Long-term imatinib diminishes ovarian reserve and impacts embryo quality

Salem, Wael; Ho, Jocelyn; Woo, Irene; Ingles, Sue A.; Chung, Karine; Paulson, Richard J.; McGinnis, Lynda K.

doi:10.1007/s10815-020-01778-7

Cited by 17 publications

(12 citation statements)

References 33 publications

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“…Blastocysts obtained from females receiving imatinib had fewer total cells (P < 0.05), and a significant shift from inner cell mass to increased trophectoderm cells. These data indicated that long-term treatment with this TKI could impact significantly the ovarian reserve and embryo developmental capacity (65).…”

Section: Infertilitymentioning

confidence: 77%

THERAPY OF ENDOCRINE DISEASE: Endocrine-metabolic effects of treatment with multikinase inhibitors

Fallahi

Ferrari

Elia

et al. 2021

European Journal of Endocrinology

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Tyrosine kinase inhibitors (TKIs) are emerging as potentially effective options in the treatment of cancer, acting on the pathways involved in growth, avoidance of apoptosis, invasiveness, angiogenesis, and local and distant spread. TKIs induce significant adverse effects, that can negatively affect patients’ quality of life. The most common adverse events (AEs) include fatigue, hand–foot skin reaction, decreased appetite, nausea, diarrhoea, hypertension, vomiting, weight loss, endocrinopaties and metabolic disorders. Patients in therapy with TKIs can develop endocrine-metabolic disorders, including dyslipidemia (∼50%), diabetes (∼15–40%), and dysthyroidism (∼20%). In some cases, patients show an improved glycemia or hypoglycemia. The effects of TKIs on adrenal or gonadal function are still not completely known. It was shown a higher prevalence of subclinical hypocortisolism in patients treated with imatinib, while an increase of cortisol was reported in patients receiving vandetanib. Long-term treatment with imatinib could impact significantly the ovarian reserve and embryo developmental capacity. It is important to evaluate patients, measure glucose levels, and manage hyperglycemia. Mild treatment-related hyperglycemia can be controlled modifying the diet and with exercise, while grade 3 and 4 hyperglycemia can lead to dose reductions and/or oral antihyperglycemic therapy. Regarding thyroid dysfunctions, it is recommendable to measure the thyroid-stimulating hormone (TSH)/free thyroxine (FT4) levels before starting the therapy, and every 3–4 weeks during the first 6 months as changes in FT4 levels precede the changes in TSH by 3–6 weeks. Additional studies are necessary to definitely clarify the mechanism of TKIs-induced endocrine-metabolic effects.

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Section: Infertilitymentioning

confidence: 77%

THERAPY OF ENDOCRINE DISEASE: Endocrine-metabolic effects of treatment with multikinase inhibitors

Fallahi

Ferrari

Elia

et al. 2021

European Journal of Endocrinology

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“…Cengiz et al reported a significant decrease in the number of follicles in mice treated with nilotinib 11 . Salem et al reported a decrease in both the ovarian reserve and embryo quality, unlike the number of acquired oocytes in mice after the long‐term administration of imatinib 3 . Cortes et al reported that dasatinib had no effects on fertility in rats 12 .…”

Section: Discussionmentioning

confidence: 99%

“…However, the number of collected oocytes may decrease during administration of TKIs 1 . Previous studies of fertility preservation using imatimib were reported; 1–3 however, there are no reports of fertility preservation related to the administration of dasatinib. We report a case of fertility preservation wherein oocytes were frozen by initiating controlled ovarian stimulation (COS) 2 days after completing remission induction therapy with dasatinib in a patient with Ph+ALL.…”

Section: Introductionmentioning

confidence: 99%

A case of ovarian stimulation for fertility preservation in a patient with Philadelphia chromosome‐positive acute lymphoblastic leukemia after treatment with dasatinib

Ogawa

Ogi

Hirata

2021

J of Obstet and Gynaecol

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Tyrosine kinase inhibitors (TKIs) are effective for treating Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ALL). However, the use of TKIs may decrease the number of collected oocytes during fertility preservation procedures. We report the case of a 19‐year‐old patient with Ph+ALL for whom 21 oocytes were frozen after controlled ovarian stimulation was initiated 2 days after the completion of 28 days of remission induction therapy with dasatinib. After collecting the oocytes, consolidation therapy was initiated immediately, and a hematopoietic stem cell transplant from her younger brother was scheduled. It is believed that a 2‐day withdrawal period is sufficient for fertility preservation or that the effect of dasatinib on the number of oocytes obtained is minimal.

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“…In a zebrafish model, imatinib feeding once, twice, or three times per day caused frequency-dependent irreversible suppression of ovarian folliculogenesis [ 14 ]. In a mouse model, long-term injections of imatinib (for 4–6 weeks) induced diminished ovarian reserve [ 15 ]. In that report, mice treated with imatinib could yield in vivo fertilized zygotes through ovarian stimulation, but the development of zygotes in vitro and implantation of subsequent blastocysts were severely hampered [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…In a mouse model, long-term injections of imatinib (for 4–6 weeks) induced diminished ovarian reserve [ 15 ]. In that report, mice treated with imatinib could yield in vivo fertilized zygotes through ovarian stimulation, but the development of zygotes in vitro and implantation of subsequent blastocysts were severely hampered [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of imatinib administration on the mouse ovarian follicle count and levels of intra-ovarian proteins related to follicular quality

Kim

Jee

2022

Clin Exp Reprod Med

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Objective: The impact of imatinib, a tyrosine kinase inhibitor, on ovarian follicles and several proteins related to follicular function and apoptosis was investigated in mice.Methods: Saline, cyclophosphamide (Cp; 50 or 75 mg/kg), or imatinib (7.5 or 15 mg/kg) was injected once intraperitoneally into female B6D2F1 mice (18 mice in each group). In multiple ovarian sections, the number of various types of follicles and the proportion of good-quality (G1) follicles were counted. The levels of six proteins (anti-Müllerian hormone [AMH], BCL-xL, BAX, acid sphingomyelinase [A-SMase], caspase-3, and α-smooth muscle actin [α-SMA]) within the whole ovaries were quantified using western blots.Results: Compared to the saline group, a significant reduction of the primordial follicle count was observed in the group treated with imatinib 7.5 and 15 mg/kg, as well as in the group treated with Cp 75 mg/kg. Administration of Cp significantly decreased the proportion of G1 primordial follicles, but administration of imatinib did not. No differences in the AMH, anti-apoptotic BCLX-L, pro-apoptotic BAX, and A-SMase levels in the ovarian tissues were observed among the five groups. However, caspase-3 and α-SMA levels were significantly higher in the imatinib and Cp groups than in the saline group.Conclusion: The administration of imatinib to mice significantly reduced the primordial follicle count and increased the protein levels of caspase-3 and α-SMA. Our findings suggest that imatinib potentially exerts ovarian toxicity via apoptotic processes, similarly to Cp.

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Long-term imatinib diminishes ovarian reserve and impacts embryo quality

Cited by 17 publications

References 33 publications

THERAPY OF ENDOCRINE DISEASE: Endocrine-metabolic effects of treatment with multikinase inhibitors

THERAPY OF ENDOCRINE DISEASE: Endocrine-metabolic effects of treatment with multikinase inhibitors

A case of ovarian stimulation for fertility preservation in a patient with Philadelphia chromosome‐positive acute lymphoblastic leukemia after treatment with dasatinib

Impact of imatinib administration on the mouse ovarian follicle count and levels of intra-ovarian proteins related to follicular quality

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