|Year : 2021 | Volume
| Issue : 2 | Page : 89-94
Chemotherapy-induced ovarian toxicity in female cancer patients from selected Nigerian Tertiary Health Care
John Abiodun Obadipe, Titilola Aderonke Samuel, Alfred Olaoluwa Akinlalu, Ayobami Omowunmi Ajisafe, Ebunoluwa Peace Olajide, Latifatu Albdulmumin
Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
|Date of Submission||28-Jan-2021|
|Date of Decision||30-Mar-2021|
|Date of Acceptance||08-Apr-2021|
|Date of Web Publication||10-Aug-2021|
Mr. John Abiodun Obadipe
Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos
Source of Support: None, Conflict of Interest: None
Introduction: Preservation of ovarian function and fertility has become one of the major qualities of life issues for patients of reproductive age undergoing chemotherapy. Thus, monitoring ovarian reserve in the course of chemotherapy is of utmost importance for prediction of patients' reproductive life span. Aim: The study investigated the ovarian toxicity of chemotherapy in female cancer patients in selected Nigerian tertiary hospitals. Materials and Methods: One hundred and sixty participants comprised hundred radiotherapy-naive female cancer patients aged 18–72 years across all stages and sixty age-matched healthy volunteers (control) randomly selected from three medical centers in South West Nigeria. Patients' demographics and cycle of chemotherapy were obtained using questionnaire. Three milliliters of blood was collected intravenously from the participants before chemotherapy and a week after chemotherapy. Anti-Müllerian hormone (AMH) and inhibin B hormone levels in the serum samples were quantified by enzyme-linked immunosorbent assay. Tukey's honestly significant difference one-way analysis of variance was employed to test for the significant difference, with the level of significance considered at P < 0.05. Results: The findings of the study revealed a significant decrease (P = 0.000) in AMH and inhibin B levels of the participants before and after receiving chemotherapy as compared to that of control. In the same way, there was a significant decrease in postchemotherapy AMH (P = 0.001) and inhibin B levels (P = 0.004) as compared to that of prechemotherapy. Conclusion: Decreased postchemotherapy ovarian reserve in cancer patients confirmed chemotherapy-induced ovarian toxicity.
Keywords: Anti-Müllerian, chemotherapy, enzyme-linked immunosorbent assay, inhibin
|How to cite this article:|
Obadipe JA, Samuel TA, Akinlalu AO, Ajisafe AO, Olajide EP, Albdulmumin L. Chemotherapy-induced ovarian toxicity in female cancer patients from selected Nigerian Tertiary Health Care. Niger J Exp Clin Biosci 2021;9:89-94
|How to cite this URL:|
Obadipe JA, Samuel TA, Akinlalu AO, Ajisafe AO, Olajide EP, Albdulmumin L. Chemotherapy-induced ovarian toxicity in female cancer patients from selected Nigerian Tertiary Health Care. Niger J Exp Clin Biosci [serial online] 2021 [cited 2021 Oct 15];9:89-94. Available from: https://www.njecbonline.org/text.asp?2021/9/2/89/323668
| Introduction|| |
Cancer remains the second leading cause of mortality in humans. Chemotherapy is one of the treatment modalities widely employed for cancer management in Nigeria. The long-term adverse effect of chemotherapy on reproductive capability in premenopausal cancer patients is still a serious clinical concern.
Reproductive life span and indirect female fertility are linked with ovarian reserve. Evaluation of ovarian reserve before and after chemotherapy helps to monitor the extent of ovarian toxicity and predicts reproductive life span in cancer patients. Therefore, this study investigated the ovarian toxicity of chemotherapy in female cancer patients in selected Nigerian tertiary hospitals.
| Materials and Methods|| |
A descriptive case–control research design was employed for this prospective study.
The participants recruited in the study comprised fifty female cancer patients across all stages which were of age range 18 years to 72 years as well as sixty age-matched healthy volunteers (control) randomly selected from three medical centers in Nigeria, namely University College Hospital (UCH), Ibadan; Lagos University Teaching Hospital (LUTH), Idi-Araba, Lagos; and Federal Medical Centre (FMC), Idi-Aba, Abeokuta.
Inclusion and exclusion criteria
Female cancer patients without radiotherapy history but presently receiving chemotherapy were included in the study. However, premenopausal patients suffering from menstrual disorders and infertility as well as patients using contraceptive drugs and patients with apparent multiple organ dysfunction were excluded from the study.
The approval for the study was obtained from the ethics review committee of the three selected medical centers: UCH, LUTH, and FMC with the following ethics committee assigned numbers: UI/EC/19/0161, CMUL/HREC/11/18/464, and FMCA/470/HREC/01/2019/010, respectively. The procedures followed were in line with the ethical standards of the ethical committee of the selected medical centers on human experimentation. Furthermore, consent in form of written documents was obtained from every participant prior to the conduction of the study.
The sociodemographics of the patients as well as the history of menstrual cycle pattern of the recruited participants after chemotherapy were obtained from the participants using a well-structured questionnaire.
Three milliliters (3 ml) of blood samples was collected intravenously from the cancer patients at two intervals: before the commencement of chemotherapy and a week after chemotherapy (based on the half-life/clearance rate of chemotherapeutic drugs) into a set of well-labeled sample bottles. Meanwhile, blood sample was collected once from healthy control. The collected blood samples were left standing for 30 min after which it was centrifuged at 3000 rpm for 10 min for serum separation. The collected serum was kept in a Bio Freezer set at −20°C until analysis.
Human anti-Müllerian hormone and inhibin B level determination
The determination of anti-Müllerian hormone (AMH) and inhibin B hormone levels in the sera of the human subjects was carried out by sandwich enzyme-linked immunosorbent assay (ELISA) as described by Su et al. using commercial ELISA kits specific for human anti-Müllerian and inhibin B hormone, purchased from Melsin Medical Co., Limited. The detection limits of AMH and inhibin B assays were 25 pg/mL and 5 pg/mL, respectively. The intra-assay coefficient of variation for AMH and inhibin B assays was 2% and <5%, respectively. Values below detection thresholds were given half of the threshold value in analyses. The hormone assays were performed in duplicate.
Mean and standard error of the mean of the collected data were computed using IBM-SPSS version 22.0 software (SPSS Inc. Company, Chicago IL, USA). Tukey's honestly significant difference multiple comparative one-way analysis of variance was employed to test for the significant difference, with the level of significance considered at P < 0.05.
| Results|| |
The percentage of different types of cancer patients included in the study is presented in [Table 1]. From the table, majority of the participants were breast cancer and cervical cancer patients as it was reflected in their percentage distribution of 58% and 15%, respectively. However, patients with tongue cancer, non-Hodgkin's lymphoma, jaw cancer, and skin cancer constituted the minority of the participants with a percentage distribution of 1%.
|Table 1: Percentage distribution of the recruited participants by cancer types|
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It was evident from [Table 2] that majority of the cancer patients who participated in the study fell under the age group of 40–49 years and 50–59 years with percentage distributions of 31% and 32%, respectively, while minority of the study group comprised cancer patients of the age group 18–28 years with a percentage distribution of 2%.
|Table 2: Percentage distribution of the recruited participants by age group|
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The percentage distribution of the menstrual status of the participants included in the study is presented in [Figure 1]. The percentage of the participants at pre- and postmenopausal stages was 60% and 40%, respectively.
|Figure 1: Menstrual status frequency and percentage distribution of the participants|
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From [Figure 2], it is evident that a higher percentage (66%) of the premenopausal participants experienced ≥3-month menstrual cycle cessation after chemotherapy as compared to that (34%) with unaffected or regular menstruation.
|Figure 2: Percentage distribution of the participants by pattern of menstrual cycle experienced after chemotherapy|
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[Table 3] reveals a significant decrease (P = 0.000) in AMH levels of the participants after receiving chemotherapy as compared to that of the healthy control group. In the same way, there was a significant decrease (P = 0.001) in AMH levels in participants at postchemotherapy as compared to that of prechemotherapy.
|Table 3: Mean values of anti-Müllerian hormone and inhibin B levels of the participants|
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For inhibin B hormone, there was a significant decrease (P = 0.000) in inhibin B levels of the pre- and postchemotherapy group as compared to the control group. In the same vein, a significant decrease in inhibin B levels of participants at postchemotherapy as compared to that of prechemotherapy was recorded (P = 0.04).
The pre- and postchemotherapy inhibin B and AMH levels of the participants of different age groups are presented in [Table 4]. The table reveals an age group-dependent decrease in the pre- and postchemotherapy AMH and inhibin B levels of the participants.
|Table 4: Inhibin B and anti-Müllerian hormone profiles of the participants across different age groups|
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Furthermore, there was a significant increase (P = 0.002) in prechemotherapy inhibin B levels in the participants of age group 18–28 years and 29–39 years as compared to that of other age groups. In the same way, the prechemotherapy inhibin B levels of age group 40–49 years were significantly higher (P = 0.002) than that of the participants of other age groups except that of 18–28 years and 29–39 years. Moreover, the postchemotherapy inhibin B levels of the participants of age group 18–49 years were significantly higher (P = 0.002) than that of other age groups.
For the AMH, the pre- and postchemotherapy AMH levels of the participants of age group 18–49 years were significantly higher (P = 0.04) than that of other age groups.
The pre- and postchemotherapy inhibin B and AMH levels of the participants with regular menstrual cycle and menstrual cycle cessation experienced after chemotherapy are presented in [Table 5]. From the table, there was a significant decrease (P = 0.04) in prechemotherapy mean inhibin B and AMH levels of the participants with ≥3-month menstrual cycle cessation as compared to that with regular menstrual cycle. However, no significant difference (P = 0.82) in the postchemotherapy inhibin B and AMH levels of participants with regular menstrual cycle and that of participants with ceased menstrual cycle was revealed in the study.
|Table 5: Inhibin B and anti-Müllerian hormone levels of the participants with different menstrual cycle patterns|
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| Discussion|| |
The preservation of ovarian function and fertility has become one of the major qualities of life issues for patients of reproductive age undergoing chemotherapy. Routine monitoring of ovarian reserve in cancer patients in the course of chemotherapy with reliable, convenient, and simple ovarian biomarkers is of utmost importance for monitoring the extent of ovarian reserve loss with chemotherapy as well as to allow the detection of differences in ovarian damage among chemotherapy regimens and to predict long-term ovarian function and woman's reproductive life span in the cancer patients receiving chemotherapy which can be of great applications in individualization of fertility preservation strategies to improve patients' quality of life. Hence, the study investigated the effects of chemotherapy on ovarian function of female cancer patients receiving chemotherapy from three selected hospitals in South West Nigeria.
The findings from the study revealed breast cancer and cervical cancer as the most frequent types of cancer of all the cancer types prevailing among the participants in the study [Table 1]. The findings of this study are consistent with the epidemiological report of Globocan in which breast cancer and cervical cancer were ranked as number 1 and number 2 most frequent female cancers in the world, respectively.
As regards to the distribution of cancer patients by age group, the findings from the study revealed the age group 50–59 years to be the group noted with the highest cancer incidence, closely followed by the age group 40–49 years [Table 2]. The result obtained is in line with the work of Akinde et al. on cancer mortality pattern in LUTH, in which age groups 51–60 and 41–50 years were reported as the most cancer prevalent age groups with a percentage distribution of 19.0% and 21.0%, respectively. More so, the age groups with most cancer prevalence revealed in the study are slightly higher than age group 40–44 years reported as the age group with the highest female cancer incidence by the work of Sowunmi et al. on trend of cancer incidence in an oncology center in Nigeria. In light of the above, advanced age is an important risk factor of cancer development.
Furthermore, the finding of the study shows that a higher percentage of premenopausal participants experienced ≥3-month menstrual cycle cessation after receiving chemotherapy [Figure 2]. Several studies in the past have reported the occurrence of chemotherapy-induced menstrual cycle changes in premenopausal female cancer patients undergoing treatment. The findings of this study corroborate with the work of Salai et al. who detected menstrual changes in most of the female cancer participants after receiving chemotherapy which eventually developed into permanent amenorrhea in some of the studied participants. Similarly, the result of this study is also in line with the study of Meng et al. who reported 14 (47%) cases of chemotherapy-induced amenorrhea among 30 breast cancer patients receiving four cycles of adriamycin-cyclophosphamide-based chemotherapeutic regimen. Cytotoxic chemotherapy may alter menstrual cycle to variable extents which may eventually result in amenorrhea.
Menstrual cycle status has been a conventional and general clinical assessment method of postchemotherapy ovarian function in premenopausal individuals. However, it does not depict actual ovarian function. Therefore, measuring ovarian reserve biomarkers including anti-Müllerian and inhibin B hormones gives a precise and better reflection of ovarian function in the premenopausal individual.
More so, the findings from the AMH study showed a significant decrease (P < 0.05) in the pre- and postchemotherapy serum AMH levels as compared to that of control [Table 3]. However, comparing the hormone levels before and after chemotherapy, a significant decrease in the postchemotherapy AMH levels in the participants as compared to that of prechemotherapy was observed in the study [Table 3]. The findings obtained in the study are in agreement with the work of Bala et al. conducted on impact of chemotherapy on AMH levels in breast carcinoma in which a significant decrease (P < 0.05) in serum postchemotherapy AMH levels as compared to that of prechemotherapy was reported. In the same way, a significant decrease in pre- and postchemotherapy AMH levels as compared to that of control was reported by the same study.
Similarly, a significant decrease in pre- and postchemotherapy inhibin B hormone levels as compared to that of control was revealed in the study [Table 3]. Based on the findings of the study, greater ovarian function in the control participants as compared to that of cancer patients before and after chemotherapy was evident.
Furthermore, a comparison of pre- and postchemotherapy inhibin B levels showed a significant decrease (P = 0.04) in postchemotherapy inhibin B levels as compared with that of prechemotherapy [Table 3]. The reduced anti-Müllerian and inhibin B hormonal levels in the participants after receiving chemotherapy as compared to that of prechemotherapy recorded in the study indicated the suppression of ovarian reserve by chemotherapy in the participants [Table 3].
Chemotherapy is known to cause harmful effects on rapidly dividing cells including the ovary and can compromise both future ovarian function and subsequent fertility, greatly affecting the quality of life of the survivorship. These findings support the fact that chemotherapy causes a deleterious effect on ovarian function by depletion of oocytes or granulosa cells leading to reduction of antral follicular pools which in turn reflect in the alteration in the levels of the hormones measured at the two intervals of time, prior to the chemotherapy and after chemotherapy.
Moreover, considering the effect of age group of the participants on the levels of these ovarian reserve hormone biomarkers, the findings of the study showed a general age-dependent decrease in the levels of the hormones in the participants before and after receiving chemotherapy [Table 4]. In addition, significant higher prechemotherapy Inhibin B and AMH levels recorded for the age groups 18-28 and 29-39 years as compared to other age groups [Table 4], was as a result of higher antral follicles in the participants of the age groups; 18-28 and 29-39 years as compared to others. The findings of the study are in agreement with the reports of several scientific studies in which female ovarian reserve has been proven to decline progressively with increasing chronological age.,,
Moreover, the findings of this study showed a significant decrease in prechemotherapy inhibin B and AMH levels of the participants with menstrual cycle cessation as compared to those with normal menstruation. In the same way, the lower levels of postchemotherapy inhibin B and AMH in participants with menstrual cycle cessation as compared to that of regular menstrual cycle were also revealed in the study. The findings on the inhibin B obtained in the study are in agreement with the work of Blumenfeld and Ritter. in which lower inhibin B levels at postchemotherapy among women who experience chemotherapy-induced hypergonadotropic amenorrhea as compared to stable levels among those who resumed menstrual function following chemotherapy were reported. Inhibin B has only been reported by three smaller studies with short follow-up and limited association of the hormone with menstrual pattern postchemotherapy.
| Conclusion|| |
Conclusively, treatment of female cancer patients with chemotherapeutic regimens is accompanied by ovarian toxicity involving decreased ovarian reserve as well as menstrual cycle cessation in female cancer patients undergoing chemotherapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tan BL, Norhaizan ME. Curcumin combination chemotherapy: The implication and efficacy in cancer. Molecules 2019;24:2527.
Chabner BA, Roberts TG Jr. Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer 2005;5:65-72.
Donnez JD, Marie M. Fertility preservation in women. N Engl J Med 2017;378:400-1.
Harold M, Ivan DA, Elkin LQ, Lius AA, Alix ED,Marbel FC, Clara EP. Ovarian Reserve Markers: An update. Biomarker. Published by Intechopen, Rijeka. 2018, Chapter 7.
Su HC, Haunschild C, Chung K, Komrokian S, Boles S, Sammel MD, et al
. Prechemotherapy antimullerian hormone, age, and body size predict timing of return of ovarian function in young breast cancer patients. Cancer 2014;120:3691-8.
Dessie N, Lema W, Aemero M. Hematological and biochemical profile of patients infected with Schistosoma mansoni
in comparison with apparently healthy individuals at Sanja Town, Northwest Ethiopia: A cross-sectional study. J Trop Med 2020;2020:4083252.
Bray F, Ferlay Jacques, Halelle S, Siegel RL, Torre LA, Ahmedin J. Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A cancer Journal for clinicians. 2018; 0: 1-31.
kinde OR, Phillips AA, Oguntunde OA, Afolayan OM. Cancer motility pattern in Lagos. University Teaching Hospital, Lagos, Nigeria J. cancer Epidemiol 2015; 5 (25).
Sowunmi A, Alabi A, Fatiregun O, Olatunji T, Samuel O, Francis A, et al
. Trend of cancer incidence in an oncology center in Nigeria. West Afr J Radiol 2018;25:52-6. [Full text]
Salai JM, Nermin JA, Kawa FD. Menstrual and hormones changes in breast cancer patients treated by adjuvant, Adriamycin and cyclophosphamide chemotherapy. J Kurdistan Board Med Special 2016;2:22-7.
Meng K, Tian W, Zhou M, Chen H, Deng Y. Impact of chemotherapy-induced amenorrhea in breast cancer patients: The evaluation of ovarian function by menstrual history and hormonal levels. World J Surg Oncol 2013;11:101.
Bala J, Seth S, Dhankhar R, Ghalaut VS. Chemotherapy: Impact on anti-Müllerian hormone levels in breast carcinoma. J Clin Diagn Res 2016;10:BC19-21.
Amanvermez R, Tosun M. An update on ovarian aging and ovarian reserve tests. Int J Fertil Steril 2016;9:411-5.
Hussein MJ, Shahia KA, Namir GA. Effect of maternal age on the ovarian reserve markers and pregnancy outcome in a sample of Kurdish women in Erbil City. Zanco J Med Sci 2018;22:1.
Al- Janabi HT, Al- Taeb HA, Alawad AS. The impact of age on anti-mullerian hormone serum level in women attending chemotherapy unit for primary breast cancer. Middle East Fertil Soc. J. 2018, Vol. 23, issue 2, Pages 126-130.
Blumenfeld Z, Ritter M. Inhibin, activin, and follistatin in human fetal pituitary and gonadal physiology. Ann N Y Acad Sci 2001;943:34-48.
Anders C, Marcom PK, Peterson B, Gu L, Unruhe S, Welch R, et al.
A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest 2008;26:286-95.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]