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Poor response—oocyte quantity or quality?
group, only 1 U of blood was transfused to two patients (each patient receiving .5 U). We do not score this condition as the “need for blood transfusion.” This blood transfusion was performed as a prophylactic precaution and was not scored as a routine procedure. Following this scheme, the need for blood transfusion could be regarded as 33.3% in the placebo group and 0% in the misoprostol group. When the nominal scale with the integers described above is used, the difference between the control and treated group is significant. The failure to spell out the comparative scaling of the blood transfusion end point was overlooked despite many revisions of the manuscript. This oversight probably occurred because of a routine procedure that is practiced in our clinic. Usually, hypovolemic patients are transfused when they need at least 2 U of blood. In cases where more units of blood must be given, patients are generally treated with other volume supplements. As seen in our article, postoperative hemoglobin (g/dL) concentration did not fall below 9 g/dL in the misoprostol group. During the study, transfusion was started in two of the misoprostol patients as a precautionary measure but subsequently discontinued. As can be understood, these two patients did not require a blood transfusion according to our criteria and were scored as 0. It is unfortunate that we did not elaborate in detail on our scoring system for summarizing the transfusion data. We apologize to our readers. The other comment of Dr. Chan, based on comparison with a previous publication from the Cochrane Database, suggests that misoprostol might be more effective than GnRH analogues in reducing intraoperative blood loss during elective myomectomy (2). In our study, the use of preoperative misoprostol was not compared with an active control, such as GnRH or vasopressin. Other methods were mentioned merely to emphasize some advantages related to the cost and ease of application of misoprostol. Husnu Çelik, M.D. Department of Obstetrics and Gynecology Firat University Medical School Elazig, Turkey December 23, 2003
References 1. C¸ elik H, Sapmaz E. Use of a single preoperative dose of misoprostol is efficacious for patients who undergo abdominal myomectomy. Fertil Steril 2003;79:1207–10. 2. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev 2001;(2):CD000547.
doi:10.1016/j.fertnstert.2004.01.011
Poor response— oocyte quantity or quality? To the Editor: Doctors De Sutter and Dhont (1) report that, in a retrospective analysis of their data, young women who responded FERTILITY & STERILITY威
well to ovarian stimulation with gonadotropins produced significantly more good-quality embryos and had significantly higher pregnancy rates with IVF than did women of the same age with a less good response. Nevertheless, whenever excellent embryos were available for transfer, even women who had responded less well had reasonable implantation and ongoing pregnancy rates. Older women tended to have lower pregnancy rates, even if they had responded well, which would suggest that a percentage of the age-related decline of oocyte quality is not predicted by the response to stimulation and that there is also a deterioration of the endometrium with age. A number of controlled longitudinal studies (2, 3) have shown that a poor response to ovarian stimulation at a relatively young age is linked to earlier ovarian aging, hence IVF can be seen as an extended dynamic assay of the ovarian reserve. On the basis of a number of clinical and laboratory observations, it has been suggested that, generally, quantity and overall quality of the remaining pool of oocytes must be closely correlated (4). Possibly the best oocytes are recruited first, at a younger age. It is also possible that women who go into menopause earlier were born with fewer oocytes. Unfortunately, the report by De Sutter and Dhont (1) does not include a follow-up of the patients, thus we do not know whether a poorer response at a young age predicted earlier ovarian aging for these women. In addition, one wonders whether a proportion of the “poor responders” in this report were, in fact, women with perfectly healthy ovaries who simply received a more “friendly” regimen. All the women in the report reached egg collection, therefore a number of true poor responders must have been excluded from the analysis and the discussion. How many were they? What were the criteria for cancellations? The authors used a cut-off limit of 225 IU/day. This might have been too low (5). Because of different FSH thresholds, some women will respond rather poorly to a relatively low dose of ovarian stimulation but much better to a slightly higher dose, although increasing beyond a limit rarely improves the outcome significantly. It is not clear in this report how the groups compared in terms of total FSH used (means and SDs), age, duration of infertility, and parity. Could the authors also provide comparative data on the fertilization rate, the rate of excellent embryos per egg collected with IVF and intracytoplasmic sperm injection, and the ongoing pregnancy per egg collected in the various groups? Can we assume that only one cycle per patient was included in the analysis and that the apparent overlap of the groups in Table 2 is a typing error? Dimitrios S. Nikolaou, M.D., M.R.C.O.G. Department of Obstetrics and Gynaecology Assisted Conception Unit Chelsea and Westminster Hospital London, United Kingdom September 24, 2003
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References 1. De Sutter P, Dhont M. Poor response after hormonal stimulation for in-vitro fertilization is not related to ovarian aging. Fertil Steril 2003; 79:1294 –8. 2. Lawson R, El-Toukhy T, Kassab A, Taylor A, Braude P, Parsons J, et al. Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis. Hum Reprod 2003;18:527–33. 3. de Boer EJ, Den Tonkelaar I, te Velde ER, Burger CW, Klip H, Van Leuwen F. A low number of retrieved oocytes at in vitro fertilization treatment is predictive of early menopause. Fertil Steril 2002;77:978 –85. 4. Nikolaou D, Templeton A. Early ovarian ageing: a hypothesis. Detection and clinical relevance. Hum Reprod 2003;18:1137–9. 5. Keay SD, Liversedge NH, Mathur RS, Jenkins JM. Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol 1997;104:521–5.
doi:10.1016/j.fertnstert.2004.01.012
To the Editor: We would like to draw attention to some incorrect suggestions put forward by De Sutter and Dhont (1) in their recent report. In this study, a retrospective analysis of young poor responders was carried out, in which they were compared with young normal responders. The authors came to the conclusion that young poor responders cannot be considered ovarian-aged patients because pregnancy rates in young poor and normal responders do not differ if embryos of similar quality are transferred. They claim that in young poor responders the outcome of IVF is determined by the number of oocytes and hence by the probability of obtaining one or two good-quality embryos. They conclude thereby that oocyte quantity is the predominant problem in those young poor responders and not oocyte quality. We think the data presented do not justify these conclusions. First, in the study of the young poor responders, patients with no oocytes retrieved or patients cancelled owing to poor or absent response were not included in the analysis, which resulted in a positive selection of the poorresponder group. Moreover, a certain number of poor responders were assigned to this group by chance and will in fact be normal responders (regression to the mean [2]) and thus contribute further to a positive selection. Second, the proportion of patients reaching a transfer of two high-quality (good or excellent) embryos was clearly lower in young poor responders (32%) compared with young normal responders (52%). In those who did not reach the high-quality embryo transfer, the pregnancy rate in the young poor responders was 15%, in contrast to the young normal responders without high-quality embryos, who reached a pregnancy rate of 32%. So, young poor responders more often did not deliver highquality embryos, and in those patients embryos were of lesser quality compared with the young normal responders. The final proof for this statement can only be given if implantation rates in this subgroup were calculated. Nevertheless, it seems justified to conclude that young poor responders do have an oocyte quality problem in a considerable percentage of cases. Third, in two independent studies,
a clear relation has been shown between the occurrence of poor response in maximal stimulation in IVF and the early presence of climacteric cycle irregularity and menopause (3, 4). This also supports the view that poor responders frequently represent a group of women with advanced reproductive age, although in young women the possibility of insufficient stimulation by exogenous FSH must be kept in mind. In all, we think the authors have drawn the wrong conclusion from the analysis of their data. At one point, however, we agree with the authors. In young poor responders, the diagnosis of advanced reproductive age should not be automatic. Additional information, such as basal FSH level and antral follicle count, as well as the effect of increased FSH dosage, should direct the way in which these patients are counseled before and during IVF treatment (5). Frank J. Broekmans, Ph.D., M.D. Iles A. J. van Rooij, M.D. E. R. Klinkert, M.D. Egbert R. te Velde, Ph.D. Division for Reproductive Medicine Department of Perinatology and Gynecology University Medical Center Utrecht, The Netherlands December 16, 2003
References 1. De Sutter P, Dhont M. Poor response after hormonal stimulation for in vitro fertilization is not related to ovarian aging. Fertil Steril 2003;79: 1294 – 8. 2. Pantos C, Thornton SJ, Speirs AL, Johnston I. Increasing the human menopausal gonadotropin dose— does the response really improve? Fertil Steril 1990;53:436 –9. 3. de Boer EJ, den Tonkelaar I, te Velde ER, Burger CW, van Leeuwen FE. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod 2003;18:1544 – 52. 4. Lawson R, El Toukhy T, Kassab A, Taylor A, Braude P, Parsons J, et al. Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis. Hum Reprod 2003;18:527–33. 5. van Rooij IA, Bancsi LF, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Women older than 40 years of age and those with elevated follicle-stimulating hormone levels differ in poor response rate and embryo quality in in vitro fertilization. Fertil Steril 2003;79:482–8.
doi:10.1016/j.fertnstert.2004.01.013
Reply of the Authors: It is with great attention that we read the letters by Drs. Nikolaou and Broekmans et al. regarding our article, and we are very pleased that our report raised such interest among experts; it shows that the subject of ovarian aging and poor response still is a controversial topic. Dr. Nikolaou states that the fact that older women tend to have lower pregnancy rates could be the result of a deterioration of the endometrium with age. We believe our data indicate that the oocytes of older women tend to be more aneuploid than those of younger women, because age was the only determinate for a decline in pregnancy rates and an Vol. 81, No. 4, April 2004
1162
References 1. C¸ elik H, Sapmaz E. Use of a single preoperative dose of misoprostol is efficacious for patients who undergo abdominal myomectomy. Fertil Steril 2003;79:1207–10. 2. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev 2001;(2):CD000547.
doi:10.1016/j.fertnstert.2004.01.011
Poor response— oocyte quantity or quality? To the Editor: Doctors De Sutter and Dhont (1) report that, in a retrospective analysis of their data, young women who responded FERTILITY & STERILITY威
well to ovarian stimulation with gonadotropins produced significantly more good-quality embryos and had significantly higher pregnancy rates with IVF than did women of the same age with a less good response. Nevertheless, whenever excellent embryos were available for transfer, even women who had responded less well had reasonable implantation and ongoing pregnancy rates. Older women tended to have lower pregnancy rates, even if they had responded well, which would suggest that a percentage of the age-related decline of oocyte quality is not predicted by the response to stimulation and that there is also a deterioration of the endometrium with age. A number of controlled longitudinal studies (2, 3) have shown that a poor response to ovarian stimulation at a relatively young age is linked to earlier ovarian aging, hence IVF can be seen as an extended dynamic assay of the ovarian reserve. On the basis of a number of clinical and laboratory observations, it has been suggested that, generally, quantity and overall quality of the remaining pool of oocytes must be closely correlated (4). Possibly the best oocytes are recruited first, at a younger age. It is also possible that women who go into menopause earlier were born with fewer oocytes. Unfortunately, the report by De Sutter and Dhont (1) does not include a follow-up of the patients, thus we do not know whether a poorer response at a young age predicted earlier ovarian aging for these women. In addition, one wonders whether a proportion of the “poor responders” in this report were, in fact, women with perfectly healthy ovaries who simply received a more “friendly” regimen. All the women in the report reached egg collection, therefore a number of true poor responders must have been excluded from the analysis and the discussion. How many were they? What were the criteria for cancellations? The authors used a cut-off limit of 225 IU/day. This might have been too low (5). Because of different FSH thresholds, some women will respond rather poorly to a relatively low dose of ovarian stimulation but much better to a slightly higher dose, although increasing beyond a limit rarely improves the outcome significantly. It is not clear in this report how the groups compared in terms of total FSH used (means and SDs), age, duration of infertility, and parity. Could the authors also provide comparative data on the fertilization rate, the rate of excellent embryos per egg collected with IVF and intracytoplasmic sperm injection, and the ongoing pregnancy per egg collected in the various groups? Can we assume that only one cycle per patient was included in the analysis and that the apparent overlap of the groups in Table 2 is a typing error? Dimitrios S. Nikolaou, M.D., M.R.C.O.G. Department of Obstetrics and Gynaecology Assisted Conception Unit Chelsea and Westminster Hospital London, United Kingdom September 24, 2003
1161
References 1. De Sutter P, Dhont M. Poor response after hormonal stimulation for in-vitro fertilization is not related to ovarian aging. Fertil Steril 2003; 79:1294 –8. 2. Lawson R, El-Toukhy T, Kassab A, Taylor A, Braude P, Parsons J, et al. Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis. Hum Reprod 2003;18:527–33. 3. de Boer EJ, Den Tonkelaar I, te Velde ER, Burger CW, Klip H, Van Leuwen F. A low number of retrieved oocytes at in vitro fertilization treatment is predictive of early menopause. Fertil Steril 2002;77:978 –85. 4. Nikolaou D, Templeton A. Early ovarian ageing: a hypothesis. Detection and clinical relevance. Hum Reprod 2003;18:1137–9. 5. Keay SD, Liversedge NH, Mathur RS, Jenkins JM. Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol 1997;104:521–5.
doi:10.1016/j.fertnstert.2004.01.012
To the Editor: We would like to draw attention to some incorrect suggestions put forward by De Sutter and Dhont (1) in their recent report. In this study, a retrospective analysis of young poor responders was carried out, in which they were compared with young normal responders. The authors came to the conclusion that young poor responders cannot be considered ovarian-aged patients because pregnancy rates in young poor and normal responders do not differ if embryos of similar quality are transferred. They claim that in young poor responders the outcome of IVF is determined by the number of oocytes and hence by the probability of obtaining one or two good-quality embryos. They conclude thereby that oocyte quantity is the predominant problem in those young poor responders and not oocyte quality. We think the data presented do not justify these conclusions. First, in the study of the young poor responders, patients with no oocytes retrieved or patients cancelled owing to poor or absent response were not included in the analysis, which resulted in a positive selection of the poorresponder group. Moreover, a certain number of poor responders were assigned to this group by chance and will in fact be normal responders (regression to the mean [2]) and thus contribute further to a positive selection. Second, the proportion of patients reaching a transfer of two high-quality (good or excellent) embryos was clearly lower in young poor responders (32%) compared with young normal responders (52%). In those who did not reach the high-quality embryo transfer, the pregnancy rate in the young poor responders was 15%, in contrast to the young normal responders without high-quality embryos, who reached a pregnancy rate of 32%. So, young poor responders more often did not deliver highquality embryos, and in those patients embryos were of lesser quality compared with the young normal responders. The final proof for this statement can only be given if implantation rates in this subgroup were calculated. Nevertheless, it seems justified to conclude that young poor responders do have an oocyte quality problem in a considerable percentage of cases. Third, in two independent studies,
a clear relation has been shown between the occurrence of poor response in maximal stimulation in IVF and the early presence of climacteric cycle irregularity and menopause (3, 4). This also supports the view that poor responders frequently represent a group of women with advanced reproductive age, although in young women the possibility of insufficient stimulation by exogenous FSH must be kept in mind. In all, we think the authors have drawn the wrong conclusion from the analysis of their data. At one point, however, we agree with the authors. In young poor responders, the diagnosis of advanced reproductive age should not be automatic. Additional information, such as basal FSH level and antral follicle count, as well as the effect of increased FSH dosage, should direct the way in which these patients are counseled before and during IVF treatment (5). Frank J. Broekmans, Ph.D., M.D. Iles A. J. van Rooij, M.D. E. R. Klinkert, M.D. Egbert R. te Velde, Ph.D. Division for Reproductive Medicine Department of Perinatology and Gynecology University Medical Center Utrecht, The Netherlands December 16, 2003
References 1. De Sutter P, Dhont M. Poor response after hormonal stimulation for in vitro fertilization is not related to ovarian aging. Fertil Steril 2003;79: 1294 – 8. 2. Pantos C, Thornton SJ, Speirs AL, Johnston I. Increasing the human menopausal gonadotropin dose— does the response really improve? Fertil Steril 1990;53:436 –9. 3. de Boer EJ, den Tonkelaar I, te Velde ER, Burger CW, van Leeuwen FE. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod 2003;18:1544 – 52. 4. Lawson R, El Toukhy T, Kassab A, Taylor A, Braude P, Parsons J, et al. Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis. Hum Reprod 2003;18:527–33. 5. van Rooij IA, Bancsi LF, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Women older than 40 years of age and those with elevated follicle-stimulating hormone levels differ in poor response rate and embryo quality in in vitro fertilization. Fertil Steril 2003;79:482–8.
doi:10.1016/j.fertnstert.2004.01.013
Reply of the Authors: It is with great attention that we read the letters by Drs. Nikolaou and Broekmans et al. regarding our article, and we are very pleased that our report raised such interest among experts; it shows that the subject of ovarian aging and poor response still is a controversial topic. Dr. Nikolaou states that the fact that older women tend to have lower pregnancy rates could be the result of a deterioration of the endometrium with age. We believe our data indicate that the oocytes of older women tend to be more aneuploid than those of younger women, because age was the only determinate for a decline in pregnancy rates and an Vol. 81, No. 4, April 2004
1162