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WYETH_Vaginal_CE_ENG 1/19/05 11:20 AM Page CE 1 A CONTINUING EDUCATION LESSON • 1.5 CEUs Approved for 1.5 CE Units Approved for 1.5 CE units by the Canadian Council on Continuing Education in Pharmacy. File # 189-1104 Objectives: Upon successful completion of this lesson, you should be able to: 1. Identify the signs and symptoms of vaginal atrophy. 2. Discuss the nonpharmacologic and pharmacologic options for the treatment of vaginal atrophy. 3. Review the benefits and risks with each of the options for the treatment of vaginal atrophy. 4. Understand the pharmacist’s role in the management of vaginal atrophy. Author: Nese Yuksel is a clinical pharmacist with the Mature Women’s Clinic and the Osteoporosis Clinic at the Grey Nuns Hospital in Edmonton. She is also an associate professor at the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta. Nese has presented numerous times on the topics of menopause, hormone replacement therapy, and symptom management in perimenopause and menopause. Instructions: 1. After carefully reading this lesson, study each question and select the one answer you believe to be correct. Circle the appropriate letter on the attached reply card. 2. Complete the card and mail, or fax to (416) 764-3937. 3. Your reply card will be marked and you will be advised of your results in a letter from Rogers Publishing. 4. To pass this lesson, a grade of 70% (14 out of 20) is required. If you pass, your CEU(s) will be recorded with the relevant provincial authority(ies). (Note: some provinces require individual pharmacists to notify them.) The Management of Vaginal Atrophy: A Primer for Pharmacists By Nese Yuksel, BScPharm, Pharm D The author, expert reviewers and Pharmacy Practice magazine have each declared that there is no real or perceived conflict of interest with the sponsor company. Introduction Vaginal atrophy is a common condition that affects up to 50% of postmenopausal women.1 Vaginal atrophy is defined as a deterioration in urogenital tissue from both vaginal tissue aging and lack of estrogen.1,2 Other terms for vaginal atrophy include atrophic vaginitis and urogenital atrophy. The most common cause of vaginal atrophy is a decline in estrogen levels with menopause. Other causes include oopherectomy, postpartum loss of placental estrogen, breast-feeding, radiation, chemotherapy, and certain medications such as gonadotrophin-releasing (GnRH) agonist analogues (e.g. leuprolide, naferelin), danazol, tamoxifen, medroxyprogesterone, and anticholinergics.3 Since smoking can increase the metabolism of estrogens, smokers may see an earlier occurrence and more severe symptoms of vaginal atrophy.4 Many women do not feel comfortable discussing symptoms of vaginal atrophy with their physician or other health-care professionals. In fact, only 25% of women with symptoms will seek treatment.5 Pharmacists need to be aware of the consequences associated with vaginal atrophy as it can have a negative impact on urogenital health and a woman’s sex- uality. Symptoms of vaginal atrophy can be uncomfortable and irritating. In patients with severe symptoms such as dyspareunia, normal sexual health can be adversely affected. It can lead to a loss of sexual interest and a decrease in selfesteem, potentially affecting a woman’s relationship with her partner.6,7 All of these factors can impact quality of life.6 The Society of Obstetrics and Gynecology of Canada (SOGC) has recently developed Clinical Practice Guidelines for the Detection and Management of Vaginal Atrophy.1 These evidence-based guidelines were developed to support practitioners in the care of women with symptoms of vaginal atrophy. This lesson focuses on the treatment approaches for vaginal atrophy and highlights the new SOGC clinical practice guidelines. Pathophysiology Estrogen is the primary hormone responsible for maintaining vaginal health. Estrogen receptors exist throughout the vagina, bladder, urethra, and pelvis.1 Other hormone receptors include progesterone receptors in the vagina, and androgen receptors in the vagina and suprapubic tissue.3 A number of physiologic changes in the vagina are seen with Supported by an educational grant from This CE lesson is published by Rogers Media Healthcare/Sante, One Mount Pleasant Rd., Toronto, Ont., M4Y 2Y5. Tel.: (416) 764-3916 Fax: (416) 764-3931. No part of this CE lesson may be reproduced, in whole or in part, without the written permission of the publisher. February 2005 CE 1 WYETH_Vaginal_CE_ENG 1/19/05 11:20 AM declining estrogen levels. The vaginal epithelium becomes thinner, atrophies and loses its rugal folds. Further changes include fragmentation of elastic fibers and degeneration of connective tissue, resulting in vagina narrowing and loss of elasticity. Blood flow to the vagina is reduced and normal vaginal secretion decrease. All of these changes contribute to vaginal dryness, loss of normal lubrication, and dyspareunia. The decline in estrogen concentrations also impacts urinary function. Normal vaginal pH is kept acidic (pH of 3.5 to 4.5) from the conversion of glycogen (from shed epithelial cells) to lactic acid by vaginal lactobacilli.5 The cellular thinning of the vaginal epithelium with declining estrogen levels reduces the amount of glycogen available, diminishing lactobacilli growth and increasing vaginal pH. Normal vaginal flora is altered leading to an increased susceptibility to vaginal and urinary tract infections. Further urogenital changes, such as thinning urethral lining, weakening bladder muscles, and atrophy of the mucosal layer of the bladder, predisposes a woman to urinary urgency, frequency and incontinence.5,8 Symptoms A decrease in vaginal lubrication is one of the earliest changes seen with vaginal atrophy. As vaginal atrophy progresses, symptoms include vaginal dryness, burning, itching, pressure, malodorous discharge and loss of vaginal secretions. Not all women will experience symptoms and the intensity of the symptoms can vary between individuals. The prevalence of vaginal dryness has been reported to range up to 55% of postmenopausal women.7,9 It has also been estimated that close to 40% of women who are taking oral hormone replacement therapy may continue to have vaginal dryness.1,10 Normal sexual function can be significantly affected during this time. Inadequate vaginal lubrication during sexual intercourse can cause dyspareunia, which has been reported in up to 41% of post-menopausal women.7 In some patients, vaginal atrophy can be severe enough to cause post-coital bleeding and CE 2 Page CE 2 vaginismus (painful spasm of vaginal muscles).1 A woman may experience anxiety with the expectation of pain on intercourse, and begin to avoid sexual intercourse. In addition, both a decrease in estrogen and androgen levels can lead to difficulties in sexual arousal and a lowered libido.11 Sexual dysfunction is multifactorial. However, all of these factors can play a part in interfering with a woman’s relationships with her partner.6,11 Common urinary symptoms associated with vaginal atrophy include urinary urgency, frequency, stress incontinence and recurrent urinary tract infections. Management Options The options for the management of vaginal atrophy are dependent on the needs of the specific patient. Therapy should be convenient and simple to use.12 LIFESTYLE MODIFICATIONS It is important to identify all reversible causes of vaginal atrophy. Obtaining a good history of when symptoms started in relation to precipitating factors may help in recognizing potential causes. Wherever possible, drugs that may have contributed should be discontinued, and exposure to any sensitizing chemicals (e.g. douches, perfumed products, etc) avoided. Since smoking increases the metabolism of estrogen and may worsen vaginal atrophy, women should be encouraged to stop smoking.1 Regular sexual activity can help maintain vaginal health in postmenopausal women. Sexual activity stimulates blood flow to the vagina. This increases vaginal secretions and maintains vaginal elasticity. Masturbation also has similar benefits.13 Cranberry juice has been traditionally used to prevent urinary tract infections, however, a recent Cochrane Review found no concluding evidence that cranberry juice decreases the risk of urinary tract infections.14 Instead, the SOGC Clinical Practice Guidelines recommend the use of the combination of cranberry-lingonberry juice in women who experience recurrent urinary tract infections (See Table 1).1 This recommendation is based on an open label, randomized controlled trial, which found the daily use of a cranberrylingonberry concentrate for six months reduced the risk of urinary tract infections by 20% as compared to placebo.15 NON-HORMONAL OPTIONS Non-hormonal options for vaginal atrophy include vaginal moisturizers and lubricants. Often considered as alternatives to hormone replacement therapy (HT), both moisturizers and lubricants can be used in conjunction with HT as well. Replens™, a vaginal moisturizer, is a bioadhesive, polycarbophil-based polymer that attaches to mucin and epithelial cells in the vaginal wall. The polymer attracts water, maintains it close to the epithelial surface of the vagina and produces a moist film over the vaginal wall.16 Regular use of the polymer can help with symptoms of vaginal atrophy such as vaginal dryness and dyspareunia. The use of Replens™ three times weekly was found to have equivalent efficacy to conjugated estrogen (CE) vaginal cream 1.25 mg/day in improving symptoms of vaginal atrophy and decreasing vaginal pH.17 Replens™ is applied intravaginally with a disposable, prefilled applicator. Replens™ should be used every three days, and does not need to be repeated prior to intercourse. In comparison, vaginal lubricants (i.e. Astroglide™, KY Jelly™) have a short duration of action and should be applied right before sexual intercourse. Most of these agents come in a watersoluble base and are made of a combination of protectants and thickening agents.3 These agents help with the irritation that occurs with intercourse.1 A variety of herbal therapies have been suggested in the lay press to help with vaginal dryness and dyspareunia. These include phytoestrogens, black cohosh, chaste tree, dong quai and wild yam creams. There is no evidence to support chaste tree or wild yam creams. Studies with dong quai as monotherapy have shown no benefit.18 Studies with black cohosh and phytoestrogens are inconclusive.3 HORMONE THERAPY EFFICACY Vaginal Atrophy In women who have no contraindications to HT, estrogen is the mainstay of February 2005 WYETH_Vaginal_CE_ENG 1/19/05 11:20 AM Page CE 3 TABLE 1: Recommendations from the SOGC Clinical Practice Guidelines for the Management of Vaginal Atrophy.1 Lifestyle Modifications 1. Regular sexual activity should be encouraged to maintain vaginal health (II-2B) 2. Women experiencing recurrent urinary tract infections should be instructed that consumption of pure cranberry-lingonberry juice, rather than cranberry juice, will decrease their risk of urinary tract infections. (I-A)* Vaginal Moisturizers 1. Vaginal moisturizers applied on a regular basis have an efficacy equivalent to local hormone replacement for the treatment of local, urogenital symptoms such as vaginal itching, irritation and dyspareunia, and should be offered to women wishing to avoid use of hormone replacement therapy. (I-A) Hormone Therapy 1. Women experiencing vaginal atrophy can be offered any of the following effective vaginal estrogen replacement therapy: conjugated estrogen (I-A), a sustained-release intravaginal estradiol ring (I-A), or a low-dose estradiol tablet. (I-A) 2. Although systemic absorption of estrogen can occur with local preparations, there is insufficient data to recommend annual endometrial surveillance in asymptomatic women using local estrogens. (III-C) Treatment of Urinary Tract Infections 1. For menopausal women experiencing recurrent urinary tract infections and who have no contraindications to local hormone replacement, vaginal estrogen therapy should be offered. (I-A) The information provided in the brackets refers to the quality of the evidence rated using the criteria described by the Canadian Task Force on the Periodic Health Examination (Table 1A) TABLE 1A: Evaluation of Evidence Criteria and Classification of Recommendations Used in the SOGC Clinical Practice Guidelines1 Level of Evidence Classification of Recommendation I A There is good evidence to support the recommendation that the condition be specifically considered in a periodic health examination. II-1 Evidence from well-designed controlled trials without randomization. B There is fair evidence to support the recommendation that the condition be specifically considered in a periodic health examination. II-2 Evidence obtained from welldesigned cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group. C There is poor evidence regarding the inclusion or exclusion of the condition in a periodic health examination, but recommendations may be made on other grounds. II-3 Evidence obtained from comparison between times or places with or without intervention. Dramatic results in uncontrolled experiments can also be included in this category. D There is fair evidence to support the recommendation that the condition not be considered in a periodic health examination. III E There is good evidence to support the recommendation that the condition be excluded from consideration in a periodic health examination. Evidence obtained from at least one properly randomized clinical trial. Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. February 2005 therapy for vaginal atrophy. Estrogens have been shown to have an overall beneficial effect on urogenital health. Estrogens enhance blood flow to the vagina, boost vaginal mucosal maturation, thicken vaginal mucus, and increase secretions.3,11,19 A number of routes of administration are available for HT including oral, transdermal and intravaginal. All routes of administration have been found to be effective for the treatment of vaginal atrophy.20 A recent systematic review of 16 trials involving intravaginal estrogens concluded that vaginal conjugated estrogen (CE) cream, vaginal estradiol tablets and estradiol vaginal ring were equally effective.21 Urinary Tract Infections Estrogens restore normal vaginal acidic pH. This helps increase the proportion of lactobacilli, and potentially reduce the risk of urinary tract infections (UTIs). Intravaginal estrogen has been shown to decrease the rate of recurrent urinary tract infections.22-24 Trials with the estradiol ring,22 intravaginal estradiol tablet,23 and estriol cream24 have all demonstrated a lower incidence of urinary tract infections as compared to placebo. Information on the efficacy of systemic estrogens on the incidence of urinary tract infections is lacking.25 In the Heart and Estrogen/Progestin Replacement Study (HERS), the combination of oral estrogen and progestin (0.625 mg CE and 2.5 mg medroxyprogesterone) did not reduce the risk of UTI.26 Urinary Incontinence The role of estrogens for urinary incontinence is controversial. A meta-analysis of estrogens used in urinary incontinence showed a subjective but not objective benefit in patients with stress incontinence.27 However, since this publication, randomized controlled trials with oral estrogens for the treatment of stress incontinence have showed no improvement of estrogen replacement therapy over placebo.28 The information on estrogens and urge incontinence is also difficult to interpret. A recent Cochrane Review suggested that estrogen therapy may improve urge incontinence, however, it is difficult to make a conclusion CE 3 WYETH_Vaginal_CE_ENG 1/19/05 11:20 AM because of the small sample sizes in the trials and the inconsistency in estrogen products, dosages and durations.29 Several recent studies have also suggested that oral and transdermal estrogens, with or without progestin, may increase development of urinary incontinence.29-31 The role of HT in the treatment of urinary incontinence remains unclear. PRODUCT CHOICES Systemic Estrogens Since the publication of the Women’s Health Initiative (WHI), there has been a great deal of controversy regarding the risks and benefits of oral hormone therapy.32 The estrogen and progestin arm of the WHI was stopped early in July 2002 because the increased risks of non-fatal MIs, venous thromboembolism, stroke and breast cancer with combined CE 0.625 mg and medroxyprogesterone 2.5 mg daily, outweighed the potential benefits of reducing the risk of fractures and colorectal cancer.33 The WHI was designed to assess the prevention of chronic diseases (primarily of coronary heart disease) with HT. More recently, the estrogen-alone portion of the WHI was halted in March 2004 after close to 7 years were completed of the planned 8year follow-up.34 The study was stopped early because the investigators felt there was sufficient data to assess the risks and benefits of estrogen, and that the study results would not be altered with one more year of data. Estrogen-alone therapy had no effect on coronary heart disease (nonfatal MIs or CHD death), which was the primary outcome. The risk of breast cancer was reduced by 23% in the estrogen-alone arm, however this was not statistically significant. There was an increased risk of stoke by 39% (absolute increased risk of 12 strokes per 10,000 women-years), and increased risk of deep vein thrombosis (DVT) by 33% (absolute increased risk of 7 DVT per 10,000 women-years). A decreased risk of hip fractures by 39% (absolute decreased risk of 6 hip fractures per 10,000 women-years) and vertebral fractures by 38% (absolute decreased risk of 6 vertebral fractures per 10,000 womenyears) were also statistically significant.35 There was no effect on the risk of colCE 4 Page CE 4 TABLE 2: Vaginal Estrogen Products Available in Canada Estrogen Preparation Strengths Administration Conjugated estrogen vaginal cream (Premarin Cream™) 0.625 mg per gram 0.5 gm (0.3 mg) daily for the first 14 days, and then 0.5 gm q 2 – 3 times weekly. 17 beta-estradiol vaginal tablet 25 µg (Vagifem™) 1 tablet daily for the first 14 days, and then 1 tablet twice weekly. 17 beta-estradiol vaginal ring (Estring™) 1 ring every 90 days 2 mg per ring orectal cancer. The results of both arms of the WHI has helped clarify that estrogen-alone therapy and the combination of estrogen and progestin together should not be used to prevent chronic diseases such as coronary heart disease. Recent position statements from the SOGC36 and the North American Menopause Society (NAMS)37 recommend HT for the treatment of moderate to severe menopause symptoms such as hot flushes, sleep disturbances and vaginal dryness. The position statement from NAMS recommends avoiding extrapolating the results from the WHI to women younger than aged 50 years, as these women were not studied in these trials. In addition, NAMS recommends extended use at the lowest effective dose for women for whom the benefits outweigh the risks and who continue to have symptoms after an attempt to withdraw the HT.37 Systemic estrogen therapy is an option in women who are experiencing symptoms of vaginal atrophy along with other menopausal symptoms such as hot flushes, night sweats, and sleep disturbances. A variety of systemic estrogen products are available in Canada including oral tablets, transdermal patches and transdermal gel. Women with an intact uterus on systemic estrogens should also be on progestin therapy to prevent endometrial hyperplasia. The lowest dose of systemic estrogens required to relieve symptoms of vaginal atrophy is not completely clear and likely should be individualized to each woman. In one study, an ultra-low-dose estrogen patch, 12.5 mg, was found to be more effective than placebo in improving vaginal dryness.38 Some women on systemic estrogens may require co-administration with an intravaginal estrogen product. Common side effects of systemic hormone replacement therapy include breast tenderness, fluid retention, nausea and vaginal bleeding. Absolute contraindications to systemic estrogen therapy include unexplained vaginal bleeding, acute liver disease, active thromboembolism, and known or suspected breast cancer.39 Vaginal Estrogen Products With vaginal products, estrogen can be given locally to the vaginal tissue at lower doses (See Table 2). The latest position statement from the North American Menopause Society recommends that in women who are considering HT solely for the symptoms of vaginal atrophy, that vaginal estrogens be considered.12,37 There may be systemic absorption of estrogens with vaginal products, however the circulating estrogen levels are very low and therefore, associated with insignificant systemic side effects. The absorption of estrogen across the vagina is higher at the start of treatment, however as the vaginal mucosa normalizes, less absorption is seen.40 Side effects with the vaginal estrogens are mild and include vaginal spotting and discharge, vaginal irritation and itching, and skin rash. It is believed that vaginal products are safe on the endometrial lining at the doses currently recommended.1,25 Conjugated estrogen vaginal cream Each gram of conjugated estrogen (CE) vaginal cream (Premarin Vaginal Cream™) contains 0.625 mg of conjugated estrogens. The efficacy of CE vaginal cream on improving vaginal atrophy symptoms is well documented.41-43 Estrogen may be absorbed into the sysFebruary 2005 WYETH_Vaginal_CE_ENG 1/19/05 11:20 AM temic circulation from the CE cream, but the systemic absorption is dosedependent and minimal at the current recommended doses (See Table 2).42,43 Dosages of the cream, as low as 0.3 mg conjugated estrogen, have been shown to be effective.43 Handa et al demonstrated that 0.3 mg CE intravaginally daily for 14 days, and then followed by 3 times weekly for 6 months, relieved symptoms of vaginal atrophy and improved vaginal cytology.43 There were no significant increases in estrogen concentrations from baseline and only one patient developed endometrial proliferation. Cases of endometrial hyperplasia have been reported with studies using higher doses of CE vaginal cream.44,45 Ten percent of patients on a 3-weeks-on and 1week-off cycle of 1.25 mg CE cream daily had mild endometrial hyperplasia after 12 weeks.44 Another study using similar high doses of CE cream resulted in 2 cases of endometrial hyperplasia and 7 cases of proliferative endometrium.45 A study using lower dosages of CE cream of 0.625 mg for 6 months found no cases of endometrial proliferation by ultrasound.46 There have been no reports of endometrial cancer with CE cream.1 The SOGC Clinical Practice Guidelines do not recommend the use of progestin therapy or performing annual endometrial ultrasound or biopsies for women using low doses of vaginal CE cream.1 The current recommended dose for maintenance therapy is 0.3 mg CE cream inserted intravaginally 2 to 3 times weekly. Women can start with an initial dose of 0.3 mg daily for the first 14 days, and then switch to the maintenance dose. CE cream is applied with a reusable plastic applicator. The easiest way to administer is to have the patients lie down with their knees bent, insert the applicator deep into the vagina, and then press the plunger of the applicator to deliver the cream. The applicator and plunger should be washed with warm, soapy water and then rinsed well with plain water. It is recommended to apply the cream at bedtime, to avoid possible leaking of the cream. A panty-liner may be suggested to avoid staining of underwear. For external irritation or dryness, a small amount of the CE cream can be February 2005 Page CE 5 applied to the outer skin folds of the vagina. Sustained-release vaginal estradiol ring The sustained-release vaginal estradiol ring (Estring™) is a flexible, silicone ring containing 2 mg 17beta-estradiol in the core. When placed in the vagina, the ring delivers 7.5 µg 17beta-estradiol a day for 12 weeks. The vaginal ring is inserted into the upper third of the vagina vault and has the advantage of providing a uniform and sustained release of estradiol directly to the vaginal tissue. In studies, the ring has resulted in low systemic estrogen levels that have been similar to the baseline mean of postmenopausal women.47 The estradiol vaginal ring has been shown to relieve symptoms of vaginal atrophy48 and decrease the occurrences of UTIs.22 In a study by Ayton et al, the estradiol ring had similar efficacy to CE cream 0.625 mg per day after 3 months of therapy.49 The most common side effects reported with the ring are vaginal discomfort, irritation or ulceration, and vaginal discharge. There have been no reports of endometrial hyperplasia in studies with the vaginal ring.47,48 The vaginal ring can be inserted and removed by most patients. Patients with limited hand mobility, smaller vaginal capacity or pelvic organ prolapse may have more difficulty.1 It is suggested to press the ring into an oval and insert as deep as possible into the upper one-third of the vaginal vault. To help with the insertion, the patient can squat, lie down with knees drawn up or stand on one leg with the other leg raised. The ring is worn continuously for 3 months, and does not need to be removed with intercourse. However, if the ring causes any discomfort for the woman or her partner, the ring can be removed prior to intercourse. If the ring is removed or falls out, it should be washed with lukewarm water and then reinserted. During treatment of a vaginal infection, the ring should be removed for the course of the treatment. Intravaginal estradiol tablets The most recent addition to the vaginal estrogen market in Canada is the vaginal estradiol tablet (Vagifem™). This sus- tained-release vaginal tablet, containing 25 µg 17beta-estradiol per tablet, forms a hydrophilic gel layer on the vagina, which allows estradiol to diffuse into the vaginal epithelium. The vaginal tablet has been shown to improve vaginal dryness and dyspareunia50,51 without significant systemic estrogen absorption50,51 or effects on the endometrial lining.45,50,51 The concentrations of estrogen that have been observed with the tablet are within the normal post-menopausal range.50,51 In an open label, randomized trial of 159 menopausal women, 25 µg 17beta-estradiol vaginal tablets twice weekly for 24 weeks, was equally effective to 1.25 mg of CE cream in relieving the symptoms of vaginal atrophy.45 Higher estradiol concentrations were observed in the patients using the CE cream compared to the vaginal tablet, and only one patient in the vaginal tablet group developed endometrial hyperplasia compared to 2 women using the CE cream. It is difficult to make any firm conclusions with this study as higher doses of the cream were used than what is currently recommended. The tablet is inserted intravaginally into the upper vagina using a single dose, disposable, prefilled applicator. One tablet daily is inserted for the first 14 days, followed by 1 tablet twice a week for maintenance. Pharmacists’ Role Pharmacists are in an ideal position to assess patients for symptoms of vaginal atrophy, and to educate patients on the options for vaginal atrophy and the benefits and risks with each option. By being aware of the many choices for delivery of estrogen therapy, and the alternatives available, a pharmacist can play an integral role in helping patients make indi- Resources for Pharmacists Society of Obstetricians and Gynecologists of Canada www.sogc.medical.org North American Menopause Society www.menopause.org American College of Obstetricians and Gynecologists www.acog.org CE 5 WYETH_Vaginal_CE_ENG 1/19/05 11:20 AM vidualized decisions. Pharmacists should also remember to assess for any precipitating factors and recommend the discontinuation of any reversible causes. It may be uncomfortable for some patients to discuss symptoms of vaginal atrophy, however by providing the right environment, that is comfortable for the patient and open to discussion, will help alleviate some of the uneasiness. Patient counselling on the various estrogen products should provide clear instructions on how to administer the various products, and details for expected outcomes and potential side effects. Patients who start on estrogen therapy for vaginal atrophy may see some improvement in symptoms after one month; however it may take up to a few months to see adequate response. Patient follow-up should include questions on response to therapy, assessment of compliance and any adverse outcomes. References 1. Johnston SL, Farrell SA, Bouchard C et al. The detection and management of vaginal atrophy. J Obstet Gynaecol Can. 2004;26:503-15. 2. Nothnagle M, Taylor JS. Vaginal estrogen preparations for relief of atrophic vaginitis. Am Fam Physician. 2004;69:2111-2. 3. Willhite LA, O'Connell MB. Urogenital atrophy: Prevention and treatment. Pharmacotherapy. 2001; 21:464-80. 4. Kalogeraki A, Tamiolakis D, Relakis K et al. Cigarette smoking and vaginal atrophy in postmenopausal women. In Vivo. 1996;10:597-600. 5. Pandit L, Ouslander JG. Postmenopausal vaginal atrophy and atrophic vaginitis. Am J Med Sci. 1997;314:228-31. 6. Bachmann GA. Influence of menopause on sexuality. Int J Fertil Menopausal Stud. 1995;40 Suppl 1:16-22. 7. Stenberg A, Heimer G, Ulmsten U, Cnattingius S. Prevalence of genitourinary and other climacteric symptoms in 61-year-old women. Maturitas. 1996; 24:31-6. 8. Hendrix SL. Long-term use of hormone therapy for urogenital complaints: Is there a role? Med Clin North Am. 2003;87:1029-37. 9. Utian, W. H. and Schiff, I. North American Society Gallup Survey on women's knowledge, information, sources, and attitudes to menopause and HT. Menopause. 1, 39-48. 1994. Ref Type: Journal (Full) 10. Notelovitz M. Urogenital atrophy and low-dose vaginal estrogen therapy. Menopause. 2000;7:140-2. 11. Bachmann GA, Leiblum SR. The impact of hormones on menopausal sexuality: A literature review. Menopause. 2004;11:120-30. CE 6 Page CE 6 12. Johnston SL. Urogenital health. Canadian consensus on menopause and osteoporosis. J Obstet Gynaecol Can. 2001;23:973-7. 13. Laan E, van Lunsen RH. Hormones and sexuality in postmenopausal women: A psychophysiological study. J Psychosom Obstet Gynaecol. 1997;18: 126-33. 14. Jepson RG, Mihaljevic L, Craig J. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2001;CD001321. 15. Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. Randomised trial of cranberrylingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ. 2001;322:1571. 16. van der Laak JA, de Bie LM, de LH, de Wilde PC, Hanselaar AG. The effect of Replens on vaginal cytology in the treatment of postmenopausal atrophy: Cytomorphology versus computerised cytometry. J Clin Pathol. 2002;55:446-51. 17. Nachtigall LE. Comparative study: Replens versus local estrogen in menopausal women. Fertil Steril. 1994;61:178-80. 18. Hirata JD, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril. 1997;68:981-6. 19. Bachmann GA, Nevadunsky NS. Diagnosis and treatment of atrophic vaginitis. Am Fam Physician. 2000;61:3090-6. 20. Cardozo L, Bachmann G, McClish D, Fonda D, Birgerson L. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: Second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1998;92:722-7. 21. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2003; CD001500. 22. Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol. 1999;180:1072-9. 23. Felding C, Mikkelsen AL, Clausen HV, Loft A, Larsen LG. Preoperative treatment with oestradiol in women scheduled for vaginal operation for genital prolapse. A randomised, double-blind trial. Maturitas. 1992;15:241-9. 24. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993; 329:753-6. 25. Crandall C. Vaginal estrogen preparations: a review of safety and efficacy for vaginal atrophy. J Womens Health (Larchmt ). 2002;11:857-77. 26. Brown JS, Vittinghoff E, Kanaya AM, Agarwal SK, Hulley S, Foxman B. Urinary tract infections in postmenopausal women: Effect of hormone therapy and risk factors. Obstet Gynecol. 2001;98:1045-52. 27. Fantl JA, Cardozo L, McClish DK. Estrogen therapy in the management of urinary incontinence in postmenopausal women: A meta-analysis. First report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1994;83:12-8. 28. Jackson S, Shepherd A, Brookes S, Abrams P. The effect of oestrogen supplementation on postmenopausal urinary stress incontinence: A doubleblind placebo-controlled trial. Br J Obstet Gynaecol. 1999;106:711-8. 29. Moehrer B, Hextall A, Jackson S. Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev. 2003;CD001405. 30. Grodstein F, Lifford K, Resnick NM, Curhan GC. Postmenopausal hormone therapy and risk of development urinary incontinence. Obstet Gynecol. 2004;103:254-60. 31. Grady D, Brown JS, Vittinghoff E, Applegate W, Varner E, Snyder T. Postmenopausal hormones and incontinence: The Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol. 2001;97:116-20. 32. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33. 33. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33. 34. Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-12. 35. Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-12. 36. Rowe T. The Canadian Consensus Conference on Menopause and Osteoporosis-2002 Update. J Obstet Gynaecol Can. 2002;24:4-11. 37. Utian, W. H., Archer DF, Gallagher, J. C., Gass ML, Gelfand, M. M., and Henderson VW. Recommendations for estrogen and progestogen use in peri-and postmenopausal woman: October 2004 position statement of the North American Menopause Society. Menopause. 10, 497-506. 2004. Ref Type: Journal (Full) 38. Nilsson K, Heimer G. Ultra-low-dose transdermal estrogen therapy in post-menopausal urogenital estrogen deficiency - a placebo-controlled study. Menopause. 1994;1:191-7. 39. Ferreira E, Brown TER. Canadian Consensus on Menopause and Osteoporosis: Pharmacotherapy. J Obstet Gynaecol Can. 2001;23:1105-14. 40. Pschera H, Hjerpe A, Carlstrom K. Influence of the maturity of the vaginal epithelium upon the absorption of vaginally administered estradiol-17 February 2005 WYETH_Vaginal_CE_ENG 1/19/05 11:20 AM beta and progesterone in postmenopausal women. Gynecol Obstet Invest. 1989;27:204-7. 41. Furuhjelm M, Karlgren E, Carlstrom K. Intravaginal administration of conjugated estrogens in premenopausal and postmenopausal women. Int J Gynaecol Obstet. 1980;17:335-9. 42. Mandel FP, Geola FL, Meldrum DR et al. Biological effects of various doses of vaginally administered conjugated estrogens in postmenopausal women. J Clin Endocrinol Metab. 1983; 57:133-9. 43. Handa VL, Bachus KE, Johnston WW, Robboy SJ, Hammond CB. Vaginal administration of low-dose conjugated estrogens: Systemic absorption and effects on the endometrium. Obstet Gynecol. 1994; 84:215-8. 44. Nachtigall LE. Clinical trial of the estradiol vaginal ring in the U.S. Maturitas. 1995;22 Suppl:S43-7. Page CE 7 46. Rioux JE, Devlin C, Gelfand MM, Steinberg WM, Hepburn DS. 17beta-estradiol vaginal tablet versus conjugated estrogen vaginal cream to relieve menopausal atrophic vaginitis. Menopause. 2000;7:156-61. 46. Botsis D, Kassanos D, Kalogirou D, Antoniou G, Vitoratos N, Karakitsos P. Vaginal ultrasound of the endometrium in postmenopausal women with symptoms of urogenital atrophy on low-dose estrogen or tibolone treatment: A comparison. Maturitas. 1997; 26:57-62. 47. Smith P, Heimer G, Lindskog M, Ulmsten U. Oestradiol-releasing vaginal ring for treatment of postmenopausal urogenital atrophy. Maturitas. 1993;16: 145-54. 48. Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I. A one-year multicenter study of efficacy and safety of a continuous, low-dose, estra- diol-releasing vaginal ring (Estring) in postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol. 1996;174:85-92. 49. Ayton RA, Darling GM, Murkies AL et al. A comparative study of safety and efficacy of continuous low dose oestradiol released from a vaginal ring compared with conjugated equine oestrogen vaginal cream in the treatment of postmenopausal urogenital atrophy. Br J Obstet Gynaecol. 1996;103:351-8. 50. Nilsson K, Heimer G. Low-dose oestradiol in the treatment of urogenital oestrogen deficiency -- a pharmacokinetic and pharmacodynamic study. Maturitas. 1992;15:121-7. 51. Nilsson K, Heimer G. Low-dose 17 betaoestradiol during maintenance therapy -- a pharmacokinetic and pharmacodynamic study. Maturitas. 1995;21:33-8. 1. Physiologic changes that occur with vaginal atrophy include a) increase in blood flow to the vagina. b) enhancement of the vaginal epithelium and lining. c) loss of vaginal elasticity. d) none of the above. 4. Some lifestyle recommendations that could be recommended for Joan to help with her symptoms include a) quit smoking. b) masturbation. c) avoid douches or perfumed products. d) all of the above. d) None of the above 2. The following are all symptoms of vaginal atrophy EXCEPT a) decreased vaginal lubrication. b) dyspareunia. c) vaginal pruritis. d) decreased urinary tract infections. 5. Which would be the most appropriate hormonal option for Joan in relieving her symptoms of vaginal atrophy? a) Transdermal estrogen such a patch, 50 µg applied twice weekly. b) Vaginal conjugated estrogen (CE) cream administered 0.3 mg daily for the first two weeks, and then twice weekly. c) Vaginal estradiol table (25 µg) once weekly. d) None of the above. QUESTIONS Case #1 Joan is a 54-year-old post-menopausal woman who has symptoms of vaginal atrophy, with her biggest complaint being vaginal dryness and pain with intercourse. She has not tried anything for vaginal dryness but would like some help in relieving the symptoms. She feels her sex life has suffered because of the pain on intercourse. She feels she is smoking more because of the increased stress in her personal life. (Questions 3 to 7 pertain to Case #1) 3. Which of the following are potential risks or concerns if Joan is not treated for her vaginal atrophy? a) Vaginal ulceration b) Vaginal cancer c) Decreased quality of life d) Endometrial hyperplasia February 2005 6. The most common side effects associated with vaginal estrogen products include all of the following EXCEPT a) vaginal discharge. b) vaginal irritation. c) decreased urinary tract infections. d) vaginal spotting. 7. If Joan had contraindications to estrogens, which would be appropriate nonhormonal options for Joan in helping relieve her symptoms of vaginal atrophy? a) A moisturizer such as Replens™ prior to sexual intercourse b) A lubricant prior to sexual intercourse c) Wild yam cream 8. Which product would NOT be an option for a post-menopausal woman with menopausal symptoms such as hot flushes, night sweats and vaginal dryness? a) Vaginal estradiol ring every 3 months b) Estrogen gel every day c) conjugated estrogen oral tablets d) Estrogen patch twice weekly 9. Which statement is TRUE from the SOGC consensus guidelines for the management of vaginal atrophy? a) Women experiencing recurrent urinary tract infections should be instructed to consume pure cranberry juice to decrease their risk of urinary tract infections. b) For menopausal women experiencing recurrent urinary tract infections and who have no contraindications to local hormone replacement, vaginal estrogen therapy can be recommended. c) Systemic absorption of estrogen can occur with vaginal estrogen preparations, progestin should be recommended in all women on vaginal estrogen. d) None of the above. 10. Which factor is NOT an absolute contraindication to the use of systemic hormone replacement therapy? a) Strong family history of heart disease b) History of breast cancer c) Unexplained vaginal bleeding d) Acute liver disease CE 7 WYETH_Vaginal_CE_ENG 1/19/05 11:20 AM Page CE 8 QUESTIONS continued Case #2 Ellen is a 56-year-old post-menopausal woman with vaginal dryness, recurrent urinary tract infections and stress incontinence. She has tried using cranberry juice to help with the urinary tract infections but it has not helped and she has been on numerous courses of antibiotics. She has also used Replens™ for the last year to help with the vaginal dryness but with no relief. She is not complaining of any menopausal symptoms. (Questions 11 to 13 pertain to Case #2) 11. What would be the next appropriate option to help with Ellen’s symptoms of vaginal atrophy? a) Estrogen gel twice weekly b) Vaginal estrogen ring (new ring every 90 days) c) Vaginal CE cream 1.25 mg every day d) Vaginal estrogen tablet (25 µg) every day 12. What would you tell Ellen about the potential benefits that she may see with vaginal estrogens in reducing her risk of urinary tract infections? a) Vaginal estrogens will have no effect on the risk of recurrent urinary tract infections. b) Vaginal estrogens will increase her risk of urinary tract infections. c) Vaginal estrogens may decrease her risk of recurrent urinary tract infections. d) Progestins should be used in combination with vaginal estrogens to see the full benefit in reducing the risk of recurrent urinary tract infections. 13. What would you tell Ellen about the potential benefits that she may see CE 8 with hormone replacement therapy in helping with her symptoms of stress incontinence? a) The role of HT in stress incontinence is unclear. b) Only the combination of estrogen and progestin has shown a benefit in urge incontinence. c) There may be a benefit for stress incontinence, however both estrogen and progestin have to be used together. d) None of the above. 14. Which of the following would be considered advantages of the vaginal estradiol ring? a) Uniform and sustained release of estradiol directly to vaginal tissue b) Very low systemic estrogen levels c) Does not need to be replaced for 3 months d) All of the above 15. Which of the following are advantages of conjugated estrogen vaginal cream? a) Very low systemic estrogen levels at doses of 0.3 mg three times weekly. b) A small amount can be applied to the outer skin folds of the vagina to relieve external irritation and dryness. c) All of the above. d) None of the above. 16. Why was the estrogen-alone arm of the Women’s Health Initiative stopped early? a) Increased risk of breast cancer b) Increased risk of coronary heart disease c) Increased risk of fractures d) None of the above 17. The estrogen and progestin arm of the Women’s Health Initiative was stopped early because the increased risk outweighed the potential benefits. What were the risks associated with estrogen and progestin? a) Increased risk of breast cancer b) Increased risk of fractures c) Increased risk of colorectal cancer d) All of the above 18. The current role of systemic HT, as recommended by SOGC and NAMS, include all of the following EXCEPT a) relief of hot flushes. b) relief of vaginal dryness. c) relief of insomnia. d) prevention of colorectal cancer. 19. Common side effect(s) of oral estrogens include a) breast tenderness. b) acne. c) hirsutism. d) all of the above. 20. Which statement(s) is/are TRUE? a) All vaginal estrogen products (ie CE cream, vaginal tablets and vaginal ring) have been found to be effective for the treatment of vaginal dryness. b) Oral estrogens have been found to be more effective for vaginal dryness than vaginal estrogen products. c) The vaginal ring has been found to have fewer side effects compared to other vaginal estrogen products. d) All of the above. February 2005 TO ANSWER THIS CE LESSON ONLINE If currently logged into our ONLINE CE PROGRAM, please return to the "Lessons Available Online" Page and click on "Link to questions" for this CE Lesson. 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