicle has to undergo before ovulation. Finally, it is noteworthy that oocyte retrieval failure rate, a parameter shown to be increased in women with follicle quality defects (Zreik et al., 2000), as well as oocyte fertilization rate and embryo morphology, remained unchanged irrespective of VI or FI values. This suggests that follicle vascularization plays a determining role in the outcome of late rather than early functions of the oocyte, such as adequate embryo genome activation, an event that takes place after the third cycle of blastomere division (Braude et al., 1988).
In conclusion, the enhanced aptitude for implantation of embryos originated from follicles presenting high FI values suggests that a close relationship exists between perifollicular blood flow dynamics and reproductive competence of luteinized pre-ovulatory follicles. Further, this phenomenon apparently is independent of oocyte fertilizability and embryo morphology. The mere quantitative identification of perifollicular blood vessels (VI) probably is a much less sensitive predictor of follicle reproductive competence than the assessment of blood flow dynamics (FI) in the whole follicle wall. These results encourage us to conduct further studies on the administration of vasodilators and/or cardio-tonics in an effort to improve follicle vascularization and, possibly, oocyte quality. Yet, the issue of whether or not the present data could be extrapolated to controlled ovarian hyperstimulated cycles deserves further investigation. If extrapolation was valid, the possibility of preferentially selecting to transfer embryos ensuing from follicles displaying high FI values may be a logical measure to improve their implantation rates and should also be the matter of additional investigation.
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Submitted on July 27, 2006; resubmitted on November 8, 2006; accepted on November 16, 2006.
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