men.ht..8.7.18 Helping Our Menopausal Patients Make Sound Decisions Regarding Hormone Therapy Andrew M. Kaunitz MD, FACOG, NCMP University of Florida Term 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
Andrew M. Kaunitz, M.D. Menopause‐related Disclosures Clinical Trials Royalties (Funding to University of Florida • UpToDate Research Foundation): • Allergan Off-label • Bayer • I refer to off-label use of LNG- • Endoceutics IUD for endometrial • TherapeuticsMD protection Advisory Boards North American Menopause ● AMAG Society Consultant • Menopause Editorial Board ● Shionogi • 2017 HT Position Statement writing group member
Helping our Menopausal Patients Make Sound Decisions re Hormone Therapy Learning Objectives I. ● Our patients will likely spend more than one third of their lifespan as menopausal women…
Learning Objectives II: ● Identify vasomotor symptoms ● Recognize risks of HT, with emphasis on breast cancer, coronary heart disease, venous thromboembolism ● Review practical issues with use of HT for treatment of symptoms and prevention of osteoporosis – Describe a case: extended use of HT Up to date OBGYNs can change the conversation, thereby helping our patients make good choices regarding HT
Abbreviations – HT = hormone therapy – ET = estrogen therapy – CE = conjugated equine estrogen,E2=estradiol – EPT = combination estrogen‐progestin therapy – VMS= vasomotor symptoms – CHD= coronary heart disease – VTE= venous thromboembolism = Women’s Health Initiative (WHI) == North American Menopause Society (NAMS) –
Vasomotor Symptoms (VMS) ● Spontaneous sensations of warmth, usually felt on chest, neck and face – ‘hot flashes’ , ‘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 �me – Mean duration bothersome VMS >10 years o Sobering observation for symptomatic women o Important for decision making re treatment EW Freeman, et al. Obstet Gynecol 2011 HD Nelson. Lancet 2008
Treatment of VMS ● Appropriate when VMS – Disrupt daytime activities and/or sleep – Impair quality of life ● Estrogen used for many decades used to treat VMS – most effective treatment o numerous randomized, placebo‐controlled trials o 75% reduction in VMS frequency o significant reduction in VMS severity o 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 – 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 ● 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 – CE/MPA v. placebo: N ~ 17,000 , stopped Summer ’02, mean follow‐up 5.2 years – CE v. placebo: N ~ 11,000 , stopped Spring ’04, mean follow‐up 6.8 years Writing Group WHI. JAMA 2002 WHI Steering Committee. JAMA 2004
EPT: Breast Cancer Invasive Breast Cancer 0.03 26% * E+P Cumulative Hazard Estrogen + Progestin Kaplan-Meier Placebo 0.02 Placebo 0.01 0 0 1 2 3 4 5 6 7 Follow-Up Year *95% nominal CI Hazard Ratio = 1.26 (1.00-1.59) Adapted from: Writing Group WHI. JAMA 2002
EPT: Coronary Heart Disease (CHD) Initially, no Coronary Heart Disease analysis by 0.03 29% * Cumulative Hazard E+P age/years Kaplan-Meier 0.02 post-menopause Placebo presented… 0.01 Estrogen + Progestin 0 0 2 4 6 Placebo Follow-Up Year Hazard Ratio = 1.29 *Statistically significant based on 95% nominal CI on Hazard Ratios Adapted from: Writing Group WHI. JAMA 2002
EPT: Pulmonary Embolism Pulmonary Embolism 0.03 113% * Estrogen + Progestin Cumulative Hazard Placebo Kaplan-Meier 0.02 Only oral HT E+P 0.01 assessed Placebo 0 0 1 2 3 4 5 6 7 Follow-Up Year *95% nominal CI Hazard Ratio = 2.13 (1.39-3.25) Adapted from: Writing Group WHI. JAMA 2002
EPT & Colorectal Cancer, Hip Fracture Colorectal Cancer Hip Fracture 0.03 0.03 37% * 34% * Cumulative Hazard Cumulative Hazard 0.02 Kaplan-Meier Kaplan-Meier 0.02 Placebo Placebo 0.01 0.01 E+P E+P 0 0 2 5 0 1 3 4 6 7 2 5 0 1 3 4 6 7 Follow-up Year Placebo Estrogen + Progestin *Statistically significant based on 95% nominal CI on Hazard Ratios Adapted from: Writing Group WHI. JAMA 2002
WHI EPT Study: Findings at Early Interruption Summer 2002 Benefits Risks Fracture VTE/PE Colon Cancer MI CVA Breast Cancer Adapted from: Writing Group WHI. JAMA 2002
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
WHI’s Impact on Use of HT in US Women ● Since 2002, use of HT has decreased substantially ● Many clinicians, including OB/GYNs, remain reluctant to treat women with bothersome menopausal symptoms Many symptomatic women not treated… PI Jewett, et al. Obstet Gynecol 2014
WHI: 13- and 18-Year Follow-up: EPT and ET… JE Manson, et al. October, 2013 & September 2017
Risk of Breast Cancer @13 Years Cumulative f/u in Participants OVERALL (all ages at randomization) ● EPT Hazard Ratios (HRs): – Persistent, significant but modest ↑ 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 1.28 HR for breast cancer mean? <1 additional case per 1,000 EPT users annually can be attributed to HT (WHI). Per WHO: ‘rare’ Elevated risk with EPT slightly higher than that seen with one daily glass of wine; less than with 2 daily glasses (Nurses Health Study) Breast cancer common with or without use of HT Only 1 in 5 breast cancers occurring in women using EPT can be attributed to HT (WHI) JE Manson, et al. 2013 WY Chen, et al. 2011
Risk of All‐cause Mortality @18 Years Cumulative f/u in Participants OVERALL (all ages at randomization) ● EPT Hazard Ratios (HRs): – All‐cause mortality: 1.02 (NS) ● ET Hazard Ratios: – All‐cause mortality: 0.94 (NS) WHI recruited women age 50‐79 years‐‐ Age stratified results… JE Manson, et al. JAMA September 2017
All‐cause Pooled (EPT+ET) Mortality Hazard Ratios at 18 Years Cumulative f/u by Age at Randomization 70‐79 years 1.03 60‐69 years 0.98 50‐59 years 0.89 Risks with age at randomization JE Manson, et al. JAMA September 2017
HT, CHD and the ‘Timing Hypothesis’ ● If initiated early in the menopausal transition, HT does not increase coronary heart disease risk – May reduce morbidity/mortality if initiated early – ‘Early’: Age 50‐59 years, or < 10 years after menopause onset – HT increases CHD risk if initiated later ● Timing hypothesis may also apply to type II diabetes and dementia J Hsia. Arch Int Med 2006 JE Rossouw. JAMA 2007 RI Pereira, et al. JCEM 2015 JE Manson. N Eng J Med 2007 S Toh. Annals Int Med 2010 B Imtiaz. Neurology 2017 Stram DO. Menopause 2011 HN Hodis,. N Engl J Med 2016 MA Allison, JE Manson. Editorial. Menopause 2011 P Tuomikoski. Obstet Gynecol 2014
Treatment of Menopausal Symptoms: Practical Issues ● Compounded bioidentical HT ● HT/SERM combination therapy ● Transdermal vs. oral ET, and risk of VTE ● One clinician’s approach to HT initiation, continuation, discontinuation – A case: extended use of HT…
Compounded Bioidentical Hormone Therapy ● Estimated 2.5 million current users – Use propelled by post‐WHI confusion/fear, and celebrity endorsements – Most users not aware that Compounded HT not FDA‐monitored or approved o 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
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