Assisted Conception Unit, 4th Floor, Thomas Guy House, Guys Hospital, St. Thomas Street, London SE1 9RT, UK e-mail: yakoub.khalaf{at}kcl.ac.uk
Dear Sir,
We thank Dr Check for his interest in our study and the issues he raised in his letter. Firstly, Dr Check raised the issue whether young women are protected from the adverse effects of reduced ovarian reserve. He made reference to a study produced in 1997 (Check et al., 1998), where the authors evaluated pregnancy and on-going pregnancy rates in a small number of women (n = 45) with raised basal FSH levels treated without the use of assisted reproductive technology (ART). It is fundamentally incorrect to compare data from IVF-treated patients with those from the general subfertility population, when multifollicular development is not as important for achieving a pregnancy. Furthermore, no distinction was made in that study (Check et al., 1998
) between patients
30 years and those between 3139 years.
In a larger study, life table analysis was used to evaluate the effect of age on pregnancy rates achieved in a group of women with reduced ovarian reserve, confirmed by an abnormal clomiphene challenge test (Scott et al., 1995). The study showed no age-related differences in pregnancy rates, which were similarly low in all age groups studied. Within the field of IVF, in addition to our study, many studies (Scott et al., 1989; Toner et al., 1991
; Margarelli et al., 1996
) have emphasized the importance of ovarian age, over chronological age alone, in predicting treatment outcome.
Secondly, Dr Check argued that oocytes remaining in the ovaries of young women with reduced ovarian reserve are of better quality than those in older women with equally reduced ovarian reserve. No convincing data to support this claim was provided. We find it difficult to accept this hypothesis. Studies in both animals and humans contradict this theory and support our conclusion. Brook et al. (1984) used the mouse model to indicate that the risk of producing aneuploid embryos is determined by the degree of reduction in ovarian reserve and distance in time from menopause, rather than by chronological age per se (Brook et al., 1984).
In humans, Levi et al. studied the reproductive outcome of over 1000 women suffering from reduced ovarian reserve and analysed the results according to age (Levi et al., 2001). The miscarriage rate, which is closely related to oocyte quality, was markedly elevated regardless of age. In our own study (El-Toukhy et al., 2002
), the miscarriage rate was comparable in women
38 years (51%) and in those >38 years (39%). We, therefore, firmly believe that reproductive senescence, as evidenced by elevated basal FSH level or poor response to superovulation protocols, is associated with a reduction in both oocyte quantity as well as quality and thus is responsible for the occurrence of subsequent reproductive events such as decline in fertility, increase in miscarriage rate and finally the onset of menopause.
Perhaps the only situation in which oocyte quantity might be reduced without a concomitant reduction in quality is when a woman undergoes reductive ovarian surgery, such as bilateral wedge resection, removal of ovarian cysts or oophorectomy (Melica et al., 1995).
Thirdly, Dr Check postulates that older women (>40 years) are more prone to the toxic effect of controlled ovarian hyperstimulation (COH) on uterine environment. He presented unpublished data on women who failed to respond adequately to COH and were subsequently treated with no or minimal gonadotrophin stimulation. The ongoing pregnancy rate in women 35 years was 27% and in those 4042 years was 21.7%. Although it is difficult to comment on data that has not been subjected to the rigour of peer review, the comparable pregnancy rates in the two age groups seem to contradict Dr Checks own argument that age alone is predictive of treatment outcome in patients with reduced response to ovarian stimulation.
Finally, it is interesting that Dr Check did not report live birth data in any of the references cited. He also failed to acknowledge that nearly half of our study population was included because of poor response to COH without elevation in their basal FSH concentrations.
References
Brook, J.D., Gosden, R.G. and Chandley, A.C. (1984) Maternal ageing and aneuploid embryosevidence from the mouse that biological and not chronological age is the important influence. Hum. Genet., 66, 4145.[ISI][Medline]
Check, J.H., Peymer, M. and Lurie, D. (1998) Effect of age 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]
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 reservean eight year study. Hum. Reprod., 17, 15191524.
Levi, A.J., Raynault, M.F., Bergh, P.A., Drews, M.R., Miller, B.T. and Scott, R.T. (2001) Reproductive outcome in patients with diminished ovarian reserve. Fertil. Steril. 76, 666669.[CrossRef][ISI][Medline]
Margarelli, P.C., Pearlstone, A.C. and Buyalos, R. (1996) Discrimination between chronological and ovarian age in infertile women aged 35 and older: predicting pregnancy using follicle stimulating hormone, age and number of ovulation induction/intrauterine insemination cycles. Hum. Reprod., 11, 12141219.[Abstract]
Melica, F., Chiodi, S., Cristofroni, P.M. and Ravera, G.B. (1995) Reductive surgery and ovarian function in the humancan reductive ovarian surgery in reproductive age negatively influence fertility and age at onset of menopause? Int. J. Fertil. Menopausal Stud., 40, 7985.[Medline]
Scott, R.T., Toner, J.F., Muasher, S.J., et al. (1989) Follicle stimulating hormone concentrations on cycle day 3 are predictive of in vitro fertilization outcome. Fertil. Steril., 51, 651654.[ISI][Medline]
Toner, J.P., Philut, C.B., Jones, G.S. and Muasher, S.J. (1991) Basal follicle stimulating hormone level is a better predictor of in vitro fertilization performance than age. Fertil. Steril., 55, 784791.[ISI][Medline]