Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Southern California, Los Angeles, CA, USA.
Department of Preventative Medicine, University of Southern California, Los Angeles, CA, USA.
J Assist Reprod Genet. 2020 Jun;37(6):1459-1466. doi: 10.1007/s10815-020-01778-7. Epub 2020 May 6.
Tyrosine kinase inhibitors (TKIs) such as imatinib are commonly used chemotherapeutics, but the effects of long-term treatments on reproductive outlook for cancer survivors are unknown. The purpose of this study was to examine the effects of long-term imatinib treatments on follicle development and embryo quality. Since prospective studies are not possible in healthy humans, we have incorporated a commonly used mouse model.
Adult female mice were treated with daily IP injections of imatinib for 4-6 weeks. Liquid chromatography-mass spectrometry was used to measure imatinib in serum and ovarian tissues. At the end of treatments, females were superovulated and mated to yield fertilized embryos. Oocytes and embryos were collected from oviducts, assessed for development by microscopy, and fertilized embryos were cultured in vitro. Blastocysts were fixed and stained for differential cell counts.
Long-term imatinib treatments caused a shift in follicle development, with imatinib-treated females having fewer primordial follicles, but an increase in primary and secondary follicles (P < 0.05). There was no effect on ovulation or fertilization rates. However, blastocysts from imatinib-treated females had fewer total cells (P < 0.05) and a significant shift from inner cell mass to increased trophectoderm cells.
This pilot study indicates that long-term TKI treatments may have significant impact on ovarian reserve and embryo developmental capacity. More studies are needed in other model systems to determine the long-term impact of TKIs in patients. Knowing the potential effects of chemotherapeutics on reproductive outlook is critical for quality of life and more research is needed.
伊马替尼等酪氨酸激酶抑制剂（TKIs）是常用的化疗药物，但长期治疗对癌症幸存者生殖前景的影响尚不清楚。本研究旨在研究长期伊马替尼治疗对卵泡发育和胚胎质量的影响。由于在健康人群中进行前瞻性研究是不可能的，因此我们采用了一种常用的小鼠模型。
成年雌性小鼠接受每日腹腔注射伊马替尼治疗 4-6 周。采用液相色谱-质谱法测定血清和卵巢组织中的伊马替尼浓度。治疗结束时，雌性小鼠进行超排卵并交配以获得受精卵。从输卵管收集卵母细胞和胚胎，通过显微镜评估发育情况，并对受精卵进行体外培养。将囊胚固定并染色进行差异细胞计数。
长期伊马替尼治疗导致卵泡发育发生转变，伊马替尼治疗组小鼠的原始卵泡减少，但初级和次级卵泡增加（P<0.05）。排卵率和受精率不受影响。然而，来自伊马替尼治疗组的囊胚总细胞数减少（P<0.05），内细胞团向滋养外胚层细胞的比例显著增加。
这项初步研究表明，长期 TKI 治疗可能对卵巢储备和胚胎发育能力产生重大影响。需要在其他模型系统中进行更多研究，以确定 TKI 在患者中的长期影响。了解化疗药物对生殖前景的潜在影响对于生活质量至关重要，需要进一步研究。
