Fatigue constitutes one of the most common side effects of cancer and its treatment1. Studies suggest that about one quarter to one third of the survivors experience persistent fatigue for up to 10 years after cancer diagnosis2. The aetiology of cancer-related fatigue (CRF) is not well understood and is likely multifactorial. Over the past two decades an array of biological mechanisms have been proposed for CRF including anaemia, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, 5-HT(hydroxytryptophan) neurotransmitter dysregulation and increased activity of various cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNF-α)3,4. The hormone status of fatigue in other medical conditions has been studied well, but in CRF, it remains largely under-explored5,6. For instance the serum levels of cortisol have been reported to have reduced in severe fatigue3 and the relationship of thyroid profile with fatigue has also been established in many diseases6. Low level of dehydroepiandrosterone sulphate (DHEAS) have also been shown in fatigued patients in chronic conditions. but not in CRF5. Similarly, oestrogen and progesterone profile has not been investigated in breast cancer survivors (BCSs) with fatigue, though these have been shown to have a correlation with fatigue in certain condition in a few studies7,8.
In view of a possible correlation of hormonal dysfunction with CRF in BCSs, this exploratory study was undertaken to assess the level of fatigue using the Brief Fatigue Inventory (BFI) scale; to estimate the hormonal levels (TSH, fT3, fT4, cortisol, DHEAS, oestrogen and progesterone) in fatigued BCSs; and to analyze the data for possible correlation of hormonal profile with CRF.
Material & Methods
This cross-sectional observational study was conducted in the department of Surgery, University College of Medical Sciences and associated Guru Teg Bahadur Hospital, Delhi, India, between December 2014 and December 2017, after obtaining approval from the Institutional Ethics Committee. A written informed consent was obtained from all the participants.
Inclusion and exclusion criteria: Breast cancer survivors (BCSs; n=148) who completed their primary treatment (surgery, chemotherapy and radiotherapy) and were disease-free with a minimum of six months follow up were included in the study.
Survivors who were on any drugs which cause fatigue (e.g. antihypertensive, statins and fibrates); known cases of endocrinopathy (e.g. thyroid disease and diabetes), and those who had chronic medical conditions associated with fatigue such as (anaemia, chronic malnutrition, multiple sclerosis, heart failure, chronic obstructive pulmonary diseases, HIV/AIDS, end-stage renal diseases, psychiatric diseases, systemic lupus erythematosus and rheumatoid arthritis) were excluded from the study. Since this was a preliminary study, a sample size of 60 was taken as a sample of convenience in lieu of similar past studies.
Demographic and clinical profile: Demographic and clinical details were recorded in a predesigned pro forma. All participants were interviewed personally and the English and Hindi versions of the BFI scale developed by Mendoza et al9 was filled out. The permission to use BFI-English and Hindi versions in the current study was obtained from MD Anderson Cancer Centre, Texas, USA. There were nine items on BFI, measured on numeric rating scales from 0 to 10. The first three items inquired about the present fatigue level of the participants; at its usual level; and at its worst level during the previous 24 h. The next six items described how much fatigue has interfered with aspects of their life during the past 24 h. The validity and reliability of the BFI (Multilingual - English, Hindi, Italian, etc.) have been established10,11. The mean value of all the responses was marked as the global score. Fatigue was classified as mild (global score: 1-3), moderate (global score: 4-6) or severe (global score: 7-10). The assessment of the hormone profile was made only in BCSs with moderate-to-severe fatigue (score >3).
Hormonal assessment: For the assessment of hormonal profile, participants were asked not to have any drinks such as alcohol, coffee or other food stimulants and not to do exercise/heavy work 12 h before the appointment for collection of samples, to eliminate any confounding effects. After 30 min of rest, 5 ml blood was withdrawn by venipuncture using sterile precaution from each participant. Levels of oestrogen, progesterone, cortisol, TSH, fT3, fT4 were measured in serum using radioimmunoassay kits and analyzers (Beckman Coulter Life Sciences, Indianapolis, USA). The main outcome measures were: (i) dimension and severity of fatigue in BCSs; (ii) changes in hormone levels in patients with moderate and severe fatigue.
Statistical analysis: All data were analyzed using SPSS version 25.0 (IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY, USA). Clinical and demographic characteristics were analyzed using simple descriptive statistics. Scoring of fatigue using BFI was done as prescribed for this inventory scale9. Independent sample Mann-Whitney U test was used to test null hypothesis for non-normal distribution in our study population. For the correlation of fatigue severity with hormones, Spearman correlation was used.
Results & Discussion
Demographic and clinical details of the study population are provided in Table I. Of the 148 BCSs participants enrolled in this study, 110 (74.32%) had fatigue. Of these 48 participants (43.63%) reported mild fatigue; 50 (45.45%) had moderate and 12 (10.91%) had severe fatigue. On analysis of BFI, we found that the largest contribution to the global score was made by fatigue interfering with walking ability (21.07%), followed by fatigue interfering with mood (19.98%).
These findings are in concurrence with other studies in literature where 30-60 per cent of participants reported to have moderate-to-severe fatigue in long-term survivors2,12. Fatigue has been reported to have a negative impact on work, social relationships, mood and daily activities. The mood has been reported to be one of the four adverse effects of survivorship13.
In case of the hormonal profile, about one fourth (25.81%) of participants had reduced fT3 levels below the reference range. Four participant (6.45%) showed reduced fT4 levels. Twenty two participants had raised TSH levels (35.48%) while only two had diminished TSH levels (Table II).
In the present study, 10 participants (16.12%) had overt hypothyroidism, while 12 (19.35%) had subclinical hypothyroidism and two had subclinical hyperthyroidism. Overall 38.7 per cent (n=24) of the participants with moderate-to-severe fatigue had deranged thyroid profiles (Table II). None of these patients were detected to have any thyroid disorder in the preoperative workup. Twelve participants (19.35%) had reduced DHEAS levels suggestive of impaired hormone synthesis in the adrenal gland. Two survivors (3.23%) had reduced morning cortisol levels while the rest had it within the normal limits. Twenty two post-menopausal survivors (35.48%) had raised oestradiol levels, while a few (n=8, 12.90%) had reduced oestradiol levels. No pre- or post-menopausal survivors had deranged progesterone levels (Table II).
TSH levels showed a significant correlation with levels of fatigue (P = –0.363). A higher level of fatigue was associated with lower levels of TSH (P<0.05). Spearman correlation coefficients of various hormones are depicted in Table II.
The relationship between thyroid dysfunction and breast cancer have so far been evaluated only by a few studies. One prospective study on the thyroid function in breast cancer showed that the overall prevalence of thyroid disease was 46 per cent in breast cancer patients as compared to 14 per cent in controls, with nontoxic goitre, Hashimoto’s thyroiditis being the most common diagnoses14. In another study, the incidence of thyroid disease was found to be higher in patients than in controls (58 vs. 18%, P<0.05), and subclinical hyperthyroidism was found to be the most frequent (31%) disorder15.
Cytotoxic agents have been suggested to influence thyroid function in BCSs, contributing to symptoms such as fatigue, weight gain, amenorrhoea, and decreased physical activity. Thyroid function may also get affected by chemotherapy, radiotherapy or cancer biology itself, either directly or through hypothalamo-pituitary-thyroid axis16.
In this study, one fifth (19.35%) of the participants had reduced levels of DHEAS. DHEAS is exclusively synthesized in the adrenal gland and is a precursor of steroid hormones. Our findings suggest a possible aetiology of the adrenal gland wherein a defect in the hormonogenesis may play a role in the genesis of fatigue. Improvement in general fatigue with DHEAS supplementation has been reported in females with primary Sjögren’s syndrome as well as the general population5. This provides some support to our hypothesis. However, the role of DHEAS in CRF needs to be explored further in detail.
It has been shown that raised endogenous sex hormones (like oestradiol) are strongly associated with breast cancer risk in postmenopausal women17. A similar trend was found in our study as well. However, lowered levels of oestradiol signify chemotherapy-induced HPA suppression and ovarian failure as shown in few of our patients.
So far, as per the author’s knowledge, this is the first study which has looked at a spectrum of hormones in Indian BCSs with fatigue. Since this was conducted as a pilot study, the sample size was small for the results to be statistically significant. Furthermore, baseline levels of hormones at the beginning of treatment were not noted, which would have strengthened the validity of the study findings.
To conclude, fatigue is a common problem among most survivors of breast cancer which needs to be addressed. Hypothyroidism and reduced DHEAS levels, indicating malfunction of thyroid and adrenal glands likely have a causative role in its pathogenesis. However, further exploration in larger studies is warranted to validate these findings.
Financial support & sponsorship: None.
Conflicts of Interest: None.
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