Reply of the Authors

Abstract

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, because this was not determined routinely at our clinic during the study period. One study that measured AMH found no difference (1Oriol B. Barrio A. Pacheco A. Serna J. Zuzuarregui J.L. Garcia-Velasco J.A. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve.Fertil Steril. 2008; 90: 1579-1582Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). 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. (2Hill M.J. Cooper J.C Levy G. Alford C. Richter K.S. DeCherney A.H et al.Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location.Fertil Steril. 2014; 101: 413-419Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). 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 ages of subjects were relatively young (34.6 and 35.1 years), and the age difference was 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 using a different stimulation protocol in the post-MTX cycle. For example, 15 of the 66 subjects underwent a luteal-phase GnRH agonist protocol before 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 (3Lashen H. Ledger W. Lopez B.A. Evans B. Barlow D. Superovulation with a high gonadotropin dose for in vitro fertilization: is it effective?.J Assist Reprod Genet. 1998; 15: 438-443Crossref PubMed Scopus (25) Google Scholar). 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. The effect of methotrexate injection for treatment of an ectopic pregnancy on ovarian reserveFertility and SterilityVol. 101Issue 4PreviewWe 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). 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. Full-Text PDF