Comparison of changes in uterine contraction frequency after ovulation in the menstrual cycle and in in vitro fertilization cycles

Size: px

Start display at page:

Download "Comparison of changes in uterine contraction frequency after ovulation in the menstrual cycle and in in vitro fertilization cycles"

Rosalyn Williamson
6 years ago
Views:

1 FERTILITY AND STERILITY VOL. 79, NO. 5, MAY 2003 Copyright 2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Comparison of changes in uterine contraction frequency after ovulation in the menstrual cycle and in in vitro fertilization cycles Jean-Marc Ayoubi, M.D., a Manuela Epiney, M.D., b Pierre Alain Brioschi, M.D., c Renato Fanchin, M.D., a Didier Chardonnens, M.D., b and Dominique de Ziegler, M.D. b,c CHU de Grenoble, Grenoble, France; and Hôpital de Nyon, Nyon, and Hôpital de Geneva, Geneva, Switzerland Received March 21, 2002; revised and accepted July 10, Reprint requests: Dominique de Ziegler, M.D., Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, 1260 Nyon, Switzerland (FAX: ; ddeziegler@compuserve. com). a Department of Obstetrics CHU de Grenoble. b Department of Obstetrics Hôpital de Nyon. c Department of Obstetrics Hôpital de Geneva /03/$30.00 doi: /s (03) Objective: To compare changes in uterine contraction (UC) frequency occurring after ovulation in the menstrual cycle and in IVF and to clarify UC anomalies encountered in IVF. Design: Prospective crossover trial. Setting: University infertility clinic. Patient(s): Six women seeking IVF for male factor infertility having regular menstrual cycles were studied during the menstrual cycle and IVF. Intervention(s): Identification of LH surge in the menstrual cycle. Measurement of plasma E 2 and P levels and assessment of UC frequency by direct ultrasound visualization on the day of LH surge in the menstrual cycle and the day of hcg administration in IVF and every 2 days thereafter for 6 days. Main Outcome Measure(s): Uterine contraction (UC) frequency and plasma E 2 and P levels. Result(s): UC frequency was similar on the day of LH surge (5/minute) and hcg administration (5.3/minute). Establishment of uteroquiescence was more prompt in the menstrual cycle than in IVF, with lower UC frequency 4 days after LH surge compared with 4 days after hcg, while E 2 and P levels were higher in IVF. Six days after LH surge/hcg administration, UC frequency was low in the menstrual cycle and in IVF. Conclusion(s): High UC frequency in IVF at the time of ET results from delayed establishment of uteroquiescence after ovulation in IVF as compared with the menstrual cycle. In IVF, low UC frequency 6 days after hcg may contribute to the higher pregnancy rates observed with blastocyst transfers. (Fertil Steril 2003;79: by American Society for Reproductive Medicine.) Key Words: IVF, uterine contractility, progesterone, embryo implantation, uterine receptivity Using E 2 and P replacement cycles designed for recipients of donor eggs in IVF as study model, we showed that the uterine contraction (UC) frequency promptly decreases after exposure of the uterus to P (1). In IVF however, UC frequency remains elevated during the luteal phase, notably, at the time of embryo transfer (ET) (2). Four days after hcg administration, we found that UC frequency remained elevated in a large fraction of women, an ominous finding for prognosis of IVF outcome (2). In a different study, we observed that in spite of being elevated at the time of ET, UC frequency was not abnormally high on the day of hcg administration in IVF (3). Based on these observations, we postulated that the excessively high UC frequency observed at the time of ET results from a state of relative resistance to the uteroquiescent properties of P in IVF. To verify these premises, we studied, in the same women, the changes in UC frequency encountered after ovulation in the menstrual cycle and hcg administration in IVF. Because direct visualization of uterine contractility on ultrasound has been validated for assessing UC frequency (4), we used this noninvasive method for our measurements. Ultrasound scans passing through the midsagittal plane of the uterus were performed every 2 days after ovulation and hcg surge or administration in the menstrual cycle and IVF, respectively. Data were analyzed by reviewing fast plays of ultrasound sequences (1) and using a three-dimen- 1101

2 sional derived approach as described elsewhere (1 4). MATERIALS AND METHODS Population Six women years of age (mean, 31.8 years) having regular menstrual cycles (28 2 days) were studied during IVF and the menstrual cycle immediately preceding IVF. All undertook IVF because of male factor infertility. All consented to this study, which was approved by our local Institutional Review Board. Study Protocol During the menstrual cycle preceding the scheduled IVF, women were instructed to self-analyze their first urine void for detecting the LH surge using urinary LH detection kits. On the presumed day of LH surge, women were instructed to report to the fertility clinic for measurement of plasma LH. If LH elevation was confirmed, women were definitively included in the study. Hormonal measurements (E 2 and P) and ultrasound scans were obtained for UC measurement. Further blood samplings and UC measurements were scheduled every 2 days until the sixth day after ovulation (LH 6). During the subsequent IVF cycle, uterine contractility was assessed on the day of hcg administration and every 2 days until the sixth day after hcg (day of retrieval, ET, and ET 2). All women underwent ET on the fourth day after hcg administration. On the days of retrieval and ET, UCs were analyzed before the clinical procedure. The IVF procedure was conducted using a classical long GnRH agonist (Decapetyl 0.1 mg; Ferring Laboratories, Switzerland) protocol followed by ovarian stimulation with highly purified hfsh (Metrodin-HP; Serono Pharmaceuticals, Switzerland). The usual criteria for triggering ovulation were applied by a clinical team not aware of the UC study and results. Luteal support was initiated on the day after oocyte retrieval using 100 mg of micronized P soft gelatin capsules (Utrogestan; Golaz Pharmaceuticals, Switzerland) administered vaginally at the dose of 200 mg three times per day. UC Frequency Measurement For UC frequency computation, 2 minute ultrasound scans were acquired using a 270 Toshiba ultrasound scanner equipped with a 5- to 7-MHz transvaginal probe (Toshiba, Tustin, CA). The ultrasound probe was positioned for obtaining optimal quality transverse scans of the uterus passing by the medial portion of the endometrial cavity. The probe was kept as still as possible during the whole image acquisition process ( 2 minutes). Ultrasound scans were immediately digitized using an off-line system and saved as sequences of digitized images for further analysis. Before computing UC frequency, each image sequence was accelerated and reviewed by one investigator (J.M.A) for quality assessment. For each recording, a 2-minute representative sequence was retained (based on image quality and stillness of the ultrasound recording). Each image sequence was then analyzed, using two distinct methodologies for assessing the number of contractile events identified as UC. First, the image sequences were fast played and reviewed and the number of UCs determined (fast-play method). Second, the same image sequences were processed for three-dimensional (3D) reconstruction using a commercially available system (IôDP, Paris, France) as described elsewhere (1 3) (3D method). Briefly, as the ultrasound probe was kept still (not swept through a given volume) during image acquisition, the third dimension (z-axis) on the generated 3D matrix became time. Therefore, the 3D reconstructions without spatial sweep during the image acquisition process allowed us to obtain electronically generated time mode (TM) graphs through any point between the cervical and fundal ends of the uterine cavity. On these electronic TM graphs, UCs were identified by vertical displacements of the endometrial-myometrial interface ( waves ), which were identified and counted, and the UC frequency was computed. Analysis For each measurement (in the menstrual cycle and IVF), mean UC frequency was computed with both methods and results compared using the paired Student s t-test and analysis of variance (ANOVA). As observed elsewhere (1), results of both methods were comparable (1). Hence, they were averaged and the mean was used for further analysis. Results obtained on the day of LH surge and hcg administration in the menstrual cycle and IVF, respectively, and each parallel measurement thereafter were compared using the 2-tailed paired t-test. Changes in UC frequency after ovulation/hcg in the menstrual cycle and IVF were compared by ANOVA. P.05 was considered statistically significant. RESULTS Hormonal Levels and IVF Data In the menstrual cycle, LH surge occurred between day 13 and day 17. In all women, results of the semiquantitative urine measurements were confirmed by a quantitative plasma assay. Plasma E 2 and P levels on the day of the LH surge and hcg administration and every 2 days thereafter for 6 days are depicted in Figure 1A and 1B. As expected, E 2 levels were higher on the day of hcg administration and at every point thereafter in IVF as compared with the values obtained at reciprocal times in the menstrual cycle. Plasma P, however, was lower at ng/ml (mean SEM) on the day of hcg administration compared with findings made on the day of LH surge ( ng/ml) in the menstrual cycle (P.05). This reflects the inhibition of the late follicular phase increase in plasma P achieved by suppressing endogenous gonadotropins with the routine use of GnRH agonists in IVF Ayoubi et al. Uterine contractions and IVF Vol. 79, No. 5, May 2003

3 FIGURE 1 Plasma E 2 (A) andp(b) levels at the time of LH surge in the menstrual cycle and hcg administration in IVF and every 2 days thereafter for the next 6 days. Results are provided on a semi-log scale and are expressed in units of pg/ml and ng/ml, respectively (mean SEM). At the time of LH surge/ hcg administration, E 2 levels were markedly higher in IVF and remained so thereafter. At the time of LH surge/hcg administration, P levels were slightly but significantly higher in the menstrual cycle. Starting 4 days after the LH surge/ hcg administration, P levels became markedly higher in IVF. *higher than IVF; **lower than IVF; P.05. Ayoubi. Uterine contractions and IVF. Fertil Steril Four days after ovulation/hcg administration, plasma P was markedly higher in IVF than in the menstrual cycle, reflecting the large number of functional corpus lutea present in IVF. As a result of IVF, two out of six patients became pregnant. UC Frequency Data UC frequency values obtained by the fast-play and 3D methods were comparable, as reported elsewhere (1). UC frequency data are depicted in Figure 2. Plotted data represent the mean of results obtained by the fast-play and 3D methods. At the end of the follicular phase when uterine contractility is maximal, mean UC frequency values were not significant (NS) comparable at UC/minute and UC/minute in the menstrual cycle (day of LH surge) and in IVF (day of hcg administration), respectively. In the menstrual cycle, a prompt decrease in UC frequency was observed. Maximal uterine quiescence was reached as early as 4 days after the LH surge (P.05). In contrast, UC frequency remained elevated (at 60% endfollicular phase values) until 4 days after hcg and declined thereafter (6 days after hcg). On the fourth day after LH surge/hcg administration, UC frequency was markedly higher at UC/minute (mean SEM) in IVF as compared with UC/minute measured in the menstrual cycle (P.05). DISCUSSION Our results showed similar UC frequency at the end of the follicular phase of menstrual and IVF cycles despite markedly higher E 2 levels in IVF. Reassuringly, menstrual cycle data concurred with prior reports using similar (4, 5) or different UC measurement techniques (4, 6). Our findings indicate, therefore, that the late follicular phase levels of E 2 seen in the menstrual cycle already exert maximal stimulation on uterine contractility. Conversely, the marked increase in E 2 levels seen in IVF does not further stimulate UC frequency. Contrasting with the similar findings made on the day of LH surge and hcg administration, different patterns of UC decline were observed after ovulation in the menstrual cycle and IVF. The prompt decline in UC frequency seen after ovulation in the menstrual cycle parallels our observations made in mock E 2 and P cycles after P administration (1). In contrast, the installation of uteroquiescence was significantly delayed by at least 2 days in IVF. Specifically, 4 days after LH surge/hcg administration, UC frequency was markedly higher in IVF than in the menstrual cycle. Elevated UC values 4 days after hcg confirm our prior observations made in IVF (2). Six days after LH/hCG, however, the uterus was equally quiescent in the menstrual cycle and IVF. Hence, our findings confirm prior reports (15) showing that UC frequency decreases at the time of blastocyst transfer. This speaks for expanding IVF culture and postponing ET when uterine contractility is excessive at the regular time of ET. The delayed decline in UC frequency observed in IVF after hcg as compared with after LH surge in the menstrual cycle occurs despite markedly higher P levels in IVF as early as 4 days after hcg administration (Fig. 1B). This leads us to postulate the existence of a relative resistance to the uteroquiescent properties of P in IVF. The factor most likely FERTILITY & STERILITY 1103

4 FIGURE 2 Uterine contraction (UC) in the menstrual cycle and IVF. On the day of LH surge/hcg administration, UC frequency was similar in the menstrual cycle and IVF. The establishment of uteroquiescence after ovulation was markedly different in the menstrual cycle and IVF. Four days after LH surge/hcg administration, UC frequency was markedly lower in the menstrual cycle (P.05), whereas the difference vanished 2 days later. *different from IVF; **different from baseline; P.005. Ayoubi. Uterine contractions and IVF. Fertil Steril responsible for the uterine resistance to P in IVF is E 2.E 2 is known to increase UC frequency and is seen as the primary agent responsible for the end follicular phase increase in UC frequency (4, 5, 7). However, that late follicular UC frequency values were similar in the menstrual cycle and IVF despite marked differences in E 2 levels does not absolve E 2 as a plausible culprit for the uterine resistance to P in IVF. Recently, Fanchin et al. (8) reported data supporting an incriminating role of the high E 2 levels in the relative resistance to the uterorelaxing properties of P. These investigators observed higher UC frequency when exogenous P was administered in women whose E 2 levels were supraphysiologically elevated by vaginal E 2 as compared with controls having E 2 levels within the physiological range. Alternate factors susceptible of generating the relative resistance to P effects seen in IVF are peptide substances normally produced by the developing follicles (inhibin B, etc.) or androgens. Like E 2, these products are produced in increased amounts in IVF because of the large cohort of follicles stimulated by controlled ovarian hyperstimulation treatments. Another hypothesis for the resistance to the uterorelaxing effects of P seen in IVF incriminates the inhibition of the late follicular slight increase in P by the routine use of GnRH agonist in IVF. This theory contends that the lack of a late follicular slight increase in P delays the uterine response even to full luteal levels of P produced after hcg administration. Supporting this contention, we previously observed that advancement in the sequence of histological changes occurring in endometrial glands depends on the duration since the first, albeit slight, increase in P rather than actual P levels (9). Support for a role of the late follicular phase slight increase in P in determining the total duration of exposure to P came from assessing the consequence of its experimental replacement in mock E 2 and P cycles (normally only replacing luteal P) (10, 11). In our earlier study, we observed that the delay in glandular changes described in conventional E 2 and P mock cycles by us (9) and others (12) was corrected when the late follicular phase slight increase in P was artificially reproduced (10, 11). These and other histological studies (13) indicate that high P levels (including high uterine tissue levels) do not make up for the delay in P exposure existing in common E 2 and P mock cycles where there is no replacement of the late follicular slight increase in P. This led us to conclude that the sequence of glandular changes depends on the duration of exposure to even the slightest elevation in P rather than absolute P levels. It is possible therefore that the myometrium s response to P also depends on the total duration of exposure to P rather than on P levels. Hence, by analogy, the delay in P exposure in IVF where there is no late follicular slight increase in P because of GnRH agonist use could also explain the delayed appearance of uteroquiescence in IVF. Our observation of significantly higher P levels on the day of LH surge (Fig. 1B) as compared with the day of hcg administration verified that the reported difference in late follicular phase levels of P actually occurred in our patients. However, at this stage we cannot either confirm or disprove a role of the late follicular levels of P in the difference in promptness with which uteroquiescence establishes itself after ovulation in the menstrual cycle and IVF. Another study comparing uterine contractility in menstrual and stimulated cycles used a parallel design and only compared findings in the follicular phase (14). Hence, to our 1104 Ayoubi et al. Uterine contractions and IVF Vol. 79, No. 5, May 2003

5 knowledge our study is the first comparing in the same patients the profile of changes in uterine contractility seen after ovulation in the menstrual cycle and in IVF. In conclusion, our results confirm the suspicion that the postovulatory establishment of uteroquiescence is different in IVF and menstrual cycles. In IVF, uteroquiescence is achieved 2 days later than in the menstrual cycle, on day 6 after hgc administration. This is clinically important because we previously observed that an increase in UC frequency on the day of ET is ominous for IVF outcome (2). As no firm data are available on the therapeutic value of uterorelaxants at the time of ET in IVF, our options are limited when UC frequency is excessive at the time of ET. Hence, delaying transfers until the blastocyst stage is probably the best practical option currently available. References 1. Ayoubi JM, Fanchin R, Kaddouz D, Frydman R, de Ziegler D. Uterorelaxing effects of vaginal progesterone: comparison of two methodologies for assessing uterine contraction frequency on ultrasound scans. Fertil Steril 2001;76: Fanchin R, Righini C, Olivennes F, Taylor S, de Ziegler D, Frydman R. Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization. Hum Reprod 1998;13: Fanchin R, Ayoubi JM, Olivennes F, Righini C, de Ziegler D, Frydman R. Hormonal influence on the uterine contractility during controlled ovarian hyperstimulation. Hum Reprod 2000;15: Bulletti C, de Ziegler D, Polli V, Diotallevi L, Del Ferro E, Flamigni C. Uterine contractility during the menstrual cycle. Hum Reprod 2000;15: Abramowicz JS, Archer DF. Uterine endometrial peristalsis a transvaginal ultrasound study. Fertil Steril 1990;54: Martinez-Gaudio M, Yoshida T, Bengtsson LP. Propagated and nonpropagated myometrial contractions in menstrual cycles. Am J Obstet Gynecol 1973;115: IJland MM, Evers JLH, Dunselman GAJ, van Katwijk C, Lo CR, Hoogland HJ. Endometrial wavelike movements during the menstrual cycle. Fertil Steril 1996;65: Fanchin R, Righini C, Schonauer LM, Olivennes F, Filho JS, Frydman R. Vaginal versus oral E(2) administration: effects on endometrial thickness, uterine perfusion, and contractility. Fertil Steril 2001;76: de Ziegler D. Hormonal strategies for preparing the human endometrium prior to oocyte donation. Sem Reprod Med 1995;13: de Ziegler D, Fanchin R, Massonneau M, Bergeron C, Frydman R, Bouchard P. Hormonal control of endometrial receptivity. The egg donation model and controlled ovarian hyperstimulation. Ann NY Acad Sci 1994;734: de Ziegler D, Fanchin R, de Moustier B, Bulletti C. The hormonal control of endometrial receptivity: estrogen (E2) and progesterone. J Reprod Immunol 1998;39: Navot D, Anderson TL, Droesch K, Scott RT, Kreiner D, Rozenwaks Z. Hormonal manipulation of endometrial maturation. J Clin Endocrinol Metab 1989;68: Younis JS, Simon A, Laufer N. Endometrial preparation: lessons from oocyte donation. Fertil Steril 1996;66: Eytan O, Halevi I, Har-Toov J, Wolman I, Elad D, Jaffa A. Characteristics of uterine peristalsis in spontaneous and induced cycles. Fertil Steril 2001;76: Fanchin R, Ayoubi JM, Righini C, Olivennes F, Schonauer LM, Frydman R. Uterine contractility decreases at the time of blastocyst transfers. Hum Reprod 2001;16: FERTILITY & STERILITY 1105

Treatment with piroxicam before embryo transfer increases the pregnancy rate after in vitro fertilization and embryo transfer

FERTILITY AND STERILITY VOL. 82, NO. 4, OCTOBER 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Treatment with piroxicam before