Effects of methotrexate on the quality of oocyte maturation in vitro

Abstract

Methotrexate (MTX), an antifolate drug, is widely used for clinical treatment of malignancies and ectopic pregnancy. Many studies have documented that MTX has strong side-effects on rapidly dividing somatic cells. However, its side-effects on female reproductive cells have not been widely reported. Combined with in vitro culture, two-photon fluorescence imaging and three-dimensional reconstruction, this study analyzed the effects of MTX on oocyte maturation time, chromosome arrangement, karyotype, spindle morphology, and the localization of microtubule organizing centers (MTOCs). Compared with a control group (84%), the rate of germinal vesical breakdown in the MTX group dropped to 73% (P < 0.05). The rate of the first polar body extrusion in the MTX group (53%) was also below the control group (63%; P < 0.05). The rate of abnormal chromosomal arrangement in the MTX group was 60%, but 24% in the control group (P < 0.05). The matured oocyte karyotypes showed 20 univalents in both control and MTX groups, while point-shaped DAPI signals were detected in the MTX group. The rate of abnormal spindle in the MTX group was 49%, but 17% in the control group (P < 0.05). MTOCs in oocytes with normal spindles concentrated at the poles, while MTOCs in oocytes with abnormal spindles were scattered around the poles or in the ooplasm. MTX changes the structures of chromosomes and spindles, potentially by interfering with DNA methylation. The above results indicate a basis for understanding negative effects of MTX on oocyte maturation quality, and provide information for the clinical application of MTX in female patients.

Persistent follicular granulosa cell senescence and apoptosis induced by methotrexate leading to oocyte dysfunction and aberrant embryo development

“…Notably, 5-6 ovulation cycles in mice may be equivalent to 5-6 menstrual cycles in humans [24]. Considering these conditions, the implementation of intervals spanning 3-6 menstrual cycles between MTX discontinuation and pregnancy for patients with previous history of MTX medication stated in the clinical guidelines [22] [14]. However, considering the metabolism of MTX in vivo and the integrity of ovaries, we focused on studying follicular changes and found that MTX administration reduced the proportion of mature follicles and increased the proportion of atretic follicles.…”

Efficacy and safety of laparoscopy versus local injection with absolute ethanol in the management of tubal ectopic pregnancy

“…In case of failure after AE local injection, it was generally suggested another dose of MTX systemic administration. However, the dosage of MTX needed to carefully calculate due to its various side effects [24,25]. In our study, 9 subjects (16.4%) with local AE injection were failure and needed another local injection and a systemic MTX administration.…”

Azathioprine During the First Trimester of Pregnancy in a Patient with Vogt-Koyanagi-Harada Disease: A Multimodal Imaging Follow-Up Study

“…It has been proven that other immunosuppressive drugs such as cyclophosphamide [9], methotrexate [10], and mycophenolate mofetil [11] should be avoided in pregnancy. Conversely, azathioprine seems to be a safe immunosuppressant drug for these patients [12].…”