Fertility, Sexuality, and Menopausal Symptom Management: Introduction
Improvements in the detection and treatment of breast cancer have resulted in a growing number of breast cancer survivors. It has been estimated that there are now more than 2 million breast cancer survivors in the United States alone, and many more worldwide.1 As these women go on to live healthy and productive lives, many will experience burdensome menopausal symptoms, such as hot flashes and vaginal dryness, and impairments in sexual functioning. Couzi et al2 reported that, of women previously diagnosed with early-stage breast cancer, 65% suffered hot flashes, 44% night sweats, 48% vaginal dryness, 26% dyspareunia, 44% difficulty sleeping, and 44% feeling depressed. Physical and emotional problems arising from the diagnosis and treatment of breast cancer may compound each other, creating a complex interplay of symptoms. Sexual problems may result from a combination of the psychosocial trauma associated with the diagnosis of breast cancer, changes in body image, and treatment side effects. Atrophic vaginitis, a constellation of symptoms including vaginal dryness and associated urogenital inflammation, atrophy, stenosis, pruritus, and dyspareunia, is particularly problematic for sexual functioning.3 Without treatment, these symptoms can be lasting and severe. Speer et al4 found that breast cancer survivors an average of 4.4 years after treatment had reduced sexual functioning in all domains except desire when compared with previously published data on women without a history of cancer. In a direct comparison with age-matched control women, Broeckels et al3 found that women who had been treated for breast cancer at least 5 years previously reported worse sexual functioning including greater lack of sexual interest, inability to relax and enjoy sex, difficulty becoming aroused, and difficulty achieving an orgasm.
Menopausal symptoms may have a substantial impact on quality of life, body image, sexual function, and self-esteem.5,6 These symptoms also impact adherence to hormonal therapies.7 For the approximately 25% of breast cancer patients who are premenopausal at diagnosis, treatment may result in amenorrhea and potential infertility. Menopausal status and fertility potential after breast cancer is an area of great concern for young cancer survivors and may impact treatment decisions.8 Understanding the factors contributing to these symptoms and long-term effects and implementing strategies to avoid or ameliorate them is likely to improve symptoms and quality of life for breast cancer survivors.
Several factors contribute to the development or worsening of menopausal symptoms, sexual dysfunction, and amenorrhea and infertility in breast cancer survivors. Peri- and postmenopausal women generally are recommended to discontinue symptom-relieving hormone-replacement therapy when they are diagnosed with breast cancer. Abrupt withdrawal often precipitates severe hot flashes and vaginal dryness, which weaning more slowly may lessen.9 Surgery and radiation therapy can impair function locally, and systemic therapy including chemotherapy and hormonal therapy may precipitate menopausal symptoms and changes in ovarian function through a number of mechanisms.
Effects of Local Therapy
Surgical treatments for breast cancer including mastectomy or partial mastectomy and lymph node surgery directly alter a woman’s body contour, which may affect body image adversely. Lasting changes in sensation often occur postoperatively, particularly in the setting of mastectomy. Chronic pain syndromes due to nerve damage in the breast and axillary area as well as impaired upper-extremity range of motion and lymphedema can also interfere with sexual functioning. Local irradiation may compound these upper body changes. Bukovic et al10 reported that rates of satisfaction with sexual life in breast cancer patients treated with mastectomy (plus radiation for more advanced tumors) and in those treated with lumpectomy plus radiation (for early-stage tumors) both dropped from 70% and 73%, respectively, before treatment to 57% and 50%, respectively, after treatment. In contrast, Monteiro-Grillo et al11 found that mastectomy had a more negative impact than lumpectomy. Surveying 61 women who had undergone breast-conserving therapy and 64 who had undergone modified radical mastectomy, these authors found that mastectomy was associated with more negative body image, more change in social behaviors, and poorer quality of life. Reconstructive surgery may be an important contributor to healthy sexuality for women who undergo mastectomy. Several studies suggest that immediate reconstruction is more protective of sexual functioning than delayed reconstruction.12-15
Effects of Systemic Therapy
Systemic therapy, including chemotherapy and hormonal therapy, may affect a woman’s sexual and reproductive functioning both directly and indirectly. In the short term, chemotherapy causes physical losses, including hair loss, nausea and vomiting, and skin and nail changes, all potentially altering body image and libido. Chemotherapy is fatiguing emotionally and physically, and fatigue may be of long duration. In pre- and perimenopausal women, chemotherapy can be directly toxic to the ovaries, resulting in amenorrhea and depletion in systemic estrogen levels, which may be temporary or permanent. This abrupt decrease in estrogen levels may cause severe menopausal symptoms, including hot flashes and vaginal dryness. Regardless of menopausal status, tamoxifen is associated with hot flashes due to its antiestrogenic effects, although it acts in a proestrogenic manner in the vagina with an associated increased incidence of vaginal discharge and rare but significant risk of uterine cancer. Aromatase inhibitors (AIs) lack this estrogenic action in the vagina and endometrium and therefore cause more vaginal dryness compared with tamoxifen (approximately 18% compared with approximately 8%).16,17 With the increasing use of AIs, the absolute number of breast cancer patients affected by symptomatic atrophic vaginitis is likely to increase. In contrast to hot flashes, vaginal atrophy usually increases over time, so treatments are likely to be required as long as the patient remains estrogen-deficient. In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial comparing these treatments in postmenopausal women with early breast cancer, women receiving the AI were more likely to report vaginal dryness (18.5% vs 9.1%), diminished libido (34.0% vs 26.1%), and dyspareunia (17.3% vs 8.1%) as compared with women receiving tamoxifen.18 In premenopausal women, ovarian suppression or bilateral oophorectomy induces a sudden menopause that often is associated with severe symptoms. A study comparing different systemic regimens for breast cancer in premenopausal women found that ovarian suppression with goserelin acetate increased temporary sexual dysfunction during treatment, but adjuvant chemotherapy increased sexual dysfunction even 3 years afterwards, likely because of more lasting damage to the ovaries from the chemotherapy.19
Sexual dysfunction, including lack of lubrication, dyspareunia, decreased libido, and difficulty with orgasm, affects at least 50% of women after breast cancer.20 Risk factors for sexual dysfunction include younger age, premature menopause, and the use of chemotherapy.21 In younger women, Burwell et al20 found that negative body image is linked with mastectomy, hair loss from chemotherapy, concern with weight gain or loss, poorer mental health, lower self-esteem, and poor communication with a partner. Fobair et al22 found that young women’s sexual difficulties are exacerbated by vaginal dryness, poor mental health, being married, and negative body image. In postmenopausal women with a history of breast cancer, Greendale et al23 found that sexual impairment was associated with older age, less time since diagnosis, poor relationship quality, vaginal discomfort, higher education, fewer hot flashes, urinary incontinence, history of mastectomy, and poorer perceived health and body image. Impaired sleep due to nocturnal hot flashes and night sweats in cancer survivors may impact sexual functioning, libido, and quality of life. Anxiety and depression after treatment for breast cancer may be compounded by hormonal changes and may add to sexual dysfunction.
Premenopausal women may become infertile due to direct gonadotoxicity of chemotherapy. Although hormonal therapy effects on ovarian function and menopausal symptoms appear to be reversible with discontinuation of the medication, fertility declines naturally over the time it takes to receive optimal hormonal treatment.
Assessment and Management of Menopausal Symptoms and Sexual Dysfunction
Assessment of menopausal symptoms should include documentation of the frequency and severity of vasomotor symptoms (hot flashes and night sweats), symptoms of atrophic vaginitis (vaginal dryness, dyspareunia, urinary urgency, and pruritus), reduced libido, and sleep disturbance.24 The decision whether to treat menopausal symptoms pharmacologically will depend on their severity, impact on activities of daily living, and patient preferences. Measuring quality of life may facilitate treatment decisions using menopause-specific instruments such as the MENQOL (Menopause-Specific Quality of Life Questionnaire) or breast cancer-specific instruments such as the FACT-ES (Functional Assessment of Cancer Therapy–Endocrine Symptoms).25,26 Sexual functioning after breast cancer can be assessed with standardized, validated instruments such as the Sexual Activity Questionnaire or the Greene Scale, although these measures are most commonly used in a research setting.27,28 Ganz et al5 proved that a comprehensive menopausal intervention program, in which pharmacologic and behavioral interventions are recommended if appropriate, can improve menopausal symptoms and sexual functioning as compared with usual care. For many women, a multifaceted approach may be warranted to improve these symptoms and related problems. Table 101-1 provides a synopsis of suggested management strategies for a variety of physical and emotional symptoms that may result from treatment for breast cancer.
|Physical||Hot flashes/night sweats||Medications including SSRIs and SNRIs|
|Cooling pillows and/or layered clothing|
|Vaginal dryness/dyspareunia||Vaginal moisturizers and lubricants, ideally nonhormonal|
|Anorgasmia/poor arousal||Lubricants, vibrators, counseling for patient and partner|
|Sleep deprivation||Sleep hygiene strategies, hypnotic medications|
|Treatment of hot flashes, depression|
|Changes in body contour||Breast reconstruction|
|Weight gain||Exercise, nutrition|
|Emotional||Anxiety||Medications including SSRIs and SNRIs|
|Depression||Medications including SSRIs and SNRIs|
|Relationship Strain||Counseling for patient and partner|
|Lack of libido||Counseling for patient and partner, cognitive restructuring|
Combined estrogen and progesterone hormone-replacement therapy is a very effective mechanism for alleviation of menopausal symptoms in women without breast cancer.29-31 However, it carries cardiovascular risks even in women without a history of cancer,32 and due to potential stimulation of cancer cells, it is likely not safe to use after breast cancer. Two Swedish randomized controlled trials, the Stockholm trial and the hormonal replacement therapy after breastcancer diagnosis—is it safe? (HABITS) trial, were both stopped early because the HABITS trial (but never the Stockholm trial) revealed increased recurrences in those receiving hormone-replacement therapy after treatment for breast cancer. In the HABITS trial of 442 breast cancer survivors in Scandinavia, women randomized to hormone-replacement therapy and followed for a median of 4 years had 3.5-fold more cancer recurrences than those randomized to placebo.33 The absence of increased risk in the Stockholm trial may result from lower-risk patients and more participants concomitantly receiving tamoxifen (which should at least blunt the stimulatory impact of estrogen on the breast cancer cells). For women on tamoxifen, hormone-replacement therapy appears to have limited efficacy in alleviating hot flashes.34 Therefore, for most breast cancer survivors, nonhormonal treatments are recommended.35 Nevertheless, for women with low-risk disease and severe symptoms, short-term hormone-replacement therapy may be appropriate.36
The natural history of vasomotor symptoms after breast cancer is not well-studied, but in spontaneous menopause, vasomotor symptoms are known to decrease in frequency and severity after 12 months of amenorrhea.37,38 Therefore, it is reasonable to take a watch-and-wait approach for some women or to try to discontinue treatments for hot flashes on an intermittent basis in order to assess whether symptoms recur. Little is known about factors regulating hot flashes arising from endocrine therapy for breast cancer. In women without cancer who are experiencing natural menopause, hot flashes are thought to be caused by the loss of estrogen’s modulating effect on the hypothalamic thermoregulating mechanism.39 After spontaneous menopause, hot flashes may be triggered by stimuli such as spicy food, hairdryers, or anxiety. For individual breast cancer survivors, recording triggers in a diary may help women to avoid triggers and prevent hot flashes. Some women find it helpful to wear natural fibers and to dress in layers so that clothes can easily be removed during hot flashes. Use of a cold pack may also lessen symptoms when they occur. Acupuncture, paced breathing, and hypnosis are promising treatment methods, but their benefit over sham procedures remains unproven.
Evidence is conflicting regarding whether hot flashes are reduced by lifestyle modifications such as weight loss (for overweight women), regular exercise, and cessation of smoking.24 In 1 study, hot flashes were found to be more severe in overweight women and in smokers.40 There is also some preliminary data suggesting that exercise reduces the risk of or ameliorates hot flashes.41
Routine nonhormonal strategies for management of hot flashes include relaxation techniques, cooling pillows, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), gabapentin, and clonidine. Details of pharmacologic therapies are provided in Table 101-2. A meta-analysis of 10 randomized controlled trials involving 1581 women in total and 14 pilot trials with 325 total participants suggested that therapeutic efficacy of treatments for hot flashes is similar in women with and without a history of breast cancer and with or without tamoxifen treatment.42 This meta-analysis found evidence that hot flashes are moderately decreased by venlafaxine, mildly to moderately decreased by fluoxetine, mildly decreased by clonidine, and not substantially decreased by vitamin E or black cohosh.42 Alternative therapies such as dong quai, evening primrose oil, and ginseng have not appeared promising in studies to date.43 Evidence for the efficacy of soy products in reducing hot flashes is contradictory.44 Furthermore, it is not clear how safe soy is for breast cancer survivors due to potential stimulation of breast cancers by the phytoestrogens it contains. Therefore, given that black cohosh has been occasionally linked to liver failure and high-dose vitamin E was shown to increase all-cause mortality in other settings, most providers favor SSRI/SNRI, gabapentin, or clonidine therapy, all of which have been studied and demonstrate some efficacy in the treatment of hot flashes in breast cancer survivors.45,46
|Efficacy: Mean difference in daily number of hot flashes vs placebo per meta-analysis (95% CI)47||−0.95(−1.44 to −0.47)||−1.13(−1.70 to −0.57)||−2.05 (−2.80 to −1.30)|
|Proven duration of action||Up to 8 weeks||Up to 6 weeks||Up to 12 weeks|
|Discontinuation due to side effects in clinical trials for hot flashes||40%60||10%-20%92||10%93|
|Common side effects insomnia or drowsiness||Dry mouth and insomnia or drowsiness||Dry mouth, blurred vision, sexual dysfunction||Dizziness, drowsiness, unsteadiness|
There are few head-to-head studies of different drugs, with most research comparing an agent with placebo in a small population of women who average more than 14 hot flashes per week, and conclusions are complicated by the significant placebo effect seen in many studies.47 Comparing venlafaxine with placebo in postmenopausal women without cancer, Evans et al48 did not find a significant benefit, but Loprinzi et al49 did find a reduction in number of daily hot flashes using 37.5 or 75 mg of venlafaxine in a larger study. Two studies by Stearns et al,50,51 each with approximately 150 participants, both showed a significant reduction with paroxetine (10-20 mg daily or 12.5-25 mg of controlled release). Kalay et al52 found that citalopram effectively improved scores on 2 scales of menopausal symptoms, but Suvanto-Luukonen et al53 did not find a significant impact of citalopram or fluoxetine over placebo. A cross-over design comparing placebo with 50 mg of sertraline on women receiving tamoxifen revealed decreased hot flashes in those taking sertraline. In those who are taking tamoxifen, medications that inhibit CYP2D6 (eg, paroxetine and fluoxetine) should be avoided because they prevent effective breakdown of tamoxifen into its most active metabolite, endoxifen.54,55 Venlafaxine and citalopram are not strong CYP2D6 inhibitors, so their use is thought to be safe even in those taking tamoxifen.56 Although the side effects of SSRIs and SNRIs can include weight gain, insomnia, and decreased libido, patients may still feel better on these medications if hot flashes are very problematic. SSRIs and SNRIs are generally contraindicated in women taking monoamine oxidase inhibitors and should be used cautiously or potentially avoided in women with bipolar disorder because of the risk of inducing mania.