Human Reproduction, Vol. 16, No. 3, 500-503,
March 2001
© 2001 European Society of Human Reproduction and Embryology
Use of microdose GnRH agonist protocol in women with low ovarian volumes undergoing IVF*
1 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
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Abstract |
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Ovarian volume measurements have been recently shown to be predictive of response to ovarian stimulation. Women with small ovarian volumes, i.e. <3 cm3, have a higher incidence of cycle cancellation, together with a lower peak oestradiol concentration, lower number of retrieved oocytes, and lower pregnancy rates, compared with women with larger ovarian volumes. We prospectively investigated whether a higher dose, microdose flare gonadotrophin-releasing hormone (GnRH) agonist protocol, can improve IVF outcome in women with a small ovarian volume. Only the first IVF cycle was reviewed. In total, 109 women aged <40 years undergoing 109 cycles were prospectively evaluated. Women with an ovarian volume of
3 cm3 noted on the day of luteal GnRH agonist administration had their stimulation regimen changed to a more aggressive microdose flare GnRH agonist protocol. In all, 30 women (27.5%) with an ovarian volume of <3 cm3, and 79 women (72.5%) with an ovarian volume of >3 cm3 were compared. Women with an ovarian volume of <3 cm3 had a significantly higher incidence of unexplained infertility as their presenting aetiology, compared with women with a larger ovarian volume (33 and 8.6%, P = 0.0036). There was a significant negative correlation between age and ovarian volume, and between day 3 FSH concentration and ovarian volume. We also report a significant positive correlation between body mass index and ovarian volume. There was also a significant positive correlation between ovarian volume and the number of oocytes retrieved. Despite a trend towards higher day 3 FSH concentrations, a significantly longer duration of stimulation, higher gonadotrophin requirements, and lower oocyte yield, the implantation and pregnancy rates were comparable between the two groups. Women with a small ovarian volume noted at baseline ultrasound can have comparable implantation and pregnancy rates to those with larger ovarian volumes with the use of a higher dose gonadotrophin, microdose GnRH agonist stimulation.
Key words: GnRH agonist/IVF/low ovarian volume/microdose protocol
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Introduction |
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Ovarian volume has been shown to be predictive of response to ovarian stimulation in IVF (Syrop et al., 1995
; Oyesanya et al., 1995; Danninger et al., 1996; Lass et al., 1997; Tomas et al., 1997; Lass and Brinsden, 1999; Syrop et al., 1999). In particular, women with a mean ovarian volume of 3 cm3, or women whose volume of the smallest ovary was 3 cm3, have a very high incidence of cycle cancellations, significantly lower number of retrieved oocytes and embryos obtained, and significantly lower pregnancy rates than women with an ovarian volume of >3 cm3 (Syrop et al., 1995, 1999; Lass et al., 1997). In addition, ovarian volume has been shown to be predictive of women at risk of developing ovarian hyperstimulation syndrome (Oyesanya et al., 1995; Danninger et al., 1996). However, all the previous investigations used standardized ovarian stimulation protocols, i.e. long luteal protocols. We prospectively evaluated the role of ovarian volume in our IVF population. In addition, we changed the stimulation protocol from a long luteal gonadotrophin-releasing hormone (GnRH) agonist protocol to a more aggressive microdose flare protocol if we detected a small ovarian volume at baseline ultrasound (day of proposed luteal GnRH agonist start). |
Materials and methods |
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Population
Data from IVF cycles in our university-based programme between April 1997 and October 1999 were analysed in this study. Exclusion criteria included women aged
40 years, women with only one ovary, women with a basal FSH concentration of >12 IU/l, those with ovarian follicles >8 mm on baseline ultrasound, those with visible endometriomata, women who had blastocyst or frozen embryo transfers, and donor oocyte-derived embryo transfers. Only the first IVF cycle was analysed to minimize selection bias.
Stimulation protocol
Women underwent either a standard long luteal leuprolide acetate (LA) protocol or a modified microdose LA flare protocol (Lupron; TAP, North Chicago, IL, USA). In the standard long LA protocol, pituitary desensitization was followed by administration of FSH (Fertinex and Gonal-F; Serono, Randolph, MA, USA; Follistim; Organon, West Orange, NJ, USA) and/or human menopausal gonadotrophin (HMG, Humegon; Organon and Repronex; Ferring, White Plains, NY, USA) starting with 2–4 ampoules per day. Patients who underwent the modified microdose LA flare protocol received 50 µg of LA two times daily together with six ampoules daily of FSH and/or HMG beginning on day 3 of a withdrawal bleed following at least 3 weeks of oral contraceptive use. When at least three follicles were >18 mm, 10 000 IU human chorionic gonadotrophin (HCG, Profasi; Serono, Randolph, MA, USA) was administered. Oocyte retrieval was performed 34–36 h later, and embryo transfer was performed 72 h after retrieval under ultrasound guidance using a Wallace catheter (Edwards-Wallace Catheter; Marlow Technologies, Willoughby, OH, USA). The luteal phase was supported using 50–100 mg of progesterone in oil i.m. daily. Biochemical pregnancies were considered a failure to conceive. An ultrasound scan to confirm the number of sacs and fetal viability was performed at 5–6 weeks gestation. Ongoing pregnancy rate implies delivered or ongoing pregnancies of >20 weeks. Implantation rate denotes the number of gestational sacs divided by the number of replaced embryos.
Ultrasound and laboratory assays
Stimulation response was monitored with serial measurements of serum oestradiol and transvaginal ultrasonic evaluation of follicle number and size. All ultrasound measurements were performed using a 6.5 MHz vaginal probe (Performa, Phoenix, AZ, USA). Ovarian volume measurements were taken on the day of potential luteal LA start. Ovarian volume was calculated using the ellipsoid formula (0.526 D1xD2xD3). Serum FSH was measured on cycle day 3 prior to initiation of stimulation protocol utilizing a microparticle enzyme immunoassay (Abbott Axsym System; Abbott Pharmaceuticals, Abbott Park, IL, USA). The upper limit of normal in our laboratory is 10 IU/l (conversion factor to SI units, 1.0). Serum oestradiol was measured using a radioimmunoassay (Coat-a-count; Diagnostic Products, Los Angeles, CA, USA).
Statistical analysis
Data are expressed as mean ± SD. The 
2, Mann–Whitney Rank sum, or Student's t-tests were used as appropriate; P < 0.05 was considered to be statistically significant.
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Results |
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Table I
shows the incidence of various infertility aetiologies. The incidence of unexplained infertility was significantly higher in women with an ovarian volume of 3 cm3 compared with women with a larger ovarian volume (33 and 8.6% respectively, P = 0.0036). There was a significant negative correlation between age and ovarian volume (P < 0.001), and between day 3 FSH and ovarian volume (P < 0.001). In addition, there was a significant positive correlation between body mass index (BMI) and ovarian volume (P < 0.001).
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Tables II and III
show the ovarian stimulation characteristics and cycle outcome. There was a trend towards a higher day 3 FSH concentrations in women with small ovarian volume, and a significantly higher number of days of stimulation in the small ovarian volume group (P = 0.05). There was a significant positive correlation between ovarian volume and the number of retrieved oocytes (P < 0.001). In addition, women with a small ovarian volume had a significantly lower number of retrieved oocytes compared with the group with larger ovarian volume (P = 0.03). The cycle cancellation rate did not differ between the two groups, despite a trend towards a higher cycle cancellation rate in the small ovarian volume group. The clinical pregnancy and implantation rates were comparable between the two groups and the miscarriage and ongoing pregnancy rates were also comparable.
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There were a total of 16 cancelled cycles (14.7%), six (20.0%) in the <3 cm3 group, and 10 (12.6%) in the >3 cm3 group (not significant, power only 12%). We also did not find any significant differences in implantation or clinical pregnancy rates when we further subdivided the >3 cm3 group into 3–5.9, 6–9, and >9 cm3 (Figure 1
).
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Discussion |
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In this study, we found that women with a small ovarian volume have a significantly higher incidence of unexplained infertility than women with a larger ovarian volume. It is important to note that all these women had normal basal FSH concentrations, and therefore small ovarian volumes are detected on ultrasound before the basal FSH concentrations become abnormal. Small ovarian volume can thus be included as a separate infertility aetiology that is easily diagnosed by ultrasound.
In agreement with most, but not all, prior studies (Syrop et al., 1995; Lass et al., 1997; Tomas et al., 1997; Sharara and McClamrock, 1999), we found a significant negative correlation between age and ovarian volume, and between day 3 FSH concentrations and ovarian volume. We found a significant correlation between ovarian volume and the number of retrieved oocytes, confirming prior studies (Syrop et al., 1995; Lass et al., 1997; Tomas et al., 1997). In addition, we are the first to report a significant positive correlation between BMI and ovarian volume.
Women with a small ovarian volume have been previously shown to have a compromised stimulation response when standardized long luteal protocols are used. In a retrospective evaluation of 188 women undergoing IVF, aged 23–45 years (Syrop et al., 1995), all women had their ultrasound examination on day 23, before initiation of down-regulation with LA. Exclusion criteria included any follicles/cysts 15 mm and prior ovarian surgery. The volume of the smallest ovary and the total ovarian volume (right + left ovarian volumes) were calculated. All women then underwent a standard long luteal protocol. Of the 188 cycles, 26 (14%) were cancelled for poor response. The mean (± SD) of the smallest ovary was 6.0 ± 3.0 cm3. Patients were then divided into three groups according to their SD (< –1 SD, mean ± SD, > +1 SD). Women whose volume of the smallest ovary was <3 cm3 (–1 SD; n = 18) had the highest cancellation rate (22%). The cancellation rate was 0% in 26 cycles if the ovarian volume of the smallest ovary was >9 cm3 (+1 SD). The cancellation rate for the 144 cycles whose ovarian volume was 3–9 cm3 was 14%. The authors also found a significant correlation between the number of retrieved oocytes, number of resulting embryos, and clinical pregnancy rate, and ovarian volume. The pregnancy rate decreased from 46 to 28% when the ovarian volume of the smallest ovary decreased from >9 to <3 cm3. If the total ovarian volume was used instead, the clinical pregnancy rate decreased from 50 to 31% between the women whose total ovarian volume was >22 and <8.6 cm3. The authors did not find a correlation between age and ovarian volume, but found a significant correlation between smoking and smaller ovarian volume (Syrop et al., 1995).
A total of 279 women were prospectively evaluated (Lass et al., 1997). Exclusion criteria included women with only one ovary, women with partial oophorectomy, and if either ovary contained a follicle/cyst of >10 mm in diameter. Women with polycystic-like ovaries were also excluded. In total, 140 women participated in the study. Again, the ovarian stimulation was a standardized long luteal protocol. Ovarian volume were calculated the day of initiation of gonadotrophins, i.e. after down-regulation. The mean ovarian volume was 6.3 ± 3.1 cm3, with a range 0.5–18.9 cm3. Group A (n = 17) included those with mean ovarian volume <1 SD, i.e. <3 cm3. Group B (n = 123) included women with a mean ovarian volume of >3 cm3. Unlike prior studies (Syrop et al., 1995; Tomas et al., 1997), but similar to our results, Lass et al. found a significant negative correlation between age and ovarian volume, and `very small ovaries were not seen only in older women but at all ages' (Lass et al., 1997), which we also noted in our patient population. Basal FSH, cycle cancellation, and number of gonadotrophin ampoules were significantly higher in group A, and number of follicles and number of retrieved oocytes were significantly lower in group A compared with B. The cycle cancellation rate was 52.9% in group A, compared with 8.9% for group B (P < 0.0001). Of note, despite the significantly higher basal FSH in group A, all values were within the normal range. Unfortunately, no information can be deduced about the correlation between ovarian volume and pregnancy rates, since both groups had low pregnancy rates (11.8 and 11.4%) (Lass et al., 1997).
In a follow-up study, Syrop et al. retrospectively reviewed the first treatment cycle for 261 patients undergoing IVF (Syrop et al., 1999). A standard stimulation regimen was used for all women. Again, the volume of the smallest ovary was also predictive of clinical pregnancy. When considered with age, smoking status, and ovarian volume, day 3 FSH values failed to be significant predictors of any ovarian stimulation outcome (Syrop et al., 1999). We agree with Syrop's observation in that FSH concentrations tend to become abnormal with smaller ovarian volume.
All the above studies measured ovarian volume either on the day of GnRH agonist start or the day of gonadotrophin start. Whether the ovarian volume measurements (and antral follicle count) are altered in response to the short course of GnRH agonist was recently addressed (Sharara et al., 1999). Using 38 women as their own controls, we found no impact of GnRH agonist on either ovarian volume or antral follicle count. We recommend that baseline ultrasound measurements should be performed before, and not after, pituitary down-regulation to leave room for a change in the stimulation protocol (Sharara et al., 1999). Antral follicle count is showing promise as a predictor of stimulation response (Fratarelli et al., 2000; Ng et al., 2000). We believe the combined use of antral follicle count and ovarian volume will become as routine as measuring basal FSH concentrations in all infertility programmes.
The cycle cancellation rate, peak oestradiol, number of retrieved oocytes, and number of resulting embryos were all improved when compared with the results obtained in the published studies (Syrop et al., 1995, 1999; Lass et al., 1997). We did not randomize our patients with small ovarian volume to undergo a standard long luteal or a microdose flare protocol because we felt the previously published data were so conclusive that we would be committing our patients to a poor outcome if we proceeded with a standard long luteal protocol. Whether other stimulation protocols besides the microdose flare (e.g. the `stop-lupron' protocol) are of benefit in women with small ovarian volume remains to be investigated. In addition, whether the use of the microdose flare protocol in women with FSH >12 IU/l and small ovarian volume can improve the low pregnancy rate in these women remains to be investigated even though we believe that, by the time both ovarian volume and FSH become abnormal, very little can be done to change the outcome of these women, other than the use of donor oocyte or adoption.
In conclusion, women with small ovarian volume noted at baseline ultrasound can have comparable implantation and pregnancy rates to women with larger ovarian volume with the use of a more aggressive ovarian stimulation, despite a significantly longer duration of stimulation, higher gonadotrophin requirements, and lower oocyte yield. Identifying these women before initiating ovarian stimulation is critical, and stimulation protocols should therefore be adjusted accordingly. A small ovarian volume necessitates a change in stimulation protocol. The measurement of ovarian volume should become a routine, non-invasive, and early step in the infertility investigation. Larger studies are needed to confirm our findings.
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Notes |
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* Presented in part at the ESHRE 16th Annual Meeting, Bologna, Italy, June 25–28, 2000
2 To whom correspondence should be addressed at present address: Fertility and Reproductive Health Center, 4316 Evergreen Lane, Annandale, VA 22003, USA. E-mail: fsharara{at}bellatlantic.net
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References |
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Danninger, B., Brunner, M., Obruca, A. and Feichtinger, W. (1996) Prediction of ovarian hyperstimulation syndrome of baseline ovarian volume prior to stimulation. Hum. Reprod., 11, 1597–1599.
Fratarelli, J.L., Lauria-Costa, D.F., Miller, B.T. et al. (2000) Basal antral follicle number and mean ovarian diameter predict cycle cancellation and ovarian responsiveness in assisted reproductive cycles. Fertil. Steril., 74, 51–57.
Lass, A. and Brinsden, P. (1999) The role of ovarian volume in reproductive medicine. Hum. Reprod. Update, 5, 256–266.
Lass, A., Skull, J., McVeigh, E. et al. (1997) Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotrophin for in-vitro fertilization can predict poor response. Hum. Reprod., 12, 294–297.
Ng, E.H, Tang, O.S. and Ho, P.C (2000) The significance of the number of antral follicles prior to stimulation in predicting ovarian responses in an IVF programme. Hum. Reprod., 15, 1937–1942.
Oyesanya, O.A., Parsons, J.H., Collins, W.P. and Campbell, S. (1995) Total ovarian volume before human chorionic gonadotrophin administration for ovulation induction may predict the hyperstimulation syndrome. Hum. Reprod., 10, 3211–3212.
Sharara, F.I. and McClamrock, H.D (1999) The effect of aging on ovarian volume measurements in infertile women. Obstet. Gynecol., 94, 57–60.[Web of Science][Medline]
Sharara, F.I., Lim, J. and McClamrock, H.D. (1999) The effect of pituitary desensitization on ovarian volume measurements prior to in-vitro fertilization. Hum. Reprod., 14, 183–185.
Syrop, C.H., Willhoite, A. and Van Voorhis, B.J. (1995) Ovarian volume: a novel predictor for assisted reproduction. Fertil. Steril., 64, 1167–1171.[Web of Science][Medline]
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Tomas, C., Nuojua-Huttunen, S. and Martikainen, H. (1997) Pretreatment transvaginal ultrasound examination predicts ovarian responsiveness to gonadotrophins in in-vitro fertilization. Hum. Reprod., 12, 220–223.
Submitted on September 1, 2000; accepted on November 27, 2000.
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