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CME REVIEW CREDIT ANNA CAMILLE MORENO, DO SABRINA K. SIKKA, MD HOLLY L. THACKER, MD Specialized Women’s Health Fellow, Center Specialized Women’s Health Fellow, Director, Center for Specialized Women’s Health, for Specialized Women’s Health, Women’s Center for Specialized Women’s Health, Department of Obstetrics and Gynecology, Wom- Health Institute, Cleveland Clinic Women’s Health Institute, Cleveland Clinic en’s Health Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Genitourinary syndrome of in survivors: Treatments are available

ABSTRACT any breast cancer survivors and wom- M en at high risk of breast cancer suffer When treating the genitourinary syndrome of menopause from genitourinary syndrome of menopause (GSM) in women with breast cancer or at high risk of (GSM), a term that encompasses any urinary, breast cancer, clinicians must balance the higher cancer genital, or related to a hy- risks associated with hormonal treatments against the poestrogenic state. Although GSM is usually severity of GSM symptoms, which can be exacerbated caused by postmenopausal loss, it can by breast cancer treatments. Options for patients who also be caused by cancer treatments such as need hormonal therapy include locally applied , chemotherapy, radiation, and systemic endo- (DHEA), and estrogen recep- crine therapy (eg, , inhib- tor agonists/antagonists, which vary in their impact on itors). These treatments can substantially de- breast cancer risk. crease systemic estrogen levels, causing GSM symptoms that can profoundly worsen quality KEY POINTS of life. Managing GSM in these women poses a In general, locally applied hormonal therapies relieve dilemma because systemic estrogen-contain- GSM symptoms without increasing breast cancer risk. ing therapies can increase the risk of breast cancer, and nonhormonal vaginal lubricants DHEA relieves vaginal symptoms without increasing and moisturizers provide only minimal benefi t. serum estrogen levels. Fortunately, there are hormonal options, in- cluding locally applied estrogen, intravaginal has antiestrogenic effects on breast tissue dehydroepiandrosterone (DHEA), and estro- that make it an attractive option for women with breast gen agonists/antagonists (ospemifene cancer. and ). Here, we review the clinical management of GSM in breast cancer survivors and women The combination of and bazedoxi- at high risk of breast cancer and the effi cacy fene offers a progesterone-free treatment for GSM symp- and safety of available treatments, including toms in women desiring systemic . their impact on breast cancer risk.

■ DRYNESS, IRRITATION, ATROPHY The term GSM describes vulvovaginal and genitourinary symptoms associated with estro- gen loss after menopause. Common symptoms are vaginal dryness, , irritation of doi:10.3949/ccjm.85a.17108 genital skin, and pruritus.

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TABLE 1 Systemic breast cancer treatments that cause genitourinary syndrome of menopause (GSM)

Treatments Breast cancer effects GSM effects Notes Endocrine therapy Aromatase Effective in suppressing serum Vaginal dryness, Third-generation aromatase inhibitors— inhibitors estrogen atrophic , exemestane, and — have largely replaced tamoxifen as the Indicated for treatment of preferred treatment for hormone receptor- estrogen receptor-positive positive breast cancer in postmenopausal breast cancers in postmeno- women pausal women Tamoxifen Indicated for metastatic breast Vasomotor symptoms, Lower rates of vaginal dryness than with cancer, adjuvant treatment of vaginal dryness, and aromatase inhibitors; may actually breast cancer, and to reduce low libido inhibit or improve vaginal dryness breast cancer incidence in induced by chemotherapy or menopause women at high risk Chemotherapy Chemotherapy, biologic Decrease levels of estrogen Vaginal dryness, Effective therapies but can induce symp- therapy, hormonal therapy and progesterone, which , toms of estrogen loss that negatively af- improves clinical outcomes for other symptoms fect long-term vaginal health and quality breast cancer of estrogen loss of life; increase risk of ovarian failure in premenopausal women

Based on information in reference 1.

Many breast cancer survivors who receive showed higher rates of cardiovascular disease tamoxifen, aromatase inhibitors, or other can- and breast cancer with systemic estrogen-pro- cer treatments develop GSM effects such as gestin use,5 the use of this hormone therapy thinner vaginal and urethral epithelium, loss declined by approximately 80%.6 Since then, of subcutaneous fat, fusion of the labia and healthcare providers have turned to local (ie, vulva, narrowing of the vaginal introitus, and vaginal) estrogen therapies to manage GSM. shrinkage of the urethra and clitoral prepuce These therapies have several advantages over (Table 1).1,2 Further, in these patients, low es- systemic hormone therapy: trogen levels can make the vagina less acidic, • Lower risk of adverse effects on the breast predisposing women to infections of the uri- and cardiovascular system nary tract and vagina. Impairment of sexual • Greater effi cacy in treating GSM function includes decreased libido, arousal, 1 • In general, no need for progesterone when and sexual satisfaction. Not only do these pa- low-dose local estrogen is given to a wom- tients have a higher incidence of GSM, they an with a .7 often have more severe symptoms, especially if they receive endocrine therapies such as Is locally applied estrogen tamoxifen and aromatase inhibitors.3,4 systemically absorbed? Despite these advantages, concerns remain as ■ LOCAL ESTROGEN THERAPY to whether therapy has ad- Systemic estrogen therapy is widely used and verse consequences associated with systemic effective for GSM, but there are concerns absorption, particularly from atrophic vaginal that it could increase the risk of breast cancer. tissues. After the Women’s Health Initiative in 2002 Santen,8 in a 2015 review of 33 studies,

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concluded that systemic absorption from low- gradually reduced to half the dose for a similar dose vaginal estrogen is minimal, which pro- time. Maintenance dosing is 1 g 1 to 3 times vides some rationale for using it to treat vul- per week. However, the ACOG statement vovaginal atrophy in postmenopausal women. notes that the FDA-approved dosages are This fi nding also suggests that the US Food higher than those proven to be effective and and Drug Administration (FDA) “black box” currently used in clinical practice, eg, 0.5 g warning of possible toxicities with vaginal es- twice a week.9 trogen is likely overstated, given that serum The FDA-approved dosage of conjugated estrogen levels remained within normal post- estrogen cream for moderate to severe dyspa- menopausal levels. reunia is 0.5 g daily for 21 days, then off for 7 Nevertheless, many providers are appre- days, or 0.5 g twice a week. hensive about prescribing vaginal estrogen in Vaginal tablets. The vaginal tablet Va- women with a history of breast cancer because gifem and its generic equivalent Yuvafem the threshold for systemic estrogen levels as- contain 10 μg of hemihydrate. The sociated with breast cancer recurrence has not FDA-approved dosage is 10 μg daily for 2 been established. weeks, followed by 10 μg twice a week, insert- ACOG statement. In 2016, a commit- ed into the lower third of the vagina. This dos- tee of the American College of Obstetricians age is signifi cantly lower than that of estrogen and Gynecologists cited data showing that creams. low-dose vaginal estrogens do not result in Vaginal insert. A newly approved vaginal sustained serum estrogen levels exceeding insert (Imvexxy) contains estradiol 4 μg (the the normal postmenopausal range, and that lowest dose of vaginal estradiol available) or the use of vaginal estrogens does not increase 10 μg, in a coconut oil vehicle. Its indications the risk of cancer recurrence.9 However, they are for moderate to severe dyspareunia due recommend caution with vaginal estrogen use, to menopause and atrophic vaginitis due to especially in women with a history of estro- menopause. A study cited in its package in- gen-dependent breast cancer, reserving it for sert (www.accessdata.fda.gov/drugsatfda_docs/ Concern patients with GSM symptoms nonresponsive label/2018/208564s000lbl.pdf) showed that, remains to nonhormonal treatment and specifying in patients who used this product, systemic about that it be used in low doses. absorption of estradiol remained within the Vaginal estrogen formulations postmenopausal range. Its effects on breast systemic cancer have not yet been studied. Vaginally applied estrogen relieves urogenital absorption symptoms of GSM and atrophic vagina. Uro- Vaginal rings. Two vaginal rings are mar- of vaginal genital tissues are highly sensitive to estrogen, keted. One (Estring) contains 17-beta estradi- ol, and the other (Femring) contains estradiol estrogen as there are estrogen receptors in the urethra, bladder, and vaginal epithelium, resulting in acetate. Only the 17-beta estradiol ring deliv- therapy increased urogenital lubrication and thicker ers a low dose to vaginal tissues, releasing 7.5 vaginal wall tissues.10 μg/day for 90 days. The ring Several types of locally applied estrogens releases 0.05 mg/day or 0.10 mg/day and is a are available, each with different properties systemic treatment meant to be used with a and affi nity for estrogen receptors. These in- progestin, not for local therapy. clude conjugated estrogens, 17-beta estradiol, ■ VAGINAL THERAPY: DHEA estradiol acetate, and estradiol hemihydrate. Three delivery systems are FDA-approved: After menopause, as the ovaries stop making creams, rings, and tablets (Table 2). estrogen from , some produc- Vaginal creams. Two vaginal creams are tion continues in other tissues, with DHEA as available, one (Estrace) containing 17-beta the primary precursor of that are estradiol and the other (Premarin) containing ultimately converted to estrogen. This has led conjugated estrogens. to the theory that the cause of GSM is not The FDA-approved dosage for 17-beta es- estrogen defi ciency but androgen defi ciency. tradiol is 2 to 4 g/day for 1 or 2 weeks, then Evidence reviewed by Labrie et al11 shows that

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TABLE 2 FDA-approved labeling notes for treatments for genitourinary syndrome of menopause Products GSM indications Breast cancer effects Estrogen products 17-beta estradiol vaginal cream Moderate to severe vulvar and All estrogen products have the following label- (Estrace) vaginal atrophy due to menopause ing notes: Conjugated estrogen vaginal cream Moderate to severe dyspareunia WHI: Estrogen alone was not associated with (Premarina) due to menopause increased risk of breast cancer; estrogen plus progestin increased the risk Atrophic vaginitis and Contraindication: known, suspected, or history of breast cancer 17-beta estradiol vaginal ring (Estring) Moderate to severe vulvar and vaginal atrophy due to menopause Warning: Estrogens with or without progestins should be prescribed at the lowest effective Estradiol hemihydrate vaginal Atrophic vaginitis due to menopause doses and for the shortest duration tablets (Vagifem, Yuvafemb) Estradiol vaginal inserts (Imvexxy) GSM, dyspareunia Combination estrogen product Conjugated estrogens/bazedoxifene Moderate to severe vasomotor (Duavee) symptoms associated with menopause Nonestrogen products vaginal tablet Moderate to severe dyspareunia Warning: Prasterone is contraindicated (Intrarosa; contains dehydro- due to menopause in women with known or suspected breast ) cancer; prasterone has not been studied in women with a history of breast cancer Ospemifene (Osphena) oral tablet Moderate to severe dyspareunia Warning: Ospemifene has not been adequately due to menopause studied in women with breast cancer; there- fore, it should not be used in women with known or suspected breast cancer or with a history of breast cancer

aPremarin vaginal cream is the only locally applied preparation with FDA approval for dyspareunia due to GSM. bYuvafem is an FDA-approved generic equivalent to Vagifem. FDA = US Food and Drug Administration; GSM = genitourinary syndrome of menopause; WHI = Women’s Health Initiative study vulvovaginal atrophy is caused by decreased of GSM symptoms.12 DHEA availability, which in turn causes sex The only DHEA product FDA-approved defi ciency-related menopausal symp- for treating GSM-related symptoms is toms.11 Thus, it is reasonable to conclude that prasterone (Intrarosa), indicated for moder- menopausal symptoms can be relieved by giv- ate to severe dyspareunia due to vulvovaginal ing DHEA. atrophy. The recommended dosing is a single This theory has been borne out in clinical 6.5-mg intravaginal tablet (0.5% prasterone) trials, in which DHEA in a vaginal tablet for- inserted nightly at bedtime. Its effi cacy for mulation increased the maturation of vaginal treating hypoactive sexual desire disorder in cells and lowered vaginal pH, leading to relief postmenopausal women is being investigated.

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Breast cancer implications pemifene decreased tumor growth in mice im- Because DHEA is converted to estrogen by planted with estrogen receptor-positive breast , healthcare providers might cancer cells.15 hesitate to use it in women who have a history In a mouse model using breast cancer cells of hormone-sensitive cancer. Data on the safe- that were biologically and histologically similar ty of intravaginal DHEA use in breast cancer to those of humans, ospemifene had strong an- survivors are limited. However, studies have tiestrogenic effects on the breast tissue.16 The found that prasterone has highly benefi cial ef- evidence suggests that ospemifene has a favor- fects on dyspareunia, vaginal dryness, and ob- able effect on vulvar and vaginal atrophy.17 jective signs of vulvovaginal atrophy without Ospemifene is FDA-approved to treat signifi cant drug-related adverse effects.12,13 In moderate to severe dyspareunia secondary to these studies, serum estrogen levels in women menopause. Recommended dosing is 60 mg/ treated with DHEA were within the values day orally with food. observed in normal postmenopausal women. Its antiestrogenic effects on breast tissue In addition, there are no aromatase make it a promising option for women with in the , so even high doses of a history of estrogen-receptor positive breast vaginal DHEA (in contrast to high doses of cancer. However, further study is needed to vaginal estrogen) will not stimulate the endo- fully understand its effects on human breast metrium. tissue. According to the manufacturer’s pack- Clinically, this evidence indicates that age insert (www.osphena.com/fi les/pdf/osphe- DHEA exerts both estrogenic and androgenic na_prescribing_information.pdf), because the activity in the vagina without increasing se- drug has not been adequately studied in wom- rum estrogen levels, making it a good alterna- en with breast cancer, it should not be used in tive to topical estrogen therapy. women with known or suspected breast cancer or a history of breast cancer. ■ OSPEMIFENE: AN ESTROGEN RECEPTOR AGONIST/ANTAGONIST ■ CONJUGATED ESTROGENS DHEA in an Ospemifene (Osphena) is an estrogen recep- PLUS BAZEDOXIFENE intravaginal tor agonist/antagonist, a class of drugs previ- The combination of conjugated estrogens and tablet ously called selective estrogen receptor modu- bazedoxifene (Duavee) is a progesterone-free lators (SERMs). It is FDA-approved to treat formulation alternative for treating various menopausal moderate to severe dyspareunia secondary to symptoms. Bazedoxifene is another estrogen relieves GSM vulvar and vaginal atrophy. receptor agonist/antagonist, and it was added symptoms Ospemifene has unique estrogenic effects to counteract estrogen’s effects on the endo- on the vaginal mucosa, having been shown to metrium, thus replacing progesterone. This increase the number of epithelial cells, lower protective effect has been validated in clini- the vaginal pH, and decrease the percentage cal trials, which also found a favorable safety of parabasal cells seen on Papanicolaou smears profi le in breast tissue.18,19 after 12 weeks of use.14 SMART trials. The effi cacy of this com- Unlike tamoxifen, another drug of this bination was studied in a series of large phase class, ospemifene does not change the endo- 3 multicenter trials called the SMART (Se- metrial lining.14 Similarly, ospemifene acts as lective Estrogens, Menopause, and Response an estrogenic agonist in bone and, thus, has to Therapy) trials.20–23 Treated patients had the potential for use in preventing and man- markedly fewer vasomotor symptoms at 1 year, aging osteoporosis or for use in women at risk along with an increase in superfi cial cells and of fractures. intermediate cells of the vaginal epithelium Breast cancer impact and a decrease in parabasal cells. They also In preclinical trials, ospemifene was found to had a substantial decrease in the incidence of have antiestrogenic effects on breast tissue, dyspareunia. similar to those seen with tamoxifen. Its effects on breast tissue were evaluated In a model using human tumor grafts, os- in the SMART-5 trial. Therapy had no net

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impact on breast density, suggesting that it has especially those treated with tamoxifen or an an estrogen-neutral effect on the breast.23 . Estimates are that 60% of These results suggest that combined con- postmenopausal breast cancer survivors and 40% jugated estrogens and bazedoxifene could be of premenopausal breast cancer survivors suffer a noteworthy treatment option for GSM in from GSM.26 Unfortunately, many women do women with a history of estrogen receptor- not seek medical attention for their symptoms. positive breast cancer, particularly in those A variety of hormonal and nonhormonal with vasomotor symptoms and bone loss. options are available for these patients. We However, the combination has not been stud- recommend an interdisciplinary approach to ied specifi cally in breast cancer survivors. treatment, with the decision to use hormonal Dosage. The FDA-approved dosing is 20 options made in collaboration with the pa- mg/0.45 mg per day orally to treat vasomotor tient’s oncologist and the patient herself, in symptoms, GSM, and osteoporosis in post- an informed, shared decision-making process menopausal women with a uterus. that takes into consideration the risks and possible benefi ts depending on the symptoms. ■ LASER THERAPY AND RADIOFREQUENCY The fi rst step in selecting a management HEAT: AN OFF-LABEL OPTION plan for GSM symptoms in women with Low-dose radiofrequency thermal therapy, de- breast cancer is to conduct a thorough assess- livered by carbon dioxide laser or by radiofre- ment to provide data for individualizing the quency heat, has been used with some success care plan. The decision to use a hormonal op- to treat urinary stress incontinence and vagi- tion should be made in collaboration with a nal laxity in postpartum women. It may be woman’s oncologist and should include an in- an option for GSM, although it is not FDA- formed decision-making process during which approved for this indication, and the FDA has the potential risks and benefi ts, including the recently issued a warning about it.24 breast cancer impact, are fully disclosed. Marketing literature promotes laser therapy Alternatives to systemic estrogen as an effective option that stimulates vaginal con- Vaginal estrogen is an effective and safe op- We recommend nective tissue to produce new collagen, which tion to treat GSM in women with either es- then promotes improved blood fl ow and tissue trogen receptor-negative or estrogen receptor- an inter- regeneration for vaginal lubrication and elasticity. positive breast cancer. It often completely disciplinary A study comparing fractional carbon di- cures the symptoms without any noticeable approach oxide vaginal laser treatment and local estro- increase in serum estrogen levels. gen therapy in postmenopausal women with Vaginal DHEA therapy is a nonestrogen to treatment, vulvovaginal atrophy found that laser therapy option shown to effectively treat GSM with- with shared, was an effective treatment for vulvovaginal out increasing systemic levels of estrogen atrophy (dyspareunia, dryness, and burning), or . This profi le makes vaginal informed 25 both alone and with local estrogen. DHEA therapy a particularly attractive treat- decision- Despite the promising effects of laser therapy ment for symptoms of GSM in women at risk making for treating vulvovaginal atrophy in GSM, stud- for breast cancer. ies have not determined its short-term or long- Use of an estrogen receptor agonist/antag- term safety profi le. Furthermore, laser therapy onist in breast cancer survivors needs careful does not improve impaired sexual function, ie, consideration. Ospemifene has antiestrogenic decreased libido, arousal, and sexual satisfaction. effects that make it a good option for women Another important consideration is that the with bone loss and those at high risk for breast cost of laser therapy in 2017 was estimated to be cancer, but it should not be used concurrently $2,000 to $3,000 per treatment, not covered by with tamoxifen or . Additionally, healthcare insurance. ospemifene does not cause uterine hyperplasia, ■ so it can be used in women with a uterus. CLINICAL APPROACH Although more study is needed, we do have Symptoms of GSM are common in breast can- options to improve the overall quality of life in cer survivors, both pre- and postmenopausal, breast cancer survivors with GSM. ■

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In the article by A.C. Moreno, S.K. Sikka, and H.L. ccjm.85a.17108), Table 2 incorrectly stated that Thacker, Genitourinary syndrome of menopause in prasterone is contraindicated in women with known or breast cancer survivors: Treatments are available, suspected breast cancer. This correction has been made Cleve Clin J Med 2018; 85(10):760–766, doi:10.3949/ online. The corrected table appears below:

TABLE 2 FDA-approved labeling notes for treatments for genitourinary syndrome of menopause Products GSM indications Breast cancer effects Estrogen products 17-beta estradiol vaginal cream Moderate to severe vulvar and All estrogen products have the following label- (Estrace) vaginal atrophy due to menopause ing notes: Conjugated estrogen vaginal cream Moderate to severe dyspareunia WHI: Estrogen alone was not associated with (Premarina) due to menopause increased risk of breast cancer; estrogen plus progestin increased the risk Atrophic vaginitis and kraurosis vulvae Contraindication: known, suspected, or history of breast cancer 17-beta estradiol vaginal ring (Estring) Moderate to severe vulvar and vaginal atrophy due to menopause Warning: Estrogens with or without progestins should be prescribed at the lowest effective Estradiol hemihydrate vaginal Atrophic vaginitis due to menopause doses and for the shortest duration tablets (Vagifem, Yuvafemb) Estradiol vaginal inserts (Imvexxy) GSM, dyspareunia Combination estrogen product Conjugated estrogens/bazedoxifene Moderate to severe vasomotor (Duavee) symptoms associated with menopause Nonestrogen products Prasterone vaginal tablet Moderate to severe dyspareunia Warning: Estrogen is a metabolite of (Intrarosa; contains dehydro- due to menopause prasterone; use of exogenous extrogen is epiandrosterone) contraindicated in women with known or suspected breast cancer; prasterone has not been studied in women with a history of breast cancer Ospemifene (Osphena) oral tablet Moderate to severe dyspareunia Warning: Ospemifene has not been adequately due to menopause studied in women with breast cancer; there- fore, it should not be used in women with known or suspected breast cancer or with a history of breast cancer

aPremarin vaginal cream is the only locally applied preparation with FDA approval for dyspareunia due to GSM. bYuvafem is an FDA-approved generic equivalent to Vagifem. FDA = US Food and Drug Administration; GSM = genitourinary syndrome of menopause; WHI = Women’s Health Initiative study

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