ACTIVITY DISCLAIMER. Menopause and Hormone Replacement Therapy: Managing Menopause: EBM Meets HRT DISCLOSURE. Learning Objectives

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1 Menopause and Hormone Replacement Therapy: Managing Menopause: EBM Meets HRT Jennifer Frank, MD, FAAFP ACTIVITY DISCLAIMER The material presented here is being made available by the American Academy of Family Physicians for educational purposes only. This material is not intended to represent the only, nor necessarily best, methods or procedures appropriate for the medical situations discussed. Rather, it is intended to present an approach, view, statement, or opinion of the faculty, which may be helpful to others who face similar situations. The AAFP disclaims any and all liability for injury or other damages resulting to any individual using this material and for all claims that might arise out of the use of the techniques demonstrated therein by such individuals, whether these claims shall be asserted by a physician or any other person. Every effort has been made to ensure the accuracy of the data presented here. Physicians may care to check specific details such as drug doses and contraindications, etc., in standard sources prior to clinical application. This material might contain recommendations/guidelines developed by other organizations. Please note that although these guidelines might be included, this does not necessarily imply the endorsement by the AAFP. DISCLOSURE Jennifer Frank, MD, FAAFP It is the policy of the AAFP that all individuals in a position to control content disclose any relationships with commercial interests upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflict of interest (COI), and if identified, conflicts are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or who agreed to an identified resolution process prior to their participation were involved in this CME activity. All individuals in a position to control content for this activity have indicated they have no relevant financial relationships to disclose. Senior Medical Director, ThedaCare Physicians, Neenah, Wisconsin; Chair, AAFP Maternity Care and Patient Safety Committee. Dr. Frank is a graduate of Boston University School Medicine, Massachusetts. She completed her family medicine residency at Dewitt Army Community Hospital, Fort Belvoir, Virginia. Dr. Frank is particularly interested in women s health, as well as management of diabetes and hypertension. She has authored or co-authored numerous articles on topics including female sexual dysfunction, hypertension management, and practice management, and she has presented at AAFP FMX several times. The content of my material/presentation in this CME activity will not include discussion of unapproved or investigational uses of products or devices. : Learning Objectives 1. Counsel post-menopausal women regarding the risks and benefits of pharmacologic and non-pharmacologic options for the relief of menopausal symptoms. 2. Assess patients current use of nutritional, herbal or dietary supplements for the relief of menopausal symptoms and provide counseling to encourage safe and effective use. 3. Educate patients regarding their increased risk of coronary artery disease and osteoporosis following menopause and how to take preventive measures, including diet and exercise. 4. Establish a group visit model for the management of patients experiencing menopausal symptoms. Audience Engagement System Step 1 Step 2 Step 3 1

2 Poll Question: Nadine is a 49 year old woman with LMP 9 months ago. How would you know if she is in menopause? A. Assess her hormonal status by checking FSH, LH, and/or estrogen levels B. Declare her post-menopausal since it has been > 6 months since her last period C. I ll know in three months Menopause is the end of menstruation and fertility occurring 12 months after the final menstrual period (FMP). Perimenopause Often the most symptomatic phase for women The time around the FMP, also called the menopause transition Begins with variation in the menstrual cycle length of >7 days associated with a rise in folliclestimulating hormone (FSH) and ends 1 year after the FMP Harlow SD Menopause 2012;19: How women view menopause Normal development A time for change 75% make some kind of lifestyle change at menopause 51% in early postmenopause said they were happier and more fulfilled than when younger Women with negative attitudes toward menopause report more menopausal symptoms Assessing Symptoms Menopause Health Questionnaire (menopause.org) Open-ended questions Avoid bias (implying disease state) Ayers Maturitas 2010;65:28 36; Woods Menopause 1999;6:167 73; NAMS Menopause 1999;5: ; NAMS Menopause 1999;6:

3 Nadine 1 year later Nadine in now 50 and hasn t had a menses in 18 months. You confidently declare her menopausal. She reports increased fatigue, insomnia, depressed mood, vaginal dryness, heart palpitations, irritability, left toenail pain, a ringing in her ears when she eats corn on the cob, and weight gain. Poll question Which of the following symptoms is most clearly linked to menopause? A. Cognitive problems B. Depression C. Hot flashes D. Sleep disturbance E. None of the above Utian W. Psychosocial and economic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes 2005;3:47. Symptoms Related to Menopausal Transition Vasomotor Hot flushes Psychological Trouble sleeping Sexual discomfort Vaginal dryness Difficulties with sexual functioning Somatic Aches and pains in joints Mishra and Kuh. Health symptoms during midlife in relation to menopausal transition: British prospective cohort study. BMJ 2012;344:e402. Menopausal Symptoms Related to Hot Flashes Poor sleep Anxiety Muscle aches Cognitive dysfunction Sexual concerns Savolainen Peitonen. Health related quality of life in women with or without hot flashes. Menopause 2014;21:732. Assessing Anna Anna is a 51 year old woman presenting with hot flashes. Her LMP was 15 months ago. Hot flashes occur throughout the day and night and are disruptive at work (starts flushing and sweating during meetings) and at home (husband s nose is turning blue because of the house temperature). She is miserable. Poll question When are Anna s hot flashes likely to stop? A. Soon hot flashes usually only last one or two years after the final menstrual period B. Probably several years C. Forever once you have them, you will always have them 3

4 Hot Flashes are a common complaint. Up to 75% of perimenopausal women Highest occurrence during perimenopause and first 2 years of postmenopause Severe in 10%-15% of women Often abate after 3-5 years; unpredictable Some persist for a lifetime but usually decrease in frequency and intensity over time May be more severe in smokers Understanding contributing factors guides treatment. Warm environment, hot drinks, spicy food, stress, higher BMI, cigarette smoking, alcohol Drugs: SERMs, SSRIs, aromatase inhibitors Disease conditions including thyroid disease, infection, leukemia, pancreatic tumors, autoimmune disorders, anxiety Serum estrogen levels are not predictive of hot flash frequency or severity Frequent Hot Flashes 6 or more days in 2 weeks Median length 7 years (4.5 years after FMP) More persistent Start earlier (pre or peri-menopausal) African American women Women with depression/anxiety Avis et al. Duration of menopausal vasomotor symptoms over the menopausal transition. JAMA Intern Med 2015;175:531. Midlife sleeplessness Both men and women report an increase in sleep disturbances at midlife At all ages, more women than men report sleep disturbances About half of women ages report sleep problems Sleep disturbances associated with fatigue, irritability, chronic illness (e.g., CVD), mood disorders (e.g., depression) National Sleep Foundation america polls/2007 women and sleep. Accessed 8/22/12; Parry BL Menopause 2007;14:812 4 Causes of sleeplessness The Differential Night sweats (typically occur in first half of night) Advancing age (early awakening more common) Sleep disorders 53% have sleep apnea, restless legs, or both Stress/depression Pain (eg, arthritis) Other conditions (eg, CVD, allergies) Drugs (eg, thyroid medication) Freedman RR Menopause 2007;14:826 9 Image courtesy of: Stuart Miles, freedigitalphotos.net Aging Career Issues Sandwich Generation Empty Nest Loss of Fertility Divorce or Loss of Partner Sleep Problems Medical Problems 4

5 Mood and Menopause Whydoes mood seem to be influenced by the menopausal transition? Impact of low estrogen on neurotransmitters Sleep disturbances contributes to mood disorders Multiple stressors coincide with menopausal onset Biological vulnerability Clayton, Ninan. Depression or menopause? Prim Care Companion J Clin Psychiatry 2010;12. Mood disorders The most predictive factor for depression at midlife and beyond is prior history of clinical depression Feelings of upset, loss of control, irritability, fatigue, and dysphoria may be caused by fluctuating hormone levels that perturb neural systems transiently Women with h/o premenstrual syndrome, significant stress, sexual dysfunction, physical inactivity, or hot flashes vulnerable to depressive symptoms Dreher JC Proc Natl Acad Sci USA 2007;104: ; Schmidt PJ Arch Womens Ment Health 2004;7:19 26; Freeman EW Arch Gen Psychiatry 2006;63: Vulvovaginal symptoms Symptoms in 20% to 40% of women many do not recognize relationship to menopause Dryness, burning, dyspareunia, vaginal discharge Effects far reaching Reduced QOL and self-esteem Negative impact on sexual function and relationship Impacts sleep Poll question - What is the next best step for Anna for treatment of hot flashes? A. If no contraindications, start a SSRI or SNRI anti-depressant. B. If no h/o cancer, start HRT. C. Two to three month trial of lifestyle measures. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Just like everything else Lifestyle comes first Break for Questions Stay cool (both physically and psychologically) Limit caffeine and alcohol and eliminate smoking Breathing exercises Healthy weight Sleep environment and insomnia women/mnflashes.pdf 5

6 Pre WHI (2002) 40% of postmenopausal women using HRT Use was for vasomotor symptoms and Prevention of CV events Prevention of cognitive impairment Manson et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the WHI s randomized trials. JAMA 2013;310:1368. Poll question - How often do you prescribe hormone replacement therapy for menopausal symptoms? A. Often despite the hype, HRT is still an awesome medication. B. Sometimes but only after shared decision making. C. Seldom after I describe the risk-benefit profile, patients usually decline. D. Never it s just not worth it for the possible harms. Poll question - What is your biggest barrier to prescribe HRT? A. I don t think it s safe. B. I m not familiar with the options out there. C. Most insurance plans don t cover it. D. My patients don t think it s safe. Three months later - Anna tried lifestyle but remains distressed. Before treatment, need to know Other symptoms (eg, vaginal dryness) History of cancer (breast/ovarian/endometrial) CV risk H/o VTE Patient s interest in HRT Status of uterus Algorithm and mobile app for menopausal symptoms management and hormonal/non hormonal therapy decision making. Menopause 2015;22:1. Hormone Therapy for Menopausal Symptoms Vasomotor Hot flushes Psychological Trouble sleeping Sexual discomfort Vaginal dryness Difficulties with sexual functioning Somatic Aches and pains in joints Mishra and Kuh. Health symptoms during midlife in relation to menopausal transition: British prospective cohort study. BMJ 2012;344:e402. HRT Effectiveness Dependent on Symptoms HRT (transdermal, ERT and combo) effective in treating: Sleep disturbance Memory and concentration disturbance Anxiety Onlydemonstrated in women with vasomotor symptoms Savolainen Peitonen. Health related quality of life in women with or without hot flashes. Menopause 2014;21:732. 6

7 Poll question What s your elevator speech for HRT and CVD? A. Don t do it it s bad all around. B. I m not sure so would talk about the weather. C. No to limited benefit for CVD prevention with significantly increased risk of stroke and VTE. D. The benefits outweigh the risk. Hormone Replacement and the Heart No benefit for HRT in primary/secondary prevention of CVD Modest benefit if started w/i 10 yrs of MP (mortality and CVD) Increased risk of stroke RR =1.24, 6/1000 women, NNH = 165 Increased risk of VTE RR = 1.92, 8/1000 women, NNH = 118) Increased risk of PE RR = 1.81, 4/1000 women, NNH = 242 Boardman HMP, Hartley L, Eisinga A, Main C, Roqué i Figuls M, Bonfill Cosp X, Gabriel Sanchez R, Knight B. Hormone therapy for preventing cardiovascular disease in post menopausal women. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD DOI: / CD pub4. Considering HRT and CV Risk 1. How long has it been since menopause? - Less than 6 years - 6 to 10 years - More than 10 years 2. What is 10 year CVD risk? - Less than 5% % - More than 10% Algorithm and mobile app for menopausal symptoms management and hormonal/non hormonal therapy decision making. Menopause 2015;22:1. Three categories remember 5/10 1. HRT okay - 10 yrs or less since menopause + <5% 10 yr CVD risk 2. HRT okay choose transdermal - 10 yrs or less since menop % 10 yr CVD risk 3. Avoid HRT - Anyone with high CVD risk (>10%) - Anyone with > 10 years since menopause Advising Anna Anna who is < 5 years post-menopause and has a 10 year CVD risk calculated at 3% has no contraindications to HRT. She is interested in trying this option. However, she has heard of this study that was done proving that HRT causes breast cancer. How do you advise her? Algorithm and mobile app for menopausal symptoms management and hormonal/non hormonal therapy decision making. Menopause 2015;22:1. 7

8 Poll question - Which of the following statements is true regarding HRT and increased breast cancer risk? Invasive Breast Cancer per 10,000 person years A. Invasive breast cancer is more common in women who are 60 years and older. B. Invasive breast cancer risk increases with any HRT use. C. Invasive breast cancer risk increases with estrogen alone but not with combined HRT (estrogen + progestin). Estrogen + Progestin Estrogen alone Active Placebo y y y y y y Algorithm and mobile app for menopausal symptoms management and hormonal/non hormonal therapy decision making. Menopause 2015;22:1. Active Placebo Breast Cancer Risk and HRT Complex issue Breast cancer more common with Estrogen + progestin Initiation of HRT closer to menopause Risk for past users returns to that of never users about 3-4 years after cessation Beral et al. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst 2011;103: Overall Outcomes from WHI - Intervention Condition Estrogen + Progestin Estrogen alone All CV events Colorectal Cancer NS Coronary Heart Disease NS NS Deep Vein Thrombosis Endometrial Cancer NS Hip Fracture/Vertebral Fracture Invasive Breast Cancer NS Stroke Manson et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the WHI s randomized trials. JAMA 2013;310:1368. Overall Outcomes from WHI Cumulative F/U Condition Estrogen + Progestin Estrogen alone All CV events NS NS Colorectal Cancer NS NS Coronary Heart Disease NS NS Deep Vein Thrombosis NS Endometrial Cancer NS Hip Fracture NS Invasive Breast Cancer NS Symptoms during Intervention Symptom Estrogen + Progestin Estrogen alone Breast tenderness Joint pain NS Urinary incontinence + + Vasomotor symptoms Stroke NS NS Manson et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the WHI s randomized trials. JAMA 2013;310:1368. Manson et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the WHI s randomized trials. JAMA 2013;310:

9 Osteoporosis and Menopause Not first-line treatment FDA approved for prevention but not treatment of osteoporosis Menostar is a low-dose transdermal estrogen that is indicated for prevention of osteoporosis Low dose oral ERT and vaginal ring (Femring) also used Hormone Therapy, Mood, and Depression Evidence is mixed on effect of estrogen therapy on mood when no depressive symptoms are present Evidence also mixed in women with depression Evidence is mixed regarding effect of progestogens on mood may worsen mood HT should not be recommended as an antidepressant NAMS The 2012 Hormone Therapy Position Statement of The North American Menopause Society. Menopause 2012;19: Hormone Therapy for Sleep Not FDA approved for sleep Oral ET improves nighttime restlessness and awakening Both ET and EPT may improve sleep quality by reducing hot flashes and night sweats Micronized progesterone at bedtime associated with improved sleep Sarti CD Menopause 2005;12:545 51; Caufriez A J Clin Endocrinol Metab 2011;96:E Treatment of Vulvovaginal symptoms Regular sexual activity Lubricants and moisturizers Vaginal estrogen therapy effective in 80 to 90% of women Compared with 75% in systemic ET Benefit in 1 to 3 months Symptoms can recur with cessation All available products with equal efficacy No short-term evidence of increased endometrial CA with ET alone Herbals (e.g. black cohosh, soy) not effective Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. FDA-approved indications for HT All oral estrogens, most transdermal estrogen, and one vaginal estrogen are approved for moderate to severe vasomotor symptoms Some oral and transdermal products are approved for prevention of postmenopausal osteoporosis, but not for treatment Local vaginal estrogen is approved for vulvovaginal symptoms Black Box warning for HT Subsequent to WHI trial, FDA requires estrogencontaining prescription therapies to carry black box warning about the adverse HT risks which include cardiovascular disorders, VTE, breast cancer, and probable dementia All HT products - including natural bioidentical and compounded hormone - assumed to have similar risks 9

10 Bioidentical hormones Hormones chemically identical or very similar to those made in the body. Available from two sources 1) FDA-approved and tested 2) unapproved and untested from compounding pharmacies Many well-tested, government-approved HT products contain bioidentical hormones Usually refers to compounded formulations Compounded preparations and salivary hormone testing not recommended NAMS. The 2012 position statement on hormone therapy by the North American Menopause Society. Menopause 2012;19: Duration of use Smallest dose Shortest duration possible Generally not in older (65+) women or prolonged use Extending EPT use is acceptable for: Women who request it and are aware of risks Prevention of osteoporosis for women at high risk of osteoporotic fracture when alternate therapies are not appropriate NAMS. The 2012 position statement on hormone therapy by the North American Menopause Society. Menopause 2012;19: Discontinuation HRs for all-cause mortality neutral for ET and EPT 50% chance of vasomotor symptoms recurring Symptom recurrence similar whether tapered or abrupt Decision to continue HT should be individualized NAMS. The 2012 position statement on hormone therapy by the North American Menopause Societ. Menopause 2012;19: Hormone Therapy summary Formulation, route of administration, and timing of initiation produce different effects Individual benefit-risk profiles are essential Absolute risks in healthy women ages are low Long-term use or HT initiation in older women has greater risks Breast cancer risk increases with EPT beyond 3-5 years ET can be considered for longer duration of use due to its more favorable safety profile NAMS. The 2012 position statement on hormone therapy by the North American Menopause Societ. Menopause 2012;19: Five Agreements 1. HRT is a reasonable treatment option in young and healthy women. 2. Preferred treatment of vaginal symptoms is low dose vaginal estrogen. 3. Uterus = progestogen 4. Blood clot risk is increased but rare in young women. 5. Breast cancer risk is increased with combined HRT after 3-5 years of continual risk but decreases after cessation. Stuenkel et al. A decade after the Women s Health Initiative the experts do agree. Menopause 2012;19. Break for Questions 10

11 Poll question - What other treatments do you prescribe for menopausal symptoms? A. Clonidine B. Gabapentin C. Ospemifine D. Paroxetine E. Venlafaxine Antidepressants for hot flashes Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine Paroxetine Escitalopram Serotonin norepinephrine reuptake inhibitors (SNRIs) Venlafaxine Desvenlafaxine Off-label use (except for paroxetine under the brand name Brisdelle) Thacker HL J Womens Health 2011;20: Other nonhormonal prescription options Nonhormonal prescription drugs (off-label use): Hypnotic Eszopiclone Anticonvulsant Gabapentin Antihypertensive Clonidine Neuropathic pain drug Pregabalin Thacker HL J Womens Health 2011;20: Ospemifene Estrogen agonist/antagonist Acts like estrogen vaginal tissue, endometrium, bone Anti-estrogen in breast Moderate-severe dyspareunia in postmenopausal women 60 mg daily Med Lett Drugs Ther Jul 8;55(1420):55 6 Nonprescription options CAM (hot flash reduction similar to placebo) Soy isoflavones Traditional Chinese medicine Acupuncture Herbs: Black cohosh, Cranberry, St. John s wort, Valerian, Chasteberry Over-the-counter hormones (dietary supplements) Topical progesterone Melatonin NCCAM science.htm. Accessed 8/27/12; Wang XY Chin J Integr Med 2011;17: Non-pharmacologic treatment for VMS Insufficient evidence to show a benefit of exercise for vasomotor symptoms Acupuncture is equal to sham but better than nothing Trials looking at phytoestrogens showed overall no benefit, although there was a strong placebo effect. Daley A. Cochrane, 2011., Dodin S. Cochrane, 2013., Lethaby A. Cochrane,

12 Black Cohosh 16 RCTs, > 2000 women Median dose 40 mg for median of 23 weeks VMS no change c/w placebo Menopausal symptom score no change c/w placebo Insufficient evidence for vulvovaginal symptoms or adverse effects Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD DOI: / CD pub2. Exercise doesn t help hot flashes but can help some symptoms of menopause. Exercise may help some symptoms: RCT trial of ~250 sedentary women Usual activity vs moderate intensity aerobic activity 3 times per week for 12 weeks No difference in VMS Small differences in insomnia, depression, and sleep quality Cochrane review found insufficient evidence of effect on VMS Sternfeld et al. Efficacy of exercise for menopausal symptoms: a randomized controlled trial. Menopause 2014;21:330. Daley A, Stokes Lampard H, Thomas A, MacArthur C. Exercise for vasomotor menopausal symptoms. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD DOI: / CD pub4. Putting It All Together Menopause is a natural part of the life cycle. Hot flashes are associated with multiple somatic complaints [SORT A]. Estrogen therapy is the most effective intervention for treatment of vasomotor symptoms [SORT A]. Adverse effects of Hormone Replacement Therapy are complex and variable but HRT can increase the risk of ischemic stroke and venous thromboembolic disease [SORT A]. Practice Recommendations Ask women about menopausal symptoms including vasomotor, psychological, somatic, and sexual. Counsel women about lifestyle options to alleviate symptoms and improve health. Consider HRT for treatment of VMS, recognizing the complexity of benefits and risks requires and individualized approach. Related Sessions Questions Now Ask the Expert: Menopause and Hormone Replacement Therapy Saturday * 1:30-2:30 pm; Room Mile High Ballroom 3A 12

13 Questions Later Jennifer Frank, MD ThedaCare Physicians 13