Why the Product Labeling for Low-Dose Vaginal Estrogen Should Be Changed

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Menopause: The Journal of The North American Menopause Society Vol. 21, No. 9, pp. 911/916 DOI: 10.1097/gme.0000000000000316 * 2014 by The North American Menopause Society

EDITORIAL Why the product labeling for low-dose vaginal estrogen should be changed

his commentary summarizes the activities of several of a highly effective local treatment of a common condition clinicians and researchers to encourage modifications with medical risks and adverse effects on quality of life. We Tto the labeling of low-dose vaginal estrogen. Motivated contend that the boxed warning for low-dose vaginal es- by concerns of practicing clinicians that the boxed warning on trogen products is unjustified based on several lines of rea- the labels and package inserts for these products overstate po- soning described below, including the following: (a) the tential risks and thus adversely affect patient care, leaders dramatic differences in blood hormone levels achieved by in the field are spearheading an effort to encourage consider- low-dose vaginal estrogen (eg, Vagifem tablets [estradiol ation of alternative labeling, as discussed below. The members 10 Kg], Estring [releasing estradiol 7.5 Kg/d], or comparable of the Working Group on Women’s Health and Well-Being in low-dose vaginal estrogen cream formulations) versus con- Menopause have affiliations with a number of medical socie- ventional systemic estrogen therapy; (b) absence of ran- ties, including The North American Menopause Society, the domized trial evidence or consistent observational evidence American College of Obstetricians and Gynecologists, the En- linking low-dose vaginal estrogen to cancer, cardiovascular docrine Society, the American Society for Reproductive Med- disease, dementia, or any of the other conditions highlighted icine, the International Society for the Study of Women’s in the boxed warning; and (c) absence of evidence that changes in Sexual Health, and other professional organizations. We appre- blood hormone levelsVof the small magnitude achieved with ciated the opportunity to share our concerns, literature review, these productsVincrease risk of these conditions. As a result and proposal for alternative labeling with members of the US of the boxed warning, a large number of older women with Food and Drug Administration (FDA) Division of Bone, Re- symptomatic VVA and genitourinary symptoms are being productive, and Urologic Products via a teleconference earlier undertreated and do not receive the substantial benefits that this year. We encourage further consideration of our rationale these medications could provide. and proposal by both the FDA and the pharmaceutical compa- We believe that women would be better served by a mod- nies that own these products. ified label that more closely reflects the safety profile of low- dose vaginal estrogen and would actually enhance safety by Overview of the proposal for label change emphasizing the key information that women and clinicians Vulvovaginal atrophy (VVA; also known as genitourinary need to know about the products. Our proposal is to state in syndrome of menopause) is a common and progressive con- the package labeling, in regular text and font, that estrogen dition that adversely affects the health and quality of life and estrogen-progestin given systemically, in higher doses, of many postmenopausal women.1 Symptomatic VVA is a have been linked to the health conditions currently noted in growing problem because of the confluence of several fac- the boxed warning, but that the relevance to low-dose vaginal tors, including the burgeoning population of older postmeno- estrogen remains unknown, given minimal increase in serum pausal women and the declining use of systemic menopausal estrogen levels with low-dose vaginal estrogen products. We hormone therapy since the initial report of the Women’s recommend bolding the phrase Breport any vaginal bleeding Health Initiative (WHI).2,3 Our view is that an additional or spotting right away while using ______.[ We also rec- factorVthe boxed warning on the package label for low-dose ommend adding in bold BWomen with a history of cancer of vaginal estrogenVdiscourages clinicians from prescribing the breast or uterus (womb), or other hormone-sensitive the product and women from taking it even after purchase. cancers, are encouraged to consult their oncologist before The boxed warning, which reflects estrogen class labeling, using this product.[ We believe that these label changes will, states BWARNING: ENDOMETRIAL CANCER, CAR- paradoxically, enhance patient safety because the relevant infor- DIOVASCULAR DISORDERS, BREAST CANCER, and mation and cautions will stand out and be highly visible, rather PROBABLE DEMENTIA[ and is based on extrapolations than being obscured by extraneous and alarming bolded and of data from clinical trials of systemic hormone therapy such boxed statements that lack proven relevance to the product. as the WHI, which involved substantially higher levels of Thus, the proposed label change would serve the purpose of in- exposure. We believe that the boxed warning is not forming women of previous research and addressing safety issues evidence-based and harms women by discouraging the use while stating that the relevance of past research findings on

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Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EDITORIAL systemic hormone therapy to low-dose vaginal estrogen is infections12,13 and overactive bladder.14,15 Although systemic unknown. The specific suggested wording of our proposed hormone therapy has been associated with an increase in stress label change is provided at the end of this commentary. incontinence,8,16 the low-dose estradiol ring has been approved for the treatment of dysuria and urinary urgency. VVA has been Prevalence of VVA (Genitourinary Syndrome of linked to considerable impairment of quality of life; nonethe- Menopause) and the impact on women’s health and less, clinical studies demonstrate that a substantial proportion of quality of life women are undertreated.1 VVA symptoms, such as vaginal dryness, lack of lubrication, Moreover, in our collective clinical experience and in those pain or spotting with intercourse, and burning with urination, of the professional colleagues we represent, among women 4,5 affect 20% to 45% of midlife and older women. In contrast who seek treatment and/or receive prescriptions for low-dose to vasomotor symptoms, which tend to improve across time vaginal estrogen, a substantial proportion ultimately choose irrespective of treatment, VVA is usually progressive and un- not to use the product or discontinue use because of concerns likely to resolve without intervention. VVA symptoms can and alarm about the boxed warning in the package insert. have a significantly adverse effect on a woman’s sexual health Testimonials by working group members during the telecon- and quality of life. In an online survey conducted in six coun- ference with the FDA highlighted the adverse impact of VVA tries, an estimated 45% of postmenopausal women reported on women’s lives, including their physical, sexual, and emo- 6 experiencing vaginal symptoms. The largest survey of US tional health; clinical experience with the marked efficacy of women, REVIVE (Real Women’s Views of Treatment Options treatment; and the deleterious effect of the boxed warning on for Menopausal Vaginal Changes), included 3,046 women with 7 women’s health by discouraging clinician colleagues from VVA symptoms. In this study, 85% of women with partners prescribing, and women from using, these highly effective B [ reported some loss of intimacy, 59% indicated that VVA low-dose vaginal estrogen products. Specifically, several cli- symptoms detracted from enjoyment of sex, 47% of women nicians reported that many women who have purchased the low- with partners reported that VVA interfered with their relation- dose vaginal estrogen products, often at significant financial cost, ship, and 27% reported that VVA had a negative effect on their ended up not using them after reading the boxed warning. general enjoyment of life. Similar results were found in the 6 VIVA (Vaginal Health: Insights, Views & Attitudes) survey. Comparative blood concentrations of estrogens associated Aging and diminished estrogen levels are major contributors to 1,8 with low-dose vaginal estrogen versus systemic estrogens VVA, atrophic vaginitis, and recurrent urinary tract infections. versus no treatment Efficacy of treatment and impact of product BLow-dose[ vaginal estrogen refers to products such as labeling/boxed warning Estring (vaginal ring releasing estradiol 7.5 Kg/d), Vagifem As emphasized in the 2013 North American Menopause (10-Kg tablets two times a week), and comparable low doses Society VVA position statement,1 the primary goal of treating of vaginal creams (eg, Estrace [estradiol]) or Premarin [con- symptomatic VVA is to alleviate symptoms. First-line thera- jugated estrogens]).17 These products are considered to have pies include nonhormonal lubricants and long-acting vaginal a more favorable risk profile than commonly used doses of moisturizers, as well as low-dose vaginal estrogen in those systemic estrogen therapy because they lead to small, if any, remaining symptomatic, assuming no contraindications.1 For increases in serum estrogen concentrations.1,18<23 When low- women with moderate to severe dyspareunia related to VVA dose vaginal estrogen is used as directed, reported serum es- who prefer nonvaginal therapy, transdermal or oral systemic trogen levels fall generally within the average postmenopausal hormone therapy and the oral estrogen agonist/antagonist range (below 20 pg/mL).1,18 Reported estradiol levels ranged ospemifene are options. Women with significant vasomotor from 5 to 10 pg/mL with use of the vaginal ring (releasing symptoms may choose systemic (oral or transdermal) hor- estradiol approximately 7.5 Kg/d)19<21 and from 3 to 11 pg/mL mone therapy, which will also treat VVA if present. Low- with use of the 10-Kg vaginal tablet.22,23 In contrast, use of 0.2 mg dose vaginal estrogen, however, is the preferred mode of (200 Kg) of estradiol cream led to serum levels of 80 pg/mL.24 treatment when vaginal symptoms are the only complaint.1 However, a small pilot study showed that using one twentieth Low-dose vaginal estrogen products can provide sufficient of the dose of estradiol cream (a 10-Kg dose) was associated local estrogen effect to relieve symptoms, decrease vaginal with full efficacy in genitourinary tissues, whereas circulat- pH, and increase maturation of the vaginal and urethral epi- ing estradiol levels measured using a highly sensitive assay thelia, with minimal systemic absorption.1,9<11 These prod- remained within the postmenopausal range of 3 to 10 pg/mL.22 ucts have been shown to be at least as effective as systemic Conjugated estrogens cream at adoseof0.3mgproducedno oral estrogen therapy in relieving VVA symptoms, with 80% change in serum estradiol levels,25 but conjugated estrogens to 90% of women reporting a favorable response compared products contain multiple estrogenic compounds, and plasma with 75% of women using oral estrogen.9,10 A2006Cochrane estradiol levels may not fully reflect estrogenic activity. review of 19 efficacy trials reported that all local estrogen Among women treated with 0.3 mg of vaginal conjugated products tested had similar efficacy in alleviating symptoms.11 equine estrogens three times a week for 6 months, the serum Therapeutic benefit of vaginal estrogen has also been observed estrone levels were 61.6 pg/mL compared with 55.6 pg/mL with conditions other than VVA, such as recurrent urinary tract at baseline.25

912 Menopause, Vol. 21, No. 9, 2014 * 2014 The North American Menopause Society

It is instructive to compare the serum estrogen concentrations treatment.22 Moreover, in a randomized study of a low-dose of women on low-dose vaginal estrogen with the endogenous vaginal estradiol ring delivering estradiol 7.5 Kg/day, estradiol estrogen levels in untreated premenopausal and postmenopausal levels increased less than 1 pg/mL above baseline (P =0.59)and women, as well as with the hormone concentrations of post- endometrial lining thickness at 12 months was similar to base- menopausal women treated with systemic estrogen. Among line, with a mean (SD) change of j0.14 (0.53) mm (P =0.54).21 untreated women in the Melbourne Women’s Midlife Health If low-dose vaginal estrogens have either regional or sys- Project, the average serum estradiol levels were 78 pg/mL temic effects beyond their local action, one would expect to (range, 39-158 pg/mL) 4 years before the final menstrual period, observe endometrial proliferation, as determined by either 31 pg/mL (range, 23-42 pg/mL) at the time of the final menstrual transvaginal ultrasoundYmeasured endometrial thickness or period, and 10 pg/mL (range, 8-11 pg/mL) 2 years after meno- endometrial biopsy. Collectively, these studies demonstrate pause.26 Among postmenopausal women treated with systemic that low-dose vaginal estrogen therapy, including assessments estrogen, serum estrogen concentrations increase markedly. of three different estradiol preparations at 12 months of eval- For example, in a 12-week trial of oral estradiol 1 mg/day, the uation, does not seem to have significant endometrial impact average estradiol level on treatment was 164 pg/mL (range, beyond the local vaginal estrogenic effects. Higher dosing, 86-243 pg/mL), representing a 9.5-fold increase from base- long-term use, and use by women with comorbidities may line menopausal levels.27 Among women in the Kronos Early carry higher risks. Estrogen Prevention Study (average age, 53 y; all within 3 y Low-dose vaginal estrogen and breast-related outcomes of their final menstrual period), estradiol levels after treatment Assessment of the potential biologic effects of low-dose with a transdermal patch containing estradiol 50 Kg/day were vaginal estrogen on breast tissue can be approached by con- more than three times higher than baseline levels; among sidering three separate endpoints: mammographic breast den- women treated with oral conjugated estrogens 0.45 mg/day, sity, breast cancer, and breast pain. Although we could find no estrone levels were more than twice as high as baseline levels.28 studies examining the endpoint of breast density in relation to Thus, treatment with systemic estrogen leads to substantial low-dose vaginal estrogens, a 2-year placebo-controlled ran- increases in blood hormone levels compared with baseline, domized trial examining a transdermal preparation delivering whereas serum hormone levels among women treated with estradiol 14 Kg/day showed no difference in breast density at low-dose vaginal estrogen remain within the reference post- 2 years compared with placebo.31 Regarding breast cancer, a menopausal range. large-scale observational study of Finnish women, including 18,314 users of vaginal estrogen, indicated no increase in the Low-dose vaginal estrogen and the endometrium risk of breast cancer associated with vaginal estrogen use.32 Endometrial tissue response is an extremely sensitive bio- Moreover, no increased risk would be expected based on the assay for estrogenic action and reflects the integration of se- results of the unopposed estrogen arm of the WHI.33,34 With rum estrogen levels with duration of estrogenic exposure. 7.2 years of oral conjugated equine estrogens (0.625 mg/d), the Three different low-dose vaginal estrogen therapies have been hazard ratios (95% CIs) were 0.79 (0.61-1.02) for the inter- evaluated, and their endometrial effects have been assessed via vention phase and 0.79 (0.65-0.97) for the 13-year cumulative either transvaginal ultrasoundYmeasured endometrial thickness follow-up phase,34 suggesting no increased risk of breast can- or endometrial biopsy. The largest trial to date is a randomized cer with unopposed conjugated equine estrogens across this double-blind controlled study of 1,612 postmenopausal women time frame. Evidence that this finding applies to other formu- in which vaginal estradiol tablets were administered at a dose of lations of estrogen remains inconclusive. However, one would 25 Kg/day for 2 weeks, followed by a dose of 25 Kg two times not expect that an even lower dose of unopposed estrogen a week for 12 months. This study demonstrated no increases given vaginally, and with minimal systemic absorption, would in serum estradiol levels at 4 and 12 months compared with have an adverse effect on breast cancer risk. Regarding breast baseline levels: (mean [SD], 15.7 [2.3] pg/mL {baseline} vs pain, this symptom has been reported with intermediate doses 15.5 [2.5] pg/mL {12 mo}).29 Vaginal ultrasoundYdetermined of vaginal estrogen. However, in a study of low-dose vaginal endometrial thickness remained essentially unchanged after estrogen (Estring), only 1 of 108 women complained of breast 12 months of therapy (mean [SD], 3.1 [0.4] mm {baseline} vs pain while the ring was in place.13 Reports on the use of 10 Kg 2.9 [0.5] mm {12 mo}).29 There was no change in uterine vol- of low-dose vaginal estrogen make no mention of breast pain.35 ume or enlargement of preexisting myomas across 12 months. Based on these collective findings, it is improbable that these In a separate study of a vaginal estradiol tablet 10 Kg/day, endo- products exert important biologic effects on the breast. metrial biopsies were performed in 297 women after 12 months of treatment; 183 women had endometrial tissue that was atrophic Special considerations for women with a history of breast cancer or inactive, whereas 111 women had no tissue or had insuffi- Despite the reassuring evidence mentioned previously, cient tissue for diagnosis. There was one case of complex hy- women with a history of breast cancer warrant special consid- perplasia without atypia.30 Similar findings have been reported eration. The clinical relevance of even very small increases in in a trial of estradiol vaginal cream given at a dose of 10 Kg/day circulating estrogen levels with low-dose vaginal estrogen for 3 weeks then 10 Kg two times a week. Endometrial thick- products in women with breast cancer remains unclear. Aro- ness remained stable at less than 5 mm during the 12-week matase inhibitors (AIs), which block 95% of estrogen synthesis,

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Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EDITORIAL are typically associated with circulating estradiol levels Effects of endogenous estrogen concentrations within the lower than 1 pg/mL.36 Thus, as would be expected, vaginal reference postmenopausal range administration of low-dose estrogen will lead to higher- The main source of endogenous estrogen in postmenopausal than-baseline serum estradiol levels in women receiving women is the peripheral conversion of steroid precursors via AI therapy.37 As any rise above baseline serum estradiol the aromatase enzyme located primarily in peripheral adipose levels may affect AI efficacy, the use of any hormone therapy and muscle tissues.45 Obesity itself is a risk factor for breast product in women with breast cancer warrants special cau- and endometrial cancers and cardiometabolic disorders.45,46 tion, especially in view of sparse research on the safety of Pathways implicated in the association of obesity with these these products in breast cancer patients. In one case-control disorders include insulin resistance, hyperinsulinemia, growth study, women receiving endocrine treatment (such as ta- factors, and inflammation,45,46 in addition to elevation of sex moxifen or AIs) for breast cancer did not have higher rates steroid hormones. Central adiposity is further associated with of recurrence with local estrogen use compared with non- dyslipidemia, type 2 diabetes, and higher levels of inflammatory use,38 but vaginal estrogen treatment by ring or tablet did cytokines,whichlikelyalsocontribute to cardiovascular disease. increase circulating estrogen levels, at least initially.39 For Thus, observational studies linking endogenous estrogen con- systemic hormone therapy, inconsistent results for breast centrations within the postmenopausal range to cardiometabolic cancer recurrence have been found in randomized trials disorders or cancer have potential for confounding by the and observational studies.40 Patients with breast cancer who abovementioned factors and are not viewed as a concern for have symptomatic VVA and do not respond to nonhormonal the use of low-dose vaginal estrogen products. therapies are encouraged to discuss the risks and benefits of low-dose vaginal estrogen therapy with their oncologist. Oral ospemifene has not been tested in women at high risk Conclusions and proposed label changes for breast cancer or with a history of breast cancer; thus, no Based on these data, we submit that revisiting the labeling recommendations can be given for its use in this population. of low-dose vaginal estrogen to include the changes below would enhance women’s safety and improve their health and well-being. As discussed previously, the boxed warning on Low-dose vaginal estrogen and cardiovascular, these products is based on extrapolations of data from trials of cerebrovascular, cognitive, and other outcomes systemic estrogen or combination estrogen-progestin hormone Compared with oral systemic estrogen and estrogen- therapy, which involve substantially higher levels of exposure. progestin, as studied in the WHI and forming the basis for It is noteworthy that there are dramatic differences in estrogen the boxed warning, low-dose vaginal estrogen has lower sys- blood levels achieved with low-dose vaginal estrogen thera- temic absorption and, similar to transdermal estradiol formu- pies compared with systemic estrogen administration. Our lations, avoids Bfirst-pass[ liver metabolism and effects on view is that the highly visible boxed warning on low-dose hepatic enzymes.1,41,42 Lower-dose transdermal estradiol has vaginal estrogen is unsubstantiated and not evidence-based been shown to have less risk of venous thromboembolism andisharmingwomenbydiscouragingtheuseofeffective (VTE)42 and possibly stroke43; thus, the significantly lower treatments that would provide substantial benefits to post- systemic absorption of low-dose vaginal estrogen makes it menopausal women with symptomatic VVA. We believe that even less likely to increase risk of VTE and other cardiovas- women would be better served by a modified label that more cular events than oral systemic estrogen.42,43 The increased closely reflects the safety profile of low-dose vaginal estro- risks of coronary heart disease, stroke, and VTE, which have gen and could ultimately enhance safety by emphasizing the been reported with oral systemic hormone therapy,1,42,43 have key information that women and clinicians need to know not been reported with low-dose vaginal estrogen therapy.1 about the products. Moreover, long-term follow-up of women in the WHI trial Our proposal, as noted above, is to mention in the product of unopposed estrogen44 showed no increased risk of cor- labeling, in regular text and font, that estrogen and estrogen- onary events or all-cause mortality, indicating that low-dose progestin given systemically, in higher doses, have been vaginal estrogen is unlikely to affect these outcomes. The linked to the health conditions currently included in the boxed 2006 Cochrane review of VVA did not find evidence of warning, but that the relevance to low-dose vaginal estrogen an increased risk of VTE with low-dose estrogen,11 but data remains unknown, given minimal increase in serum estrogen for women at high risk for these events are lacking. An in- levels with low-dose vaginal estrogen products. We recom- crease in probable dementia was observed in the WHI among mend bolding the phrase Breport any vaginal bleeding or women aged 65 years or older who were treated with oral spotting right away while using ______.[ We also recom- systemic estrogen-progestin therapy (equivocal results for mend adding in bold BWomen with a history of cancer of systemic oral estrogen alone); there is no evidence that the the breast or uterus (womb), or other hormone-sensitive minimal absorption of low-dose vaginal estrogen prepara- cancers, are encouraged to consult their oncologist before tions would have the potential to affect dementia risk among using this product.[ This label change would serve the purpose women in any age group or would have biologic plausibility of informing women of previous research and addressing to do so. safety issues while stating that the relevance of past research

914 Menopause, Vol. 21, No. 9, 2014 * 2014 The North American Menopause Society

Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. EDITORIAL findings on systemic hormone therapy to the current vaginal Add in bold: Women with a history of cancer of the breast products is unknown. or uterus (womb), or other hormone-sensitive cancers, Regarding other statements in the boxed warning, we pro- are encouraged to consult their oncologist before using pose the following (all would be listed in regular and unbolded this product. font, except as noted; none of the text would be boxed):

What is the most important information I should know about Include the statement below in regular unbolded font: _____? & You and your healthcare provider should talk regularly about whether you still need treatment with ______. & Instead of: Using estrogen alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using We believe that these label modifications will improve ______. Vaginal bleeding after menopause may be a warn- women’s health. ing sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find the cause. Financial disclosure/conflicts of interest: J.E.M., R.W.R., Change to: Using higher doses of estrogen alone is asso- P.F.S., J.L.S., M.L.S.G., and W.H.U. report no disclosures. S.R.G. is a consultant to, and has received payment for lectures/ ciated with an increased chance of getting cancer of the service on speakers’ bureaus for, Shionogi and Pfizer. R.K. is uterus (womb), but the relevance of these findings to low- a consultant to, and has received payment for lectures/service dose vaginal estrogen is unknown. Nonetheless, report on speakers’ bureaus for, Pfizer, Novo Nordisk, Noven, and any vaginal bleeding or spotting right away while you Shionogi. A.M.K. serves on advisory boards for Actavis. J.H.L. are using ______. Vaginal bleeding after menopause is on the Advisory board for Noven, Pfizer, and Shionogi. J.V.P. is a consultant (fees to the University of Virginia) for may be a warning sign of cancer of the uterus (womb). Pfizer, Novo Nordisk, and Shionogi. C.A.S. has served as a Your healthcare provider should check any vaginal consultant to Pfizer. All authors are current or past members of bleeding or spotting to find the cause. the NAMS Board of Trustees. & Include: Do not use estrogen alone to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function). Comment: Include this in regular unbolded font, not boxed. JoAnn E. Manson, MD, DrPH, NCMP1 Steven R. Goldstein, MD, NCMP2 & Instead of: Using estrogen alone may increase your chances Risa Kagan, MD, NCMP3 of getting strokes or blood clots. Andrew M. Kaunitz, MD, NCMP4 James H. Liu, MD5 Change to: Using higher doses of estrogen may increase JoAnn V. Pinkerton, MD, NCMP6 your chances of getting strokes or blood clots, but the Robert W. Rebar, MD7 relevance of these findings to low-dose vaginal estrogen, Peter F. Schnatz, DO, NCMP8 Jan L. Shifren, MD, NCMP1 which leads to minimal increase in blood estrogen levels, 9 is unknown. Cynthia A. Stuenkel, MD, NCMP Margery L.S. Gass, MD, NCMP5 & Insteadof:Usingestrogenalonemayincreaseyour Wulf H. Utian, MB Bch, PhD, DSc(Med)5 chance of getting dementia, based on a study of women aged 65 years or older. for the Working Group on Women_s Health and Well-Being Change to: Using higher doses of estrogen may increase in Menopause your chance of getting dementia, based on a study of women aged 65 years or older, but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen levels, is unknown.

& Instead of: Using estrogens with progestins may increase 1 2 your chance of getting breast cancer. From the Harvard Medical School, Boston, MA; New York University School of Medicine, New York, NY; 3University of California, San Francisco, San Francisco, CA; 4University of Florida College Change to: Using estrogens with progestins may increase of Medicine-Jacksonville, Jacksonville, FL; 5Case Western Reserve 6 your chance of getting breast cancer, but the relevance of University School of Medicine, Cleveland, OH; University of Virginia, Charlottesville, Charlottesville, VA; 7University of Alabama, Birmingham, these findings to low-dose vaginal estrogen without pro- Birmingham, AL; 8Jefferson Medical College, Philadelphia, PA; gestins is unknown. and 9University of California, San Diego San Diego, CA.

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916 Menopause, Vol. 21, No. 9, 2014 * 2014 The North American Menopause Society