Factors related to the experience of menopausal symptoms in women prescribed tamoxifen

Introduction

Hot flushes and night sweats (HFNS), the main symptom of the menopause, typically involve a sudden sensation of heat and warmth, accompanied by reddening of the skin and sweating. They are thought to result from disturbances of the temperature regulating mechanism in the hypothalamus, triggered by reduced oestrogen levels [1]. Whilst HFNS can vary significantly between individuals, women with breast cancer are five times more likely than age matched controls to experience these symptoms and are also more likely to experience longer, more frequent and more severe HFNS [2–4]. Women who take tamoxifen are twice as likely to experience HFNS [2] and more likely to report severe to intolerable HFNS [5] than other breast cancer survivors.

Tamoxifen, or a similar class of drugs (aromatase inhibitors), are prescribed to up to three quarters of breast cancer survivors in order to reduce the risk of recurrence [6]. They are prescribed to women with oestrogen receptor positive breast cancer and work by blocking the effects of oestrogen on cancer cells. Tamoxifen is prescribed mainly to pre-menopausal women, whereas aromatase inhibitors are prescribed only in post-menopausal women. Recent evidence suggests that survival benefits are enhanced if tamoxifen is taken for an additional 5 years [7,8]. This increase in treatment duration, accompanied by a rise in breast cancer survival rates, means that increasing numbers of women may be suffering from HFNS as a consequence of tamoxifen. Studies have indicated that HFNS prevalence in breast cancer survivors may be as high as 80% [9–11]. Tamoxifen is associated with a range of other side effects including weight gain, insomnia, joint pain and vaginal dryness [12,13]. Whilst not life threatening, these symptoms can have a considerable impact on quality of life [11]. HFNS in breast cancer survivors are associated with anxiety, sleep problems, poor emotional functioning [10] and poor physical health [14]. Furthermore, these symptoms can undermine adherence to tamoxifen [15,16].

One of the key treatments for HFNS, hormone replacement therapy (HRT) [17], is contraindicated in breast cancer survivors due to a potential increased risk of cancer recurrence, which severely limits treatment options for HFNS in these patients. There are some non-hormonal options, such as venlafaxine or gabapentin [18], but many breast cancer survivors are keen to avoid additional medications which likely have side effects [10]. Several recent papers have called attention to the lack of research into HFNS in breast cancer survivors [1,19] and highlighted a need to understand the experiences of these women, with a view to identifying safe and effective treatments [10,19,20].

Factors associated with HFNS in the general population include lower levels of education [21,22], African American race [23,24], younger age [25] and being without a partner [26,27]. The cognitive model of HFNS explains how the perception, attribution and appraisal of menopausal symptoms are influenced by cognitive factors, beliefs and mood [28]. For example, stress or negative affect can reduce the threshold for detection of physical sensations, and increase the likelihood that women will attend to, and therefore report, HFNS [28,29]. Anxiety has been shown to precede hot flushes [30]; however, studies suggest that there is a complex bi-directional relationship between HFNS and depression whereby HFNS can cause depressed mood, but may also be a result of depression [1,28,31].

Moreover, anxiety and depression are associated with negative beliefs, which in turn affect cognitive appraisal of symptoms [28]. For example, negative thoughts such as embarrassment, disgust and worry are linked to more problematic hot flushes [32]. The common sense model of illness representations posits that how patients represent symptoms and where they attribute them will likely guide how they cope with the symptom [33]. This may influence emotional reactions, illness outcomes and health behaviours such as treatment adherence or help seeking [34–37]. The cognitive model of HFNS has informed the development of cognitive behavioural therapy (CBT) for HFNS, which has been shown to reduce the impact of HFNS [38,39].

Whilst the cognitive model of HFNS is well accepted in the general population [1,40], the experience of menopausal symptoms in women taking tamoxifen remains under-researched. This is important considering the increasing rates of breast cancer, partnered with greater survivorship and increased duration of tamoxifen treatment. This paper aimed to explore the experience and attribution of menopausal symptoms in women prescribed tamoxifen and, using the cognitive model and other sociodemographic predictors, identify factors related to the experience of HFNS.

Methods

The study was approved by the Northampton National Research Ethics Committee (Ref.: 14/EM/1207), with site specific approvals for each site.

Results

Discussion

This paper examined the experience of menopausal symptoms in breast cancer survivors taking tamoxifen and explored factors contributing to the experience of HFNS. Results showed that 84% of women had experienced hot flushes and 80% had experienced night sweats. This is consistent with previous research in the community indicating a prevalence of around 80% [9–11], but is much higher than the prevalence of 29–45% found in several large RCTs comparing tamoxifen with aromatase inhibitors [49]. This may be because some women who experienced negative side effects discontinued treatment and were removed from the RCTs. However, previously, less was known regarding the severity of HFNS in women taking tamoxifen [50]. This paper adds new information, by showing that around 60% of women experiencing HFNS reported severe symptoms. The extent and severity of these symptoms reinforces the need to identify who is more at risk and to find ways to help patients manage these symptoms [1,19,20]. Participants also reported high levels of joint pain, vaginal discharge/dryness/itchiness, loss of libido, mood swings and weight gain. The prevalence of fatigue and sleep problems was slightly lower than previously reported in patients taking tamoxifen [13,51], but loss of libido, vaginal symptoms and mood swings were higher than previous reports have indicated [13,52,53]. Again, all symptoms were reported at a greater frequency than found in a review of RCTs [49].

Previous studies have suggested that HFNS are less problematic after one year of tamoxifen treatment [54,55] and patients are often advised that their symptoms will reduce after a few months. However, this study shows that the prevalence of HFNS remains stable (around 80%) regardless of whether the patient is in her first or fifth year of treatment. The severity of symptoms also remains high up until the fourth year of treatment. This highlights the need to identify effective strategies to help women to manage their HFNS across the duration of treatment. CBT has been shown to reduce HFNS frequency and problem rating in breast cancer survivors and can teach women long-term self-management strategies [38,39,56].

Up to two-thirds of participants attributed HFNS to tamoxifen. Participants also associated other symptoms to tamoxifen, including fatigue, sleep difficulties, joint pain, vaginal discharge/dryness/itchiness and weight loss/gain. These symptoms are established side effects of tamoxifen [13]. Women who attributed HFNS to tamoxifen were three to four times more likely to experience severe symptoms than those who did not attribute their symptoms to tamoxifen. More research is needed to confirm the direction of this effect and to establish the consequences of attributing symptoms to tamoxifen treatment. Previous studies have suggested that symptom attribution is likely to affect coping behaviours [33], but this was not tested in the current study.

After controlling for demographic factors and mood, women who had chemotherapy were twice as likely to report hot flushes than women who had not had chemotherapy. This conflicts with previous studies in breast cancer patients, showing no association between HFNS and chemotherapy [11,57]. However, previous studies included mainly postmenopausal women, and the association between chemotherapy and HFNS may be stronger in premenopausal women [58]. Chemotherapy can induce an early menopause in some patients, increasing the incidence of HFNS [59], which could explain the increased HFNS in premenopausal women who have received chemotherapy.

Women who were employed were twice as likely to experience HFNS and more likely to experience severe hot flushes. This has important implications for supporting women in the workplace. Studies have shown that menopausal symptoms cause difficulty at work and may impact negatively on work performance [1,60,61]. Working women have discussed fears around embarrassment and others’ reactions [62], which is likely to exacerbate the severity of hot flushes. CBT may be helpful to moderate negative thoughts around menopausal symptoms in the workplace and to reduce anxiety around stigma.

Higher scores on the depression scale were associated with twofold increased odds of HFNS incidence and increased odds of severe HFNS. This supports the cognitive model of HFNS [28], which proposes that depressed mood can affect how patients perceive and appraise their symptoms. However, it is likely that there is a bi-directional relationship between HFNS and depression, and it is unclear in this study if the depressed mood is a result of the HFNS or if it is increasing the likelihood that women will report symptoms. Anxiety was associated with increased odds of HFNS in the univariate analysis, but was not significant after controlling for other variables. This contrasts with previous studies showing a clear relationship between anxiety and hot flushes [30]. However, the lack of relationship between anxiety and HFNS has been shown previously in breast cancer patients [63].

Age was significantly related to HFNS prevalence in the univariate analysis, but was not significant in the multivariate analysis. This is likely due to shared variance between age and menopausal status at diagnosis. Younger age has been found to be associated with increased risk of hot flushes in breast cancer survivors [5]; however, this effect has not been consistently shown [11,13]. Previous studies have shown that ethnicity is related to hot flush frequency [64]. African-American women tend to report more hot flushes than Caucasian women and Japanese women have been shown to report fewer symptoms [24,65,66]. However, these effects are not always shown [67] and the current study found no effect of ethnicity on HFNS prevalence or severity. This may be due to the lack of ethnic diversity in the study; only 8% of women self-identified as not White British.

Overall, the results suggest that a high proportion of women experience symptoms such as HFNS as well as fatigue, joint pain and vaginal symptoms. These symptoms are often severe and women report experiencing them even in their fifth year of treatment. As HRT is contraindicated, only 21% of breast cancer survivors receive any treatment for these symptoms [11] and there is a need to identify non-hormonal treatments. The North American Menopause Society (NAMS) has reviewed evidence for non-hormonal treatments and has found some degree of efficacy for selective serotonin reuptake inhibitors in menopausal women [68], but results are not conclusive and breast cancer survivors have expressed a preference for non-medical treatments [10]. CBT, which is based on the cognitive model of HFNS, is recommended by NAMS [69] and The National Institute for Health and Care Excellence [17]. CBT has been shown to improve HFNS problem rating and may provide patients with long lasting self-management strategies. There is a need to identify patients who are taking tamoxifen and have received chemotherapy, as they may be more at risk of hot flushes. Furthermore, the results stress a need to support women who have returned to work following breast cancer.

The strengths of this study were the large sample size, use of validated measures and good response rate. This is one of the largest samples used to investigate the experience of HFNS in women taking tamoxifen. However, that we measured symptom severity and not bother is a limitation of this study. Measuring perceived bother from symptoms as opposed to the severity may provide a more thorough understanding of the impairment associated with these symptoms [66]. An additional limitation was the use of cross-sectional data which prohibits causal assumptions for some effects, such as the relationship between hot flushes and depression. All measurements were subjective; therefore, the hot flush frequency may be more of an assessment of how people perceive their symptoms rather than an objective physiological measure. Data were not collected on use of additional medications. Some women may be prescribed anti-depressants to manage their HFNS, and this could have impacted on their mood. A final limitation with the study was the lack of a comparison group, such as breast cancer patients not receiving endocrine therapy, with whom to compare the results to.

Conclusion

Prevalence and severity of HFNS, as well as other symptoms such as vaginal dryness and joint pain, are high in breast cancer survivors taking tamoxifen. There is a need to identify non-hormonal treatment options such as CBT to help support patients with these symptoms, especially as they persist for longer than previously believed. Furthermore, this study shows that women who are in employment, received chemotherapy, attribute HFNS to tamoxifen and have high depression scores may require more targeted support to manage HFNS.

Disclosure statement

The authors report no conflicts of interest.