INVESTIGATION / RESEARCH
Potential effect of Imatinib on some sex hormones for male patients of Chronic Myelogenous Leukemia in Baghdad province
Abeer Anwer Ahmed1, Khaleed J Khaleel2, Alaa Abbas Fadhel3 *
Available from http://dx.doi.org/10.21931/RB/2021.06.04.9
Imatinib Mesylate is an oral chemotherapy drug that has been used to treat Chronic Myelogenous Leukemia (CML). It works as an inhibitor of oncogene tyrosine kinase BCR-ABLI as a target therapeutic agent. Despite the drug is well tolerated in most patients, impaired testosterone production and Gynecomastia after therapy might happen. The current study aims to evaluate the impact of Imatinib Mesylate on sex hormones of CML male patients in Baghdad province. Blood specimens were collected from (42) CML patients aged 23 to 68 years who used Imatinib drug for more than two years, and (45) normal persons aged 25 to 65 years as a control group. Exclusion criteria were performed for both control and CML patient's groups, including people with diabetes, hypertensive, and males complaining of infertility after taking medical history for every participant. The blood level of hemoglobin (Hb), white blood cells (WBC), platelet count, testosterone, LH, and FSH were evaluated and investigated. The obtained results showed a significantly lower level of testosterone (2.73+- 0.97) ng/mL than the control group (4.72 ±1.02) ng/mL with a p-value of 0.000. While LH (4.53±2.1) mIU/mL and FSH (5.12 ± 2.83) mIU/mL were significantly higher than the control group (3.77± 0.8) mIU/mL and (3.85±0.807) mIU/mL with p-value of 0.026 and 0.005 respectively. Moreover, the outcomes revealed a moderate positive correlation (r = +0.348) between LH hormone levels with a duration increasing time of using Imatinib, while platelet showed a moderate negative correlation (r = -0.321) with time-consuming using that drug. In conclusion, Imatinib might harm testis functions and some hematological parameters that could increase using this drug.
Keywords: Imatinib, Sex hormones, Myelogenous Leukemia, Patients
During the last two decades, the treatment of Chronic Myeloid Leukemia (CML) has changed because of the introduction of tyrosine kinase inhibitor. The survival rate had been increased in patients with Leukemia and lymphoma 1. Besides that, the infertility complications were raised in parallel with that disease. The chance of getting CML can be increased at the 4th decade of life or a younger age group where reproductive functions are crucial in affected men 2,3. It has been identified many side effects about sexual function by using drugs for CML therapy. However, CML as a disease may adversely affect male fertility even before any therapy 4, 5. The introduction of tyrosine kinase inhibitor has increased the survival rate significantly, highlighting issues related to the quality of life with an important area of fertility and paternity. The gonadal dysfunction induced by therapy depends in general on age dosages and types of the therapies used in CML treatment 6.
Moreover, animal studies on Imatinib using standard dosages have shown non significantly impaired adult male fertility 4-7. The effect of Imatinib on spermatogenesis seems to be dose dependably 8. c-KIT is essential for developments of Leydig cells and migration survival and proliferation of spermatogonia. Also, Platelets derived growth factors (PDGF) and (PDGF-R) are very important for developing Myeloid and Leydig cells 9. This study aimed to investigate the potential testicular effects of using imatinib drugs for CML patients (testicular Leydig cell function and androgen status) by measuring and characterizing reproductive hormones such as Follicle-stimulating Hormone (FSH), Luteinizing Hormone (LH), and testosterone.
MATERIALS AND METHODS
The investigation was a spin-off study for (42) male patients with CML that attended the National center for hematological diseases at Al-Mustanseria University. Participant patients have been using a standard dose of 400 mg of tyrosine kinase inhibitor (Imatinib) per day for equal or more than two years, and their ages ranged from 23 years to 68 years old. Patients in the above center that included in this spin-off protocol were invited to participate in this study only if they already agreed to be included. A healthy control group of (45) males aged 25 years to 65 was also involved. Exclusion criteria for both control and CML patients groups were performed for people with diabetes, hypertensive, and males complaining of infertility after taking medical history for each one. Blood samples were taken from both groups. Blood specimens were collected in EDTA tubes for Hb, white blood cells, platelets, and differential count for WBC analysis. The mentioned hematological parameters were estimated using an electronic counter (Mandray Company, France), and the blood films were performed on all patients and control groups using Giemsa stain. In addition, gel tubes were used to assess LH, FSH, and testosterone hormones concentrations by using the ELISA method through a micro plate reader (AWARENESS, USA). The ELISA kits were DRG from Germany.
All statistics in the present study were performed by using SPSS Ver. 23 for windows. Quantitative values were presented as Mean and Standard deviation (SD) of all variables. An independent t-test was used to exhibit the significance of differences. The confidence interval (95%) p-value £ 0.05 was considered statistically significant, while the probability p-value > 0.05 indicates statistically not significant. Moreover, correlation analysis between parameters was assessed by Pearson's.
RESULTS AND DISCUSSION
Nowadays, the new molecular design of cancer treatments such as tyrosine kinase inhibitors can be applied into therapy, and the strategy for young adults and children and the latent effect on testis functions should be considered. The role of these drugs in some of specific physiological signals cascade modulated may be varied with the maturation state and age, and the effectiveness and the side effects of these agents in young adults and children may be different. It is well known that the introduction of the tyrosine kinase inhibitor has revolutionized the therapy of CML that leads to prolonged survival and significant improvement in the quality of life that results in increasing the number of patients that wish to be the father. According to previous animal studies on the effect of tyrosine kinase inhibitor as treatment, there is a mild to moderate impairment of the male reproductive system 10,11, 12.
In general, hormones act upon the phases of the spermatogenesis (like LH and FSH) act directly on the testis to stimulate somatic cells functions that support spermatogenesis 13. It had been reported that FSH is mainly regulated spermatogonial development 14, 15, while LH is working on Leydig cell to secrete testosterone. In the case of testosterone, it is the primary male steroid sex hormone and plays a crucial role in developing male reproductive tissue such as testis and prostate as well as secondary sexual characteristics 16. Testosterone regulates the later phase of spermatogenesis, which takes about 74 days. Despite semen analysis not being performed in the current study, however, there is an effect of Imatinib on tail protein PY phosphorylation in human is related to sperm motility. The deficiency of this protein during therapy with tyrosine kinase inhibitor (Imatinib) may be associated with decreased motility of the sperm 17-20. For hematological edge, the present study showed that platelets count is significantly higher than the control group (13.81 ± 1.28) and (13.70 ± 0.79), respectively, with p-value of 0.03. Even though the patients and control group are within the normal range, our explanation regarding these results may be due to the small sample size. While for Hb and WBC account the obtained result exhibited that the is non-significant differences between health and the patient group were Hb 13.70 ± 0.79 (g/dL) and 13.81 ± 1.28 (g/dL), and 5.88 ± 1.21, 6.81 ±3.39 for WBc respectively), Table 1.
Table 1. Hematological parameters for patients and control health group
The results of the hormonal, biochemical assay showed in the case of testosterone that the mean level of the patient's group (2.73 ± 0.97) ng/mL is significantly lower than the control group (4.72 ± 0.72) ng/mL with p-value of (0.00) this finding is consistent with several studies 14, 15. Also, the LH hormone in the patient's group is significantly higher than the control group 4.53 ± 2.1 mIU/mL and 3.77 ± 0.8 mIU/mL, respectively, with p-value 0.026. The same is true for FSH hormone; the patient's group is also significantly higher than the health group 5.12 ± 2.83 mIU/mL and 3.85 ± 0.807 mIU/mL, respectively, p-value 0.005. our results were different from that reported by (21). However, our data is consistent with that reported (22).
Table 2. Hormonal biochemical parameters for patients and control groups
The correlation for all measured parameters with duration increasing time for Imatinib was assessed. Regarding that, the results showed a moderate positive correlation ( r= +0.348) of LH hormone with increasing time duration of the mentioned treatment with p-value 0.026 as shown in table 3. while for platelet number, the results exhibited that there is a moderate negative correlation (r = - 0.321) with increasing time consumed of the Imatinib drug with p-value (0.038). For all other parameters, the outcomes revealed that there is a non-significant correlation with duration consuming time, this is maybe due to our results dealing with a small number of samples. However, these results are consistent with that reported by (23) that stated Imatinib decreases the viability of normal Leydig cells in a manner not time-dependent. Moreover, Imatinib has an antiangiogenic effect that inhibits the vascular endothelial growth factor 23, 24. Imatinib delays or may block migration of gonocytes from the center of the seminiferous cord to basement members to form a spermatogonial stem cells pool. Inhibition of migration was probably due to blockage of the c-kit receptor. The presence of c-kit antiserum in Sertoli cells inhibits migration of gonocytes 25, 26. Imatinib interferes with several maturation processes in the rat-like spermatogonial stem cell and Leydig cells that produce testosterone and proliferation of differentiation type A spermatogonial. The low testosterone level is derived from the hypothalamus pituitary axis and LH; FSH levels will increase significantly secondary to low testosterone levels 27.
Table 3. the correlation coefficient of some parameters with increasing consuming time of Imatinib drug.
The therapy of tyrosine kinase inhibitor for male CML patients adversely affects testosterone levels with increased LH and FSH levels. However, it is unlikely to knock down the sperms production. It is advisable to have sperm banking in young adult patients before starting prolonged treatment by Imatinib that can be easily applied. However, the present study's limitation is the small sample size of CML patients included in the present data. A larger sample size is highly recommended to enforce those original results. Also, seminal fluid analysis was not done because most patients were unwilling to provide us with their semen.
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Received: 26 September 2021
Accepted: 23 October 2021
Abeer Anwer Ahmed1, Khaleed J Khaleel2, Alaa Abbas Fadhel3 *
1,2 Iraqi Center for cancer and medical genetics research// Al-Mustansiriyah University, Iraq..
3 Al- Mussaib Technical College / Al-Furat Al-Awsat Technical University, 51009, Babylon, Iraq.
*Corresponding author at Al- Mussaib Technical College / Al-Furat Al-Awsat Technical University, 51009, Babylon, Iraq., Iraq.