Atrophic vaginitis in breast cancer survivors: a difficult survivorship issue

Joanne Lester, Gaurav Pahouja, Barbara Andersen, Maryam Lustberg, Joanne Lester, Gaurav Pahouja, Barbara Andersen, Maryam Lustberg

Abstract

Management of breast cancer includes systematic therapies including chemotherapy and endocrine therapy can lead to a variety of symptoms that can impair the quality of life of many breast cancer survivors. Atrophic vaginitis, caused by decreased levels of circulating estrogen to urinary and vaginal receptors, is commonly experienced by this group. Chemotherapy induced ovarian failure and endocrine therapies including aromatase inhibitors and selective estrogen receptor modulators can trigger the onset of atrophic vaginitis or exacerbate existing symptoms. Symptoms of atrophic vaginitis include vaginal dryness, dyspareunia, and irritation of genital skin, pruritus, burning, vaginal discharge, and soreness. The diagnosis of atrophic vaginitis is confirmed through patient-reported symptoms and gynecological examination of external structures, introitus, and vaginal mucosa. Lifestyle modifications can be helpful but are usually insufficient to significantly improve symptoms. Non-hormonal vaginal therapies may provide additional relief by increasing vaginal moisture and fluid. Systemic estrogen therapy is contraindicated in breast cancer survivors. Continued investigations of various treatments for atrophic vaginitis are necessary. Local estrogen-based therapies, DHEA, testosterone, and pH-balanced gels continue to be evaluated in ongoing studies. Definitive results are needed pertaining to the safety of topical estrogens in breast cancer survivors.

References

    1. DeSantis C.E., Lin C.C., Mariotto A.B., Siegel R.L., Stein K.D., Kramer J.L., Alteri R., Robbins A.S., Jemal A. Cancer treatment and survivorship statistics. CA Cancer J. Clin. 2014;64:252–271. doi: 10.3322/caac.21235.
    1. Santoro N., Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J. Sex Med. 2009;6:2133–2142. doi: 10.1111/j.1743-6109.2009.01335.x.
    1. Pfeifer G., Glatz C., Konigsberg R. Vaginal estriol to overcome side-effects of aromatase inhibitors in breast cancer patients. Climacteric. 2011;73:339–344. doi: 10.3109/13697137.2010.529967.
    1. Rosenberg S.M., Partridge A.H. Premature menopause in young breast cancer: Effects on quality of life and treatment interventions. J. Thorac. Dis. 2013;5:S55–S61.
    1. Kelley C. Estrogen and its effect on vaginal atrophy in post-menopausal women. Urol. Nurs. 2007;27:40–45.
    1. Kyvernitakis I., Ziller V., Hars O., Bauer M., Kalder M., Hadji P. Prevalence of menopausal symptoms and their influence on adherence in women with breast cancer. Climacteric. 2011;17:252–259. doi: 10.3109/13697137.2013.819327.
    1. Stika C.S. Atrophic vaginitis. Dermatol. Ther. 2010;23:514–522. doi: 10.1111/j.1529-8019.2010.01354.x.
    1. Chin S.N., Trinkaus M., Simmons C., Flynn C., Dranitsaris G., Bolivar R., Clemons M. Prevalence and severity of urogenital symptoms in postmenopausal women receiving endocrine therapy for breast cancer. Clin. Breast Cancer. 2009;9:109–117. doi: 10.3816/CBC.2009.n.020.
    1. Nappi R.E., Kokot-Kierepa M. Women’s voices in the menopause: Results from an international survey on vaginal atrophy. Maturitas. 2010;67:233–238. doi: 10.1016/j.maturitas.2010.08.001.
    1. Lester J.L., Bernhart L., Ryan-Wenger N. A self-report instrument that describes urogenital atrophy in breast cancer survivors. West. J. Nurs. Res. 2012;34:72–96. doi: 10.1177/0193945910391483.
    1. Willhite L.A., O’Connell M.B. Urogenital atrophy: Prevention and treatment. Pharmacotherapy. 2001;21:464–480. doi: 10.1592/phco.21.5.464.34486.
    1. Lester J.L., Bernhard L.A. Urogenital atrophy in breast cancer survivors. Oncol. Nurs. Forum. 2009;36:693–698. doi: 10.1188/09.ONF.693-698.
    1. Crandall C., Petersen L., Ganz P.A., Greendale G.A. Association of breast cancer and its therapy with menopause-related symptoms. Menopause. 2004;11:519–530. doi: 10.1097/01.GME.0000117061.40493.AB.
    1. Castelo-Branco C., Cancelo M.J., Villero J., Nohales F., Juliá M.D. Management of post-menopausal vaginal atrophy and atrophic vaginitis. Maturitas. 2005;52:S46–S52. doi: 10.1016/j.maturitas.2005.06.014.
    1. Moegele M., Buchholz S., Seitz S., Ortmann O. Vaginal estrogen therapy in postmenopausal breast cancer patients treated with aromatase inhibitors. Arch. Gynecol. Obstet. 2012;285:1397–1402. doi: 10.1007/s00404-011-2181-6.
    1. Fallowfield L., Cella D., Cuzick J., Francis S., Locker G., Howell A. Quality of life of postmenopausal women in the arimidex, tamoxifen, alone or in combination (ATAC) adjuvant breast cancer trial. J. Clin. Oncol. 2004;22:4261–4271. doi: 10.1200/JCO.2004.08.029.
    1. Ganz P.A., Greendale G.A., Petersen L., Zibecchi L., Kahn B., Belin T.R. Managing menopausal symptoms in breast cancer survivors: Results of a randomized controlled trial. J. Natl. Cancer Inst. 2000;92:1054–1064. doi: 10.1093/jnci/92.13.1054.
    1. Sturdee D.W., Panay N. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric. 2010;13:509–522. doi: 10.3109/13697137.2010.522875.
    1. Levine K.B., Williams R.E., Hartmann K.E. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among active postmenopausal women. Menopause. 2008;15:661–666. doi: 10.1097/gme.0b013e31815a5168.
    1. Kingsberg S.A., Wysocki S., Magnus L., Krychman M.L. Vulvar and vaginal atrophy in postmenopausal women: Findings from the REVIVE (REal Women’s Views of Treatment Options for Menopausal Vaginal ChangEs) Survey. J. Sex Med. 2013;10:1790–1799. doi: 10.1111/jsm.12190.
    1. Krychman M. Impact of vaginal atrophy on quality of life and sexuality. Obstet. Gyncol. Manage. 2010;22:S14–S19.
    1. Kingsberg S.A., Kellogg S., Krychman M. Treating dyspareunia caused by vaginal atrophy: A review of treatment options using vaginal estrogen therapy. Int. J. Womens Health. 2010;1:105–111.
    1. Kokot-Kierepa M., Bartuzi A., Kulik-Rechbergber B., Rechberger T. Local estrogen therapy-clinical implications-2012 update. Ginekol. Pol. 2012;83:772–777.
    1. The North American Menopause Society Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause. 2013;20:888–902.
    1. Kingsberg S.A., Krychman M.L. Resistance and barriers to local estrogen in women with atrophic vaginitis. J. Sex Med. 2013;10:1567–1574. doi: 10.1111/jsm.12120.
    1. Nilsson K., Risberg B., Heimer G. The vaginal epithelium in the postmenopause—Cytology, histology and pH as methods of assessment. Maturitas. 1995;21:51–56. doi: 10.1016/0378-5122(94)00863-3.
    1. Greendale G.A., Zibecchi L., Petersen L., Ouslander J.G., Kahn B., Ganz P.A. Development and validation of a physical examination scale to assess vaginal atrophy and inflammation. Climacteric. 1999;2:197–204. doi: 10.3109/13697139909038062.
    1. Tan O., Bradshaw K., Carr B.R. Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: An up-to-date review. Menopause. 2012;19:109–117. doi: 10.1097/gme.0b013e31821f92df.
    1. Lieblum S.R., Hayes R.N., Wanser R.A., Nelson J.S. Vaginal dryness: A comparison of prevalence and interventions in 11 countries. J. Sex Med. 2009;6:2425–2433. doi: 10.1111/j.1743-6109.2009.01369.x.
    1. Minton S.E., Munster P.N. Chemotherapy-induced amenorrhea and fertility in women undergoing adjuvant treatment for breast cancer. Cancer Control. 2002;9:466–472.
    1. Cella D., Fallowfield L.J. Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy. Breast Cancer Res. Treat. 2008;107:167–180. doi: 10.1007/s10549-007-9548-1.
    1. Goodwin P.J., Ennis M., Pritchard K.I., Trudeau M., Hood N. Risk of menopause during the first year after breast cancer diagnosis. J. Clin. Oncol. 1999;17:2365–2370.
    1. Loibl S., Lintermans A., Dieudonne A.S., Neven P. Management of menopausal symptoms in breast cancer patients. Maturitas. 2011;68:148–154. doi: 10.1016/j.maturitas.2010.11.013.
    1. Keen J.C., Davidson N.E. The biology of breast carcinoma. Cancer. 2003;97:825–833. doi: 10.1002/cncr.11126.
    1. Hoskins J.M., Carey L.A., McLeod H.L. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat. Rev. Cancer. 2009;9:576–586. doi: 10.1038/nrc2683.
    1. Wills S., Ravipati A., Venuturumilli P., Kresge C., Folkerd E., Dowsett M., Hayes D.F., Decker D.A. Effects of vaginal estrogens on serum estradiol levels in postmenopausal breast cancer survivors and women at risk of breast cancer taking an aromatase inhibitor or a selective estrogen receptor modulator. J. Oncol. Pract. 2012;8:144–148. doi: 10.1200/JOP.2011.000352.
    1. Forbes J.F., Cuzick J., Buzdar A., Howell A., Tobias J.S., Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008;9:45–53. doi: 10.1016/S1470-2045(07)70385-6.
    1. Jakesz R., Jonat W., Gnant M., Mittlboeck M., Greil R., Tausch C., Hilfrich J., Kwasny W., Menzel C., Samonigg H., et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005;366:455–462. doi: 10.1016/S0140-6736(05)67059-6.
    1. Jin H., Tu D., Zhao N., Shepherd L.E., Goss P.E. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: Analysis adjusting for treatment crossover. J. Clin. Oncol. 2012 doi: 10.1200/JCO.2010.33.7899.
    1. Jassem J. Intergroup Exemestane Study mature analysis: Overall survival data. Anticancer Drugs. 2008;19:S3–S7. doi: 10.1097/01.cad.0000277608.23376.bc.
    1. Bliss J.M., Kilburn L.S., Coleman R.E., Forbes J.F., Coates A.S., Jones S.E., Jassem J., Delozier T., Andersen J., Paridaens R., et al. Disease-related outcomes with long-term follow-up: An updated analysis of the intergroup exemestane study. J. Clin. Oncol. 2012;30:709–717. doi: 10.1200/JCO.2010.33.7899.
    1. Regan M.M., Price K.N., Giobbie-Hurder A., Thürlimann B., Gelber R.D. Interpreting Breast International Group (BIG) 1-98: A randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer. Breast Cancer Res. 2011;13:e209. doi: 10.1186/bcr2837.
    1. Thürlimann B., Keshaviah A., Coates A.S., Mouridsen H., Mauriac L., Forbes J.F., Paridaens R., Castiglione-Gertsch M., Gelber R.D., Rabaglio M., et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N. Eng. J. Med. 2005;353:2747–2757. doi: 10.1056/NEJMoa052258.
    1. Morales L., Neven P., Timmerman D., Christiaens M.R., Vergote I., van Limbergen E., Carbonez A., van Huffel S., Ameye L., Paridaens R., et al. Acute effects of tamoxifen and third generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs. 2004;15:753–760. doi: 10.1097/00001813-200409000-00003.
    1. Teft W.A., Mansell S.E., Kim R.B. Endoxifen, the active metabolite of tamoxifen, is a substance of the efflux transporter P-glycoprotein (multidrug resistance 1) Drug Metab. Dispos. 2011;39:558–562. doi: 10.1124/dmd.110.036160.
    1. Chism L.A. Overcoming resistance and barriers to the use of local estrogen therapy for the treatment of vaginal atrophy. Int. J. Womens Health. 2012;4:551–557. doi: 10.2147/IJWH.S36026.
    1. Kalogeraki A., Tamiolakis D., Relakis K., Karvelas K., Froudarakis G., Hassan E., Martavatzis N., Psaroudakis E., Matalliotakis J., Makrigiannakis A., et al. Cigarette smoking and vaginal atrophy in postmenopausal women. In Vivo. 1996;10:597–600.
    1. Payne K.A., Binik Y.M., Amsel R., Khalifé S. When sex hurts, anxiety and fear orient attention towards pain. Eur. J. Pain. 2005;9:427–436. doi: 10.1016/j.ejpain.2004.10.003.
    1. Pruthi S., Simon J.A., Early A.P. Current overview of the management of urogenital atrophy in women with breast cancer. Breast J. 2011;17:403–408. doi: 10.1111/j.1524-4741.2011.01089.x.
    1. Bygdeman M., Swahm M.L. Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women. Maturitas. 1996;23:259–263. doi: 10.1016/0378-5122(95)00955-8.
    1. Nachtigall L.E. Comparative study: Replens versus local estrogen in menopausal women. Fertil. Steril. 1994;61:178–180.
    1. Loprinzi C.L., Abu-Ghazaleh S., Sloan J.A., vanHaelst-Pisani C., Hammer A.M., Rowland K.M., Jr., Law M., Windschitl H.E., Kaur J.S., Ellison N. Phase III randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer. J. Clin. Oncol. 1997;15:969–973.
    1. Hickey M., Saunders C., Partridge A., Santoro N., Joffe H., Stearns V. Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer. Ann. Oncol. 2008;19:1669–1680. doi: 10.1093/annonc/mdn353.
    1. Suckling J., Lethaby A., Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst. Rev. 2006 doi: 10.1002/14651858.CD001500.
    1. Rozenberg S., Vandromme J., Antoine C. Postmenopausal hormone therapy: Risks and benefits. Nat. Rev. Endocrinol. 2013;9:216–227. doi: 10.1038/nrendo.2013.17.
    1. Maclennan A.H., Broadbent J.L., Lester S., Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flashes. Cochrane Database Syst. Rev. 2004 doi: 10.1002/14651858.CD002978.pub2.
    1. Langer R.D. Efficacy, safety, and tolerability of low-dose hormone therapy in managing menopausal symptoms. J. Am. Board Fam. Med. 2009;22:563–573. doi: 10.3122/jabfm.2009.05.080134.
    1. Simon J., Nachtigall L., Gut R., Lang E., Archer D.F., Utian W. Effective treatment of vaginal atrophy with an ultra-low-dose estradiol vaginal tablet. Obstet. Gynecol. 2008;112:1053–1160. doi: 10.1097/AOG.0b013e31818aa7c3.
    1. Holmberg L., Iverson O.E., Rudenstam C.M., Hammar M., Kumpulainen E., Jaskiewicz J., Jassem J., Dobaczewska D., Fjosne H.E., Peralta O., et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J. Natl. Cancer Inst. 2008;100:475–482. doi: 10.1093/jnci/djn058.
    1. Schover L.R., Baum G.P., Fuson L.A., Brewster A., Melhem-Bertrandt A. Sexual problems during the first 2 years of adjuvant treatment with aromatase inhibitors. J. Sex Med. 2014;12:3102–3111. doi: 10.1111/jsm.12684.
    1. Kendall A., Dowsett M., Folkherd E., Smith I. Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann. Oncol. 2006;17:584–587. doi: 10.1093/annonc/mdj127.
    1. Ponzone R., Biglia N., Jacomuzzi M.E., Maggiorotto F., Mariani L., Sismondi P. Vaginal oestrogen therapy after breast cancer: Is it safe? Eur. J. Cancer. 2005;41:2673–2681. doi: 10.1016/j.ejca.2005.07.015.
    1. Trinkaus M., Chin S., Wolfman W., Simmons C., Clemons M. Should urogenital atrophy in breast cancer survivors be treated with topical estrogens? Oncologist. 2008;13:222–231. doi: 10.1634/theoncologist.2007-0234.
    1. Labrie F., Cusan L., Gomez J.L., Côté I., Bérubé R., Bélanger P., Martel C., Labrie C. Effect of one-week treatment with vaginal estrogen preparations on serum estrogen levels in postmenopausal women. Menopause. 2009;16:30–36. doi: 10.1097/gme.0b013e31817b6132.
    1. Dew J.E., Wren B.G., Eden J.A. A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Climacteric. 2003;6:45–52. doi: 10.1080/713605341.
    1. Von Schoultz E., Rutgvist L.E. Menopausal hormone therapy after breast cancer: The Stockholm randomized trial. J. Natl. Cancer Inst. 2005;97:533–555. doi: 10.1093/jnci/dji071.
    1. Le Ray I., Dell’Aniello S., Bonnetain F., Azoulay L., Suissa S. Local estrogen therapy and risk of breast cancer recurrence among hormone treated patients: A nested case-control study. Breast Cancer Res. Treat. 2012;135:603–609. doi: 10.1007/s10549-012-2198-y.
    1. Morris E.P., Wilson P.O., Robinson J., Rymer J.M. Long term effects of Tibolone on the genital tract in postmenopausal women. Br. J. Obstet. Gynaecol. 1999;106:954–959. doi: 10.1111/j.1471-0528.1999.tb08436.x.
    1. Sismondi P., Kimmig R., Kubista E., Biglia N., Egberts J., Mulder R., Planellas J., Moggio G., Mol-Arts M., Kenemans P. Effects of Tibolone on climacteric symptoms and quality of life in breast cancer patients—Data from LIBERATE trial. Maturitas. 2011;70:365–372. doi: 10.1016/j.maturitas.2011.09.003.
    1. Santos I., Clissold S. Urogenital disorders associated with oestrogen deficiency: The role of romestriene as topical oestrogen therapy. Gynecol. Endocrinol. 2010;26:644–651. doi: 10.3109/09513591003767948.
    1. Bachmann G., Bobula J., Mirkin S. Effects of bazedoxifene/conjugated estrogens on quality of life in postmenopausal women with symptoms of vulvar/vaginal atrophy. Climateric. 2010;13:132–140. doi: 10.3109/13697130903305627.
    1. Witherby S., Johnson J., Demers L., Mount S., Littenberg B., Maclean C.D., Wood M., Muss H. Topical testosterone for breast cancer patients with vaginal atrophy related to aromatase inhibitors: A phase I/II study. Oncologist. 2011;16:424–431. doi: 10.1634/theoncologist.2010-0435.
    1. Labrie F., Archer D., Bouchard C., Fortier M., Cusan L., Gomez J.L., Girard G., Baron M., Ayotte N., Moreau M., et al. Serum steroid levels during 12-week intravaginal dehydroepiandrosterone administration. Menopause. 2009;16:897–906. doi: 10.1097/gme.0b013e31819e8930.
    1. Labrie F., Cusan L., Gomez J.L., Côté I., Bérubé R., Bélanger P., Martel C., Labrie C. Effect of intravaginal DHEA on serum DHEA and eleven of its metabolites in postmenopausal women. J. Steroid Biochem. Mol. Biol. 2008;111:178–194. doi: 10.1016/j.jsbmb.2008.06.003.
    1. Juraskova I., Jarvis S., Mok K., Peate M., Meiser B., Cheah B.C., Mireskandari S., Friedlander M. The acceptability, feasibility, and efficacy (Phase I/II study) of the OVERcome (olive oil, vaginal exercise, and moisturizer) intervention to improve dyspareunia and alleviate sexual problems in women with breast cancer. Inter. Sex Med. 2013;10:2549–2558.
    1. Lee Y.K., Chung H.H., Kim J.W., Park N.H., Song Y.S., Kang S.B. Vaginal pH-balanced gel for the control of atrophic vaginitis among breast cancer survivors: A randomized controlled trial. Obstet. Gynecol. 2011;117:922–927. doi: 10.1097/AOG.0b013e3182118790.
    1. Berga S.L. Profile of ospemifene in the breast. Reprod. Sci. 2013;20:1130–1136. doi: 10.1177/1933719113497290.
    1. Rutanen E.M., Heikkinen J., Halonen K., Komi J., Lammintausta R., Ylikorkala O. Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: A double-blind, randomized trial. Menopause. 2003;10:433–439. doi: 10.1097/01.GME.0000063609.62485.27.
    1. Komi J., Lankinen K.S., Harkonen P., DeGregorio M.W., Voipio S., Kivinen S., Tuimala R., Vihtamäki T., Vihko K., Ylikorkala O., et al. Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women. Menopause. 2009;12:202–209. doi: 10.1097/00042192-200512020-00015.
    1. Bachmann G.A., Komi J.O. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: Results from a pivotal phase 3 study. Menopause. 2010;17:480–486.
    1. Portman D.J., Bachmann G.A., Simon J.A. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20:623–630.
    1. Soe L.H., Wurz G.T., Kao C.J., Degregorio M.W. Ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy: Potential benefits in bone and breast. Inter. J. Womens Health. 2013;5:605–611.

Source: PubMed

3
Sottoscrivi