James Hopkisson

A prospective, comparative analysis of anti-Müllerian hormone, inhibin-B, and three-dimensional ultrasound determinants of ovarian reserve in the prediction of poor response to controlled ovarian stimulation

OBJECTIVE To compare three-dimensional ultrasound parameters, antral follicle count (AFC), ovarian volume, and ovarian vascularity indices with anti-Müllerian hormone (AMH) and other conventional endocrine markers for the prediction of poor response to controlled ovarian hyperstimulation (COH) during assisted reproduction treatment (ART). DESIGN Prospective study. SETTING University-based assisted conception unit. PATIENT(S) One hundred thirty-five women undergoing the first cycle of ART. INTERVENTION(S) Transvaginal three-dimensional ultrasound assessment and venipuncture in the early follicular phase of the menstrual cycle immediately before ART. MAIN OUTCOME MEASURE(S) Poor ovarian response and nonconception. RESULT(S) Antral follicle count (Exp(B): 0.65) and AMH (Exp(B): 0.13) were the most significant predictors of poor ovarian response on multiple regression analysis and their predictive accuracy was similar, with an area under the curve (AUC) of 0.935 and 0.905, respectively. The AFC and AMH, as a combined test, did not significantly improve the level of prediction (AUC = 0.946). The sensitivity and specificity for prediction of poor ovarian response were 93% and 88% for AFC and 100% and 73% for AMH at an optimum cutoff values of < or =10 and < or =0.99 ng/mL, respectively. Age (Exp(B): 1.191) was the only significant predictor of nonconception, although its predictive accuracy was also low (AUC = 0.674). CONCLUSION(S) The AFC and AMH are the most significant predictors of poor response to ovarian stimulation during ART. The AMH and AFC, either alone or in combination, demonstrate a similar predictive power but are not predictive of nonconception, which is dependent on the womans age.

The cohort of antral follicles measuring 2–6 mm reflects the quantitative status of ovarian reserve as assessed by serum levels of anti-Müllerian hormone and response to controlled ovarian stimulation

OBJECTIVE To evaluate the relationship between serum anti-Müllerian hormone (AMH) and antral follicle size, and to ascertain which cohort of antral follicles is most predictive of the response to controlled ovarian stimulation during assisted reproduction treatment (ART). DESIGN Prospective study. SETTING University-based Assisted Conception Unit. PATIENT(S) One hundred thirteen women undergoing first cycle of ART. INTERVENTION(S) Transvaginal 3D-ultrasound assessment and venipuncture in the early-follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S) Serum AMH levels, number of mature oocytes retrieved and poor ovarian response. RESULT(S) The antral follicle cohorts measuring 2 to 3 mm, >3 to 4 mm, >4 to 5 mm, and >5 to 6 mm were most significantly correlated with AMH (r = .30, .27, .30, and .41, respectively) and the number of mature oocytes retrieved (r = .28, .23, .29, and .34, respectively). Although these follicle cohorts of 2-6 mm were significant predictors of the number of mature oocytes retrieved on regression analysis, their discriminative ability (area under the curve [AUC]: 0.829) for the prediction of poor ovarian response was similar to total counts made using cohorts of 2 to 4 mm, 2 to 5 mm, 2 to 8 mm, and 2 to 10 mm (AUCs: 0.794, 0.812, 0.852, and 0.826, respectively). CONCLUSION(S) The number of antral follicles measuring 2 to 6 mm is most reflective of the quantitative ovarian reserve. However, the ability of this group of antral follicles to predict poor ovarian response appears similar to that of the follicular cohorts of 2 to 4 mm, 2 to 5 mm, 2 to 8 mm, and 2 to 10 mm.

INTEGRINS ALPHA 3 AND ALPHA 6 ARE DIFFERENTIALLY EXPRESSED IN ENDOMETRIUM AND ENDOMETRIOSIS

The expression of integrin subunits has been investigated in the stroma and epithelium of eutopic and ectopic endometrial tissues, using immunohistochemistry and fluorescently activated cell‐sorting techniques. Integrin subunits exhibited tissue‐specific expression in both eutopic and ectopic endometrium. Integrin α3 subunit was up‐regulated in ectopic endometrium compared with the eutopic counterpart, whereasα6 integrin subunit was down‐regulated in the ectopic tissues. Cycle stage‐dependent expression ofαv andβ3, observed in eutopic endometrium, was absent in the ectopic counterpart. It is concluded that the development and regeneration of the endometrium involve complex integrin–ligand interactions and that regulation of specific adhesive events is lost in endometriosis.

A randomised controlled trial of 300 versus 225 IU recombinant FSH for ovarian stimulation in predicted normal responders by antral follicle count

Please cite this paper as: Jayaprakasan K, Hopkisson J, Campbell B, Johnson I, Thornton J, Raine‐Fenning N. A randomised controlled trial of 300 versus 225 IU recombinant FSH for ovarian stimulation in predicted normal responders by antral follicle count. BJOG 2010;117:853–862.

Validation of a novel computer-assisted sperm analysis (CASA) system using multitarget-tracking algorithms

OBJECTIVE To determine the accuracy and precision of a novel computer-assisted sperm analysis (CASA) system by comparison with existing recommended manual methods. DESIGN Prospective study using comparative measurements of sperm concentration and motility on latex beads and immotile and motile sperm. SETTING Tertiary referral fertility center with strong academic links. PATIENT(S) Sperm donors and male partners of couples attending for fertility investigations. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Achievement of Accubead target value for high and low concentration suspensions. Repeatability as demonstrated by coefficients of variation and intraclass correlation coefficients. Correlation and limits of agreement between CASA and manual methods. RESULT(S) The CASA measurements of latex beads and sperm concentrations demonstrated a high level of accuracy and repeatability. Repeated Accubead measurements attained the required target value (mean difference from target of 2.61% and 3.71% for high- and low-concentration suspensions, respectively) and were highly reproducible. Limits of agreement analysis suggested that manual and CASA counts compared directly could be deemed to be interchangeable. Manual and CASA motility measurements were highly correlated for grades a, b, and d but could not be deemed to be interchangeable, and manual motility estimates were consistently higher for motile sperm. CONCLUSION(S) The novel CASA system was able to provide semen quality measurements for sperm concentration and motility measurements which were at least as reliable as current manual methods.

Establishing the intercycle variability of three-dimensional ultrasonographic predictors of ovarian reserve

OBJECTIVE To estimate the intercycle variability of antral follicle counts (AFCs) and ovarian volume, as measured by using three-dimensional ultrasound, and to compare these to the variation in basal FSH levels. DESIGN Prospective study. SETTING University-based assisted conception unit. PATIENT(S) One hundred women undergoing two cycles of assisted reproductive technology. INTERVENTION(S) Transvaginal three-dimensional ultrasound assessment and venepuncture in the early follicular phase of the menstrual cycle, immediately before assisted reproductive technology. MAIN OUTCOME MEASURE(S) Intercycle variability of AFC, ovarian volume, and basal FSH. RESULT(S) The limits of agreement between cycles were +4.03 and -3.71 for AFC, +2.67 and -3.03 cm(3) for ovarian volume, and +4.36 and -4.52 IU/L for FSH levels. The AFC showed the least degree of variation, with a range of 0.48 times its own mean, in contrast to corresponding values of 0.73 and 1.29 for ovarian volume and basal FSH levels, respectively. The intraobserver variability for AFC and ovarian volume and the intraassay variability for FSH were 0.37, 0.17, and 0.42 times the mean of those respective variables. CONCLUSION(S) The AFC demonstrates a lower intercycle variability than do ovarian volume and basal FSH level. The observed intercycle variability of the AFC may primarily be caused by observer variability, and the true biological variation may be minimal.

Timing of oocyte maturation and egg collection during controlled ovarian stimulation: a randomized controlled trial evaluating manual and automated measurements of follicle diameter

OBJECTIVE To evaluate the effect of a new automated technique of follicle measurement (Sono automated volume calculation [SonoAVC]) on the timing of oocyte maturation and subsequent oocyte retrieval. DESIGN Prospective randomized controlled trial. SETTING University-based Assisted Conception Unit. PATIENT(S) Seventy-two women undergoing their first cycle of assisted reproduction treatment. INTERVENTION(S) The timing of final follicle maturation and oocyte retrieval based on follicle tracking with use of either conventional two-dimensional (2D) ultrasound or SonoAVC. MAIN OUTCOME MEASURE(S) The number of mature oocytes retrieved and clinical pregnancy rate. RESULT(S) The number of the mature oocytes collected (10.70 +/- 6.08 vs. 11.43 +/- 6.17), the number of fertilized oocytes (7.27 +/- 4.78 vs. 7.97 +/- 5.25), and the clinical pregnancy rates (42% vs. 43%) were similar with both 2D ultrasound and SonoAVC methods. CONCLUSION(S) Automated follicle tracking using SonoAVC identifies a comparable number of follicles to real-time 2D ultrasound in this preliminary study. Timing final follicle maturation and egg retrieval on the basis of these automated measures does not appear to improve the clinical outcome of assisted reproduction treatment.

Effect of pituitary desensitization on the early growing follicular cohort estimated using anti-Mullerian hormone

BACKGROUND This study evaluated the effect of pituitary desensitization on the early growing follicle population through assessment of serum anti-Mullerian hormone (AMH) concentration. Other markers of ovarian reserve, basal follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol, inhibin-B and three-dimensional ultrasound ovarian parameters were also assessed for comparison. METHODS One hundred and two subjects aged <40 years with FSH levels <12 IU/l underwent venepuncture and transvaginal ultrasound in the early follicular phase of the menstrual cycle and after 14 days of down-regulation using gonadotrophin releasing hormone (GnRH) agonists. Serum levels of AMH and other markers of ovarian reserve measured during the early follicular phase were compared with those measured following down-regulation. RESULTS While AMH levels increased significantly by approximately 32% (P < 0.01), there was a significant decline of approximately 40-50% (P < 0.01) in the levels of inhibin-B, FSH, LH and estradiol. Down-regulation treatment was also associated with a decrease (P < 0.01) in mean ovarian volume and in ovarian blood flow, but no difference was seen in the antral follicle count. CONCLUSIONS Pituitary desensitization results in a significant increase in AMH levels, which implies that either the secretion of AMH by early growing follicles is enhanced or that the size of this follicle cohort is increased. The number of antral follicles visualized on ultrasound in the early follicular phase and at down-regulation appears unchanged, suggesting that any effect is restricted to the smaller selectable follicles. Our results may explain the enhanced ovarian response to conventional controlled ovarian stimulation and higher pregnancy rates when pretreatment with GnRH-agonists is employed.

The predictive value of the automated quantification of the number and size of small antral follicles in women undergoing ART

BACKGROUND Sono-automatic volume calculation (SonoAVC) automatically identifies and measures the dimensions of hypoechogenic areas within datasets acquired using three-dimensional ultrasound. The objective of this study was to evaluate the predictive value of automated antral follicle counts according to their relative sizes in women undergoing assisted reproduction treatment (ART). METHODS A total of 156 subjects aged < or =40 years with a baseline FSH < or =15 IU that undergo their first cycle of ART were prospectively recruited. SonoAVC was used to measure the datasets and record the number of antral follicles measuring < or =9 mm in diameter. These follicles were then grouped into subsets according to their relative sizes: < or =2.0, 2.1-4.0, 4.1-6.0, 6.1-8.0 and 8.1-9.0 mm. The primary outcome was viable pregnancy confirmed on ultrasound 5 weeks following embryo transfer. RESULTS A total of 142 subjects were included for analysis of primary end-point. Those subjects who conceived had significantly more antral follicles measuring < or =2 (P = 0.041) and 2.1-4.0 mm (P < 0.001) than those who had unsuccessful treatment. There were no significant differences between the groups in the number of antral follicles measuring 4.1-6.0 (P = 0.191), 6.1-8.0 (P = 0.203) and 8.1-9.0 mm (P = 0.601). Multiple logistic regression showed that antral follicles measuring 2.1-4.0 mm were an independent predictor of pregnancy [Exp(B) = 1.234, 95% CI = 1.092-1.491; P = 0.004; AUC = 0.693]. CONCLUSION SonoAVC provides automated measures of antral follicle number and size. Using this technique, the number of antral follicles measuring 2.1-4.0 mm in diameter is an independent, significant predictor of pregnancy following in vitro fertilization treatment.

The three-dimensional ultrasonographic ovarian vascularity of women developing poor ovarian response during assisted reproduction treatment and its predictive value

OBJECTIVE To test the hypothesis that ovarian vascularity is decreased in women who demonstrate poor ovarian response to controlled ovarian stimulation as part of assisted reproduction treatment. DESIGN Prospective study. SETTING University-based Assisted Conception Unit. PATIENT(S) One hundred forty-one women undergoing their first cycle of assisted reproduction treatment (ART). INTERVENTION(S) Transvaginal 3D ultrasound assessment and venepuncture in the early follicular phase of the menstrual cycle immediately before ART. MAIN OUTCOME MEASURE(S) Ovarian vascularity indices (VI, FI, and VFI), ovarian volume (OV), and antral follicle count (AFC). RESULTS The ovarian VI (7.5 +/- 5.3 vs. 8.6 +/- 7.3), FI (38.9 +/- 6.9 vs. 38.0 +/- 5.5), and VFI (3.2 +/- 2.6 vs. 3.5 +/- 3.1) were similar in both poor and normal responders. AFC and OV were significantly lower in women who developed poor response (9 +/- 3.3 and 6.3 +/- 3.5 cm(3), respectively) than in normal responders (19.2 +/- 9.9 and 8.9 +/- 4.8 cm(3), respectively). Antral follicle count and basal FSH were the only significant predictors of poor ovarian response on multiple regression analysis. CONCLUSION(S) Ovarian blood flow, as measured by 3D ultrasound, is not decreased in women who demonstrate a poor response to ovarian stimulation and is not predictive of poor response during IVF treatment. The AFC is the single best predictor of poor ovarian response.