Postmenopausal vaginal atrophy Presentation by the International Menopause Society for World Menopause Day October 18th, 2010

Urogenital atrophy Estrogen receptors present in: Vagina Urethra Bladder trigone Pelvic floor

Döderlein's lactobacilli convert glycogen from sloughed vaginal cells Glycogen formation Mucus layer Vaginal pH (3.5-4.5) Lactic acid Protects from: Streptococcus Staphylococcus Coliform Diphtheroid infections Estrogen Maintains thickness of squamous vaginal epithelium, rugae, pink color, and moisture Proliferation of connective tissue Fragmentation of elastin Hyalanization of collagen

Postmenopausal changes in the vaginal epithelium 4 Postmenopausal changes in the vaginal epithelium PREMENOPAUSAL POSTMENOPAUSAL Erectile tissue Folds or rugae Loss of folds Muscular coat Loss of inner lining and glandular function Inner lining contains large amount glycogen Samsioe G. A profile of the Menopause, 1995:49 (Figure 6.4) 4

Vaginal histology H & E, magnification  10 Premenopause 5 Vaginal histology H & E, magnification  10 Premenopause Well-estrogenized epithelium, multi-layered with good blood supply; superficial cells rich in glycogen Postmenopause Estrogen-deficiency atrophy with marked thinning of the epithelium, reduced blood supply and loss of glycogen 5

Vaginal wall smear under the microscope 6 Vaginal wall smear under the microscope Normal: Superficial cells predominate Low nuclear/cytoplasmic ratio Pyknotic nuclei Atrophic: More parabasal cells High nuclear/cytoplasmic ratio Inflammatory exudate 6

Symptoms of urogenital atrophy Vaginal Dryness Burning Pruritus Dyspareunia Prolapse Urinary Urgency Frequency Dysuria Urinary tract infection Incontinence Voiding difficulties

Prevalence of symptoms in women treated for breast cancer Menopause Rating Scale; n = 200 Symptom Symptoms (%) Moderate – severe (%) Hot flushes/sweats 85 63 Sexual problems 60 45 Urinary problems 55 39 Vaginal dryness 34 Gupta P, et al. Climacteric 2006;9:49–58

Increase in vaginal dryness with menopause 47% 32% 25% 21% 3% 4% Pre- menopause (n = 172) Early perimenopause (n = 148) Late perimenopause (n = 106) Post- menopause 1 year (n = 72) Post- menopause 2 years (n = 54) Post- menopause 3 years (n = 31) Dryness increased significantly in late perimenopause and postmenopause (p <0 .001) Dennerstein L, et al. Obstet Gynecol 2000;96:351–8 1Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol. 2000;96:351-358. 9

Prevalence of superficial dyspareunia and vulvovaginal atrophy by menopausal age Perimenopause (n = 133) 0–1 year (n = 52) 2–3 years (n = 39) 4 years (n = 67) Atrophy increased significantly with increase in menopausal age (p <0 .001) Adapted from Versi E, et al. Int Urogynecol J 2001;12:107–10 1Sadovsky R. Management of Dyspareunia and Vaginismus. Am Fam Physician. 2000. Available at: www.aafp.org/afp/20000415/ tips/21.html. Accessed January 6, 2003. 2Versi E, Harvey M-A, Cardozo L, Brincat M, Studd JWW. Urogenital prolapse and atrophy at menopause: a prevalence study. Int Urogynecol J. 2001;12:107-110. 10

Dyspareunia (intensity) Lower estrogen levels are associated with increased prevalence of sexual problems 60 <184 pmol/l (50pg/ml) estradiol >184 pmol/l (50pg/ml) estradiol 50 40 30 % Reporting problems 20 10 Vaginal dryness Bothered by problem Dyspareunia (intensity) Pain with penetration Burning n = 93; significance not reported Sarrel PM. J Womens Health Gend Based Med 2000;9:S25–32 Adapted from Sarrel PM. Obstet Gynecol 1990;75(4 Suppl):26–30S 1Sarrel PM. Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause. J Womens Health Gend Based Med. 2000;9:S25-S32. 2Sarrel PM. Sexuality and menopause. Obstet Gynecol. 1990;75:26S-30S. 11

Prevalence of vaginal atrophy Up to 40% of postmenopausal women experience vaginal atrophy Only 25% of them seek medical assistance Bachman GA, et al. Am Fam Physician 2000;61:3090–6 Cardozo L, et al. Obstet Gynecol 1998;92:722–7

How to discuss vaginal atrophy with postmenopausal women (1) Health-care professionals are not asking postmenopausal women about problems such as vaginal dryness Initiate the discussion about vaginal dryness; your patient may be reluctant Consider that relationship/sexual issues may present as vaginal discomfort

How to discuss vaginal atrophy with postmenopausal women (2) Remember that women using systemic estrogen therapy can still develop vaginal symptoms Be mindful that some urinary symptoms occur concurrently with vaginal atrophy and also respond positively to vaginal estrogen therapy Encourage women to select a vaginal therapy most comfortable for them

Principles of treatment Restoration of urogenital physiology Alleviation of symptoms

Treatment of vaginal atrophy (1) Vaginal moisturizers: Primarily used to relieve vaginal dryness during intercourse Do not provide a long-term solution

Treatment of vaginal atrophy (2) Local/topical estrogen: Logical treatment Pessaries/vagitories, creams, tablets, or ring Systemic estrogen

Menopausal women suffering from atrophic vaginitis 18 Menopausal women suffering from atrophic vaginitis Physician‘s perspective: Women without systemic HRT Women with systemic HRT Patients suffering from atrophic vaginitis Patients not suffering from atrophic vaginitis 39% 27% 61% 73% Over half of postmenopausal women will have urogenital discomfort associated with estrogen deficiency Although many women use oral hormone replacement therapy, urogenital symptoms persist Notelovitz M, et al. Obstet Gynecol 2002;99:556–62 18

Systemic HRT concerns Breast cancer Endometrial cancer Venous thromboembolism Stroke

How much local estrogen is absorbed into the circulation? Effects on other tissues Safety implications Duration of treatment Difficulty in measuring estrogens other than 17β-estradiol

Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet Estring (Pharmacia Upjohn), silastic vaginal ring containing 2 mg 17β-estradiol, releasing 8 µg per 24 h over 90 days (n = 126) Vagifem (Novo Nordisk), mucoadhesive tablet containing 25 µg 17β-estradiol (n = 59) Mean age = 58 (46–81) years Weisberg E, et al. Climacteric 2005;8:83–92

Estrogen levels during vaginal therapy Weeks 24 48 Estring Estradiol (pmol/l) 16 ± 22 49 ± 64 20 ± 19 Estrone (nmol/l) 1.0 ± 0.67 1.4 ± 0.86 1.57 ± 0.89 Vagifem 15 ± 33 36 ± 51 36 ± 50 Estrone (nmol/l) 1.14 ± 1.76 1.39 ± 0.82 1.69 ± 1.48 Weisberg E, et al. Climacteric 2005;8:83–92

Endometrial thickness during vaginal estrogen therapy Weeks 48 Estring (mm) [range] 2.5 [0.8-5.0] 2.6 [1.0-19.0] Vagifem (mm) [1.0-4.5] 2.7 [0.6-9.0] Weisberg E, et al. Climacteric 2005;8:83–92

Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet Conclusion Equivalent endometrial safety and efficacy in the relief of the symptoms and signs of urogenital estrogen deficiency were demonstrated for the 12 months’ use of both preparations Weisberg E, et al. Climacteric 2005;8:83–92

Endometrial histology: Vagifem vs. CEE cream (n = 159 treated for 24 weeks) Rioux JE, et al. Menopause 2000;7:156–61

Conclusions and recommendations (1) Treatment should be started early and before irrevocable atrophic changes have occurred Treatment needs to be continued to maintain the benefits All local estrogen preparations are effective and patient preference will usually determine the treatment used

Conclusions and recommendations (2) Delay in starting local treatment will reduce degree of response Initial loading dose to stimulate receptors followed by low maintenance dose once or twice per week

Conclusions and recommendations (3) Additional progestogen is not indicated when appropriate low-dose, local estrogen is used, although long-term data (more than 1 year) are lacking

Conclusions and recommendations (4) Following gynecological cancer, the use of local estrogen may not be contraindicated; these women should receive appropriate counselling regarding the risks and benefits, taking into account their individual risk factors Use of local estrogen therapy in women on tamoxifen or aromatase inhibitors needs careful counselling and discussion with the oncology team

Further reading www.imsociety.org IMS Writing Group. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 2010;13:509–22