Treatment of Menopausal Symptoms: A 2017 Update for Clinicians Andrew M. Kaunitz MD, FACOG, NCMP University of Florida Research Foundation Professor and Associate Chairman Department of Obstetrics and Gynecology University of Florida College of Medicine - Jacksonville Medical Director, and Director of Menopause & GYN Ultrasound Services UF Southside Women’s Health Specialists FOMA.District2.men.ht. 5 21 17

Learning Objectives: Menopause & Hormone Therapy 5/11/2018 Learning Objectives: Menopause & Hormone Therapy Our patients will likely spend more than one third of their lifespan as menopausal women… By remaining up to date, we can help our patients make sound choices regarding HT Identify vasomotor symptoms (VMS) and recommend hormonal / nonhormonal treatment Recognize risks of HT, with emphasis on breast cancer, venous thromboembolism (VTE), and coronary heart disease (CHD) 2

Abbreviations HT = hormone therapy ET = estrogen therapy CE = conjugated equine estrogen,E2=estradiol EPT = combination estrogen-progestin therapy = Women’s Health Initiative (WHI)

Andrew M. Kaunitz, M.D. DISCLOSURES 5/11/2018 Andrew M. Kaunitz, M.D. DISCLOSURES Clinical Trials (Funding to University of Florida Research Foundation): Bayer TherapeuticsMD Advisory Boards Allergan Mithra Pfizer Consultant Shionogi Royalties UpToDate North American Menopause Society Menopause Editorial Board Board of Trustees HT Position Statement writing group member   4

Vasomotor Symptoms (VMS) Spontaneous sensations of warmth, usually felt on chest, neck and face may be called ‘hot flushes’ or ‘night sweats’ often associated with perspiration, palpitations and anxiety may impair quality of life Variable in frequency, duration and severity usually < 5 minutes Can be triggered by warm environments, hot drinks, emotional stress VMS: Most common reason women seek care at time of menopausal transition HD Nelson. Lancet 2008

Prevalence and Timing of VMS Experienced by > 50% of menopausal women Substantial increase in frequency and severity during menopausal transition (perimenopause) For some women, VMS persist 6 months to several years, with ↓ frequency and intensity over time Mean duration bothersome VMS 10.2 years EW Freeman, et al. Obstet Gynecol 2011 HD Nelson. Lancet 2008

Treatment of VMS Treatment appropriate when VMS disrupt daytime activities and/or sleep Estrogen used for many decades used to treat VMS most effective treatment  numerous randomized, placebo-controlled trials 75% reduction in VMS frequency significant reduction in VMS severity Oral and transdermal estrogen have similar efficacy Progestin therapy, including DMPA and megestrol also effective in treating VMS HD Nelson. JAMA 2004 AH MacLennan, et al. Cochrane Database Syst Rev 2004 HD Nelson. Lancet 2008

Hormone Therapy Clear Controversial VMS: most common indication for HT 5/11/2018 Hormone Therapy Clear VMS: most common indication for HT HT’s efficacy in treating VMS well-established Controversial Our understanding of HT’s safety….

WHI: Women’s Health Initiative 5/11/2018 Multicenter, double-blind, placebo-controlled trial of women age 50-79 years at baseline, designed to assess HT’s impact on cardiovascular disease Mean age at screening 63-64 years Planned 10-year trial; stopped early CEE/MPA v. placebo: N= 16,608 , stopped Summer ’02, mean follow-up 5.2 years CEE v. placebo: N = 10,739 , stopped Spring ’04, mean follow-up 6.8 years Largest RCT of menopausal hormone therapy Writing Group WHI. JAMA 2002 WHI Steering Committee. JAMA 2004

WHI EPT Study: Findings at Early Interruption Summer 2002 5/11/2018 WHI EPT Study: Findings at Early Interruption Summer 2002 Risks Benefits Fracture VTE/PE Colon Cancer MI CVA Breast Cancer Adapted from: Writing Group WHI. JAMA 2002

WHI ET Initial Findings: Summary as of 2004 5/11/2018 WHI ET Initial Findings: Summary as of 2004 ET component of study stopped early after 6.8 years of follow-up ET not found to significantly impact risk of breast cancer, CHD, PE, or colorectal cancer significant reduction in hip fracture risk Overall safety of ET appears greater than EPT 2004 findings received less attention than 2002 report WHI Steering Committee. JAMA 2004 Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.

WHI’s Impact on Use of HT in US Women 5/11/2018 WHI’s Impact on Use of HT in US Women Since 2002, use of all HT has decreased substantially Main initial conclusion from WHI is that HT not appropriate to prevent coronary heart disease Nonetheless, following WHI findings in 2002, many clinicians remain reluctant to treat women with bothersome menopausal symptoms Many symptomatic women not treated… PI Jewett, et al. Obstet Gynecol 2014 J Shifren and I Schiff. Obstet Gynecol 2010 Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333. 12

WHI: 13-Year Follow-up: EPT and ET… 5/11/2018 WHI: 13-Year Follow-up: EPT and ET… JE Manson, et al. October 2, 2013

EPT Hazard Ratios (HRs): Significant ↑ risk breast cancer: 1.28 Risk of Breast Cancer @13 Years Cumulative f/u in Participants OVERALL (all ages at randomization) EPT Hazard Ratios (HRs): Significant ↑ risk breast cancer: 1.28 ET Hazard Ratios: Significant ↓ risk breast cancer: 0.79 JE Manson, et al. JAMA October 2, 2013

EPT and Elevated Risk of Breast Cancer What does an HR of breast cancer of 1.28 mean? Putting HR of 1.28 in context: <1 additional case per 1,000 EPT users annually (WHI) can be attributed to HT HR with EPT slightly higher than that seen with one daily glass of wine; less than HR with 2 daily glasses (Nurses Health Study) 1 in 5 breast cancers occurring in women using EPT can be attributed to HT JE JE Manson, et al. 2013 WY Chen, et al. 2011

WHI recruited women age 50-79 years… Risk of All-cause Mortality @13 Years Cumulative f/u in Participants OVERALL (all ages at randomization) EPT Hazard Ratios (HRs): All-cause mortality: 0.99 (NS) ET Hazard Ratios: WHI recruited women age 50-79 years… JE Manson, et al. JAMA October 2, 2013

50-59 years ET: 0.78 EPT: 0.88 60-69 years ET: 1.02 EPT: 0.99 All-cause Mortality Hazard Ratios* at 13 Years Cumulative f/u by Age at Randomization 50-59 years ET: 0.78 EPT: 0.88 60-69 years ET: 1.02 EPT: 0.99 70-79 years ET: 1.06 EPT:1.04 * All p-values>0.05; but trend by age is meaningful JE Manson, et al. JAMA October 2, 2013

Overall, R:B ratio more favorable for ET than EPT Conclusions: WHI EPT+ET Trial-- 13 Years of Follow-Up, and Published Literature Overall HT Risk: Benefit ratio most favorable when initiated in younger menopausal women HT appropriate for symptomatic patients in their 50s or within 10 years of menopause onset Overall, R:B ratio more favorable for ET than EPT AM Kaunitz, JE Manson. Obstet Gynecol 2015

Compounded Bioidentical Hormone Therapy Use growing in the US, with an estimated 2.5 million current users Use propelled by celebrity endorsements Most users not aware that Compounded HT not FDA monitored or approved Salivary testing often employed by MDs prescribing compounded HT Such testing does not correlate with serum steroid levels Compounded Progesterone cream often Rxed… JV Pinkerton, N Santoro. Menopause 2015 ; AM Kaunitz, JD Kaunitz. Menopause 2015; M Gass, et al. Menopause 2015

Compounded Bioidentical Hormone Therapy National survey: cases of endometrial cancer in women using compounded HT FDA-approved bioidentical HT formulations available: estradiol patches, tablets, vaginal cream/tablets, progesterone in oil capsules JV Pinkerton, N Santoro. Menopause 2015 ; AM Kaunitz, JD Kaunitz. Menopause 2015; M Gass, et al. Menopause 2015

VTE & CVA Risk and Route of ET: 7 Observational Studies Oral estrogen therapy: ↑ risk VTE & CVA Transdermal ET: no ↑ risk Biologic plausibility (transdermal=no first pass hepatic effect) PY Scarabin, et al. Lancet 2003 M Canonico, Arterioscler Thromb Vasc Biol 2010 A Bergendal et al.; JA Simon et al. Menopause 2016 C Renoux, et al. J Thromb Haemost 2010 C Renoux, et al. BMJ 2010 L Laliberté, et al. Menopause 2011 RE Roach, et al. J Thromb Haemost 2012

Oral vs. Transdermal Estrogen No randomized trial data comparing benefits and risks Given consistency and biologic plausibility of observational data, reasonable to conclude transdermal estrogen safer re risk of VTE Clinicians and women should discuss this safety issue when making decisions regarding route of HT Transdermal route particularly appropriate for overweight/obese and other HT users at elevated baseline risk Reasonable starting dose 0.05 mg estradiol patch (equivalent to 1.0 mg oral estradiol, or 0.625 mg conjugated equine estrogen) PY Scarabin, et al. Lancet 2003 M Canonico, Arterioscler Thromb Vasc Biol 2010 A Bergendal et al.; JA Simon et al. Menopause 2016 C Renoux, et al. J Thromb Haemost 2010 C Renoux, et al. BMJ 2010 L Laliberté, et al. Menopause 2011 RE Roach, et al. J Thromb Haemost 2012

Menopausal Hormone Therapy: A Clinician’s Evidence-based 2017 Perspective The pendulum is swinging…towards an evidence-based perspective on use of hormone therapy Clinicians who remain up to date can help patients make sound choices regarding treatment of menopausal symptoms Systemic HT: appropriate to initiate for most healthy women with bothersome VMS who are <age 60, or within 10 years of menopause onset Thank you!