Patients who experience a sudden loss of ovarian function as a result of surgery experience more severe CRF. Our main finding was that 97.63% of the patients recruited in this study reported fatigue; of these, 18.48% of women reported severe and moderate CRF following treatment for ovarian cancer. Ovarian cancer is the eighth most common form of cancer to affect women worldwide. The incidence of this condition varies markedly around the world. Previous studies have reported that 80–96% of patients undergoing chemotherapy for cancer complain of CRF [5]. The form of treatment used for ovarian cancer depends on the stage and type of cancer, and includes surgery, chemotherapy, radiation, targeted therapy, hormone therapy, and immunotherapy [6]. CRF is one of the main factors that can influence the quality of life of patients following cancer treatment. Research has shown that CRF may persist for years after chemoradiation therapy and can significantly impair both the quality of life (QoL) and treatment outcome [7].
In our study, we found that patients who had undergone surgery prior to menopause could become fatigued more easily than patients who received surgery after menopause. The CRF score in patients who had experienced a menstrual period prior to treatment was significantly higher than patients who became menopausal before undergoing treatment. We identified a significant association between menopausal symptoms and fatigue within 1 and 2 years of treatment.
It is possible that CRF may be related with sudden changes in the levels of sex hormones. Most ovarian cancers are treated with platinum-based and multi-cycle forms of chemotherapy. Furthermore, the standard treatment for ovarian cancer includes removal of the ovaries prior to chemotherapy [8]. Research has also shown that the removal of both ovaries in premenopausal women with gynecological cancer can result in a series of menopausal symptoms, including hot flushes, emotional disorders, sleep disturbances, and sexual dysfunction; collectively, these factors can exert significant effect on the quality of life (QoL) [9].
A series of scientific experiments, involving rodent models, have proved strong evidence to support the ability of androgenic and estrogenic sex hormones to augment the activation of satellite cells and modulate inflammatory dynamics during the regeneration of muscles. It is possible that humans may adopt a similar mechanism, although this has yet to be proven.
Research has also shown that the iatrogenic symptoms of menopause are usually considerably more severe in comparison to those following a naturally occurring menopause and might adversely affect the QoL in young females who have survived cancer [10]. Premenopausal women undergoing treatment for ovarian cancer can benefit from hormone replacement therapy (HRT); however, there is a lack of consensus with regards to the safety of HRT when administered to this particular group of patients [9]. The Swedish National Guidelines for ovarian cancer recommend that women with iatrogenic symptoms of menopause after undergoing primary treatment for epithelial ovarian cancer can be treated with HRT without any known risk of disease recurrence or reduced survival [11]. HRT has also been reported to improve the QoL in patients with ovarian tumors, although the precise relationship between HT and CRF has yet to be investigated. It therefore appears that the positive effects of HRT in maintaining the QoL outweighs the doubt that exists with regards to the increased risk of recurrence. Thus far, very few studies have investigated the effect of HRT after surgery in patients with epithelial ovarian cancer; furthermore, these existing studies have led to contradictory conclusions [12]. Some scholars suggest that HRT is associated with angiogenesis and may stimulate residual ovarian cancer cells or visible disease in women receiving EOC, or induce new hormone-dependent diseases, such as breast cancer.[9]
As treatment options are improving, the life expectancy of patients with ovarian cancer are beginning to improve; outcomes related to QoL are therefore very important. HRT can relieve menopausal symptoms in women with early-stage ovarian cancer and improve the QoL of those with advanced stages of the disease [13]. Due to the sudden fall in hormone levels caused by the removal of the ovaries, the risks associated with premature menopause, including osteoporosis, cardiovascular disease, venous thromboembolic disease, and stroke, may outweigh the risk of using HRT [14].
We found that the fatigue caused by chemotherapy reached maximal levels within the first two years of treatment but then began to decline. One notable finding from baseline evaluations was the profound difference in the level of fatigue experienced by patients and controls. Previous studies have suggested that fatigue can remain a significant problem for several years following chemotherapy. We observed clear improvement in the fatigue experienced by our patients over the two years of follow up; this finding supported previous work and was reassuring, although patients remained more fatigued than controls when tested two years after chemotherapy. Cognitive dysfunction, menopausal symptoms, and fatigue are important adverse effects of chemotherapy but improve slowly over the following two years in most patients. In addition, fatigue has been found to co-exist with inflammation-associated anemia caused by a reduction in iron levels in response to thyroid insufficiency or the impaired function of the IL-6-mediated the hypothalamic-pituitary-adrenal axis [15].
The clear interaction between fatigue and menopausal symptoms raises the possibility that nocturnal vasomotor symptoms interfere with the quality or duration of sleep. In our study cohort, we found that CRF and cancer-related sleep disorders were positively correlated with fatigue. Most studies in this area found that sleep disorders were more severe in fatigued than non-fatigued patients, and also that sleep disorders were a significant predictor of fatigue. A recent meta-analysis of cross-sectional data from 24 studies reported a higher odds of experiencing sleep disturbance in perimenopause (1.60), postmenopause (1.67), and surgical menopause (2.17) when compared to premenopausal women [16]. In another study, Savard and Morin reviewed the epidemiology of insomnia in patients with cancer and concluded that insomnia created an additional risk for intense and persistent fatigue following cancer treatment. Other investigators have suggested that CRF and sleep disorders should be considered as a clinical syndrome [17]. Another study reported that increasing levels of follicle stimulating hormone (FSH) were associated with a greater odds of waking up several times during the night, and that decreased levels of estrogen were associated with a higher odds of difficulty falling asleep and staying asleep [18]. Consequently, it is evident that sleep quality can be affected by hormonal changes and result in increased levels of fatigue. Moreover, several recent reviews have indicated that a strong inter-relationship exists between sleep disorders and CRF and that the strength of this association changes with differing times of diagnosis and treatment .
In the present study, we carried out linear regression analysis and identified a negative correlation between hemoglobin level and CRF but failed to identify any such significant correlation between these factors in our multivariate linear regression analysis. Anemia appears to be particularly prevalent in cancer patients receiving surgery and chemotherapy. This form of anemia is multi-factorial but is sustained in part by concurrent chemotherapy and the relative deficiency in endogenous erythropoietin that is associated with chronic disease [19]. However, it is well known that anemia is one of the main factors responsible for fatigue in patients with cancer. In a previous study, Littlewood et al. reported that hemoglobin concentrations were associated with improvements in fatigue and that patients achieving a 2g/dl increase in the level of hemoglobin also showed improvements in the FACT fatigue subscale; patients who did not achieve a change in hemoglobin level experienced a decline in the fatigue subscale [20].Our study found no significant difference in CRF when compared between patients receiving different platinum-based chemotherapy regimens. The mechanism underlying chemotherapy-induced fatigue has yet to be elucidated in detail. However, it is evident that the energy supply to cells will decrease if there are disruptions in the structure and function of mitochondria [21, 22]. Research involving patients receiving chemotherapy has demonstrated that chemotherapy always targets the skeletal musculature in a non-specific manner, particularly, the mitochondria; inevitably, this will induce adverse side effects due to low energy supply and high levels of oxidative stress [23]. Mitochondrial dysfunction plays a major role in the development of diseases associated with energy metabolism. It has also been established that impaired energy production, or the longitudinal depletion of ATP, induces increased levels of physical disability, such as that observed in CRF or chronic fatigue syndrome (CFS).
Previous researchers proposed that chemotherapy drugs such as oxaliplatin competitively substitute copper (Cu2+) on the copper transporter 1 (CT1) protein, thus reducing the transportation of Cu2 + and leading to a reduction in the mitochondrial pool of Cu2+. The mitochondrial Cu2 + pool is known to be critical for the function of complex IV and COX17 as well as oxidative phosphorylation [24].
Patients treated extensively with chemotherapy have reported a lower QoL, increased levels of fatigue, and less vigor, when compared with patients with earlier stages of disease and receiving less-intensive treatments.
This study has certain limitations that need to be considered. First, this is a retrospective study; our findings should be confirmed in larger prospective study. Secondly, our study lacked interventions to verify the specific factors associated with CRF. Finally, none of our patients were treated with HRT.