Hum. Reprod. Advance Access originally published online on September 9, 2004
Human Reproduction 2004 19(12):2811-2815; doi:10.1093/humrep/deh500
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Effect of pituitary downregulation on antral follicle count, ovarian volume and stromal blood flow measured by three-dimensional ultrasound with power Doppler prior to ovarian stimulation
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, People's Republic of China. Email: nghye{at}hkucc.hku.hk
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Abstract |
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BACKGROUND: Despite the extensive use of gonadotrophin releasing hormone agonists (GnRH ag) for pituitary downregulation, the literature regarding their effect on ultrasound parameters for predicting ovarian responses are few and conflicting. The aim of this prospective study was to compare antral follicle count (AFC), ovarian volume and ovarian stromal blood flow measured by three-dimensional (3D) power Doppler ultrasound before and after pituitary downregulation. METHODS: All patients received a long protocol of intranasal Buserelin from the mid-luteal phase of the cycle. In the early follicular phase of the preceding cycle before downregulation and on the second day of the treatment cycle after downregulation, patients underwent a blood test for serum FSH, LH and estradiol and a transvaginal scanning with 3D power Doppler to determine AFC, ovarian volume and ovarian 3D power Doppler flow indices. RESULTS: Out of 104 women scanned, 85 women were analysed. Polycystic ovaries were encountered in 14 (16.5%) women. No significant differences in any of the ultrasound parameters were demonstrated before and after downregulation, in patients with normal ovaries or in those with polycystic ovaries. CONCLUSION: AFC, ovarian volume and ovarian 3D power Doppler flow indices did not significantly change after a short-term treatment of GnRH agonist for pituitary downregulation.
Key words: antral follicle count/ovarian stromal blood flow/ovarian volume/pituitary downregulation/three-dimensional power Doppler
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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Recruitment and development of multiple follicles in response to gonadotrophin stimulation are the key factors leading to successful outcomes of in vitro fertilization/embryo transfer (IVF/ET) treatment. Ovarian stimulation is therefore used in the majority of assisted reproduction units in order to increase the number of good quality embryos available for transfer. Gonadotrophin releasing hormone agonists (GnRH ag) and more recently antagonists are now routinely employed to prevent premature LH surges, which occur in
20% of the cycles using gonadotrophin alone (Janssens et al., 2000
). A meta-analysis (Hughes et al., 1992) of randomized controlled trials found that the adjunctive use of GnRH ag in assisted reproduction cycles significantly reduced cancellation rates, increased the number of oocytes recovered, and improved pregnancy rates.
Ultrasound is essential in the modern management of couples undergoing IVF treatment because it is used to predict and monitor the ovarian response, assess the endometrial receptivity, guide the transvaginal aspiration of oocytes and subsequent transcervical transfer of embryos to the uterus. The role of three-dimensional (3D) ultrasound in IVF treatment has been recently reviewed (Raine-fenning, 2004). Several ultrasound parameters have been examined to predict the ovarian response to gonadotrophins, including ovarian volume (Syrop et al., 1995, 1999; Lass et al., 1997), antral follicle count (AFC; Tomás et al., 1997; Chang et al., 1998a,b; Frattarelli et al., 2000; Ng et al., 2000; Hsieh et al., 2001; Nahum et al., 2001; Bancsi et al., 2000; Kupesic and Kurjak, 2002; Popovic-Todorovic et al., 2003) and ovarian stromal blood flow (Zaidi et al., 1996; Bassil et al., 1997; Engmann et al., 1999a; Kupesic and Kurjak, 2002; Järvelä et al., 2003a; Popovic-Todorovic et al., 2003). Despite the extensive use of GnRH ag for pituitary downregulation, the literature regarding their effects on these ultrasound parameters are few and conflicting. The changes in these ultrasound parameters after pituitary downregulation, if present, may have significant impacts on the subsequent ovarian response.
The aim of this prospective study was to compare AFC, ovarian volume and ovarian stromal blood flow measured by three-dimensional (3D) power Doppler ultrasound before and after pituitary downregulation.
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Materials and methods |
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Infertile patients attending the Assisted Reproduction Unit at the Department of Obstetrics and Gynaecology, University of Hong Kong, for the first IVF/ET cycle were recruited for study when both ovaries were present and they did not have any history of ovarian surgery. Those with ovaries poorly visualized because of abdominal position or an ovarian cyst of >20 mm in diameter on scanning were retrospectively excluded. Every patient gave a written informed consent prior to participating in the study, which was approved by the Ethics Committee, Faculty of Medicine, University of Hong Kong.
They attended the unit for a transvaginal 3D ultrasound examination and a blood test for FSH, LH and estradiol in the early follicular phase (Day 2–4) of the cycle preceding the IVF treatment and then received a long protocol of Buserelin (Suprecur, Hoechst, Frankfurt, Germany) nasal spray 150 µg four times a day from the mid-luteal phase. The 3D ultrasound examination and the blood test were repeated again on the second day of the following period induced by downregulation. Pituitary downregulation was confirmed when there was an absence of ovarian cysts >20 mm in diameter on scanning and serum E2 was <200 pmol/l. Serum FSH, LH and estradiol concentrations were measured using commercially available kits (Automated Chemiluminescence System, Bay Corporation, NY). The sensitivity of the FSH assay was 0.3 IU/l and the intra- and inter-assay coefficients of variation (CVs) were 1.7% and 2.8%, respectively. The sensitivity of the LH assay was 0.07 IU/l and the intra- and inter-assay CVs were 4.5% and 5.2%, respectively. The sensitivity of the E2 assay was 36.7 pmol/l and the intra- and inter-assay CVs were 8.1% and 8.7%, respectively.
The details and reliability of 3D volume acquisition and data analysis were as previously described (Chan et al., 2003; Ng et al., 2004). All 3D ultrasound examinations were performed at 8–10 AM by EHYN using Voluson 730 (Kretz, Zipf, Austria), after the patients had emptied their bladders. AFC was obtained in the multi-planar view and the intra-observer coefficient of variation for AFC was 7%. Polycystic ovaries (Balen et al., 2003) were recorded, if present. Both ovaries were then scanned with the power Doppler mode. The setting condition for this study was: Frequency: Mid, Dynamic set: 2, Balance: G > 140, Smooth: 5/5, Ensemble: 12, Line Density: 7, Power Doppler Map: 5; and the setting condition for the sub-Power Doppler mode was: Gain: –6.0, Balance: 140, Quality: normal, Wall Motion Filter: low1, Velocity range: 0.9 kHz. The 3D ultrasound images were stored for later analysis by EHYN.
The built-in virtual organ computer-aided analysis (VOCAL) Imaging Program for the 3D power Doppler histogram analysis was used to determine the ovarian volume and indices of vascularization and blood flow. Vascularization index (VI) measures the number of colour voxels representing the blood vessels in the ovary and is expressed as a percentage (%) of the ovarian volume. Flow index (FI) is the mean colour value in the colour voxels and represents the average intensity of flow inside the ovary. Vascularization flow index (VFI) made by multiplying VI and FI is a combination of vascularity and flow (Pairleitner et al., 1999). During the analysis and calculation, the manual mode of the VOCAL Contour Editor was used to cover the whole 3D volume of the ovary with a 15° rotation step. Hence, 12 contour planes were analyzed for each ovary to cover 180°.
Statistical analysis
The primary outcome measures included AFC, ovarian volume, VI/FI/VFI of the ovary. Continuous variables were not normally distributed and were given as median (range), unless indicated. Statistical tests were carried out by Wilcoxon signed-rank test. P-value (two-tailed) of <0.05 was taken as significant.
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Results |
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A total of 104 consecutive eligible women were scanned and 19 patients were excluded from the analysis: poor visualization of ovaries in five patients; an ovarian cyst on the second day before pituitary downregulation in nine women and an ovarian cyst on the second day after pituitary downregulation in another five patients. Therefore, 85 women were included in the final analysis: 21 tubal factors; 7 endometriosis; 46 male infertility; 7 unexplained and 4 mixed causes. Fifty-seven (67.1%) women had primary infertility and six (7.1%) women smoked. Polycystic ovaries were encountered in 14 (16.5%) women. The median duration of intranasal Buserelin was 10 days (range: 5–20 days). All patients had serum E2 concentration <200 pmol/l on the second day of the treatment cycle after pituitary downregulation.
No significant differences in AFC, ovarian volume and ovarian VI/FI/VFI were demonstrated in patients before and after pituitary downregulation (Table I). The results were essentially the same when patients with normal ovaries and with polycytic ovaries (Table II) were separately analyzed. Serum FSH, LH and oestradiol concentrations were significantly lower after pituitary downregulation (Table I).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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Our results showed that AFC, ovarian volume and ovarian 3D power Doppler flow indices did not significantly change after a short-term treatment of GnRH ag for pituitary downregulation, both in patients with normal ovaries or in those with polycystic ovaries. The effects of pituitary downregulation on these ultrasound parameters are still controversial in the literature, despite extensive use of GnRH ag for pituitary downregulation in IVF cycles. AFC (Sharara et al., 1999
; Hansen et al., 2003) and ovarian volume (Sharara et al., 1999) did not change after pituitary downregulation. However, a significant decrease in AFC (Järvelä et al., 2003b) and in ovarian volume (Dada et al., 2001; Järvelä et al., 2003b) was observed after pituitary downregulation. Resistance index (RI) of the utero-ovarian arterial blood flow was not affected by the GnRH ag administration (Vrtacnik-Bokal and Meden-Vrtovec, 1998). Engmann et al. (1999b) demonstrated that there was a significant decline in mean ovarian stromal artery peak systolic velocity (PSV) after GnRH ag treatment but no effect on ovarian stromal artery pulsatility index (PI). Similarly, ovarian stromal PSV was significantly reduced and ovarian PI and RI were significantly increased after the GnRH ag treatment (Dada et al., 2001). Järvelä et al. (2003b) recently reported that ovarian stromal blood flow measured by 3D power Doppler ultrasound was not affected by pituitary downregulation.
Discrepancies in the literature may be partly related to different timing and techniques of ultrasound examination. Scanning was first performed in the early follicular phase, i.e. Day 2–4, and then repeated 2 to 3 weeks after the start of GnRH ag (Vrtacnik-Bokal and Meden-Vrtovec, 1998; Engmann et al., 1999b; Dada et al., 2001). In these studies, ovarian stromal vascular impedance was determined by two-dimensional (2D) colour Doppler ultrasound. Power Doppler is better suited to the study of the ovarian stromal blood flow as it is more sensitive to lower velocities and is essentially angle-independent (Rubin et al., 1994). In combination with 3D ultrasound, power Doppler provides a unique tool with which to examine the ovarian stromal blood supply as a whole as opposed to analysis of small individual stromal vessels in 2D planes. Järvelä et al. (2003b) performed 3D power Doppler scanning in mid to late follicular phase, i.e. Day 8–16, and after 2 weeks of GnRH ag, and demonstrated that there was a significant decrease in the volume and number of follicles after downregulation. The dominant ovary was also larger in volume before pituitary downregulation. The follicular development of the dominant ovary in mid to late follicular phase would certainly affect the assessment of AFC, ovarian volume and ovarian stromal blood flow in the study of Järvelä et al. (2003b). In the present study, all patients underwent both 3D ultrasound examinations in the early follicular phase of the cycle.
The administration of GnRH ag causes an initial stimulation of gonadotrophins and sex hormones followed by a downregulation of GnRH receptors and suppression of gonadotrophins and gonadal function. Receptors for GnRH have been identified in granulosa and luteal cells of the ovary, but not in ovarian artery endothelium (Broekmans, 1996). AFC likely reflects the pool of remaining primordial follicles and thus the reproductive age of women (Ng et al., 2003; Scheffer et al., 2003). AFC should not be affected by the use of GnRH ag although there would be inter-cycle variation of AFC (Hansen et al., 2003). The effects of GnRH ag on ovarian volume and ovarian stromal blood flow are related to the hypoestrogenic state as a result of pituitary downregulation. In the present study, ovarian volume and ovarian 3D power Doppler flow indices were comparable before and after pituitary downregulation while serum E2 concentration was significantly lower after pituitary downregulation. The effect of declining E2 concentration on ovarian volume and ovarian stromal blood flow may be dependent on a particular E2 threshold level and the duration of the hypoestrogenic state, which will be achieved after profound or long-term pituitary suppression. There is a linear relationship between ovarian volume and menopause age (Tepper et al., 1995). Long-term GnRH ag treatment increases uterine artery blood flow impedance in patients with uterine fibroids (Reinsch et al., 1994).
Different types, routes of administration and doses of GnRH ag may lead to different degree of pituitary downregulation (Janssens et al., 2000; Wong et al., 2001; Albuquerque et al., 2002). Daily subcutaneous Buserelin injections were used for 2 to 3 weeks in most of the above studies (Vrtacnik-Bokal and Meden-Vrtovec, 1998; Engmann et al., 1999b; Dada et al., 2001; Järvelä et al., 2003) and subcutaneous Lupron was given daily for 1 week in the report of Sharara et al. (1999). All patients in this study received intranasal Buserelin daily from the mid-luteal phase of the cycle prior to the treatment cycle and the median duration of GnRH ag was 10 days. Although different criteria have been used to define pituitary downregulation (Calhaz-Jorge et al., 1995), optimal doses of GnRH ag for IVF should be those that prevent a premature endogenous surge and ovulation before scheduled egg collection (Janssens et al., 2000). Excessive pituitary downregulation may lead to decrease in ovarian stromal blood flow and reduced delivery of gonadotrophins to the ovaries during ovarian stimulation. This may increase both the duration and dosage of gonadotrophins used.
In summary, AFC, ovarian volume and ovarian 3D power Doppler flow indices did not significantly change after a short-term treatment of GnRH ag for pituitary downregulation, both in patients with normal ovaries and with polycystic ovaries. This implies that the assessment of these ultrasound parameters in the prediction of ovarian response can be performed either before or after pituitary downregulation.
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This study was funded by the Hong Kong Research Grant Council (HKU 7280/01M).
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Submitted on June 21, 2004; accepted on August 4, 2004.
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