Hum. Reprod. Advance Access published online on May 2, 2008
Human Reproduction, doi:10.1093/humrep/den128
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Quantification of the effect of pituitary down-regulation on 3D ultrasound predictors of ovarian response
Nottingham University Research and Treatment Unit in Reproduction (NURTURE), Academic Division of Reproductive Medicine and Surgery, School of Human Development, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
1 Correspondence address. Tel: +44-115-823-0700; Fax: +44-115-823-0651; E-mail: k.jayaprakasan{at}nottingham.ac.uk, jayaprakasan{at}hotmail.co.uk
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Abstract |
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BACKGROUND: This study evaluated the effect of pituitary desensitization on ovarian volume, antral follicle count (AFC), and ovarian blood flow indices and their value as predictors of ovarian response during assisted reproduction treatment.
METHODS: A total of 115 subjects aged <40 years with follicle-stimulating hormone (FSH) levels <12 IU/l underwent transvaginal ultrasound in the early follicular phase of the menstrual cycle and after 14 days of down-regulation using gonadotrophin-releasing hormone agonists. 3D power Doppler was used to quantify ovarian volume, AFC and ovarian blood flow. The relationship between these ultrasound variables and treatment outcome was evaluated using multiple regression analysis.
RESULTS: Although a significant decrease in the ovarian volume (P < 0.05) and flow index (FI; P < 0.01) was demonstrated after pituitary desensitization, no differences were seen in the AFC. The total AFC, regardless of whether this was measured before or after down-regulation, was a significantly better predictor of the number of oocytes retrieved (P < 0.001) and poor ovarian response (P < 0.05) than age, FSH, ovarian volume and vascular indices although pre-treatment ovarian volume (P < 0.05) and FI (P < 0.05) were also predictive of the number of oocytes retrieved.
CONCLUSIONS: Pituitary desensitization results in a significant reduction in ovarian volume and vascularity, but has no effect on the AFC. AFC is the single best predictor of ovarian response regardless of whether the assessment is performed before or after down-regulation.
Key words: in vitro fertilization/antral follicle count/3D power Doppler ultrasound/ovarian reserve/Down-regulation
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Introduction |
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Controlled ovarian stimulation is currently used for conventional in vitro fertilization (IVF) treatment as it promotes the recruitment and development of multiple follicles. This increases the likelihood of obtaining a sufficiently high number of mature, and therefore fertilizable, oocytes for insemination which in turn generally increases the number of good quality embryos thereby allowing selection of the best one or two for transfer (Arslan et al., 2005
). In the conventional ‘long protocol’, it is necessary to obtain control over the hypothalamic–pituitary–ovarian axis through the induction of pituitary ‘down-regulation’ using a continuous and supra-physiological dose of gonadotrophin-releasing hormone (GnRH) agonist (Marcus and Ledger, 2001). This prevents a premature surge in luteinizing hormone (LH), which occurs in up to 23% of cycles when gonadotrophins alone are used and facilitates the timing of oocyte retrieval therefore (Janssens et al., 2000). The use of GnRH agonists in assisted reproduction treatment (ART) has been shown to increase the number of oocytes retrieved, to improve pregnancy rates and to significantly reduce the chance of cancellation (Hughes et al., 1992).
Pre-treatment assessment of ovarian reserve allows prediction of the probable response to ovarian stimulation during ART (Hendriks et al., 2005). In addition to the conventional markers, age and basal follicle-stimulating hormone (FSH) level, a variety of ultrasound parameters including ovarian volume (Syrop et al., 1995), antral follicle number (Tomas et al., 1997), and ovarian stromal blood flow (Zaidi et al., 1996), have been suggested as independent predictors of ovarian reserve. However, the timing of the ultrasound assessment in relation to down-regulation and ovarian stimulation has not been standardized. Although some investigators perform ultrasound in the early follicular phase of a menstrual cycle preceding treatment (Zaidi et al., 1996; Ng et al., 2000), others report assessment prior to the initiation of gonadotrophin stimulation after confirming down-regulation (Lass et al., 1997b; Tomas et al., 1997; Engmann et al., 1999). This variation in the timing of assessment could affect the predictive value of each of the purported ultrasound markers due to the effects of down-regulation on ovarian morphology and vascularity. Although a few studies have reported the effects of down-regulation on the 3D ultrasound predictors of ovarian response (Jarvela et al., 2003a; Yu Ng et al., 2004), none of them have compared the predictive power of each parameter measured before and after down-regulation with regard to ovarian response and IVF outcome.
In this prospective study, we evaluated the effects of pituitary down-regulation, using GnRH agonists as part of a conventional IVF long protocol, on ovarian volume, antral follicle count (AFC) and ovarian stromal vascularity as measured by 3D ultrasound and power Doppler angiography. The predictive values of these ultrasound markers to determine ovarian response and treatment outcome, both before and after down-regulation, were then compared.
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Materials and Methods |
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Experimental design
A total of 130 consecutive subjects aged under 40, with regular menstrual cycles of 21–35 days duration, and an early follicular phase FSH level of less than 12 IU/l, were prospectively recruited. All subjects underwent a 3D transvaginal ultrasound assessment in the early follicular phase (Days 2–4) of the spontaneous menstrual cycle immediately prior to their first cycle of controlled ovarian stimulation as part of ART. The ultrasound examination was repeated following 14 days treatment with a GnRH agonist, given in a continuous fashion to induce pituitary desensitization, commenced in the luteal phase of the same cycle as the incident ultrasound assessment. Subjects were excluded if they had a history of ovarian surgery or if they were found to have an ovarian cyst or follicle measuring 20 mm or more in diameter during any of the two ultrasound assessments. The study was approved by the National Health Service research ethics committee and informed written consent was obtained prior to the enrollment of each subject.
Data acquisition
All subjects had a transvaginal scan performed by one of two investigators (KJ or JC) using a Voluson Expert 730TM (GE Medical Systems, Zipf, Austria) and a 4D 5–9 MHz transvaginal probe. Subjects were scanned with their legs supported by stirrups in a modified Lloyd Davies position to limit discomfort and ensure free manipulation of the transvaginal transducer.
Our technique for the acquisition of 3D volumetric and power Doppler data has been described in detail (Raine-Fenning et al., 2003a,b) but briefly this included an initial 2D ultrasound assessment of the pelvis to exclude any obvious pathology before the application of a region of interest over the ovary which defined the volume to be acquired. An automated mechanical sweep of this region through 90° was then undertaken using the slow sweep mode and the resultant multiplanar display examined to ensure that the entire ovary had been captured. Power Doppler was then applied using predefined settings, which offer the best compromise between small ovarian vessel detection and artefact (Raine-Fenning et al., 2002) and these were kept constant for every patient: pulse repetition frequency 1.0, power 4.0, colour gain 38.4, wall motion filter 75, rise 0.2, persistence 0.8, reject 82 and with the central frequency set to mid. The volume mode was entered once an adequate power Doppler signal had been obtained. The resultant truncated sector defining the area of interest was then moved and adjusted and the sweep angle set to 90° to ensure that a complete ovarian volume was obtained. Every effort was made to avoid movement artefacts by asking the subjects to remain as still as possible and by limiting movements of the transducer by the ultrasonographer. If the acquired volume was complete and considered of sufficient quality, with no power Doppler artefact, the dataset was saved to the hard drive of the ultrasound machine. Two volume acquisitions for each ovary, one with grey scale and the other with power Doppler information, were obtained. The data were subsequently transferred to a personal computer via a digital video disk without any data compression.
Data measurement
All measurements were made on a personal computer using 4D View (version 5.3; GE Medical Systems, Zipf, Austria) by a single investigator (KJ). The investigator was blinded to the subject’s name and age. The interval between assessments of the datasets obtained at the early follicular phase and at 14 days of down-regulation for each subject was at least 2 weeks in order to avoid any recall bias. The 3D grey-scale ovarian volume dataset was initially displayed in the multiplanar view (Fig. 1) and the total number of antral follicles measuring 2–10 mm in diameter was counted as previously described (Jayaprakasan et al., 2007a). Briefly, this involved an initial assessment of the largest follicles, which were assessed in two planes to establish their mean diameter. Follicles measuring more than 10 mm were excluded and the remainder added to calculate the total AFC within the ovary. Virtual Organ Computer-aided AnaLysis (VOCAL®; GE Medical Systems, Zipf, Austria) was used to measure ovarian volume through the delineation of the ovarian cortex in the B (transverse image) plane as the volume was rotated 180° through 9° rotation steps (Raine-Fenning et al., 2003a). Quantification of power Doppler information within the resultant 3D ovarian model was performed using ‘histogram facility’. Three indices of vascularity were generated: the Vascular Index (VI) represents the ratio of power Doppler information within the total dataset relative to both colour and grey information, the FI is proportional to the power Doppler signal intensity and the vascularization FI (VFI) reflects a combination of the two (Raine-Fenning et al., 2004b).
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As the 3D technique has two components, volume acquisition and off-line measurement, the reproducibility of both for the assessment of AFC, ovarian volume and ovarian vascularity, has previously been established (Raine-Fenning et al., 2003a
,b, 2004a; Jayaprakasan et al., 2007b). In this study, two measurements of each variable were made from each dataset and the mean value used for analysis. The mean intraclass correlation coefficient (ICC) and 95% confidence interval (CI) for measurement of the number of antral follicles and ovarian volume were 0.983 (0.968–0.992) and 0.989 (0.960–0.997), respectively, for intra-observer measurements and was indicative of a high degree of reliability. The measurements of vascular indices also showed good intra-observer reliability with mean ICCs (95% CI) of 0.982 (0.974–0.0.991), 0.985 (0.977–0.993) and 0.983 (0.976–0.990) for the VI, FI and VFI, respectively.
Treatment protocol
All subjects underwent conventional IVF treatment using a standard long protocol. This involved down-regulation with GnRH agonists (500 µg/day of Buserelin; Suprefact®, Aventis Pharma, Kent, UK or 800 µg/day of Nafarelin; Synarel®, Pharmacia, Milton Keynes, UK) started in the mid-luteal phase of the menstrual cycle 7 days prior to the expected date of menstruation. Successful ovarian suppression was confirmed 2 weeks later through ultrasound evidence of a thin endometrium, defined as one measuring less than 5 mm at the junction of the upper third and lower two-thirds in the longitudinal plane, absent ovarian activity and a serum estradiol (E2) level below 200 pmol/l. Controlled ovarian stimulation was then commenced using either recombinant FSH (FSH; Gonal-F; Serono Pharmaceuticals Ltd, Feltham, UK) or purified urinary human menopausal gonadotrophin (hMG: menopur, Ferring Pharmaceuticals, Berks, UK). The starting dose used for stimulation was based on the subject’s age (150 IU for women under 30 years of age, 225 IU for women aged between 30 and 38 years and 300 IU for women aged 38 years or more) and adjusted according to the ovarian response which was monitored daily by serial transvaginal ultrasound and serum E2 measurements from the fifth day of stimulation. Human chorionic gonadotrophin (hCG; 6500 IU of Ovitrelle; Serono Pharmaceuticals Ltd, Feltham, UK or 10 000 IU of Pregnyl; Organon Laboratories Ltd, Cambridge, UK) was administered when there were at least three follicles measuring 18 mm or more in diameter and oocyte retrieval performed 36 h later. Subjects who did not develop at least three follicles measuring 18 mm or more in diameter were cancelled or converted to intrauterine insemination treatment dependent on other clinical factors including tubal patency and seminal fluid analysis. A maximum of two normally cleaved embryos were transferred into the uterus 2 days after oocyte retrieval and the level of serum hCG measured 16 days later to determine the outcome. If the test was positive (hCG >50 IU/l), a transvaginal ultrasound was arranged 2 weeks later to confirm the viability of the pregnancy.
Statistical analysis
Statistical analysis was undertaken using the Statistical Package for the Social Sciences (version 14.0; SPSS, Chicago, IL). The distribution of the data was checked for normality using a normal probability plot. The paired t-test for normally distributed data and the Wilcoxon signed rank test for skewed data were used to examine for significant differences in each variable between the assessment made during the early follicular phase and the one made following down-regulation. A P-value of 0.05 or below was considered statistically significant. The correlation between ovarian volume, AFC, and the three vascular indices measured before and after down-regulation and the total number of oocytes retrieved was calculated using the Pearson correlation coefficient. The difference between pairs of correlation coefficients was assessed using Fisher’s z transformation and the significance of any difference determined using the t-statistic. Multiple linear regression analysis with least-squares regression was applied to evaluate the predictive value of age, basal FSH and each ultrasound parameter, measured both before and after down-regulation, on the number of oocytes retrieved. Multiple logistic regression analysis was used to assess the effect of the same variables on the prediction of poor response and non-conception. Receiver operating characteristic (ROC) curve analysis was performed to quantify the ability of the different ultrasound variables to discriminate between poor and normal responders and between pregnant and non-pregnant subjects. Areas under the ROC curves (AUCROC) were compared using the MEDCALC 9.2.0 software package (Hanley and McNeil, 1983).
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Results |
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Out of the 130 subjects recruited five were excluded as they had had ovarian surgery in the past. A further 10 subjects had ovarian follicles or cysts measuring more than 20 mm in diameter during one of the two ultrasound assessments leaving a final study group of 115 subjects for analysis. The final group, with a mean (±SD; range) age of 33.2 (±3.7; 23–39) years, had a mean (±SD; range) early follicular phase FSH level of 7.2 (±1.8; 2.8–11.8) IU/l, a mean (±SD) body mass index of 23.7 (±3.5) kg/m2 and a mean (±SD) duration of infertility of 47.2 (±33.6) months. These subjects had a variety of causative factors for their subfertility including tubal disease (30 subjects; 26%), endometriosis (10 subjects; 9%), male factor (40 subjects; 35%), combined factors (seven subjects; 6%) and unexplained subfertility (28 subjects; 24%). None of them had ovulatory dysfunction or polycystic ovary.
Overall, eight subjects (7%) experienced poor ovarian response as defined by cycle cancellation or the retrieval of less than four oocytes (Bancsi et al., 2002). Five subjects (4.3%) were cancelled for inadequate ovarian response. The mean (±SD) number of oocytes retrieved was 10.5 (±5.2). One subject (0.9%) experienced failed fertilization and two (1.7%) had failed cleavage. The mean (±SD) fertilization rate per treated oocytes was 62.9 ± 22.1%. Embryo transfer was performed in 104 subjects with a mean (±SD) number of 1.92 ± 0.27 embryos and resulted in 55 pregnancies (47.8% per cycles initiated and 52.9% per embryo transfer). Six of these (10.9%) were biochemical pregnancies as there was no evidence of a pregnancy on ultrasound 2 weeks later at 6 weeks gestation. The clinical pregnancy rate was 42.6% per cycles initiated and 47.1% per embryo transfer therefore. Three pregnancies miscarried during the next 6 weeks resulting in an ongoing pregnancy rate, defined as a viable pregnancy on ultrasound at 12 weeks gestation, of 40% per cycles initiated (46/115) and 44.2% per embryo transfer (46/104).
The effects of down-regulation on the ultrasonographic and endocrine parameters are summarized in Table I. Serum FSH, LH and E2 significantly decreased, as expected, following treatment with GnRH agonists for 2 weeks. However, while the down-regulation treatment effected a significant decrease in the mean ovarian volume and in ovarian blood flow as measured by the ovarian FI, no differences were seen in the other 3D ovarian vascular indices (the VI and VFI) or in the number of antral follicles over the same time period.
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The correlation between the follicle count and the number of oocytes retrieved were similar irrespective of whether the measurements were made before (r = 0.448) or after down-regulation (r = 0.476). Similarly, the correlation between all the other ultrasound parameters of ovarian reserve measured before or after down-regulation and the ovarian response was similar.
Multiple linear regression analysis of age, basal FSH and the three ultrasound variables was conducted by defining two models based on the timing of the assessment: pre-treatment and after down-regulation (Table II). The total AFC was the best predictor of the number of oocytes retrieved regardless of whether this was calculated before or after down-regulation. The ovarian volume and mean ovarian FI were predictive in model one in which the measurements were made in the early follicular phase prior to treatment but not in the second model following down-regulation. Neither age nor basal FSH was predictive of the number of oocytes retrieved in either of the two models.
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Multiple logistic regression analysis showed that the AFC, regardless of when it was measured, was also the best predictor of poor ovarian response (Table III). Although age was also a significant predictor in model one in which the measurements were made in the early follicular phase prior to treatment, AFC was the only significant predictor (<0.01) after controlling for age and other variables within the model.
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All the variables were included in the model as all of them are considered to be clinically important. ROC curve analysis showed AFCs measured both prior to treatment and after down-regulation offered a similar discriminative potential to predict poor response (Tables III and IV). The AUCROC for follicle counts performed before and after down-regulation are 0.895 (95% CI: 0.824–0.944) and 0.930 (95% CI: 0.867–0.969), respectively, and are depicted in Fig. 1. None of the parameters tested, including age, basal FSH, AFC, ovarian volume and the 3D vascular indices were predictive of non-conception irrespective of whether the assessment was performed before or after down-regulation (Table V).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionFundingAcknowledgementReferences |
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This is the first study in which the effect of down-regulation on ultrasound predictors of ovarian reserve and the predictive value of these variables measured both before and after down-regulation has been examined and compared. The data in this study indicate that pituitary down-regulation with GnRH analogues results in a significant reduction in ovarian volume and blood flow, as measured by the FI, but has no effect on other 3D vascularity indices or the total number of antral follicles. AFC proved to be the single best predictor of the number of oocytes that will be retrieved at oocyte collection irrespective of the timing of the ultrasound assessments. The value of AFC for the prediction of the number of oocytes retrieved and as a tool to identify poor ovarian response was similar when measurements were made during the early follicular phase prior to treatment and following down-regulation. Ultrasound parameters, either alone or in conjunction with age and basal FSH, were unable to predict non-conception.
Other authors also have shown that the AFC is unaffected by down-regulation (Sharara et al., 1999; Hansen et al., 2003; Yu Ng et al., 2004). As the AFC reflects the remaining primordial follicle population, and basal follicle growth up to the early antral follicle stage is independent of gonadotrophin levels and continues to occur even in prolonged hypogonadotrophic states (Gougeon, 1998), the follicle count is not expected to be affected by 2 weeks of down-regulation. A recent study in which the down-regulation protocol included GnRH agonists used in conjunction with the combined oral contraceptive pill (COCP) reported a significant decrease in the total number of antral follicles (18.3 ± 11.3) compared with the basal state (25.2 ± 13.1) (Frattarelli, 2006). The decrease was apparent after 21 days of treatment (18.1 ± 10.6) and no further change noted after 14 days of GnRH agonist treatment. Although the reason for this apparent adverse effect of priming with the COCP is difficult to explain, a potentially more pronounced FSH suppression associated with the use of the COCP may have induced atresia of the larger, gonadotrophin-dependent antral follicles and a resultant decrease in the total number of antral follicles. However, the study by Frattarelli et al. may have been biased by the reliability of measurements as the mean basal AFC in the study was 25.2, at which both the intercycle variability (Hansen et al., 2003) and inter-observer variability (Scheffer et al., 2003) are very high. To reduce intra-observer variability in this study all ultrasound measurements, including the AFC, were conducted twice and the mean value used for analysis.
The performance of the AFC as a predictor of poor ovarian response was similar both before and after down-regulation with a comparable sensitivity (100%), specificity (81.3%) and post-test probability (31%) at an optimum cut-off value of 9 or 10 follicles. This substantiates that the AFC can be performed either before treatment begins or after down-regulation. However, assessment prior to treatment has an additional advantage in that it provides an opportunity for a pre-treatment evaluation of pelvis to screen for pathology such as a hydrosalpinx, endometrial polyp, uterine anomaly and endometriotic cysts all of which have been shown to have an adverse effect on IVF outcome and are amenable to surgery (Lass et al., 1999; NICE, 2004).
Although the majority of studies have reported the total AFC to be a significant predictor of ovarian response irrespective of the measurement method and timing of the assessment (Tomas et al., 1997; Chang et al., 1998; Bancsi et al., 2002; Hendriks et al., 2005; Jayaprakasan et al., 2007a), the predictive value of ovarian volume (Lass et al., 1997b; Tomas et al., 1997; Hendriks et al., 2007) and vascularity (Zaidi et al., 1996; Ng et al., 2006) has been more controversial. In this study, the mean ovarian FI and ovarian volume measured before down-regulation were significant predictors of the number of oocytes retrieved although these variables were less predictive than the AFC. None of the ovarian parameters measured after down-regulation, apart from the AFC, was predictive of poor ovarian response owing to the changes induced in these variables by the process of down-regulation. The follicle count has been shown to be positively correlated with ovarian volume, in both histological (Lass et al., 1997a) and ultrasonographic (Tomas et al., 1997) studies, and ovarian vascularity, as assessed by 3D power Doppler angiography (Kupesic and Kurjak, 2002). Invariably these studies conclude that, of the three ovarian ultrasound parameters, the AFC is the single most significant predictor of ovarian response. The reported relationship between volume and vascularity may therefore primarily reflect the close relationship of these variables to the total number of antral follicles.
The only other study with a similar design based on 3D ultrasound did not identify any changes in ovarian volume or vascularity following down-regulation despite a significant decrease in estrogen levels in 85 subjects (Yu Ng et al., 2004). This discrepancy may reflect the absolute degree of hypo-estrogenaemia as the estrogen levels fell only by 26% (115.5–86 pmol/l) in the study by Yu Ng et al. in contrast to a more profound 62% fall (159.4–60.61 pmol/l) in our subjects. Moreover, 14 subjects (16%) in the study by Yu Ng et al. had polycystic ovarian disease and demonstrated no change in serum estrogen levels from the basal state to down-regulation. The significant decrease in ovarian volume and ovarian FI is most likely due to the direct effect of hypo-estrogenic state induced by pituitary down-regulation as estrogen levels have been shown to be positively correlated with ovarian stromal volume (Mango et al., 1988) and ovarian stromal blood flow (Pellizzari et al., 2002; Carmina et al., 2005). If adequate pituitary desensitization is important for successful IVF treatment then measurement of stromal blood flow and ovarian volume may provide better confirmation of down-regulation than the AFC.
The two other 3D indices of ovarian vascularity, the VI and VFI, were not affected by down-regulation. This observation is in keeping with other studies that have reported heterogeneous variation in these indices both within the same subjects over time (Raine-Fenning et al., 2004b) or within different patient populations (Jarvela et al., 2003b; Lam and Raine-Fenning, 2006). The exact relationship of these indices to true blood flow remains to be determined but they are unlikely to simply reflect variations in vascularity (the VI), flow (the FI) or perfusion (the VFI) as has been suggested (Pairleitner et al., 1999). Preliminary phantom work has shown a rather more complex relationship between these variables but such studies are limited by the absence of a robust and reliable vascular phantom (Dubiel et al., 2006). At present, they remain an interesting research tool but their variation within subjects and populations and, more importantly, the absolute values often cited should be interpreted with caution (Raine-Fenning, 2002).
It is important to remember that tests of ovarian reserve appear to define quantity rather than quality (Broekmans et al., 2006) and none of the ovarian ultrasound variables, regardless of whether they were measured before or after down-regulation, were predictive of non-conception. The chance of conception following IVF is primarily dependent on embryo quality which is itself dependent on oocyte and sperm quality. Prediction of poor ovarian response prior to IVF remains important as these women are likely to have a greatly reduced chance of conception due to cycle cancellation or retrieval of a limited number of oocytes available for insemination. This allows appropriate counselling of couples who can then make a more informed decision before embarking on IVF treatment which has significant physical, financial and psychological implications. It also allows the identification of subjects who could be entered into prospective randomized controlled trials evaluating different treatment protocols and drug regimens to see if these offer any advantage.
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Conclusion |
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Pituitary desensitization with GnRH agonists in an ART programme results in a significant reduction in ovarian volume and vascularity, as reflected by a fall in the 3D FI, but has no effect on the number of antral follicles. The AFC is the single best predictor of poor ovarian response and the number of oocytes retrieved at oocyte collection following controlled ovarian stimulation. AFCs have a similar accuracy for the prediction of ovarian response regardless of whether the assessment is performed before treatment is commenced or after down-regulation. Ultrasound parameters, including AFCs used alone or in conjunction with age and basal FSH, are unable to predict the likelihood of non-conception.
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Funding |
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This study was sponsored by the University of Nottingham, Nottingham, UK.
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Acknowledgement |
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The authors would like to thank Sarah Armstrong, Trent Research and Development Support Unit, the University of Nottingham for her assistance with the statistical analysis.
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References |
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Submitted on September 26, 2007; resubmitted on March 10, 2008; accepted on March 21, 2008.
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