To the Editor:
We read with great interest the paper “Does methotrexate administration for ectopic pregnancy after in vitro fertilization (IVF) impact ovarian reserve or ovarian responsiveness?” by Boots et al. (1). In the article, the authors evaluated the effects of methotrexate (MTX) on the future fertility of women undergoing IVF by comparing markers of ovarian reserve (day 3 FSH, antral follicle count), measures of ovarian responsiveness (duration of stimulation, peak E2 level, total dose of gonadotropins, number of oocytes retrieved, fertilization rate), and time from MTX administration to subsequent IVF cycle, in the IVF cycle before and after an ectopic pregnancy (EP) treated with MTX. They concluded that MTX treatment of an EP does not compromise ovarian reserve or ovarian responsiveness in subsequent cycles. However, other studies have demonstrated that when gonadotropin stimulation dose remains unchanged, fewer oocytes may be collected after MTX is taken as management of an ectopic pregnancy, suggesting a decrease in ovarian reserve (2).
In spite of their conclusions, Boots et al.’s results did show that a statistically and clinically significant increased dose of total gonadotropin was used after MTX administration (4217 IU vs. 3678 IU) to obtain a statistically similar peak estradiol level, number of oocytes, and number of 2PN embryos. They hypothesized that this difference was a result of increased patient age or physician preference of a higher medication dosage and does not demonstrate an MTX-induced change in ovarian reserve. Although, it is true that mean age increased by 0.6 years between the two IVF cycles, patients prior to MTX on average were young (34 years old), had 7.3 (2PN) embryos, and 9.5 MII oocytes collected (extrapolated from data provided). They all achieved a pregnancy. Therefore, the treating physician does not necessarily need to increase the dosage of gonadotropins for the next cycle of treatment. The alternate explanation is that higher doses of gonadotropins were needed to obtain similar numbers of oocytes to compensate for decreased ovarian response to stimulation, post MTX treatment.
We applaud the authors’ effort in reporting the largest study to date addressing the questions of ovarian reserve, ovarian responsiveness, and IVF outcomes in patients treated with MTX for EPs. However, based on their results, the ovarian responsiveness to gonadotropin stimulation and possibly ovarian reserve were decreased after MTX treatment, since a higher dose of gonadotropins needed to be used to obtain equivalent stimulation parameters.
ChengWei Xiao, M.D., McGill University Health Center, Royal Victoria Hospital
Michael H. Dahan, M.D., F.A.C.O.G., F.R.C.S.C., McGill University Health Center, Reproductive Center, Royal Victoria Hospital
Montreal, QC, Canada
1. Boots CE, Gustofson RL, Feinberg EC. Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness? Fertil Steril 2013;100:1590-3.
2. McLaren JF, Burney RO, Milki AA, Westphal LM, Dahan MH, Lathi RB. Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation. Fertil Steril 2009;92:515-9.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2014.01.004
The authors respond:
We would like to thank you for this thought-provoking consideration of our data. In our study, we measured both ovarian reserve, a surrogate marker to approximate the supply of oocytes remaining in the ovary, and ovarian responsiveness, the ability of the ovary to recruit follicles in response to heightened gonadotropin stimulation. Currently, the best markers for ovarian reserve are antimüllerian hormone (AMH) and antral follicle count (AFC). Unfortunately, we were unable to analyze AMH as this was not drawn routinely at our clinic during the study time period. One study that measured AMH found no difference (2). To date, no studies analyzing AFC before and after methotrexate therapy have detected a significant difference, including a recent large retrospective study by Hill et al. (1).
Ovarian reserve markers are only prognostic indicators of ovarian response, whereas responsiveness is the ultimate measure of ovarian potential. In our analysis, the only parameter suggesting a possible decrease in responsiveness was an increase in the total dose of gonadotropins after methotrexate (MTX). This increased dosing may be due to several factors. As we previously mentioned, the increased age of the women in the subsequent cycle may be contributing to this increased requirement. However, the mean age of subjects is relatively young (34.6 and 35.1 years), and the age difference is only 0.61 years.
A more likely reason for the increased dosing is that changes were made to the post-MTX stimulation based on the results of the pre-MTX cycle. With a mean number of 9.5 oocytes retrieved, it is within our standard of care to increase the dose of gonadotropin stimulation to push for a higher number of oocytes on subsequent cycles. Additionally, the total dose could also be attributed to utilizing a different stimulation protocol in the post-MTX cycle. For example, 15 of the 66 subjects underwent a luteal phase GnRH agonist protocol prior to MTX and an antagonist cycle after MTX, while only one subject underwent the reverse scenario.
Although it is possible that the higher dose represents a decrease in responsiveness, it is debatable whether higher doses of gonadotropins increase the number of eggs retrieved above a certain threshold (3). Therefore, we cannot conclude that intrinsic damage to the ovary has occurred based on this single parameter.
With a small study size, we may be unable to detect subtle effects on the ovary as measured by parameters of reserve and responsiveness. It is possible that subtle damage causes significant impact but only in women of theoretically increased risk, such as women of advanced maternal age or with diminished ovarian reserve. Pooling data from multiple centers would allow the opportunity to stratify by high-risk features and will enlighten our understanding of this clinically intriguing question.
Christina E. Boots, M.D., Washington University, St. Louis, Missouri
Robert L. Gustofson, M.D., Colorado Center for Reproductive Medicine, Denver, Colorado
Eve C. Feinberg, M.D., NorthShore University Health System, Fertility Centers of Illinois, Highland Park, Illinois
1. Oriol B, Barrio A, Pacheco A, Serna J, Zuzuarregui JL, Garcia-Velasco JA. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve. Fertil Steril 2008;90:1579-82.
2. Hill MJ, Cooper JC, Levy G, et al. Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location. Fertil Steril 2013: In press.
3. Lashen H, Ledger W, Lopez BA, Evans B, Barlow D. Superovulation with a high gonadotropin dose for in vitro fertilization: is it effective? J Assist Reprod Genet 1998;15:438-43.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2014.01.005