TWSHF has found that women with breast cancer often complain about the sexual difficulties they are having while on aromatase inhibitors, and it is not unusual for their medical oncologist to not have addressed these issues with them prior to initiating this therapy. The below article enables women to educate themselves and to advocate to find solutions to their sexual function concerns.
Curr Oncol. 2007 December; 14(Supplement 1): S20–S40.
Copyright 2007 Multimed Inc.
C. Derzko, MD,* S. Elliott, MD,† and W. Lam, BSc(Pharm) MD‡
* Obstetrics and Gynecology and Reproductive Endocrinology, St. Michael’s Hospital, and University of Toronto, Toronto, Ontario
† BC Center for Sexual Medicine, Vancouver Hospital, and Departments of Psychiatry and Urology, University of British Columbia, Vancouver, British Columbia.
‡ Burnaby Hospital Regional Cancer Centre, Burnaby, British Columbia
Correspondence to: Christine Derzko, St. Michael’s Hospital, 61 Queen St. E, 4th Floor, Toronto, Ontario M5C 2T2. E-mail: firstname.lastname@example.org
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements—all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement—most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)—may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be attended with potential risk. Therefore, non-hormonal alternatives should in all cases be initially tried with the expectation that symptomatic relief can often be achieved.
First-line therapy for urogenital symptoms, notably vaginal dryness and dyspareunia, should be the non-hormonal group of preparations such as moisturizers and precoital vaginal lubricants. In patients with estrogen-dependent breast cancer (notably those receiving anti-estrogenic adjuvant therapies) and severely symptomatic vaginal atrophy that fails to respond to non-hormonal options, menopausal hormone replacement or prescription vaginal estrogen therapy may considered. Systemic estrogen may be associated with risk and thus is best avoided. Judicious use of hormones may be appropriate in the well-informed patient who gives informed consent, but given the potential risk, these agents should be prescribed only after mutual agreement of the patient and her oncologist.
Keywords: Aromatase inhibitor therapy, breast cancer, gynecologic side effects, hormone therapy, sexual dysfunction, side effect management, side effect treatment
With more than a million new cases and more than 400,000 deaths worldwide annually, breast cancer is a major cause of morbidity and mortality1. The clinical efficacy of adjuvant endocrine therapies in hormone-dependent breast cancer is the key to successful intervention. However, therapeutic standards and guidelines also emphasize that effective patient compliance requires that safety and tolerability be addressed.
Because of their greater efficacy in reducing recurrences as well as their better tolerability profile, the third-generation aromatase inhibitors (ais), including anastrozole (Arimidex: AstraZeneca, Mississauga, ON), letrozole (Femara: Novartis Pharmaceuticals Canada, Dorval, QC), and exemestane (Aromasin: Pfizer Canada, Kirkland, QC), are increasingly being recommended as adjuvant therapy in postmenopausal women with breast cancer. In contrast to a selective estrogen receptor modulator such as tamoxifen, which acts as an estrogen agonist in some tissues (for example, bone or endometrium) and an antagonist in others (for example, breast), ais produce profound suppression of estrogen in all tissues by blocking the cytochrome P450 aromatase complex that converts androgens to estradiol, which underlies the estrogen receptor (er)–positive mammary carcinogenesis2–4.
The steroidal inhibitor exemestane, at a single oral dose of 25 mg, leads to prolonged reduction in plasma and urinary estrogen levels, with maximal suppression of circulating estrogens occurring 2–3 days after dosing and persisting for 4–5 days3. Exemestane inactivates aromatase irreversibly, inhibiting peripheral aromatase by 97%–98%4. The nonsteroidal ais—anastrozole, at a dose of 1 mg daily, and letrozole, at a dose of 2.5 mg daily—produce nearly 97%–99% inhibition of estrogen biosynthesis5,6, suppressing total-body aromatization, plasma estrone, and estradiol levels in postmenopausal women with metastatic breast cancer5,7. Furthermore, these third-generation ais do not compromise glucocorticoid or mineralo-corticoid production or thyroid function8,9.
Tamoxifen exerts its estrogen agonist effect by binding to the er on endometrial epithelial and stromal cells, thereby stimulating abnormal cellular proliferation and increasing the risk of polyps, hyperplasia, and endometrial cancer by a multiple of 2–4 times compared with patients not receiving tamoxifen10–18. Overall, nearly 10% of tamoxifen-treated patients develop endometrial pathology within 5 years19. Within 3 months of initiation of tamoxifen therapy, significant increases in endometrial thickness and in uterine volume are reported, including endometrial cysts and polyps and growth of pre-existing fibroids20.
The American Society of Clinical Oncology Technology Assessment Panel (2005) supports the use of ais as appropriate initial treatment for women with contraindications to tamoxifen, or for example, in women who develop invasive breast cancer while taking a selective estrogen receptor modulator for breast cancer reduction or bone loss21. Clinical studies have clearly demonstrated the safety of steroidal and nonsteroidal ais from a gynecologic viewpoint.
2. AIs AND GYNECOLOGIC HEALTH
Data from the four major phase iii trials of ais, including the Arimidex, Tamoxifen, Alone or in Combination study (atac), ma.17, the Breast International Group (big) study 1–98, and the International Exemestane Study, have shown a lower incidence of endometrial cancer and vaginal bleeding or discharge with the ais than with tamoxifen treatment 22,23.
Each of the ais is associated with its own side effect profile. For most women, the ai-induced hypoestrogenic side effects are manageable. Nonetheless, to appropriately address side effects, a careful and comprehensive clinical evaluation needs to be undertaken to determine which of the gynecologic symptoms are attributable to menopause and which are attributable to other causes.
2.1 Anastrozole (Arimidex)
Results from the atac trial, investigating upfront treatment with anastrozole as compared with initial tamoxifen therapy in postmenopausal women with early breast cancer, showed a significantly lower incidence of hot flushes, endometrial cancer, and vaginal bleeding and discharge with anastrozole24. As well, anastrozole was associated with significantly fewer adverse gynecologic events in four categories25:
Vaginal haemorrhage with no definitive diagnosis: 115 vs. 186, p < 0.0001
Leucorrhea (discharge from the vagina or uterine cavity, or both): 61 vs. 218, p < 0.0001)
Endometrial hyperplasia: 16 vs. 136, p < 0.0001
Endometrial neoplasia: 23 vs. 118, p < 0.0001 (Distler D, on behalf of the atac Trialists’ Group. Fewer gynaecological adverse events, gynaecological intervention, endometrial changes and abnormalities with anastrozole than with tamoxifen: findings from the atac trial. Poster presented at the 10th International St. Gallen Oncology Conference; St. Gallen, Switzerland; March 14–17, 2007)
Notable also was the fact that, of the patients who experienced gynecologic adverse events, those on anastrozole required fewer diagnostic (21.8% vs. 29.4%) and therapeutic (8.4% vs. 15.4%) interventions than did those on tamoxifen. Furthermore, patients on anastrozole underwent hysterectomy at a quarter of the frequency seen among patients on tamoxifen [1.3% vs. 5.1%, p < 0.0001 (Distler D, on behalf of the atac Trialists’ Group. Fewer gynaecological adverse events, gynaecological intervention, endometrial changes and abnormalities with anastrozole than with tamoxifen: findings from the atac trial. Poster presented at the 10th International St. Gallen Oncology Conference; St. Gallen, Switzerland; March 14–17, 2007)]. Most of the gynecologic adverse events and endometrial abnormalities in the atac trial occurred within the first 2.5 years of tamoxifen therapy (Figure 1). The subprotocol analyses also revealed both fewer endometrial abnormalities and fewer medical interventions during the first 2 years with anastrozole therapy than with tamoxifen26. This finding suggests that starting postmenopausal patients with early breast cancer on an ai upfront, rather than initiating adjuvant treatment with tamoxifen with the intention of changing to an ai after 2–3 years may be advantageous25 (Distler D, on behalf of the atac Trialists’ Group. Fewer gynaecological adverse events, gynaecological intervention, endometrial changes and abnormalities with anastrozole than with tamoxifen: findings from the atac trial. Poster presented at the 10th International St. Gallen Oncology Conference; St. Gallen, Switzerland; March 14–17, 2007).
Incidence of specific gynecologic adverse events having a lower recorded incidence with anastrozole use than with tamoxifen use (>3% total difference), by time of occurrence in patients with an intact uterus at baseline in the Arimidex, Tamoxifen, (more ...)
These results are consistent with findings from an open-label randomized trial that compared, in postmenopausal breast cancer patients, the effects of switching to anastrozole following adjuvant tamoxifen treatment (after more than 12 months, but fewer than 48 months) with the effects of continued use of tamoxifen, histologically confirming tamoxifen-induced endometrial pathology (polyps, hyperplasia, and glandulocystic atrophy)27. The difference between groups in recurrent vaginal bleeding [anastrozole: 4 of 83 patients (4.8%); tamoxifen: 9 of 88 patients (10.2%)] was not significant (p = 0.18). However, 6 months later, mean endometrial thickness was significantly less in patients who switched to anastrozole than in those who continued tamoxifen treatment (p < 0.0001). Also, significantly fewer patients who switched to anastrozole required repeat hysteroscopy or dilatation and curettage as compared with patients who continued on tamoxifen [4 of 83 patients (4.8%) and 29 of 88 patients (33.0%) respectively; p < 0.0001)27.
By inhibiting estrogen synthesis, the third-generation ais reduce endometrial thickness and uterine volume in patients previously treated with tamoxifen (Figure 2)20. However, patients receiving anastrozole alone reported more vaginal dryness, painful intercourse (dyspareunia), and loss of sexual interest, but significantly fewer cold sweats and less vaginal discharge28,29 than did patients on tamoxifen alone.
Changes in double endometrial thickness (DET) from baseline to 3 months of treatment with tamoxifen and with aromatase inhibitors20.
2.2 Letrozole (Femara)
For patients who are intolerant to tamoxifen, switching to letrozole has been shown to reduce the frequency of hot flashes30. In the big 1–98 trial, patients on letrozole experienced fewer hot flashes than did those on tamoxifen (33.6% vs. 38.1%)31. However, in the ma.17 trial, letrozole was associated with a higher incidence of hot flashes (58%) but with less frequent vaginal bleeding than was placebo (54%)32. In subset analyses, women receiving letrozole experienced more bodily pain and menopausal symptoms and a greater compromise in sexual function33.
2.3 Exemestane (Aromasin)
As compared with tamoxifen, the steroidal aromatase inhibitor exemestane has been shown to result in more frequent vaginal dryness, but less vaginal discharge and bleeding34,35.
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What is of interest to TWSHF are some of the suggested solutions as outlined below.
6.4 Management Options
The guidelines approved by the sogc recommend initiation of safe and proven therapies for clinical management as indicated by basic pelvic examination, examination of the vulva, and laboratory tests (Table VI)60.
Society of Obstetricians and Gynaecologists of Canada clinical practice guidelines for the detection and management of vaginal atrophy60
6.4.1 Vaginal Atrophy. Options for the management of vaginal atrophy depend on the specific clinical symptoms. Treatment options range from lifestyle modifications to non-hormonal and hormonal interventions.
Lifestyle: The sogc guidelines 60 encourage regular vaginal coital activity to increase blood circulation to the pelvic organs and avoidance of products that pose a risk of contact dermatitis of the vulva. Contact dermatitis of the vulva may be caused by irritants such as perfumed or dyed toilet tissue; tight-fitting garments, underwear, or bathing suits; soaps, detergents, or fabric softeners; talcum powder; hygiene sprays; deodorant pads; spermicidal foams, creams, or jellies; rubber products, including diaphragms or condoms; poison ivy or similar plants; and talcs 104. The sogc has emphasized the lack of evidence to support any beneficial effects of dietary estrogens or supplements such as dong quai. However, the sogc does encourage consumption of pure cranberry and lingonberry juice concentrates to avoid urinary tract infections60,105. Smoking is associated with decreased estrogen levels and consequent vaginal estratrophy—yet another reason to encourage smoking cessation60.
Vaginal Moisturizer: A non-hormonal moisturizing gel containing purified water, glycerine, mineral oil, polycarbophil, carbopol 974P, hydrogenated palm oil glyceride, and sorbic acid (Replens: Wellspring Pharmaceutical Corporation, Bradenton, FL, U.S.A.)—the only vaginal moisturizer available in Canada— used three times weekly has proven efficacy in increasing vaginal moisture and vaginal fluid and in decreasing vaginal itching, irritation, and dyspareunia60,106.
Lubricants for Coital Comfort: Several lubricants that can be used to reduce immediate irritation during coital activity are available to women in Canada, but no evidence currently exists that these products have any long-term therapeutic effect60. Water-soluble vaginal lubricants that relieve vaginal dryness and moisten tissue can substitute for estrogen96, but most water-based lubricants contain glycerine, and patients prone to yeast infection should avoid them.
Lubricants for Vaginal Dryness: Orally administered or locally applied vitamin E in daily doses of 100–600 IU has been found to increase vaginal lubrication and to relieve the dryness and irritation that accompany atrophic and other forms of vaginitis. KY Jelly (KY) with vitamin E is another possibility. Vitamin D and analogs used in postmenopausal osteoporosis are also involved in growth and differentiation of stratified squamous epithelium of the vagina. Homeopathic and natural health supplements of bryonia, belladonna, lycopodium have been used, although these remedies have failed in randomized trials of safety and efficacy.
Hormonal Therapies for Urogenital Atrophy, Vaginitis, and Dyspareunia: In general, non-hormonal treatments are the first-line recommendation in breast cancer patients107,108. However, expert recommendations reviewed and revised by the Breast Disease Committee of sogc concluded that hrt after treatment for breast cancer has no adverse impact on recurrence and mortality, and therefore hrt is an option in postmenopausal women with previously treated breast cancer. Careful evaluation of the indication for hrt and limiting the duration of postmenopausal hrt to the shortest duration possible were recommended37. However, the findings from the habits and Stockholm trials raise additional questions and emphasize the need for careful consideration, review, and collaborative discussion of all the risks and benefits in each individual case. Some evidence also suggests that the small risk of ovarian cancer and endometrial cancer observed with hrt is evident only with therapies that use estrogen alone109.
Because minimal systemic absorption occurs with use of the recommended doses, the opinion of the sogc is that women with a history of breast cancer may still use local intravaginal estrogen preparations in the recommended doses for the treatment of symptoms of urogenital atrophy110. Tested topical estrogen replacement therapies available in Canada include a conjugated equine estrogen (cee) cream, vaginal estradiol tablets, and an estradiol-containing Silastic vaginal ring.
Available systemic estrogen therapies (oral and transdermal patches, and gels) reduce vasomotor symptoms (hot flashes) and sleep disturbance. They also estrogenize urogenital tissues, although, not uncommonly, additional local treatment (vaginal tablets, creams, rings) is needed. The Canadian Consensus Conference on Menopause and 2006 Updated sogc guidelines and recommendations43 indicate that local estrogen can ameliorate dyspareunia associated with vulvovaginal atrophy. Low doses may suffice. For example, half an applicator of cee cream (Premarin) intravaginally once or twice weekly, or one intravaginal estradiol tablet (Vagifem) twice weekly is usually adequate. On occasion, a small amount of cee cream (less than dime size) applied to the peri-introital and peri-urethral area once weekly, or even less frequently, may provide symptomatic relief with minimal dosing.
An alternative treatment proposed in the sogc guidelines is use of a sustained-release intravaginal ring that slowly and constantly releases 5–10 μg of estradiol daily from its estradiol-loaded core over a 3-month period. Use of the Estring (Pfizer Canada) effectively relieves symptoms of atrophic vaginitis and restores normal vaginal pH and cytology, maintains serum estradiol levels in the menopausal range, and does not induce endometrial proliferation111.
Despite the efficacy of vaginal estrogen preparations in treating vaginal atrophy, a small study of 7 postmenopausal women on ais who were using Vagifem vaginal estradiol tablets noted an increase in serum estradiol levels (>19 pmol/L over low baseline postmenopausal estradiol levels) that it was feared might reverse the activity of the ais being used (Table VII) 112. Despite the very small size of this study, physicians are cautioned, in the absence of other reassuring data, to avoid this treatment combination and to recommend non-hormonal preparations instead.
Estradiol levels in women on Vagifem (Novo Nordisk, Princeton, NJ, U.S.A.) and aromatase inhibitor therapy112
Although good data from Sarrel68 and others suggest that estrogen therapy (possibly including vaginal estrogen treatment) improves local genital sensitivity and sexual response, thereby potentially improving sexual interest and motivation44, others disagree. Safety is the overriding consideration. In the opinion of the sogc, as reported in their clinical practice guidelines107, the presence of estrogens at concentrations considerably higher than those attained with current hrt preparations does not negatively influence the efficacy of breast cancer management, as has already been demonstrated by other studies113–115. Data from ongoing prospective randomized clinical trials should offer definitive conclusions.
In brief, if appropriate, replacement of missing hormones or enhancement of depleted levels in breast cancer patients can add to quality of life and should be considered in particular for the treatment of vaginal dryness.