PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSION 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.

中文翻译：

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长期伊马替尼会减少卵巢储备并影响胚胎质量。

目的 伊马替尼等酪氨酸激酶抑制剂 (TKI) 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。本研究的目的是检查长期伊马替尼治疗对卵泡发育和胚胎质量的影响。由于不可能在健康人类中进行前瞻性研究，因此我们采用了常用的小鼠模型。方法 成年雌性小鼠每天腹腔注射伊马替尼，持续 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。治疗结束时，雌性超数排卵并交配以产生受精胚胎。从输卵管收集卵母细胞和胚胎，通过显微镜评估发育情况，并在体外培养受精胚胎。固定囊胚并染色以进行差异细胞计数。结果 长期伊马替尼治疗导致卵泡发育发生变化，接受伊马替尼治疗的女性原始卵泡减少，但初级和次级卵泡增加（P < 0.05）。对排卵或受精率没有影响。然而，伊马替尼治疗雌性的囊胚细胞总数较少（P < 0.05），并且从内细胞团显着转变为滋养外胚层细胞增加。结论 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 对患者的长期影响。了解化疗对生殖前景的潜在影响对于生活质量至关重要，需要进行更多研究。