The Oncologist, Vol. 13, No. 3, 222-231, March 2008; doi:10.1634/theoncologist.2007-0234
© 2008 AlphaMed Press
Should Urogenital Atrophy in Breast Cancer Survivors Be Treated with Topical Estrogens?
Mateya Trinkausa,
Sheray China,
Wendy Wolfmanb,
Christine Simmonsa,
Mark Clemonsa
aDepartment of Hematology and Medical Oncology, Princess Margaret Hospital, Toronto, Canada;
bDepartment of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, Canada
Key Words. Breast cancer • Urogenital atrophy • Aromatase inhibitor • Tamoxifen • Estrogen replacement therapy • Toxicity
Correspondence: Mark Clemons M.D., Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Telephone: 416-946-4534; Fax: 416-946-2983; e-mail: mark.clemons{at}uhn.on.ca
Received November 29, 2007;
accepted for publication January 18, 2008.
Disclosure: The article discusses Replens® (Wellspring Pharmaceutical) as a vaginal lubricant/moisturizer and Estring® (Pfizer) and Vagifem® (Novo Nordisk) as topical estrogen replacements. W.W. has received an honorarium from Wyeth and Berlex as a guest speaker at CME events. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
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Learning Objectives
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After completing this course, the reader will be able to:- Describe the urogenital consequences of antiestrogen treatment among women with a prior diagnosis of breast cancer and the effects that these side effects have on quality of life and medication compliance.
- Advise on the standard treatment of urogenital atrophy, including alternatives to topical estrogen replacement, in the non–breast cancer and breast cancer populations.
- Evaluate the evidence for the current recommendations of estrogen replacement therapy among women with a prior diagnosis of breast cancer.
Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com
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ABSTRACT
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Breast cancer survivors represent a unique patient population with a high prevalence of menopausal symptoms. Given the improved longevity of cancer patients, the consequences of menopause have become an increasingly important and challenging management issue. To date, considerable attention has been paid to the management of menopausal vasomotor symptoms and bone health among breast cancer patients. As a result, numerous nonhormonal treatment options have been developed for the management of these issues. The treatment of urogenital symptoms among this population is poorly understood and relatively understudied. Although systemic or topical estrogen replacement is the most effective method for treating hypoestrogenemic urogenital symptoms, women with a prior diagnosis of breast cancer are cautioned from taking exogenous estrogens in order to avoid a potential contribution to recurrent breast cancer risk. This review focuses on the urogenital consequences of estrogen deprivation therapy in breast cancer patients and provides practitioners with a simple guide of current and future strategies for managing these symptoms.
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INTRODUCTION
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It was estimated that 270,000 North American women would be diagnosed with breast cancer in 2007 [1, 2]. The majority (75%) of these breast cancers will express estrogen receptors (ERs) and/or progesterone receptors [3]. The presence of hormone receptors makes endocrine manipulation one of the most useful therapeutic options for these women. Multiple forms of endocrine therapy now exist with proven efficacy in improving both disease-free and overall survival times.
Factors guiding the oncologist's decision on the type and duration of endocrine therapy include the patient's menopausal status, response to prior trials of endocrine treatment, and consideration of side-effect profiles. Tamoxifen, a selective ER modifier, may be used in pre-, peri-, and postmenopausal women [4]. Alternative options for premenopausal and perimenopausal women who have contraindications to tamoxifen use include ovarian suppression and ablation [5–7]. Multiple studies are under way to assess the impact that ovarian suppression and/or ablation may have in combination with endocrine treatment.
In postmenopausal women, where the majority of estrogen is derived from the peripheral conversion of androgens to estrogen, the incorporation of aromatase inhibitors (AIs) into treatment regimens has shown benefits in the early [8–11] and advanced [12–15] settings. AIs are not recommended among premenopausal and perimenopausal women because reduced estrogen levels from aromatase inhibition may induce increased gonadotropin secretion, and thereby stimulate further ovarian estrogen production [14]. Fulvestrant, a potent ER downregulator, is also an effective endocrine manipulation for postmenopausal patients with advanced disease [16, 17]. It is important to stress that AI use is contraindicated in both pre- and perimenopausal women [18]. While fulvestrant is not contraindicated for pre- and perimenopausal women, however, its use is not common practice, and its role remains to be solidified in phase III clinical trials within this setting.
While endocrine therapy has benefited the spectrum of disease from breast cancer prevention to the management of patients with metastatic disease, the side effects of estrogen deprivation therapy are significant. In particular, depending on the type of hormonal treatment, patients have a higher incidence of osteoporosis [19], vasomotor symptoms [20], and gynecologic symptoms (Table 1). The range and magnitude of menopausal symptoms reflect the degree of estrogen deficiency achieved with each endocrine manipulation. Indeed, in recent years, the increased use of AIs over tamoxifen for postmenopausal women means that profound estrogen deprivation, to levels well below those seen in normal postmenopausal women (i.e., <25 pmol/l) [15], is being experienced by a growing number of patients. Not surprisingly, the addition of antiestrogen therapy to this already postmenopausal patient population, many of whom may already require some form of hormone replacement therapy (HRT) for climacteric symptom control, often results in menopausal symptoms that are more severe than would be expected.
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Table 1. Relative prevalence of estrogen deprivation conditions after treatment with various forms of endocrine therapy
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Considerable attention has been paid to the management of menopausal vasomotor symptoms and bone health among breast cancer patients. The management of these side effects includes highly effective nonhormonal therapeutic options. On the other hand, treatment options for urogenital symptoms among breast cancer survivors are poorly understood and understudied. The purpose of this review is to highlight the urological and gynecologic side effects of endocrine therapy, with a discussion of the types and safety of treatment alternatives for these symptoms among women with a prior diagnosis of breast cancer.
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EFFECTS OF NORMAL MENOPAUSE ON THE UROGENITAL SYSTEM
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Estrogen is fundamental for the normal development of multiple organ systems including the reproductive tract, mammary glands, bone, and blood vessels. To date, two ERs have been isolated, ER-
and ER-β, with a varied proportion of each type of receptor in various tissues [21]. In general, the activation of these receptors at the nuclear level by estrogen and/or other cofactors is needed to induce cell growth and differentiation.
ERs are heavily concentrated in the vulva, vagina, pelvic floor musculature, endopelvic fascia, bladder, and urethra [22, 23] (Fig. 1). As a result, the urogenital system is exquisitely sensitive to estrogen deprivation. A decline in estradiol concentrations results in a reduction in squamous epithelial cells in the vulvovaginal area and uroepithelial lining with a predominance of basal cells [24] (Fig. 2). Moreover, collagen, glycogen, mucopolysaccharides, and hyaluronic acid significantly decline in hypoestrogenemic urogenital epithelium. The vaginal walls therefore become thin, friable, pale, and hyposecretory, and lose their elasticity with progressive stenosis, while the urethra develops increased atrophy and laxity [24]. The uterus, ovaries, vagina, and vulva also shrink in size [25]. Symptoms of estrogen deprivation include: vaginal dryness, itchiness, discharge, incontinence, burning, and pain during sexual intercourse. Concomitant with these changes is a reduction in the vaginal Lactobacillus population, which in turn leads to greater vaginal alkalinity (pH >5) and further contributes to the greater risk for urinary tract infections [26].
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Figure 1. Highlighted areas represent regions with a high concentration of estrogen receptors. Illustration by Tony Zakrajsek.
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Figure 2. Histologic appearance of atrophic and mature vaginal epithelium. (A): Atrophic vaginal epithelium with few epithelial cells; (B): Mature stratified squamous epithelium in the vagina. Note the highly vascular stroma. Photographs courtesy of Murray A. Freedman, M.S., M.D., Clinical Professor, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia.
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PREVALENCE OF GENITOURINARY SYMPTOMS AMONG BREAST CANCER PATIENTS
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The prevalence and severity of genitourinary symptoms among women with a prior history of breast cancer have been reported using a variety of quality of life scales, making an overview analysis challenging. Nonetheless, the literature has demonstrated a clear increase in the incidence and progression of gynecologic symptoms following chemotherapy and/or endocrine therapy. Ganz et al. [27] reported that up to 50%–75% of breast cancer survivors experience one or more urogenital symptoms. Treatment with both chemotherapy and tamoxifen seems to compound the severity of symptoms versus treatment with either agent alone [28]. Vulvovaginal atrophy in turn contributes to increasing sexual dysfunction, reported as dyspareunia, diminished libido, and decreased sexual satisfaction [29–31]. In a separate study, the severity of sexual symptoms and vaginal dryness negatively correlated with self-perceived quality of life, and perception of partner quality of life [32].
In recent years, multiple endocrine therapy trials have prospectively evaluated the prevalence of gynecologic symptoms in studies comparing tamoxifen with AIs. Reported results of urogenital side effects from AIs suggest less tolerable vulvovaginal symptoms in comparison with those observed with tamoxifen. Morales et al. [33] found an increase in severe or intolerable dyspareunia among women started on nonsteroidal AIs, from 11% at baseline to 25% after 3 months of treatment, which was significantly associated with vaginal dryness. Similarly, a cohort of women in the Arimedex, Tamoxifen, Alone or in Combination trial after 5 years of treatment with anastrozole reported rates of dyspareunia, diminished libido and decreased sexual satisfaction, and vaginal dryness of 17.3%, 34.0%, and 18.5%, respectively. In comparison, among patients taking tamoxifen, reported side effects for dyspareunia, diminished libido and decreased sexual satisfaction, and vaginal dryness were significantly lower at 8.1%, 26.1%, and 9.1%, respectively (p < .05) [34]. An overview of reported genitourinary symptoms among women treated with various forms of antiestrogen therapy is shown in Table 2. Gynecologic symptoms of women treated with fulvestrant have not been well characterized to date.
The incidence of urinary tract infections among menopausal women varies depending on the presence of risk factors such as diabetes [35] or the presence of urinary prolapse [36], with reported incidences in the range of 5%–8% [36, 37]. Similar cystitis rates have been reported among women on estrogen deprivation therapy. Two phase III trials revealed a combined incidence of urinary tract infections among women treated with fulvestrant of 6.1% [38]. Rates of urinary tract infections among women taking the AI anastrozole have ranged between 3.5% [38] and 8% [39], while the incidence of urinary tract infections among women taking tamoxifen has been reported to be as high as 10% [39].
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MANAGEMENT OF UROGENITAL SYMPTOMS IN THE NON–BREAST CANCER POPULATION
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There is extensive literature on the management of urogenital symptoms in the non–breast cancer population. Women with gynecologic symptoms should be counseled initially on adopting lifestyle changes to ameliorate vulvovaginal atrophy and the onset of urinary tract infections. Smoking cessation should be encouraged, as cigarette smoking is associated with accelerating vaginal atrophy [40]. Regular sexual intercourse has been shown to improve vaginal atrophy presumably as a result of stimulating increased blood flow to these organs [41]. Vaginal lubricants (e.g., K-Y® Jelly; New Brunswick, NJ) may be useful in reducing discomfort during intercourse, but are mostly felt to increase vaginal dryness and are not considered vaginal moisturizers (see below). Patients should be discouraged from using scented soaps, lotions, or panty liners, which all tend to dry the vulvovaginal area. The multifactorial etiology of sexual dysfunction requires the clinician to inquire about and treat underlying depression because treatment of depression may improve sexual desire and functioning. Finally, there is conflicting evidence regarding the benefit of cranberry juice in preventing urinary tract infections [42, 43].
Replens® (WellSpring Pharmaceutical Corporation, Bradenton, FL), a polycarbophil gel, is the most popular nonhormonally based vaginal moisturizer prescribed to women in Canada for symptoms related to vaginal dryness. Studies have shown inconsistent results regarding the efficacy of Replens®, with one study showing equivalent symptomatic benefit to topical estrogen replacement therapy (ERT) [44]. However, a Cochrane Review found intravaginal estrogen preparations to be the most effective means to alleviate the symptoms of vulvovaginal atrophy [45]. While some women have symptoms of vaginal dryness ameliorated with regular use of Replens®, it has not been shown to improve the maturation index of the vaginal lining [46], or reduce vaginal pH [47]. The effect that Replens® has on the incidence of urinary tract infections has not been formally studied.
Local hormonal treatments for urogenital symptoms include estrogen-containing creams, pessaries, silicone rings, and tablets. These agents work to restore vaginal epithelial maturation and vaginal lubrication, with an improvement in both symptoms and signs of estrogen deprivation (Fig. 3). Both Estring® (Pfizer Pharmaceuticals, New York), a sustained-release intravaginal estradiol ring, and Vagifem® (Novo Nordisk Inc., Princeton, NJ), a hydrophilic tablet that slowly releases 25 µg of 17β-estradiol (administered daily for 2 weeks and then twice per week), are preferred by patients over vaginal creams and pessaries [44, 48, 49]. Estring® is inserted into the upper vagina where it remains for up to 3 months while releasing 5–10 µg per day of estradiol. Estring® and Vagifem® have demonstrated an approximate 90% improvement in relief of the symptoms of atrophic vaginitis: vaginal dryness, itching, and discharge [48, 50, 51]. Both agents have been shown to dramatically reduce the frequency of urinary tract infections among postmenopausal women [52, 53]. The time to improved symptoms with topical vaginal estrogens is roughly 4 weeks [49]. Importantly, Vagifem® and Estring® have not been found to significantly increase endometrial thickness after 48 weeks of treatment [51].
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Figure 3. Examples of external genitalia during estrogen-deficient and estrogen-replete states. (A): Photograph of a 55-year-old woman treated with tamoxifen for 2 years. Note the prominent urethra, stenosis, and loss of elasticity in the introitus. (B): Comparatively, the vulvovaginal area of a 68-year-old woman that is estrogen replete shows a well-vascularized, highly elastic vestibule (area between the labia minora). Photographs courtesy of Murray A. Freedman, M.S., M.D., Clinical Professor, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia.
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ERT USE AMONG WOMEN WITH A PRIOR DIAGNOSIS OF BREAST CANCER
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Current guidelines strongly discourage the use of topical estrogen therapy or systemic ERT for the alleviation of menopausal symptoms in women with a prior diagnosis of breast cancer [54]. The evidence to support or refute the use of ERT among breast cancer patients is at best conflicting. Among healthy postmenopausal women, systemic ERT has been shown to increase breast cancer risk when combined with progestin. The Women's Health Initiative (WHI) demonstrated that combined estrogen and progestin HRT increased the risk for primary invasive breast cancer by 8 per 10,000 person-years after 5.2 years of use [55]. Moreover, recent Surveillance, Epidemiology, and End Results registry data have shown an 8.6% decline in the age-adjusted incidence of breast cancer in the U.S. between 2001 and 2004, a decline evident only in women above the age of 50, which coincided with a 38% reduction in combined estrogen–progestin therapy prescriptions [56]. However, the WHI also found no greater risk for breast cancer among postmenopausal women treated with unopposed conjugated equine estrogen for an average of 6.8 years [57].
Trials investigating the impact that systemic ERT has on breast cancer recurrence are frequently limited by their observational nature. Several observational studies and systematic reviews suggest no greater risk for breast cancer recurrence among breast cancer survivors treated with HRT [58, 59]. Two randomized trials yielded opposing results. The Hormonal Replacement Therapy After Breast Cancer—Is It Safe? trial randomized breast cancer survivors with menopausal symptoms to HRT or placebo and found a relative hazard for breast cancer recurrence of 3.3 (95% confidence interval [CI], 1.5–8.1). The Stockholm trial, however, with a similar design, found a relative hazard of 0.82 (95% CI, 0.35–1.9) [60, 61]. These paradoxical results are not easily explained and may be a result of confounding variables such as selection bias, use of tamoxifen in up to half of the hormone receptor–positive patients in each trial, and/or variable types and durations of HRT use. Whether hormone receptor status has any bearing on breast cancer recurrence after exposure to ERT has yet to be conclusively determined.
Few studies have investigated the impact of local vaginal estrogen preparations for the treatment of gynecologic symptoms with regard to breast cancer recurrence and mortality. A small cohort study of 69 women, some of whom were taking tamoxifen, suggested that vaginal estrogen cream or tablets did not increase the risk for recurrent breast cancer and resulted in a hazard ratio for disease recurrence of 0.57 (95% CI, 0.20–1.58; p = .28) [62].
A separate study of seven women taking AIs with subsequent intolerable urogenital side effects documented serum estradiol levels after treatment with Vagifem® 25 µg. Estradiol levels rose from a mean baseline level of <5 pmol/l to a mean of 72 pmol/l at 2 weeks, and then declined at 4 weeks to a median of 16 pmol/l. Two women had high estradiol levels after 7 weeks of treatment [63] (Fig. 4). A drop in serum estradiol levels following consistent use with either Estring® or Vagifem® has also been well documented among menopausal women without a prior history of breast cancer [51, 64]. This fall in serum estradiol levels is likely a reflection of vaginal epithelial maturation, which further inhibits systemic absorption of estrogen.
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Figure 4. Serum estradiol levels of women on concurrent aromatase inhibitors and Vagifem®. From Kendall A, Dowsett M, Folkerd E et al. Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 2006;17:584–587. Reprinted by permission of Oxford University Press.
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Of concern is whether even minor changes in serum estradiol levels from vaginal absorption of topical estrogen replacement agents increase breast cancer recurrence. Among postmenopausal women, the Endogenous Hormones and Breast Cancer Collaborative Group found an association between high levels of endogenous estrogen and higher breast cancer risk. However, this overview found a large range of median estrogen values of 21.7–101 pmol/l among the control group resulting from variations in laboratory analyses [65]. Given the variation in results, a threshold estradiol level that was clearly associated with elevated breast cancer risk could not be established. Further highlighting the need for a sensitive estradiol assay for women taking AIs was a small study of 10 patients before and after AI use who had up to a 70% difference in estradiol levels when measured by direct assay versus being measured after pre-extraction with an organic solvent [66]. Retrieval and storage of serum may also impact estradiol levels; delaying blood sample processing by 1 day has been shown to spuriously increase estrogen levels by 7.1% (95% CI, 3.2%–11.3%) [67].
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THE CHALLENGE OF TREATING UROGENITAL SYMPTOMS IN BREAST CANCER PATIENTS
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Gynecologic symptoms among breast cancer patients are a "silent" toxicity given that, on average, only one fifth of women (without breast cancer) disclose menopausal urogenital symptoms to their health practitioner [68]. Breast cancer patients may be more reluctant to disclose symptoms associated with vaginal atrophy because of concerns that their potentially life-saving treatment may be withdrawn or because of shame and embarrassment. Moreover, in clinical practice, oncologists do not commonly discuss gynecologic symptoms with their patients. Indeed, oncologists often lack training to adequately assess the signs of vulvovaginal atrophy. Improved communication with our patients, with an open dialogue that allows for symptom assessment and education, is a vital first step in treating this condition.
Another concern is that endocrine-deprived urogenital symptoms reduce quality of life and may lead to poorer compliance and withdrawal from endocrine treatment. Multiple studies have reported noncompliance or discontinuation rates of >20% because of toxicities from antiestrogen treatment [34, 69–71]; the prevalence of poor compliance specifically resulting from vulvovaginal side effects is not well documented. This high rate of endocrine therapy withdrawal is in part a reflection of the limited number of treatments available to manage these symptoms. Figure 5 provides a stepwise approach for treating women with urogenital side effects from endocrine therapy. Unfortunately, despite a trial of lifestyle recommendations and Replens®, many women do not have their vulvovaginal symptoms ameliorated, leaving both patients and clinicians faced with the dilemma of considering the use of ERT.
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Figure 5. Proposed management of intolerable urogenital side effects after antiestrogen treatment.
Abbreviations: AI, aromatase inhibitor; ERT, estrogen replacement therapy; GP, general practitioner; GU, genitourinary.
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The decision to use estrogen-containing agents in the breast cancer population comes with tremendous stigma. In a group of 250 women previously diagnosed with breast cancer, 78% would not consider the use of systemic ERT for the relief of menopausal symptoms or osteoporosis prevention predominantly because of their fear that ERT would contribute to cancer relapse. Negative physician opinion of ERT use among these patients also contributed to the reluctance to consider ERT [72]. Importantly, systemic ERT is not recommended over the use of topical estrogen therapy when symptoms are localized to the urogenital tract, given the benefit of reduced estrogen absorption when topical agents are used [73]. Falling along these lines, in a supervised setting, breast cancer patients were more agreeable to using local estrogen therapy to alleviate their urogenital symptoms, particularly if they were sexually active [74]. The acceptability and safety of local estrogen therapy among this special population remain to be determined.
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CONCLUSION
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The prognosis for breast cancer patients has significantly improved over the past 30 years. Not only has the number of patients receiving antiestrogen therapy dramatically increased, but also, with the results of recent trials, the prolonged use of endocrine therapy is becoming increasingly common [9].
While overall and disease-free survival are paramount considerations for this population of women, it is clear that given the improved survivorship of women diagnosed with invasive cancer, minimizing the toxicity of endocrine agents is a priority. There has been considerable interest in aiding clinicians to identify and manage bone health and hot flashes for breast cancer survivors; however, gynecologic side effects from endocrine treatment have largely remained a poorly reported toxicity. Given the potential for reduced quality of life and poor compliance, the identification and treatment of urogenital side effects is a fundamental component of patient care.
There is clearly a gap in the development of treatment alternatives for urogenital symptoms among women previously diagnosed with breast cancer. The best treatment for vulvovaginal atrophy is topical estrogen therapy; however, there is justifiable concern surrounding the administration of exogenous estrogen to breast cancer patients and survivors. In our experience, many women with severe urogenital symptoms who do not benefit from lifestyle suggestions or a vaginal moisturizer would seriously consider using estrogen preparations under the supervision of their physician, or discontinue endocrine therapy all together. We will shortly be starting a randomized trial of Vagifem® and Estring® use in women who are receiving treatment with AIs, focusing on changes in quality of life, serum estradiol levels, and vulvovaginal epithelial maturation. Hopefully, through a combination of innovative studies, we will be able to improve our capacity to deliver these agents with limited toxicity and improve patient quality of life.
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ACKNOWLEDGMENTS
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We would like to thank Dr. M.A. Freedman for the photographs provided (Figs. 2 and 3) and Mr. Tony Zakrajsek for his illustration (Fig. 1).
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FOOTNOTES
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Conception/design: Mark Clemons
Collection/assembly of data: Mateya Trinkaus, Sheray Chin, Christine Simmons
Manuscript writing: Mateya Trinkaus
Final approval of manuscript: Wendy Wolfman, Mark Clemons
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Abstract
