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A Dermatologist’s Approach to Genitourinary Syndrome of Menopause Matthew Hum1, BSc, MD; Dr. Marlene Dytoc2, MD, PhD, FRCPC Faculty of Medicine and Dentistry, University of Alberta1; Division of Dermatology, University of Alberta2. Learning Objective of the Presentation: To provide an approach relevant to Dermatologists in diagnosing and managing GSM. Take Away Message of the Poster Vulvovaginal conditions are common and often co-exists with GSM which may exacerbate symptoms or impair treatment. Recognizing and treating GSM will help with treating other vulvovaginal dermatoses. First-line therapy with low-dose vaginal estrogen, moisturizers and lubricants is safe, effective and rewarding. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The Authors declare that there is no conflict of interest. CDA Sponsor: Dr. Marlene Dytoc Author contact: [email protected] Introduction Definition Genitourinary Syndrome of Menopause (GSM) is a debilitating condition that often presents with vaginal dryness and dyspareunia as well as other genital, sexual and urinary symptoms1. Previously known as atrophic vaginitis, the term GSM is now used as it is considered more accurate and publicly acceptable1,2. This syndrome has been defined as a constellation of signs and symptoms with changes to the genitourinary tract caused by a decrease in estrogen and other sex steroids2. Prevalence Surveys of Western and European populations suggest that up to 45% of post-menopausal woman experience significant symptoms3. Populations with temporary or chronically low estrogen levels are also at greater risk of GSM, such as post-menopausal breast cancer survivors who have a higher prevalence4. Other risk factors include postpartum period, surgical menopause, the use of gonadotropin-releasing hormone agonists and hypothalamic amenorrhea5. With approximately 25 million women passing into menopause each year, a significant number of women are affected by GSM6,7. Methods 218 articles were identified using Pubmed and screened in December 2015. Articles in English from December 2005 and onward were selected. An emphasis was placed on Dermatology related articles. Keywords: atrophic vaginitis; atrophic vulvovaginitis, genitourinary syndrome of menopause 1. 2. 3. 4. 5. 6. Kim et al. J Menopausal Med. 2015;21(2):65-71. Portman and Gass. J Sex Med. 2014;11(12):2865-2872. Nappi and Kokot-Kierepa. Climacteric. 2012;15(1):36-44. Crandall et al. Menopause. 2004;11(5):519-530. Management of symptomatic vulvovaginal atrophy: 2013 position statement of the north american menopause society. Menopause. 2013;20(9):888-902. Lund. Med Clin North Am. 2008;92(5):1253-71, xii. Pathophysiology8-12 Hypoestrogenism Thinning of vaginal epithelium Decreased exfoliation Decreased glycogen release and conversion to lactic acid Increased susceptibility to trauma, pain and bleeding Reduction in autonomic nerves Reduction in vaginal blood vessels Atrophy of urethral tissue Impaired vasodilation Decreased transudates from surrounding vessels Decreased closing pressure and sensory threshold of urethral smooth muscle Dyspareunia, post-coital bleeding Vaginal pH rises leading to a loss of commensal flora and overgrowth of pathogenic bacteria Vaginal dryness Urgency or frequency Inflammation and recurrent urinary tract infections Fig 1. Flow chart demonstrating the pathophysiology of GSM. With menopause, declining estrogen has broad effects in the female pelvis as estrogen receptors are abundant in the labia majora and minora, clitoris, vestibule, introitus, vagina, urethra and bladder1,5. The main effect of hypoestrogenism is the transformation of a thick vaginal epithelium to a thin, pale epithelium2. 8. Mac et al. Mayo Clin Proc. 2010;85(1):87-94. 9. Brotman et al. Menopause. 2014;21(5):450-458. 10. Lara et al. J Sex Med. 2009;6(1):30-39. 11. Lindahl. Int J Womens Health. 2014;6:307-312. 12. Calleja-Agius amd Brincat. Climacteric. 2015;18 Suppl 1:18-22. Diagnosis GSM is a clinical diagnosis requiring some or all of the signs and symptoms to be present. The symptoms should be bothersome and not better accounted for by another condition2. Clinical Evaluation Symptoms of GSM1,13,15 Many patients consider the symptoms of GSM to be embarrassing and may not approach a clinician about the symptoms. Thus, clinicians should identify the presence of symptoms, whether they are bothersome and their effect on function and quality of life (QOL)5,13. As dyspareunia is common, a sexual history is also important13. A complete medical history looking at medications, surgical, gynecologic and obstetric history is also necessary to identify other causes of genitourinary symptoms and avoid misdiagnosis of GSM11,13. In addition, asking about vulvar hygiene practices may reveal potential vulvar irritants14. Local Sexual Urinary Dryness Bleeding Pruritus Burning Postcoital bleeding Secondary vaginismus Dysuria Frequency and urgency Recurrent UTIs Stress incontinence and prolapse Morphology of GSM15-17 Fig 2. Illustration depicting normal vulvar anatomy. During the pelvic exam, the presence of these structures should be assessed, especially the labia minora and clitoris. Adopted from Anatomy and Physiology, Connexions website. May 22, 2016. 13. Lev-Sagie. Clin Obstet Gynecol. 2015;58(3):476-491. 14. Thorstensen and Birenbaum. J Midwifery Womens Health. 2012;57(3):260-275. Absent rugae/epithelial folds Smooth epithelium Mildly erythematous patches Pale, shiny and dry epithelium Petechiae, erosions and ulcers Scarce pubic hair Yellow or greenish discharge Urethral caruncle 16. Jan et al. Menopause. 2012;19(1):109-117. 17. Goldstein et al. Sex Med. 2013;1(2):44-53. Fig 3. Atrophic vaginal epithelium in a post menopausal woman. Adopted from 15. Sitka. Dermatologic Therapy. 2010 (23): 514-512. Investigations Although GSM is a clinical diagnosis, certain investigations may be useful for aiding diagnosis or assessing treatment response. Vaginal pH In GSM, the vaginal pH will be increased from an acidic range (3.5 – 5.0) to neutral (pH 6.0 – 8.0) and has been shown to have some correlation with clinical symptoms2,18. The pH can be measured when the cervix has been visualized by placing a Litmus test strip against the lateral vaginal wall in the middle third of the vagina, ensuring that the strip is fully moistened. Vaginal Maturation Index (VMI): Compares the numbers of basal cells, intermediate cells and superficial cells on a vaginal smear19. The sample is collected by gently scraping exfoliative squamous cells from the upper one third or proximal vaginal wall with a spatula19. VMI is more commonly used to assess treatment response as the VMI has poor correlation with clinical presentation18,19. Pap test Not recommended as poor correlation with symptoms21. Wood’s Light22 Reading the Vaginal Maturation Index (VMI)15,19,20 𝐴𝐴 − 0/30/70 𝐵𝐵 − 20/40/30 𝐶𝐶 𝑉𝑉𝑉𝑉𝑉𝑉 = 0.5 % 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 + 1(% 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐) The VMI is read from left to right and with atrophy, the percentage of parabasal cells and intermediate cells on the left will be higher while superficial cells will be lower on the right. (B) represents a “left shift” to atrophy when compared to (A). Another method is to use a formula, as in (C), where values from 0-49 indicates absent estrogen, 5064 as moderate estrogen effect and 65-100 as a large estrogen effect. Fig 4 (left). Preliminary findings by Ulubay et al. (2015) using a transparent speculum and Wood’s light. GSM shows a pale royal green color (left image). The image on the right shows a normal vagina using Wood’s light. 18. Constantine et al. J Sex Med. 2014;11(4):1033-1041. 19. Weber et al. Int Urogynecol J. 2015;26(1):15-28. 20. Jaisamrarn et al. Climacteric. 2013;16(3):347-355. 21. Crothers et al. Arch Pathol Lab Med. 2012;136(11):1332-1338. 22. Ulubay et al. J Clin Diagn Res. 2015;9(1):QC05-8. Current Management First line therapy: Local vaginal estrogen The first-line treatment for moderate-to-severe GSM is local vaginal estrogen therapy which has proven efficacy and safety11,17,23. Low-dose vaginal estrogen is preferred to reduce systemic absorption. A 2014 systemic review of 44 studies found that all commercially available formulations of vaginal estrogens were effective23. Patients had significant improvement with topical estrogen in up to a week24. The authors also found that there was no difference in adverse events compared to placebo. Of note, there were no reported cases of thromboembolism or breast cancer. Similarly there were no significant changes to serum estrogen levels with the exception of creams containing high-dose conjugated equine estrogen23. Contraindications to vaginal estrogen are undiagnosed vaginal or uterine bleeding and estrogen-sensitive cancers such as breast or endometrial cancer1. First line therapy: Moisturizers and Lubricants Patients can achieve symptom relief of vaginal dryness using longacting moisturizers regularly, either daily or up to twice weekly1,15. 23. Rahn et al. Obstet Gynecol. 2014;124(6):1147-1156. 24. Edwards. Dermatol Clin. 2010;28(4):727-735. 25. Beecker. Dermatol Clin. 2010;28(4):639-648. 26. Health Canada. Drug product database online query. 27. The North American Menopause Society, ed. Approved prescription products for menopausal symptoms in the united states and canada. ; 2015. Local Estrogen Formulations Approved for Use in Canada26,27 Vehicle Tablet Trade Name Vagifem Dosage 10 mcg estradiol Application 1 tab PV daily for the first 2 weeks Then, 1 tab PV twice a week Cream Premarin 0.625 mg/g Initial dosing of 0.5 g daily conjugated PV for 21 days and then off estrogens for 7 days Maintenance using low dose of 0.5 g twice weekly PV Cream Estragyn 0.1% w/w 2.0 – 4.0 g PV daily adjusted estrone to lowest amount that controls symptoms 3 weeks on, 1 week off Ring Estring 2 mg 17 βReplace ring every 3 months Estradiol Maximum duration of 2 years The severity of symptoms and patient preference should guide the choice of treatment. Certain topical preparations such as creams or gels tend to cause vaginal irritation; compounding estrogen into an ointment base may be less irritating13,24. Creams also tend to contain more preservatives or additives which increase the risk of irritant or allergic contact dermatitis25. In patients who find topical vehicles such as creams or ointments messy, using a tablet or ring form of estrogen may be preferable25. Second-line/Future Therapies Hormonal treatments Ospemifene (Osphena)18,28 - Oral estrogen receptor agonist/antagonist indicated for dyspareunia secondary to GSM A recent review in 2015 describes Ospemifene as well-tolerated with proven benefits in clinical trials. The most common adverse effect reported was hot flushes. However, these trials were limited by a short duration of 1 year FDA approved but not available for use in Canada Prasterone29 - Intravaginal suppository ovules of DHEA Single clinical trial shows improvement in vaginal dryness and dyspareunia without adverse effects Neither FDA or Health Canada approved - Non-hormonal treatments Fractional CO2 Laser30-33 - Three non-randomized clinical trials showed significant benefit and safety at 12 weeks A review suggests insight into long-term use is needed Erbium:YAG Laser34 - A pilot study showed benefits up to 6 months in a pilot study. Using three treatments spaced 1 month apart, there were rapid improvements in both subjective and objective outcomes, comparable to a local estrogen treatment group Transcutaneous temperature controlled radiofrequency - In a clinical trial looking at vulvovaginal laxity, there were concurrent benefits in treating GSM. In a second study evaluating specifically for dyspareunia and GSM, all 25 patients reported resolution of their symptoms which lasted up to 9-12 months. In both studies, this treatment was well tolerated with no complications. FDA and Health Canada approved 35,36 - 28. Pinkerton and Kagan. Expert Opin Pharmacother. 2015;16(17):2703-2714. 29. Labrie et al. Menopause. 2016;23(3):243-56. 30. Salvatore et al. Climacteric. 2014;17(4):363-369. 31. Salvatore et al. Climacteric. 2015;18(2):219-225. 32. Perino et al. Maturitas. 2015;80(3):296-301 33. Hutchinson-Colas and Segal. Maturitas. 2015;82(4):342-345. 34. Gambacciani et al. Climacteric. 2015;18(5):757-763. 35. Alinsod. PRIME. 2015(July):16-21. 36. Alinsod R. Journal of Minimally Invasive Gynecology. 2015;22(6,Supplement):S226-S227. Fig 5. Algorithm demonstrating an approach to GSM. GSM History Vaginal Sx Urinary Sx Dryness Dyspareunia Pruritus Burning Bleeding Dysuria Recurrent UTIs Frequency Urge/stress incontinence For Diagnosis: 1. Symptoms must be bothersome 2. Only some or all symptoms must be present Erythematous patches Pale, smooth, dry vaginal epithelium Petechiae, erosions Yellow-green discharge Pelvic Exam Investigations Vaginal pH 6.0 – 8.0 Wood’s light Pale Royal Green VMI to assess treatment response Management Referral to vulvar clinic First-line therapy Low-dose Vaginal Estrogen Symptom relief Moisturizers and Lubricants e.g. Vaginal Hyaluronic Acid Gel, pH-balanced Gel A Dermatologist’s Role GSM is not well-known to patients5; a Dermatologist is a potential point to be proactive in educating patients at risk or starting treatment in affected patients. Since vulvar symptoms are non-specific, visual pattern recognition of vulvar lesions is a specific role that Dermatologists can provide in differentiating GSM from other causes of vaginitis. As well, given their familiarity with such therapies, Dermatologists will be a valuable source in counselling patients about using laser or radiofrequency treatments. GSM is a common and often debilitating problem that suffers from barriers to diagnosis and treatment. Using a streamlined approach (Figure 5) may be a good starting point to overcome such barriers. Although GSM can significantly impair quality of life, current treatments are quick, safe and rewarding. Moreover, by becoming familiar with GSM, physicians can have frank discussions with patients which ultimately may alleviate the negative or embarrassing image that some patients may associate with GSM.