CAPA 2015 Annual Conference Abracadabra The Magical World of Genitourinary Syndrome of Menopause(GSM) Michael L Krychman MD Southern California Center for Sexual Health and Survivorship Medicine Associate Clinical Professor VCF- UCI AASECT Certified Sexual Counselor Unmet need 157 million women in the USA 41% are postmenopausal Approximately 64 million postmenopausal women 34 million atrophic women 40% of life in the postmenopause Only 7% receive prescription treatment – 2.3 million treated women Krychman M, Wysocki S., Kingsberg S., REVIVE Survey October 2012: NAMS poster presentation Genital Syndrome of Menopause previously known as VVA Symptoms of VVA, including dryness, irritation, itching, dysuria, and dyspareunia, can affect QOL and sexual function. VVA is also associated with lower urinary tract symptoms, such as dysuria, urgency, frequency, nocturia, incontinence, and recurrent UTIs. VVA is underDX and underTX. Many postmenopausal women lack knowledge about vulvovaginal health and treatment options for vulvovaginal discomfort. Both patients and (HCPs) may be hesitant to discuss vulvovaginal health. 1 CAPA 2015 Annual Conference Manifestation of Estrogen and/or Androgen Loss: Symptoms Over Time Range of Estrogen secretion levels (pg/mL) Onset insidious with significant individual variability Long-term symptoms Short-term symptoms Mood, sleep, and/or Hot acute cognitive changes flushes Urogenital symptoms Decreased sexual activity Decreased arousal Decreased libido 40 45 50 55 60 65 70 ≥75 Age (y) ©2005 JL Alexander, http://www.afwh.org. 4 Physical Symptoms of AV Atrophic epithelium (pale, smooth, shiny) Loss of rugae Increased friability Sparse pubic hair Fusion of labia Introital stenosis Bachman G, et al. Am Fam Physician. 2000; Parsons A, et al. Menop Med. 2003 5 VVA SYMPTOMS Vaginal and vulvar dryness Decreased lubrication with IC Discomfort with Sexual Activity Irritation, burning, Itching Dysuria Urinary frequency, urgency Recurrent UTI 2 CAPA 2015 Annual Conference pH Confirms VVA Premenopausal vaginal luminal pH is acidic – –pH 4.5–6.0 – –~6.5 before ovulation Estrogen loss → more alkaline pH –pH 6.5–7.0 Ph test is medicare eligible Routine measurement of vaginal pH may improve compliance Department of Health & Human Services. Centers for Medicare and Medicaid Services. New Waived Tests – December 17, 2002. Available at: http//www.cms.gov/transmittals/ downloads/AB03013.pdf Accessed May 10, 2010. Menopause is Not the Only Condition Associated with VVA Hormonal Contraception Chemotherapy Post-Partum Diabetes Artherosclerosis IVF Radiation Medications – Antihistamines, decongestants, anti-cholinergics Cellular Shift Changes Premenopausal Superficial Intermediate Parabasal Post menopausal 15% 80% 5% Superficial Intermediate Parabasal 1% 60% 39% 3 CAPA 2015 Annual Conference Vaginal and Sexual Pain Painful sex Avoidant Behavior Partner may feel guilt, anxious Change is sexual relationship Marital ↑ Tension No sex Partner may feel rejected, angry 4 CAPA 2015 Annual Conference Impact of Vaginal Atrophy on Sexual Function Vaginal Atrophy Dyspareunia Lack of Lubrication Irritation Loss of interest in Sexual Activity Discomfort During Sexual Intercourse Goals of Treatment Relieve symptoms Reverse anatomical changes Improve sexual function and quality of life Vulvovaginal Atrophy Can Impact Overall Well-Being Dsypareunia affects more than interest in sex—relationships, mood, and self-esteem suffer Strongly agree Somewhat agree Strongly disagree Neither agree nor disagree Percentage of Patients 35 Somewhat disagree N=506 30 25 20 15 10 5 0 Sexual interest Mood Self-esteem Relationships Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas. Altman A. OBG Management. 2009. 15 15 5 CAPA 2015 Annual Conference Management of Vaginal Atrophy Lubricants Moisturizers Systemic Estrogen Local Vaginal Estrogen Selective Estrogen Receptor Modulator Off label/compounded options Laser “rejuvenation” Adjuncts – Physical Floor Therapy – Dilators – Intravaginal Valium Lubricants and Moisturizers Lubricants are considered temporary measures to relieve vaginal dryness during intercourse – Short duration of action – Must be applied frequently – Sexual aid Moisturizers are promoted as providing long-term relief of vaginal dryness – Continuous use- several times a week – Everyday aid Both OTC and FDA approved as cosmetics ď‚—Moisturizer = Maintenance ď‚—Lubricant = Love making 6 CAPA 2015 Annual Conference Lubricants Minimize friction and irritation – Around the clitoris, labia and vaginal entrance – Both partners’ genitals Gel or liquid Water-based, oil-based, silicone-based Avoid lubricants that contain perfumes, flavors or warming ingredients Water based Oil Based Silicone Based Thickening agents in a watersoluble base differ by: Oil: mineral, almond, olive.. Petrolatum Silicone Dimethicone Dry quickly Needs reapplication Stay slippery Messy/Greasy Stay slippery “Coating” effect Compatible with latex condoms Breaks condoms, diaphragms Not compatible with silicone rubber sex toys Sticky Bad smell Bad taste consistency (watery – thick), feel , how long they last Contains preservatives, antiseptics, glycerin Non-irritating Non-irritating wash away easily water-resistant: difficult to wash off body, staining clothes or sheets water-resistant: difficult to wash off body, clothes or sheets Needs soap to remove KY, Astroglide, Slippery stuff, Yes Oil: mineral, almond, olive.. Petrolatum, Yes Eros, Pink, ID Millenium, Wet Platinum Oil Based • Not condom compatible • Increased vaginal yeast infections Vaseline • Not condom compatible • 2X increase in Bacterial vaginosis Brown, et al. Intravaginal Practices and risk of Bacterial Vaginosis among a Cohort of Women in the United States ObGyn Vol 121, No 4, April 2013 7 CAPA 2015 Annual Conference Advantages inexpensive available toy compatible condom compatible easily washes off Advantages more slippery lasts longer less irritating no glycerine condom compatible Disadvantages sticky short acting many have preservatives (irritation and infection) Disadvantages expensive not as readily available not toy compatible can stain sheets “Specialty” Lubes Flavored Lubes – Water based-edible – Silicone based-not edible, but not toxic. Warming Lubes – capsaicin 8 CAPA 2015 Annual Conference Watch for Irritating Ingredients Benzyl Alcohol Maybe drying agent Glycerin Can be considered a drying agent Maybe irritant for some women with severe atrophy May be associated with yeast infections Consider avoidance in vulvodynia patients May upset balance of vaginal flora Lubricant Analysis Vulvar Contact Dermatitis Suspect via history: – – – – Sudden onset Intense pruritus Vesiculation Weeping lesions Common vulvar irritants – Spermicide, Bactericides Common vulvar allergens – Benzocaine – Chlorhexidine (KY jelly) – Parabens and propylene glycol – Latex – Lanolin Treatment Stop all irritants Stop overzealous hygiene Topical steroids - Low potency - daily for 5-7 days Bland emollients – A&D, mineral oil Sleep aid for sedation avoid scratching Antibiotics prn infections 9 CAPA 2015 Annual Conference Vaginal Moisturizers- Mode of Action Bio adhesive-based polymers Attach to mucin and epithelial cells on the vaginal wall Carries up to 60 times its weight in water Holds water in place on vaginal epithelial surface until it is sloughed off Require only two to three applications a week and does not require reapplication before sexual intercourse. Bachmann GA, Clin Pract Sex 1991;7: 1-8 Moisturizers Product Ingredients Use Price Replens Polycarbophil Every 3 days $17.5/14 app Yes Me again Hyaluronic acid 7 days > 2/wk $18/8 app HA-yes KY Liquibeads (ovules) Dimethicone, Gelatin, KY long lasting Various polymers Glycerin, mineral oil Studies Propylene glycol, paraben ? No Glycerin, Dimethiconol ? $16/6 app No Glycerin, mineral oil Emerita personal moisturizer Aloe Vera Gel, Calendula, Vitamin E, Ginseng, Chamomile, Allantoin As needed $16/4 oz No Moist Again Carbomer, aloe vera As needed $7/4 oz No glycerin, chlorhexidine Hyalofemme Hyaluronic acid 7 days > 2/wk $17/30gram HA-yes Pre-seed Hydroxyethylcellulose, As needed $20/9 app Yes Pluronic, Arabinogalactan 10 CAPA 2015 Annual Conference Hybrid: Moisturizer/Lubricant Luvena Antibiotic® Vaginal moisturizer and lubricant No paraben, no glycerin, no estrogens Contains Pre-biotic lacto-peroxidase (helps to maintain pH and decrease BV) Lactoferrin – antagonists against yeast Dual effect moisturizer and lubricant Laser Treatment Persistent Dyspareunia Post Treatment Evaluate tissue Dilator Assessment Hypertonic Pelvic floor 11 CAPA 2015 Annual Conference When Lubricants & Moisturizers are Not Enough.. Vulvovaginal atrophy: *BURNING *DRYNESS *ITCHING *RAWNESS *PAIN *THIN, PALE, FRAGILE EPITHELIUM *DECREASED SUBCUTNAEOUS FAT *PATCHY ERYTHEMA *INCREASES FRIABILITY *DYSPAREUNIA *SYMPTOMS DO NOT ABATE AND OFTEN PROGRESS OVER TIME Local Vaginal Estrogens Boxed Warnings Dementia Increased risk of stroke, DVT, PE Increased risk of endometrial cancer Increased risk of invasive breast Cancer Effects of Local Estrogen Improve sensory perception Increase central and peripheral nerve transmission Increase lubrication Reduce pH Increase peripheral blood flow Augment capacity to develop muscle tension Increase vibratory sensation Increase vaginal vault relaxation Increase vaginal vault size Increase tissue elasticity Increase vaginal collagen content – Sarrel PM. Sexuality in the middle years. Obstet Gynecol Clin North Am. 1987; 14: 49-52. Gescheider GA, Verillo RT, McCann JT, et al. Effects of the menstrual cycle on vibrotactile sensitivity. Percept Psychophys 1984; 36: 586-592. Kow L, Pfaff D. Effects of oestrogen treatment o the size of receptive field and response threshold of the pudendal nerve in the female rat. Neuroendocrinology 1973; 13: 299-313. Lara LA, et al. J Sex Med. 2009;6:30-39. NIH State-of-the-Science Conference Statement on management of menopause- 12 CAPA 2015 Annual Conference Minimally Absorbed Local Vaginal Topical Estrogens Composition Dosing Vaginal Cream 17 B Estradiol cream Initial 2-4 g 1-2 wk Maintenance: 1g/d(0.1mg active ingredient /g) Conjugated estrogens 0.5-2.0 g/d ( 0.625 mg active ingredient/g) (Formally conjugated equine estrogens) Vaginal Ring 17 Beta Estradiol Device contains 2mg Releases 7.5 microgram per day for 90 d Vaginal tablet Estradiol hemihydrate Initial dose: 1 tab q/day for 14day Maintenance 1 tab BIW (Tablet 10.3 mcg of estradiol hemihydrate, equivalent to 10mcg of estradiol) North American Menopause Society. Menopause. 2007;14:357-369. Cirigliano M. J Women's Health (Larchmt). 2007;16:600– 631. Simon JA, et al. Obstet Gynecol. 2008;112:1053-1060. Simon JA, et al. Obstet Gynecol. 2010; 116 (4): 1-8 Is Local Really Local? Kendall et. al. cautions that vaginal estradiol is contraindicated in postmenopausal women on adjuvant aromatase inhibitors1. Labrie et. al. demonstrate that even small doses of vaginal preparations – Vagifem 25 μg; Premarin Vaginal Cream result in significant systemic absorption through estrogen naive vaginas(2). Naessen et al showed that 7.5 μg/24h could improve the lipid profile and bone density without affecting the endometrium3-5. 1Kendall A, et. al. Ann Oncol 2006;17:584-587. 2Labrie F, et. al. Menopause 2009;16:30-36. 3-5Naessen T, et. al. J Clin Endocrinol Metab 2001;86:2757-2762.; Am J Obstet Gynecol 1997;177:115-119.; Am J Obstet Gynecol 2002;186:944-947. Current Overview of the Management of Urological Atrophy in Women with Breast Cancer Pruthi S, Simon JA, Early AP. Breast J. 2011 Jul-Aug;17(4):403-8. doi: 10.1111/j.1524-4741.2011.01089.x. Epub 2011 Jun 6 13 CAPA 2015 Annual Conference Perivaginal Blood Flow During Estrogen Replacement Therapy Milliwatts (mW) 250 244.7 240 236.6 230 225.8 220 210 208.4 200 190 Baseline 1 Month 3 Months 6 Months Increase in blood flow values in women estrogen-deprived at baseline, and then administered conjugated estrogens. Semmens J et al. JAMA. 1982;248:445-448. Normalized Change in Clitoral Volume Subjects 5–12 Subject 5 Subject 6 Subject 7 Subject 8 Subject 10 Subject 12 25 20 Normalized to pre-erotic time point Volume (cc) 15 10 5 0 -5 Erotic Video Neutral Video Neutral Video Dynamic MRI Time Points MRI = magnetic resonance imaging. Courtesy of Ken Maravilla, MD - Seattle, WA, 2003 Alternative Intravaginal DHEA Intravaginal testosterone Intravaginal Oxytocin Intravaginal Bovine Colostrum Intravaginal Estriol ORAL: Osphena® ORAL: DuaVee ® 14 CAPA 2015 Annual Conference Intravaginal DHEA (Vaginorm/Prasterone ®) Labrie et al – Journal of Steroid Biochemistry and Molecular Biology 111 (2008) 178-194 Treatment – One ovule of DHEA 0.0%, 0.5%, 1.0% or 1.8% – 7 days vaginal PH was significantly decreased – Serum Estradiol and Testosterone remained within normal postmenopausal values at all DHEA values – DHEA permits rapid effects for local beneficial effects against vaginal atrophy, without changes in estradiol thus avoiding the increased risk of breast cancer associated with the current intravaginal or systemic estrogenic formulations Labrie et al. Menopause vol 16 no 5 907-922 Ospemifene (Osphena(r) Vaginal Estrogen Receptor Agonist 2010 RCT Stage III: SERM ospemifene – Quatrix Inc/ Shionogi Inc 827 women randomized either 30, 60 mg or placebo for 12 weeks 60 mg was shown to be effective, well tolerated for vaginal dryness and dyspareunia No proliferative effect on endometrium Side effect: 8 % hot flashes – 0.7% severe in 60mg group – one participant (0.4%) in the 60 mg group discontinued because of hot flashes. – Bachman et al. Menopause: 17:3:: 480-486 Interesting: Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in Mtag.TG Transgenic Mouse. – Burich et al Menopause 19:1: 96-103 Ospemifene and The Breast Breast Antagonist Pre-clinical Trials: Ospemifene shrunk breast tumors in rats Clinical Trials: Breast neutral Patient with breast cancer or at risk for breast cancer is the ideal candidate. 15 CAPA 2015 Annual Conference Neogyn Feminine Cream Cellular Lysate Cream that has been shown to be soothing for vulvar tissues MORE THAN 100 CYTOKINES; GROWTH FACTORS; INTERFERONS AND ANTI-INFLAMMATORY INTERLEUKINS IL-1RA, IL-4, AND IL-10. *In clinical Studies improvement in symptoms of atrophy vulvar pain disorders vulvodynia, lichen sclerosus No evidence that local vaginal estrogen use increases recurrence NAMS position Statement give “permission” Many physicians still reluctant to prescribe local estrogen to women with breast cancer Even with physician reassurance, most women are reluctant to use a local vaginal estrogen 16 CAPA 2015 Annual Conference Dilators GOAL: Reconnection with the vagina; Vaginal biofeedback Center Program – Use 2-3 times a week – Use lubricant with exercises – Slowly and progressive ( 2-3 weeks per size) – Gradually increase size and time – Premedication is allowed – Lidocaine and lubricant should be used – Relaxation and distraction techniques during medical exercise – Frequent follow up visits Self stimulation is a medical treatment Write it on a prescription pad The Impact of Atrophy Emotional Isolation Physical changes Atrophy Relationship Discord Decreased Sexual Self Esteem 50 Summary Aging is a natural, progressive process Sexual dysfunction affects the couple, not just the individual Chronic diseases play a major role in sexual health status The neurohormonal connection facilitates desire and the arousal response Multiple therapy options exist for both partners 17