McGill Reproductive Center, Department of Obstetrics and Gynecology, Royal Victoria Hospital, McGill University, Montreal, Quebec, H3A 1A1, Canada
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Abstract |
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Key words: endometrial thickness/endometrial volume/pituitary suppression/serum estradiol/3D-ultrasound
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Introduction |
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The endometrium acts as a bioassay for circulating serum estradiol (Nakamura et al., 1996). Ultrasonographic measurement of endometrial thickness may therefore be used as a marker for serum hyper- or hypo-estrogenism and can be used to confirm pituitary suppression prior to ovarian stimulation during IVF treatment (Barash et al., 1998
). The advantages of this approach over routine serum estradiol testing in all patients are that (i) the number of blood tests required during an IVF cycle is reduced and (ii) ultrasound imaging identifies pelvic pathology, including ovarian cysts or endometrial polyps, that may adversely affect cycle outcome. Surprisingly, though widely used as a predictor of pituitary suppression, only two studies have examined the value of ultrasound measurement of endometrial thickness or volume in screening for pituitary down-regulation during IVF (Barash et al., 1998
; Yaman et al., 2000
). Both studies focused on selecting endometrial thresholds that best identified women who were pituitary suppressed, not those with failed suppression. It is arguably more important to identify pituitary non-suppressed patients, since they may be at increased risk of a blunted follicular response to ovarian stimulation.
Yaman and colleagues examined the role of three-dimensional (3D) endometrial volume estimation in predicting pituitary suppression in an IVF programme (Yaman et al., 2000). However, their study included 46 patients of whom only four had serum estradiol concentrations >60 pg/ml, and positive and negative values of the test were not calculated. In particular, the aim of their study was to identify pituitary suppressed patients rather than women with failed suppression.
The aim of the present study is to extend the observations of Yaman et al. with a much larger group of 164 cycles in order to document the role of 3D endometrial volume and thickness estimation in predicting both failed and successful pituitary suppression.
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Materials and methods |
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Ultrasound scans were performed using a machine with two-dimensional (2D) and 3D capabilities (Voluson 530D, Medison Inc., CA, USA) attached to a 57.5 MHz transvaginal probe. Scans were performed by one of two experienced ultrasonographers: T.J.C. or C.S. Patients were asked to empty their bladder prior to examination. First, a 2D ultrasound scan was performed in order to measure endometrial thickness. The uterus was visualized in the longitudinal plane, ensuring that the complete endometrial echo from cervix to fundus was clearly seen. The endometrial thickness was taken as the maximum distance between the two myometrialendometrial interfaces at right angles to the cavity. The machine was then switched to volume mode and the slow sweep speed selected for maximum image resolution. The volume box was placed over the endometrium. Volume acquisition was commenced and the transducer held still for a few seconds during the crystal sweep. The scanned volumes were stored on the machine's hard drive for later analysis.
The contour method was used to measure the endometrial volume. We have previously demonstrated high reliability and reproducibility of 3D endometrial volume measurements using this method (Kyei-Mensah et al., 1996), as have subsequent investigators (Yaman et al., 1999
). All measurements were performed by one investigator (T.J.C.). The volume was computed by the ultrasound machine from several parallel cross-sections from the fundal part of the endometrium to the internal os. The intra-observer reliability of endometrial thickness and volume estimation was calculated by measuring the endometrial thickness and volume of 10 patients three times. The intra-class correlation coefficients were calculated as 0.96 (volume) and 0.92 (thickness). These results indicate high intra-observer reliability.
Following the ultrasound scan, all patients had a blood sample taken for estradiol assay. This was performed using the ACS:180 Estradiol-6 II assay (Bayer Corporation, Tarrytown, NY, USA). The assay had between-runs coefficients of variation (CV) of 27.6% at a mean of 77 pmol/l, 15.3% at 191 pmol/l, and 7.5% at 352 pmol/l estradiol concentrations. The endometrial volume for each patient was calculated before running the estradiol assay.
Statistical analysis was performed using receiver operating characteristic (ROC) curve analysis. The ROC curve represents the probability of true positive results (sensitivity) as a function of the probability of false positive results (1specificity). In order to calculate each curve, a particular threshold value for the state variable (serum estradiol concentration) must be selected. This is the arbitrary value at which pituitary suppression is defined. Since no consensus exists on the optimal degree of pituitary suppression as measured by serum estradiol concentration, we calculated ROC curves for each of four commonly used thresholds; 100 pmol/l, 150 pmol/l, 200 pmol/l and 250 pmol/l. For each estradiol threshold, separate curves were produced for volume and thickness measurements, making a total of eight ROC curves. The sensitivity and specificity of a particular endometrial volume (or thickness) cut-off, as a screening test for pituitary suppression or non-suppression, changes depending on the selected estrogen threshold. The possible combinations of sensitivity and specificity obtained when varying the endometrial cut-off point for a particular estradiol threshold are combined into an area under the curve (AUC). The AUC measures how good (AUC close to 1.0) or poor (AUC close to 0.5) a test is. To compare 2D and 3D endometrial measurement as a test, the AUC for thickness is compared against the AUC obtained for volume measurements at the same estradiol threshold. Four such comparisons were performed using the statistical method of Hanley and McNeil (Hanley and McNeil, 1983), i.e. volume versus thickness for each of the concentrations 100, 150, 200, and 250 pmol/l estradiol. Analyses were performed using SPSS (SPSS, Chicago, IL, USA).
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Results |
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Discussion |
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Previous studies have attempted to determine the endometrial thickness or volume thresholds that best predict pituitary suppression rather than non-suppression. The difference is subtle but important. For instance, from the data of Yaman and colleagues (Yaman et al., 2000), an endometrial volume of 1.8 ml has a sensitivity and specificity for diagnosing pituitary suppression (when defined as serum estradiol <40 pg/ml, equivalent to ~150 pmol/l) of 91.2 and 33.3% respectively. The use of this volume threshold means that only 33.3% of non-suppressed women will be identified. Put another way, two-thirds of pituitary non-suppressed women would fall into the `low' endometrial volume range on ultrasound and ovarian stimulation would be commenced unnecessarily.
Our data suggest that different endometrial thickness or volume thresholds should be selected, depending on whether one wishes to screen for suppression or non-suppression. For example, if suppression is considered as an estradiol concentration <150 pmol/l, then an endometrial thickness of <5.9 mm will identify (sensitivity) 91.7% of suppressed patients (Table I). However, only 41.9% (Table I
) of non-suppressed women will have an endometrial thickness of >5.9 mm and be identified as having failed pituitary suppression. For the same estradiol threshold of 150 pmol/l, an endometrial thickness of
3.7 mm will identify 80.6% of non-suppressed patients (Table II
). If a higher sensitivity is preferred (higher likelihood of identifying non-suppressed women), then the endometrial threshold thickness may be reduced further. However, the positive predictive value will also reduce, meaning that more patients with an endometrium thicker than the threshold are in fact suppressed and will undergo a needless blood test.
When selecting endometrial thresholds for screening for pituitary suppression, there appears little advantage of endometrial volume over thickness measurement (Table I), since the sensitivities and specificities between the two methods are similar. This confirms the findings of Yaman and colleagues (Yaman et al., 2000
).
When screening for failed suppression, 3D volume estimation achieved higher test sensitivities for similar test specificities (Table II). This could be because in comparison with pituitary suppressed patients, those with failed suppression have a greater endometrial mass. Measurement of high endometrial mass could conceivably be more accurately estimated by volume rather than thickness measurement. However, endometrial volume measurement was only shown to be significantly superior to thickness measurement (AUCs significantly different) when using an estradiol threshold of 200 pmol/l.
Though endometrial volume measurement is simple to perform, the calculation takes longer than the measurement of the endometrial thickness. The volume is calculated from serial tracings of the endometrial outline from internal cervical os to fundus. In addition, when the endometrium is very thin, it may be difficult to identify the myometrialendometrial interface when tracing the endometrial outline on the serial cross-sections. Each measurement takes between 3 and 5 min.
In summary, the current data support and extend previous work suggesting that 3D endometrial volume estimation provides a new tool in assessing the degree of pituitary suppression during IVF treatment. When selecting endometrial thresholds to screen for pituitary suppression, the sensitivities and specificities obtained were similar between volume and thickness measurements. However, when selecting endometrial thresholds to screen for failure of pituitary suppression, which is perhaps of greater clinical use, 3D volume estimation performed slightly better as a test. Ultrasonographic measurement of endometrial volume or thickness can replace routine measurement of serum estradiol as a predictor of the state of pituitary suppression.
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Notes |
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References |
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Biljan, M.M., Mahutte, N.G., Dean, N., Hemmings,. R, Bissonnette, F. and Tan, S.L. (1998) Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates. Fertil. Steril., 70, 10631069.[ISI][Medline]
Engmann, L., Maconochie, N., Bekir, J. and Tan, S.L. (1999a) Progestogen therapy during pituitary desensitization with gonadotropin-releasing hormone agonist prevents functional ovarian cyst formation: a prospective, randomized study. Am. J. Obstet. Gynecol., 181, 576582.[ISI][Medline]
Engmann, L., Sladkevicius, P., Agrawal, R., Bekir, J.S., Campbell, S. and Tan, S.L. (1999b) Value of ovarian stromal blood flow velocity measurement after pituitary suppression in the prediction of ovarian responsiveness and outcome of in vitro fertilization treatment. Fertil. Steril., 71, 2229.[ISI][Medline]
Hanley, J.A. and McNeil, B.J. (1983) A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology, 148, 839843.[Abstract]
Ibrahim, Z.H., Matson, P.L., Buck, P., Critchlow, J.D., Newman, M.C., Horne, G., Hughes, S. and Lieberman, B.A. (1990) Use of buserelin in an IVF programme for pituitary-ovarian suppression prior to ovarian stimulation with exogenous gonadotrophins. Hum. Reprod., 5, 258262.[Abstract]
Kyei-Mensah, A., Maconochie, N., Zaidi, J., Pittrof, R., Campbell, S. and Tan ,S.L. (1996) Transvaginal three-dimensional ultrasound: reproducibility of ovarian and endometrial volume measurements. Fertil. Steril., 66, 718722.[ISI][Medline]
Nakamura, S., Douchi,T., Oki, T., Ijuin, H., Yamamoto, S. and Nagata, Y. (1996) Relationship between sonographic endometrial thickness and progestin-induced withdrawal bleeding. Obstet. Gynecol., 87, 722725.
Tan, S.L., Maconochie, N., Doyle, P. Campbell, S., Balen, A., Bekir, J., Brinsden, P., Edwards, R.G. and Jacobs, H.S. (1994) Cumulative conception and live-birth rates after in vitro fertilization with and without the use of long, short, and ultrashort regimens of the gonadotropin-releasing hormone agonist buserelin. Am. J. Obstet. Gynecol., 171, 513520.[ISI][Medline]
Templeton, A., and Morris, J.K. (1998) Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N. Engl. J. Med., 339, 573577.
Yaman, C., Sommergruber, M., Ebner, T., Polz, W., Moser, M. and Tews, G. (1999) Reproducibility of transvaginal three-dimensional endometrial volume measurements during ovarian stimulation. Hum. Reprod., 14, 26042608.
Yaman, C., Ebner, T., Sommergruber, M., Hartl, J., Polz, W. and Tews, G. (2000) Three-dimensional endometrial volume estimation as a predictor of pituitary down-regulation in an IVF-embryo transfer programme. Hum. Reprod., 15, 16981702.
Submitted on April 15, 2002; accepted on August 19, 2002.