7447 Old York Road, Melrose Park, PA19027, USA e-mail: laurie{at}ccivf.com
Dear Sir,
I read with interest the manuscript by El-Toukhy et al. who concluded that "young age does not protect against the adverse effects of reduced ovarian reserve" (El-Toukhy et al., 2002). They do include in their literature review two manuscripts that suggest that the outcome from younger women with decreased ovarian reserve and increased early follicular phase serum follicle stimulating hormone (FSH) level may have a more favourable outcome (Roest et al., 1996
; Hanoch et al., 1998
). However, the reader is left with the impression that these aforementioned conclusions have been refuted not only by the data presented in the study by El-Toukhy et al. but the large number of other cited references that the authors have included in their manuscript to help support their conclusions. Furthermore El-Toukhy et al. point out in their discussion that neither the studies of Roest et al. (1996)
or Hanoch et al. (1998)
provided pregnancy rates. I would like to supply some additional data from our own studies that reach opposite conclusions to El-Toukhy et al. which do provide pregnancy rates and outcome.
One study evaluated 6-month pregnancy rates without the use of assisted reproductive technology in women with elevated day 3 serum FSH levels according to age (Check et al., 1998). The mean FSH level (mIU/ml) for the younger (
39 years) group (n = 26) was 18.9 and was 20.8 for those
40 years (n = 19). The 6-month clinical (ultrasound evidence of pregnancy) and ongoing (viable past the first trimester) pregnancy rates were 46.1 and 34.6% for the younger group and was 10.5 and 5.3% for the older group (Check et al., 1998
). Treatment consisted of luteal phase support with vaginal progesterone and the use of smaller doses of follicle maturing drugs only if follicular maturation was not achieved naturally (Check et al., 1988
).
We also evaluated the effect of age in women with elevated day 2 FSH levels who required IVF (Check et al., 2002). The mean serum FSH (mIU/ml) was 19.4 in the younger (age
38 years) versus 16.9 for the older (
39 years) group. The clinical and ongoing pregnancy rates were 28.6 and 21.4% per transfer for the younger group versus 5.5% and 5.5% for the older group. Implantation rates were 10.0 versus 1.9%.
In their discussion El-Toukhy et al. suggest that lower pregnancy rates in younger women with elevated gonadotrophins may be associated with a "concomitant increase in the number of chromosomal abnormalities particularly aneuploidy". Our data do not support his hypothesis especially when one also considers that we studied a group with even less ovarian reserve based on the fact that the FSH levels were about twice as high in our study than El-Toukhy et al.s study. My own theory is that older women are more apt to go through a more natural selection process where the best oocytes have been used up and the depleted ovarian reserve is composed predominantly of oocytes with chromosome abnormalities. However, the younger women are more apt to have damage to a large proportion of the ovaries, but the oocytes remaining may have similar quality to their age peers with normal FSH. I am not sure what differences in techniques allow us to get better pregnancy outcome in younger women with hypergonadotrophism, but it is clear that an explanation of ageing oocytes irrespective of chronological age does not fit, though this group may be relatively less fertile related to factors other than abnormal chromosomes. There are data suggesting that some patients develop a toxic uterine environment related to the use of controlled ovarian hyperstimulation (COH) (Check et al., 1999). Perhaps women with high FSH are even more prone to the toxic effect of COH (Check et al., 2002
). We have data that we are about to present at a future meeting, that show, in more than 100 women not able to stimulate multiple follicles following COH, that performing IVF and embryo transfer with no or minimal gonadotrophin stimulation resulted in ongoing pregnancy rates of 27.3% for women
35 years, 30.8% for women 3639 years, 21.7% for women aged 4042 years, and 0% for women
43 years. These new data not only support our previous two studies and are opposite to the conclusions reached by El-Toukhy et al. but also may support the theory of toxic uterine environment from COH, since the ongoing pregnancy rates for women
39 years were comparable with the study using COH, yet far fewer embryos were transferred. Also, the group aged 4042 years did much better, lending support to the concept that the dismal prognosis for women
40years with increased FSH, and COH followed by IVF may be partially related to COH having a relatively greater adverse effect on the uterine environment in older versus younger women. Perhaps not until
43 years of age do we find the group with very few normal oocytes.
References
Check, J.H., Nowroozi, K., Wu, C.H., Adelson, H.G. and Lauer, C. (1988) Ovulation-inducing drugs versus progesterone therapy for infertility in patients with luteal phase defects. Int. J. Fertil., 33, 252256.[ISI][Medline]
Check, J.H., Peymer, M. and Lurie, D. (1998) Effect of age on pregnancy outcome without assisted reproductive technology in women with elevated early follicular phase serum follicle-stimulating hormone levels. Gynecol. Obstet. Invest., 45, 217220.[CrossRef][ISI][Medline]
Check, J.H., Choe, J.K., Katsoff, D., Summers-Chase, D. and Wilson, C. (1999) Controlled ovarian hyperstimulation adversely affects implantation following in vitro fertilization-embryo transfer. J. Assist. Reprod. Genet., 16, 416420.[CrossRef][ISI][Medline]
Check, J.H. (2002) Progesterone therapy versus follicle maturing drugs possible opposite effects on embryo implantation. Clin. Exp. Obst. Gyn., 29, 510.
El-Toukhy, T., Khalaf, Y., Hart, R., Taylor, A. and Braude, P. (2002) Young age does not protect against the adverse effects of reduced ovarian reserve-an eight year study. Hum. Reprod., 17, 15191524.
Hanoch, J., Lavy, Y., Holzer, H., Hurwitz, A., Simon, A., Revel, A. and Laufer, N. (1998) Young low responders protected from untoward effects of reduced ovarian response. Fertil. Steril., 69, 10011004.[CrossRef][ISI][Medline]
Roest, J., van Heusden, A.M., Mous, H., Zeilmaker, G.H. and Verhoeff, A. (1996) The ovarian response as a predictor for successful in-vitro fertilization treatment after the age of 40 years. Fertil. Steril., 66, 969973.[ISI][Medline]