A Recent Review of the Management of Postmenopausal Symptoms in Breast Cancer Survivors

Vasomotor symptoms

In most cases, postmenopausal women present with vasomotor symptoms, including hot flashes and night sweats. More than half of women undergoing tamoxifen maintenance treatment experience hot flashes, which cause a considerable decline in the patient’s quality of life [2]. Aromatase inhibitors are also associated with vasomotor symptoms. Hormone replacement therapy is the most effective treatment for vasomotor symptoms. However, the hormonal nature of breast cancer make systemic hormonal treatment inadequate for these patients.

Non-hormonal pharmacological options for the management of vasomotor symptoms include selective serotonin reuptake inhibitors (SSRIs), noradrenaline reuptake inhibitors (SNRIs), gabapentin, pregabalin, and clonidine. Several studies have previously shown that SSRIs and SNRIs alleviate vasomotor function in postmenopausal women, and a review focused on cancer survivors provides evidence that these drugs are related to improvement of symptoms in postmenopausal women who underwent cancer treatment [3]. Among SSRIs, 10–25 mg/day of paroxetine and 10–20 mg/day of escitalopram reduced vasomotor symptoms. For SNRIs, 100 to 150 mg/day of desvenlafaxine and 37.5–150 mg/day of venlafaxine can be used. SSRIs and SNRIs are contraindicated in those with prior neuroleptic syndrome, serotonin syndrome, and concurrent use of monoamine oxidase inhibitors [4].

Meanwhile, in women taking tamoxifen, the use of SSRIs may lead to the inhibition of CYP2D6, an enzyme that converts tamoxifen to its active metabolite. The most potent effect on inhibition of CYP2D6 occurs with paroxetine and fluoxetine; therefore, these drugs should not be prescribed in patients receiving tamoxifen [5]. SNRIs can be used as alternatives. In two sequential studies, breast cancer survivors received a low dose (37.5 mg/day) and a high dose (75 mg/day) of these medications, and both doses significantly decreased the frequency and severity of the vasomotor symptoms [6].

Gabapentin is an antiepileptic drug used to treat partial seizures and neuropathic pain. Since it was first reported in 2000, gabapentin has become a nonhormonal therapeutic option to relieve vasomotor symptoms in postmenopausal women [7]. In one study, 420 patients with breast cancer were administered 900 mg of gabapentin daily for 8 weeks. Vasomotor symptom frequency and severity were significantly decreased compared to those in the placebo group [8]. Pregabalin had been considered to treat VMS and there were several randomized controlled trials (RCTs) to prove the effectiveness. However, side effects such as dizziness, cognitive difficulties, and weight gain have been identified, and pregabalin is classified as a Schedule V controlled substance due to its potential for abuse. Thus, pregabalin is currently not recommended [9].

Clonidine is an α-adrenergic agonist that is primarily used to treat hypertension. It was known to be effective in reducing vasomotor symptoms, but it has been reported to be less beneficial than SSRIs, SNRIs, and gabapentin. In addition, clonidine can cause adverse effects including hypotension, headache, dizziness, sedation, and constipation. Thus, due to its lower effectiveness compared to other drugs and its significant adverse effects, it is not recommended in the latest guidelines [9].

Psychophysiological symptoms

Postmenopausal women can experience psychological problems such as depression and sleep problems. In patients with breast cancer, emotional stress and fatigue related to the illness or treatment can coexist. When a depressive disorder is diagnosed, physicians should consider the use of pharmacological agents. As mentioned above, several antidepressants are used to treat vasomotor symptoms and may have a dual therapeutic effect in breast cancer patient with depression.

However, studies have shown only a slight effect of antidepressants on depression in patients with breast cancer or showed no differences when compared to placebo. In an 8-week, multicenter, randomized clinical trial involving 179 women with breast cancer and depression, both paroxetine and amitriptyline were associated with significant improvements in depression and quality of life [10]. In a randomized, placebo-controlled study, 549 cancer patients (259 with breast cancer) undergoing chemotherapy were administered 20 mg of paroxetine or a placebo for 8 weeks. The patients were not required to meet the criteria for major depressive disorder. There were no significant differences in fatigue or depressive symptoms between the paroxetine and placebo groups [11].

As mentioned above, patients who use tamoxifen cannot use SSRIs owing to potential drug interactions. In such cases, non-pharmacological treatments can be used as alternatives. Cognitive behavioral therapy can be effective for psychological distress and improvement in health-related quality of life. In a meta-analysis of 14 RCTs, cognitive behavioral therapy in patients with breast cancer had clinically significant effects on insomnia and sleep quality [12]. In another randomized trial of 48 patients with breast cancer, the study group underwent a 12-week aerobic exercise program at the gymnasium and a home-based resistance exercise program. The participants in the control group were encouraged to maintain a normal level of physical activity. This study showed that exercise improved the quality of life and decreased depression levels in patients with breast cancer [13].

Genitourinary syndrome of menopause

Estrogen deficiency leads to structural modifications in the urogenital epithelium and connective tissue. This causes vaginal blood flow reduction, loss of lactobacilli, decreased lubrication, and increased vaginal pH. Patients may experience symptoms such as vaginal irritation, impaired sexual function, and recurrent urinary infections [14].

Topical application of low-dose vaginal estrogen shows some degree of systemic uptake. However, this was remarkably lower than that with systemic therapy. Several large observational studies have not demonstrated an increased risk of recurrence in women undergoing vaginal estrogen therapy [15, 16]. Some studies have suggested that patients taking tamoxifen, an antiestrogen agent, might be at a lower risk than those who do not receive tamoxifen because systemic estrogen absorption could be blocked. In a case-control study, the concurrent use of tamoxifen and local estrogen was not associated with an increased risk of breast cancer recurrence [17]. Despite the research results, international guidelines suggest considering topical estrogen for breast cancer survivors with persistent, bothersome genitourinary symptoms who have not responded to alternative treatments, indicating that further studies are needed [18].

Nonhormonal options for managing genitourinary symptoms in patients with breast cancer include vaginal moisturizers and lubricants. While the range of available products is diverse, there is a lack of high-quality evidence to support the use of one product over another. Vaginal moisturizers are used chronically to normalize vaginal pH, and lubricants can be added before intercourse. When combined with topical lidocaine, lubricants reduce pain during intercourse in women after breast cancer treatment [19].

Another approach for the nonpharmacological treatment of genitourinary symptoms may involve the use of vaginal laser therapy. This therapy reduces the vaginal mucosal lining using a fractional carbon dioxide laser. Ongoing research is examining the use of vaginal laser therapy to support collagen formation and increase vaginal epithelial blood flow.

Musculoskeletal pain

Estrogen depletion due to menopause and aromatase inhibitor use can lead to musculoskeletal pain and arthralgias. This adverse effect appears as joint pain in the fingers, hands, wrists, knees, lower back, hips and shoulders. Approximately 50% of patients report new-onset or worsening joint pain one year after the initiation of aromatase inhibitor therapy [20]. There are no standardized guidelines; however, studies have shown the effectiveness of some non-pharmacological treatments [21].

Nutritional supplementation has also been explored as a potential therapeutic option. High-dose vitamin D supplementation (50,000 IU/day) for 12 weeks significantly decreased debilitating symptoms [22]. Supplementation with glucosamine sulfate (1,500 mg/day) and chondroitin sulfate (1,200 mg/day) for 24 weeks led to a significant decrease in joint stiffness and improved range of motion and grip strength [23]. Acupuncture can also be used to relieve musculoskeletal pain. A large randomized controlled trial examined patients undergoing weekly full-body acupuncture for 6–12 weeks and found that pain scores and joint stiffness significantly improved [24].

Nevertheless, physicians should always evaluate pain and immobility and consider rheumatologic consultation if the symptoms do not improve.

Osteoporosis

Estrogen has a protective effect on the bone and reduces the levels of the hormone that triggers bone loss. Breast cancer treatment, including chemotherapy and aromatase inhibitors, can cause bone loss and associated fractures. Tamoxifen has been reported to reduce bone mineral density in premenopausal women, but it is also known to have a bone loss prevention effect in postmenopauseal women [25]. In a retrospective analysis of a prospective, randomized trial, tamoxifen did not offer protection against fractures in old age and may increase the risk of fractures [26]. Meanwhile, a population-based study reported a protective effect of tamoxifen against osteoporotic fractures [27]. Women who are premenopausal before cancer treatment may experience menopause earlier than those who do not have breast cancer. Several strategies have been studied for reducing the risk of osteoporosis.

A diagnosis and initiation of treatment of osteoporosis in general population is when the bone mineral density (BMD) T-score is < –2.5 standard deviation (SD), but the argument is gaining strength that stricter criteria should be applied for diagnosis and treatment of osteoporosis in women with breast cancer. Latest guidance suggests that treatment should be considered in cases with BMD T-score is < –2.0 SD or 2 risk factors including a BMD T-score < –1.0. Clinical risk factors include prior fragility fractures, parental history of hip fracture, type 1 or 2 diabetes, rheumatoid arthritis, and history of at least 2 falls in past year [28].

Bisphosphonates have long been used to treat osteoporosis and malignant bone diseases. These can help prevent bone loss and subsequent skeletal morbidities in postmenopausal women with breast cancer [29]. In one study, oral alendronate increased the BMD of breast cancer survivors by 15.6% after three years of treatment [30]. In another trial, the parenteral agent zoledronic acid was administered to breast cancer survivors either immediately after treatment or after some delay. As a result, the lumbar spine BMD increased in the group that received immediate zoledronic acid compared to that in the group that received delayed zoledronic acid, resulting in a BMD difference of 5.7% between the two groups after 24 months [31]. The anti-RANK ligand antibody denosumab is also a therapeutic option to prevent treatment-induced bone loss in breast cancer survivors. It has been shown to extend the time to first fracture in postmenopausal women treated with aromatase inhibitors [32].

Lifestyle modifications are required to prevent bone loss and fractures. Although studies have not proven the significant effect of preventing the loss of BMD in women with breast cancer, adequate calcium and vitamin D intake is commonly recommended for women undergoing breast cancer treatment [33]. Exercises, including weight-bearing and resistance exercises, are also important components of osteoporosis treatment and prevention. These activities include walking, climbing stairs, and lifting weights [34].

Cardiovascular risk

Estrogen has cardioprotective effects in women. It works by supporting endothelial function, minimizing atherosclerosis, and maintaining favorable lipid profiles. Thus, studies have been conducted under the hypothesis that patients with breast cancer receiving anti-estrogen therapy would have a higher cardiovascular risk. In a large case-control study of 13,642 patients with breast cancer with a history of any kind of treatment, patients who received chemotherapy and radiation therapy showed a higher 10-year cumulative incidence ratio of heart failure and cardiomyopathy than controls. Patients treated with tamoxifen showed a higher risk of cardiovascular disease-related death than controls without breast cancer, but there were no statistically significant associations with any other cardiovascular outcomes [35]. In another meta-analysis comparing tamoxifen and aromatase inhibitors, tamoxifen was more strongly associated with venous thromboembolism than aromatase inhibitors, while aromatase inhibitors were related to stroke, angina, myocardial infarction, and heart failure compared to tamoxifen. However, these differences were not statistically significant [36]. Consequently, it is necessary to recognize the high cardiovascular risk in patients with breast cancer and include it when considering the treatment strategy.