Secondary Logo

Journal Logo

Original Articles

WISDOM survey: attitudes and behaviors of physicians toward vulvar and vaginal atrophy (VVA) treatment in women including those with breast cancer history

Kingsberg, Sheryl A. PhD1; Larkin, Lisa MD2; Krychman, Michael MD3; Parish, Sharon J. MD4; Bernick, Brian MD5; Mirkin, Sebastian MD5

Author Information
doi: 10.1097/GME.0000000000001194
  • Open
  • Editorial

Abstract

In the United States, 41.7 million women were reaching or were currently of menopausal age in 2010.1 Menopausal symptoms are common, affecting up to 75% of menopausal women, and can negatively impact women's quality of life, personal and intimate relationships, and productivity.2,3 Of the women afflicted with menopausal symptoms, up to 45% experience symptoms of vulvar and vaginal atrophy (VVA), such as vaginal dryness, irritation, itching, dysuria, and pain or bleeding with sexual activity.4,5 VVA, a component of the genitourinary syndrome of menopause (GSM),6 can be progressive and may not resolve without treatment.7

Breast cancer is the most common cancer in US women with an estimated 250,000 women diagnosed in 2017.8 Most diagnoses of breast cancer are in postmenopausal women, with a median age of 62 years at diagnosis,8 and are hormone receptor-positive breast tumors.9 More than 60% of postmenopausal breast cancer patients report symptoms of VVA, notably vaginal dryness and dyspareunia.10,11 These VVA symptoms are often the most poorly addressed side-effects of women on adjuvant endocrine therapy (e.g. Aromatase inhibitors).7 Aromatase inhibitors, a standard treatment for many postmenopausal breast cancer patients, reduce breast cancer recurrence by inducing a profound estrogen-deficiency state prevented by the conversion of androgens to estrogens.7 Such a low estrogen state can lead to VVA due to a lack of estrogen in the vaginal tissues.7,12,13

Vulvar and vaginal atrophy symptoms can be managed successfully with over-the-counter (OTC) products or US Food and Drug Administration (FDA)-approved prescription therapies, such as local estrogen therapy (ET).7 In women with a history of estrogen-dependent breast cancer who are experiencing significant VVA, the American College of Obstetricians and Gynecologists (ACOG), The North American Menopause Society (NAMS), and the International Menopause Society (IMS) recommend the short-term use of vaginal low-dose ET in those who are unresponsive to lubricants and moisturizers, a recommendation which should be made in coordination with their oncologist.7,14,15

In the past decade, many international, large-scale surveys have been aimed towards understanding the attitudes of menopausal women regarding hormone therapy (HT) use,5,16-20 whereas few physicians have been surveyed.21-25 The aim of the WISDOM survey was to evaluate and compare physicians’ behaviors and attitudes regarding VVA treatment in menopausal women, with a focus on women with an elevated risk or personal history of breast cancer.

METHODS

Survey conduct and design

Rose Research, a market research firm, conducted an Internet survey assessing physicians’ behaviors and attitudes towards VVA treatment. TherapeuticsMD, a pharmaceutical company focused on research and development of products exclusively for women's health, commissioned the survey. The project was managed entirely by Rose Research, which included questionnaire design, data tabulations, and analysis; Global Market Insite (GMI) was contracted to obtain a nationally representative sample of US physicians. GMI is an institutional review board-approved panel source, is a member of ESOMAR (the World Association for Opinion and Marketing Research), and complies with the International Chamber of Commerce/ESOMAR International Code on Market and Social Research. GMI's Global Panels are recruited and managed expressly for the purpose of conducting marketing research.

The WISDOM survey contained 23 multipart questions (17 are reported here) on the number and types of patients seen in a month, treatments used for VVA, types of prescriptions recommended, reasons why products were prescribed, barriers to prescription therapy, reasons for prescription therapy discontinuation, beliefs about local ET use, and use of vaginal estrogen in women with a predisposition or history of breast cancer (Table 1). This survey focused on prescription therapies that have a primary indication for VVA treatment, such as local ET (creams, tablets, rings), dehydroepiandrosterone (DHEA), oral ospemifene; it does not include oral HT or ET. Panel members received $23 in cash for completing the survey. Only completed surveys were included in the analysis. Responses were entered into an SPSS software package (SPSS, Inc, Chicago, IL) data file and summarized using crosstabs. Results were summarized, and responses between the two physician groups were compared and presented descriptively.

TABLE 1
TABLE 1:
Questions included in the WISDOM survey

Inclusion and exclusion criteria

The survey was conducted between August and September, 2016. Eligible survey participants included obstetricians and gynecologists (OB/GYNs), who saw at least 50 menopausal women per month, and primary care physicians (PCPs), who saw at least 25 menopausal women per month. PCPs were defined as physicians working in internal medicine, family practice, or general practice. Exclusion criteria were physicians who cited conflicts of interest, did not work in a US community-based practice, and managed or treated less than 15 patients with VVA per month.

RESULTS

Demographics

At least 2,424 physicians were invited to participate in the survey and 945 responded; 369 OB/GYNs and 275 PCPs completed the survey (27% completion rate). The majority of respondents were male (61% for OB/GYNs and 68% for PCPs), between 40 and 59 years of age (64%), and had been practicing for more than 15 years (66%; Table 2). On average, OB/GYNs and PCPs saw 111 and 99 menopausal women (mean age not known) per month, respectively; of these women, 61 (55%) and 44 (44%) were reported to have had VVA symptoms, and 64 (58%) and 51 (52%) were reported to have VMS symptoms, respectively.

TABLE 2
TABLE 2:
Demographic characteristics of WISDOM survey respondents

Attitudes toward VVA treatments

The most common VVA treatment recommended by physicians was prescription therapy (alone or in conjunction with other therapies), followed by OTC products alone, no treatment, behavioral/lifestyle management alone, and vaginal laser therapy alone (Fig. 1A). Overall, more OB/GYNs preferred to treat VVA with prescription therapy compared with PCPs (53% vs 43%) and wrote more prescriptions per month (44 vs 35 per month). Compared with PCPs, OB/GYNs prescribed more estradiol cream (Estrace vaginal cream; Allergan Pharmaceutical International Limited, Madison, NJ), 17β-estradiol vaginal tablets (Vagifem; Novo Nordisk Health Care AG, Plainsboro, NJ), oral ospemifene (Osphena, Duchesnay USA, Rosemont, PA), and estradiol ring (Estring, Pfizer, New York, NY), whereas PCPs prescribed more conjugated equine estrogen cream (Premarin vaginal cream, Pfizer, New York, NY) and compounded therapies (Fig. 1B).

FIG. 1
FIG. 1:
(A) Treatment recommended by physicians to patients with VVA; (B) VVA treatments prescribed by physicians. With or without any other type of treatment; vaginal lubricants and moisturizers; increased sex, vaginal dilation, other; §intrarosa was not approved at the time of the survey. DHEA, dehydroepiandrosterone; OB/GYNs, obstetricians and gynecologists; OTC, over the counter; PCPs, primary care physicians; VVA, vulvovaginal atrophy.

Reasons why physicians prescribed VVA treatments (vaginal ET, DHEA, ospemifene; not OTC products) were similar between OB/GYNs and PCPs, with the most common being effectiveness (77% and 76%, respectively), followed by patient out-of-pocket cost (33% and 34%), patient preference (28% and 30%), and ease of product use (29% and 28%). More OB/GYNs prescribed VVA treatments because of free sample availability for distribution and sales support from pharmaceutical companies than PCPs (18% vs 9%), whereas more PCPs prescribed them because of their personal preference (24% vs 15%). Out-of-pocket cost and fear of estrogen's risks were believed to be the main barriers for women choosing not to use prescription therapy, although these were followed closely by symptoms were not severe enough for treatment, and dissatisfaction with current therapies (Fig. 2A). OB/GYNs and PCPs also believed that the main reasons why women discontinue treatment were because of cost, symptom improvement, and concerns about long-term estrogen exposure (Fig. 2B).

FIG. 2
FIG. 2:
Physicians’ perspectives on (A) barriers to prescription therapy; (B) reasons for discontinuing prescription therapy. Options were ranked 1 (primary reason) through 5 (least important reason). Options shown are those ranked 1 or 2 by each physician. Symptoms are not severe enough and patients prefer to deal with symptoms without prescription therapy; applicators, discharge from products, dosing issues, and so on. OB/GYNs, obstetricians and gynecologists; PCPs, primary care physicians.

Opinions of OB/GYNs and PCPs on statements about VVA treatments are in Table 3. Approximately 40% of OB/GYNs and PCPs agreed or strongly agreed with the statement that their ability to treat VVA was limited by the currently available choices and that VVA only required treatment if the symptoms negatively impacted a patient's quality of life. More OB/GYNs (72%) than PCPs (47%) disagreed or strongly disagreed that VVA was best treated with OTC products than prescription products; however, only 10% of OB/GYNs and 27% of PCPs agreed with the statement. Most OB/GYNs and PCPs agreed that they were comfortable prescribing local ET for menopausal women and that local ET were preferred over other types of therapies for VVA (Table 3). Overall, 84% of both OB/GYNs and PCPs queried considered it important to use the lowest effective dose of HT when treating women experiencing VVA symptoms; only 2% thought it was not important.

TABLE 3
TABLE 3:
Opinions of OB/GYNs and PCPs on statements about VVA treatments

Prescribing VVA therapies and breast cancer

Almost all OB/GYNs (95%) and most PCPs (80%) agreed they felt comfortable prescribing existing VVA therapies (vaginal ET, DHEA, ospemifene) to women with no personal history or predisposition (family history or BRCA mutations); only 1% of OB/GYNs and 5% of PCPs were not comfortable or less comfortable doing so (Fig. 3A). In contrast, when asked about prescribing VVA therapies to women with a predisposition to breast cancer (family history, BRCA mutations, etc), 49% of OB/GYNs and 23% of PCPs felt comfortable doing so, whereas 23% of OB/GYNs and 44% of PCPs were not comfortable or less comfortable (Fig. 3B). Similarly, in women with a personal history of breast cancer, the percentages dropped to 34% for OB/GYNs and 17% for PCPs; 39% of OB/GYNs and the majority of PCPs (61%) felt less comfortable or not comfortable doing so (Fig. 3C).

FIG. 3
FIG. 3:
How comfortable are OB/GYNs and PCPs prescribing VVA therapy to women with (A) no personal history or predisposition to breast cancer; (B) a predisposition to breast cancer, such as family history or a BRCA mutation; or (C) a personal history of breast cancer. VVA therapies included vaginal estrogen therapy, Osphena, Estring, DHEA, or other existing VVA products. DHEA, dehydroepiandrosterone; OB/GYNs, obstetricians and gynecologists; PCPs, primary care physicians; VVA, vulvovaginal atrophy.

DISCUSSION

Overall, both OB/GYNs and PCPs had generally similar attitudes and behaviors regarding VVA treatment for menopausal women; but more OB/GYNs than PCPs prescribed VVA treatment, especially vaginal estrogens. Most physicians were comfortable prescribing vaginal ET for VVA and prefer it over other products. However, this comfort level lowered for prescribing VVA therapies for menopausal women with an elevated risk or personal history of breast cancer. As recommended by most medical societies, most physicians thought it was important to prescribe the lowest effective dose possible of US FDA-approved vaginal estrogens.

Physicians reported that patients had concerns over the safety of ET as a reason for not starting therapy, and also discontinuing treatment, which was consistent with other published studies. In the Women's EMPOWER survey, 43% of women did not use hormonal products for VVA symptoms (such as vaginal ET) because of concern over risk of side effects, and 30% of women had concern over hormone safety in women with cancer or history of familial cancer.18 In this same survey, women also stopped taking prescribed VVA products because they became concerned about the risks (31%) and side effects (17%).18 Other reasons for discontinuing prescribed VVA therapies cited by the Women's EMPOWER18 and REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs-Europe26 surveys included symptoms stopped or were not bothersome enough to warrant an intervention, medication was not deemed to be efficacious, and the cost of the medication being too high. While the cost of treatment was cited in this survey as one of the most important barriers to treatment, in the Women's EMPOWER survey, only 12% of women did not use prescribed VVA therapies because of high costs.18 However, in REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs-USA, 32% of women currently using vaginal ET had concerns about costs.16

While OB/GYNs and PCPs felt comfortable prescribing VVA therapies to women with no personal history of breast cancer, they felt less comfortable doing so in women with either an elevated risk or a personal history of breast cancer. These results are similar to the ones obtained from Italian oncologists surveyed in 2015, which revealed that only 24% prescribed vaginal ET for patients with nonhormone-dependent breast cancer, and only 7.5% prescribed it to patients with hormone-dependent breast cancer.23 Not surprisingly, a major concern of prescribing vaginal estrogens in breast cancer survivors is the potential risk of systemic exposure with potential for absorption and possible adverse breast effects.7,23

Multiple medical organizations have published clinical guidelines recommending that nonhormonal vaginal moisturizers and lubricants should be used as first-line treatment for breast cancer survivors.7,14,27 While systemic HT and tibolone are contraindicated in women with a history of breast cancer due to an increase in breast cancer recurrence,28-30 medical societies, such as ACOG, NAMS, and IMS, support the short-term use of vaginal estrogens in women with a history of estrogen-dependent breast cancer who are unresponsive to nonhormonal therapies for the treatment of moderate-to-severe VVA.7,14,27 In addition, such decisions should be made in consultation with their oncologist.7,14,27 Although use of local or systemic menopausal ET for the treatment of VVA is currently contraindicated as per their prescribing information for women with known, suspected, or a history of breast cancer, these medical societies offer these recommendations because of the evidence suggesting the lack of or low systemic absorption of low-dose vaginal estrogens.31-38 Furthermore, data do not show an increased risk of cancer recurrence in women with a history of breast cancer who use minimally absorbed local vaginal estrogen products for VVA symptoms.27,39,40 A retrospective study of data from the US Cancer Surveillance System found that women with breast cancer had no increase in breast cancer recurrence with vaginal ET versus never use (relative risk 0.46, 95% confidence interval [CI] 0.21-1.01).39 Similar results were observed in an analysis of the UK General Practice Research Database of women with breast cancer (n = 13,479), which found no increase in breast cancer recurrence with vaginal ET compared with non-users (relative risk 0.78, 95% CI 0.48-1.25).40

The use of low-dose vaginal ET for the treatment of moderate-to-severe VVA in women with a history of breast cancer may be considered based on several studies showing users with improved vaginal symptoms having very low to no systemic absorption of estradiol.41-46 Systemic absorption can also be minimized with different estradiol formulations and if products are applied to the lower part of the vagina as compared with the upper part.43,47,48

Online surveys generally have several limitations, including self-reporting biases.49,50 One limitation of this survey was that respondents were not randomly selected, but were chosen from a pool of physicians. While this pool was meant to be a nationally representative sample of physicians, physicians who like to complete market research surveys may be different from those who do not, and therefore results may not be applicable to the general physician population. The percentage of physicians who completed the survey could also be a limitation; while the number of completed surveys was not very high (27%), it was also not particularly low when compared with the completion rates other surveys (10%–41%) in the published medical literature.18,21,22,24 In addition, the demographics of the respondents were fairly similar to the data of the 2016 Physician Specialty Data Report, which reported that males account for 46% of OB/GYNs and 62% of family medicine/general practice physicians in the United States, with the majority (56% and 58%, respectively) being under the age of 55.51 Physicians who completed the survey also received an incentive, which could have affected how they answered the questions. Another limitation of this survey is that one of the questions inadvertently did not have an answer that covered a popular option of prescription therapy use. Specifically, when surveying the physicians’ attitudes regarding VVA treatments, “VVA is best treated with OTC products first, then prescription products,” a recommended treatment option from medical societies, was not included as an answer. This survey had several strengths, including the fact that the GMI panel is compliant with research industry standards and uses various methods to remove any fraudulent survey answers. Overall, this survey provides a current perspective on physicians’ behaviors and attitudes regarding VVA treatment in menopausal women.

CONCLUSIONS

More OB/GYNs than PCPs prescribed VVA treatment, especially vaginal estrogens, for menopausal women, but overall, both types of physicians had generally similar attitudes and behaviors regarding VVA treatment. Most physicians preferred prescribing US FDA-approved vaginal ET at the lowest effective dose possible and were comfortable prescribing it. However, fewer were comfortable prescribing vaginal ET to women with an elevated risk or personal history of breast cancer, despite medical societies supporting its use in consultation with an oncologist when nonhormonal therapies fail to improve symptoms. Vaginal products that have negligible absorption of estradiol may be viable choices for these women, suggesting the need for more studies in this population.

Acknowledgments

The authors would also like to acknowledge the medical writing assistance of Dominique Verlaan, PhD of Precise Publications, LLC, which was supported by TherapeuticsMD.

REFERENCES

1. US Census Bureau. Age and sex composition: 2010 Census Briefs; 2011. Available at: http://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf. Accessed April 14, 2015.
2. Whiteley J, DiBonaventura M, Wagner JS, Alvir J, Shah S. The impact of menopausal symptoms on quality of life, productivity, and economic outcomes. JWomens Health (Larchmt) 2013; 22:983–990.
3. Simon JA, Nappi RE, Kingsberg SA, Maamari R, Brown V. Clarifying Vaginal Atrophy's Impact on Sex and Relationships (CLOSER) survey: emotional and physical impact of vaginal discomfort on North American postmenopausal women and their partners. Menopause 2014; 21:137–142.
4. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med 2009; 6:2133–2142.
5. Simon JA, Kokot-Kierepa M, Goldstein J, Nappi RE. Vaginal health in the United States: results from the Vaginal Health: Insights, Views & Attitudes survey. Menopause 2013; 20:1043–1048.
6. Portman DJ, Gass ML. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause 2014; 21:1063–1068.
7. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013; 20:888–902.
8. National Cancer Institute. SEER Cancer Statistics Review 1975-2014; Cancer of the Female Breast. Available at: https://seer.cancer.gov/csr/1975_2014/results_merged/sect_04_breast.pdf. Accessed July 20, 2017.
9. Anderson WF, Katki HA, Rosenberg PS. Incidence of breast cancer in the United States: current and future trends. J Natl Cancer Inst 2011; 103:1397–1402.
10. Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc 2010; 85:87–94.
11. Crandall C, Petersen L, Ganz PA, Greendale GA. Association of breast cancer and its therapy with menopause-related symptoms. Menopause 2004; 11:519–530.
12. Cella D, Fallowfield L, Barker P, et al. Quality of life of postmenopausal women in the ATAC (“Arimidex”, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for early breast cancer. Breast Cancer Res Treat 2006; 100:273–284.
13. Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005; 23:6931–6940.
14. de Villiers TJ, Hall JE, Pinkerton JV, et al. Revised global consensus statement on menopausal hormone therapy. Climacteric 2016; 19:313–315.
15. Management of menopausal symptoms. Practice Bulletin No. 141. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014; 123:202–216.
16. Kingsberg SA, Wysocki S, Magnus L, Krychman ML. 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.
17. Krychman M, Graham S, Bernick B, Mirkin S, Kingsberg SA. The Women's EMPOWER survey: women's knowledge and awareness of treatment options for vulvar and vaginal atrophy remains inadequate. J Sex Med 2017; 14:425–433.
18. Kingsberg S, Krychman M, Graham S, Bernick B, Mirkin S. The Women's EMPOWER Survey: identifying women's perceptions on vulvar and vaginal atrophy (VVA) and its treatment. J Sex Med 2017; 14:413–424.
19. Nappi RE, Kingsberg S, Maamari R, Simon J. The CLOSER (CLarifying Vaginal Atrophy's Impact On SEx and Relationships) survey: implications of vaginal discomfort in postmenopausal women and in male partners. J Sex Med 2013; 10:2232–2241.
20. Parish SJ, Nappi RE, Krychman ML, et al. Impact of vulvovaginal health on postmenopausal women: a review of surveys on symptoms of vulvovaginal atrophy. Int J Womens Health 2013; 5:437–447.
21. Power ML, Schulkin J, Rossouw JE. Evolving practice patterns and attitudes toward hormone therapy of obstetrician-gynecologists. Menopause 2007; 14:20–28.
22. Constantine GD, Archer DF, Graham S, Bernick BA, Mirkin S. Prescribing of FDA-approved and compounded hormone therapy differs by specialty. Menopause 2016; 23:1075–1082.
23. Biglia N, Bounous VE, D’Alonzo M, et al. Vaginal atrophy in breast cancer survivors: Attitude and approaches among oncologists. Clin Breast Cancer 2017; 17:611–617.
24. Devi G, Sugiguchi F, Pedersen AT, Abrassart D, Glodowski M, Nachtigall L. Current attitudes on self-use and prescription of hormone therapy among New York City gynaecologists. Menopause Int 2013; 19:121–126.
25. Rolnick SJ, Jackson J, Kopher R, Defor TA. Provider management of menopause after the findings of the Women's Health Initiative. Menopause 2007; 14:441–449.
26. Nappi RE, Palacios S, Panay N, Particco M, Krychman ML. Vulvar and vaginal atrophy in four European countries: evidence from the European REVIVE Survey. Climacteric 2016; 19:188–197.
27. American College of Obstetricians and Gynecologists. The use of vaginal estrogen in women with a history of estrogen-dependent breast cancer. Committee Opinion No. 659. Obstet Gynecol 2016; 127:e93–e96.
28. Holmberg L, Iversen OE, Rudenstam CM, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008; 100:475–482.
29. von Schoultz E, Rutqvist LE. Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst 2005; 97:533–535.
30. Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol 2009; 10:135–146.
31. Wills S, Ravipati A, Venuturumilli P, et al. 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.
32. Donders G, Neven P, Moegele M, et al. Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor((R))) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety, and efficacy phase I clinical study. Breast Cancer Res Treat 2014; 145:371–379.
33. Dew JE, Wren BG, Eden JA. A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Climacteric 2003; 6:45–52.
34. Kendall A, Dowsett M, Folkerd E, Smith I. Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 2006; 17:584–587.
35. Biglia N, Peano E, Sgandurra P, et al. Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. Gynecol Endocrinol 2010; 26:404–412.
36. Pfeiler G, Glatz C, Konigsberg R, et al. Vaginal estriol to overcome side-effects of aromatase inhibitors in breast cancer patients. Climacteric 2011; 14:339–344.
37. Manson JE, Goldstein SR, Kagan R, et al. Why the product labeling for low-dose vaginal estrogen should be changed. Menopause 2014; 21:911–916.
38. Ponzone R, Biglia N, Jacomuzzi ME, Maggiorotto F, Mariani L, Sismondi P. Vaginal oestrogen therapy after breast cancer: is it safe? Eur J Cancer 2005; 41:2673–2681.
39. O’Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst 2001; 93:754–762.
40. 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 ResTreat 2012; 135:603–609.
41. Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol 2008; 111:67–76.
42. Dorr MB, Nelson AL, Mayer PR, et al. Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis. Fertil Steril 2010; 94:2365–2368.
43. Pickar JH, Amadio JM, Bernick BA, Mirkin S. Pharmacokinetic studies of solubilized estradiol given vaginally in a novel softgel capsule. Climacteric 2016; 19:181–187.
44. Archer DF, Constantine GD, Simon J, et al. TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol. Menopause 2017; 24:510–516.
45. Santen RJ, Pinkerton JV, Conaway M, et al. Treatment of urogenital atrophy with low-dose estradiol: preliminary results. Menopause 2002; 9:179–187.
46. Eugster-Hausmann M, Waitzinger J, Lehnick D. Minimized estradiol absorption with ultra-low-dose 10 microg 17beta-estradiol vaginal tablets. Climacteric 2010; 13:219–227.
47. Cicinelli E, De Ziegler D, Morgese S, Bulletti C, Luisi D, Schonauer LM. First uterine pass effect” is observed when estradiol is placed in the upper but not lower third of the vagina. Fertil Steril 2004; 81:1414–1416.
48. Cicinelli E, Di NE, De ZD, et al. Placement of the vaginal 17beta-estradiol tablets in the inner or outer one third of the vagina affects the preferential delivery of 17beta-estradiol toward the uterus or periurethral areas, thereby modifying efficacy and endometrial safety. Am J Obstet Gynecol 2003; 189:55–58.
49. Choi B, Pak A. A catalog of biases in questionnaires. Prevent Chronic Dis 2005; 2:1–13.
50. Adams AS, Soumerai SB, Lomas J, Ross-Degnan D. Evidence of self-report bias in assessing adherence to guidelines. Int J Qual Health Care 1999; 11:187–192.
51. Association of American Medical Colleges. 2016 Physician Specialty Data Report. Available at: https://www.aamc.org/data/workforce/reports/457712/2016-specialty-databook.html. Accessed June 29, 2018.
Keywords:

Attitudes; Menopause; Survey; Vaginal estrogen therapy; Vulvar and vaginal atrophy (VVA)

Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.