Department of Reproductive Medicine, Division of Perinatology and Gynecology, University Medical Center Utrecht, The Netherlands; Email: e.r.klinkert{at}azu.nl
Dear Sir,
We read with interest the paper by Kailasam et al. (2004) on the definition of poor ovarian response in IVF. To enable a meaningful comparison of the many studies published on poor response, the development of a uniform definition is important, if feasible. The authors conclude that the degree of ovarian stimulation should be included in the definition of poor ovarian response. Although we do agree that only an insufficient ovarian reaction to a sufficient stimulation dose should be called a poor response, we are concerned about some methodological aspects of the study that led to this conclusion.
The authors suggest that the need for a total dose of 3000 IU of FSH during stimulation objectively identifies a poor response in women aged <40 years. However, all patients aged
35 years who were included in this study received a starting dose of 300 IU of FSH, whereas younger patients started their stimulation with 150 IU per day. It is therefore not possible to determine whether the difference in poor response and pregnancy rate in the repeat cycle in patients stimulated with high doses compared with patients stimulated with lower doses is dose related or age related. We believe that the low implantation rates and pregnancy rates the authors observed in women who used
3000 IU can be partly, if not fully, explained by the fact that most of these women will be >35 years of age. The age of a woman undergoing IVF treatment is known to be an important factor affecting the outcome of the treatment (Roseboom et al., 1995
; Templeton et al., 1996
). Also, the implantation rate shows a significant age-related decrease, with an acceleration of this decrease from 37 years onwards (van Kooij et al., 1996
). The authors did not compare the age of the patients treated with <3000 IU with that of the patients treated with
3000 IU. It can, however, be assumed that there is a large and significant age difference, explaining the higher cancellation and lower pregnancy rates.
In our opinion, the definition of poor response suggested by the authors cannot be called objective, as they have wrongly assumed that patients older than 35 years of age need a higher dose of gonadotrophins than younger patients. Most patients will respond maximally to 150 IU of gonadotrophins. Young poor responders may respond better to higher FSH dosages (Out et al., 2000), but often do not need it because on the quality level they perform quite well. Older poor responders will usually not benefit from higher dosages as both cohort size and oocyte quality are diminished. As such, not the stimulation dose, but female age is the key factor. Although this study certainly is a valuable contribution to the discussion on the subject of poor response, we feel that our alternative interpretation is crucial to prevent the ill-validated use of a high dosage of gonadotrophins in older poor responders.
References
Kailasam C, Keay SD, Wilson P, Ford WC and Jenkins JM (2004) Defining poor ovarian response during IVF cycles, in women aged <40 years, and its relationship with treatment outcome. Hum Reprod 19, 15441547.
Out HJ, Braat DD, Lintsen BM, Gurgan T, Bukulmez O, Gökmen O, Keles G, Caballero P, González JM, Fábregues F et al. (2000) Increasing the daily dose of recombinant follicle stimulating hormone (Puregon) does not compensate for the age-related decline in retrievable oocytes after ovarian stimulation. Hum Reprod 15, 2935.
Roseboom TJ, Vermeiden JP, Schoute E, Lens JW and Schats R (1995) The probability of pregnancy after embryo transfer is affected by the age of the patient, cause of infertility, number of embryos transferred and the average morphology score, as revealed by multiple logistic regression analysis. Hum Reprod 10, 30353041.[Abstract]
Templeton A, Morris JK and Parslow W (1996) Factors that affect outcome of in-vitro fertilisation treatment. Science 348, 14021406.
Van Kooij RJ, Looman CW, Habbema JD, Dorland M and te Velde ER (1996) Age-dependent decrease in embryo implantation rate after in vitro fertilization. Fertil Steril 66, 769775.[ISI][Medline]