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 10/11/2019 Andrew M. Kaunitz, M.D. Menopause-related Disclosures Clinical Trials (Funding to University of Florida Research Foundation): Allergan Bayer Endoceutics TherapeuticsMD Advisory Boards AMAG Consultant Shionogi Royalties UpToDate Off-label I refer to off-label use of LNG-IUD for endometrial protection North American Menopause Society Menopause Editorial Board 2017 HT Position Statement writing group member   2

10/11/2019 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… 3

Learning Objectives II: 10/11/2019 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 4

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 time Mean duration bothersome VMS >10 years Sobering observation for symptomatic women 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  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 10/11/2019 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 10/11/2019 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 26%* Invasive Breast Cancer Follow-Up Year 10/11/2019 EPT: Breast Cancer Invasive Breast Cancer 0.03 26%* E+P Estrogen + Progestin 0.02 Placebo Kaplan-Meier Cumulative Hazard Placebo 0.01 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) 10/11/2019 EPT: Coronary Heart Disease (CHD) Coronary Heart Disease Initially, no analysis by age/years post-menopause presented… 0.03 29%* E+P 0.02 Placebo Kaplan-Meier Cumulative Hazard 0.01 Estrogen + Progestin 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 10/11/2019 EPT: Pulmonary Embolism Pulmonary Embolism 0.03 Estrogen + Progestin 113%* Placebo 0.02 Kaplan-Meier Cumulative Hazard Only oral HT assessed 0.01 E+P Placebo 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 10/11/2019 EPT & Colorectal Cancer, Hip Fracture Colorectal Cancer Hip Fracture 0.03 0.03 37%* 34%* 0.02 0.02 Kaplan-Meier Cumulative Hazard Placebo Cumulative Hazard Kaplan-Meier Placebo 0.01 0.01 E+P E+P 1 2 3 4 5 6 7 1 2 3 4 5 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 10/11/2019 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 10/11/2019 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 10/11/2019 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 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. 18

WHI: 13- and 18-Year Follow-up: EPT and ET… 10/11/2019 WHI: 13- and 18-Year Follow-up: EPT and ET… JE Manson, et al. October, 2013 & September 2017

EPT Hazard Ratios (HRs): 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

EPT Hazard Ratios (HRs): All-cause mortality: 1.02 (NS) 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 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 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 ACOG and NAMS Recommend against using Compounded HT unless compelling reason present JV Pinkerton, N Santoro. Menopause 2015 ; AM Kaunitz, JD Kaunitz. Menopause 2015; M Gass, et al. Menopause 2015

Alternatives to Systemic Progestin when a Uterus is Present 10/11/2019 Alternatives to Systemic Progestin when a Uterus is Present CE 0.45mg + bazedoxifene 20mg tablets indicated to treat vasomotor symptoms and to prevent osteoporosis in menopausal women with an intact uterus Contraindications/warnings similar to those for conventional EPT Less bleeding than with EPT In contrast with EPT, does not ↑ mammographic breast density LNG IUD (smaller or larger) can be used off-label for endometrial protection in women taking ET JV Pinkerton. JCEM 2014 JA Harvey, JV Pinkerton. Menopause 2013 H Depypere, P Inki. Climacteric 2015 29

EPT: Pulmonary Embolism 10/11/2019 EPT: Pulmonary Embolism Pulmonary Embolism 0.03 Estrogen + Progestin 113%* Placebo 0.02 Kaplan-Meier Cumulative Hazard Oral estrogen used in WHI - ↑ hepatic production of clotting factors - transdermal estradiol does not ↑ clotting factors 0.01 E+P Placebo 1 2 3 4 5 6 7 Follow-Up Year *95% nominal CI Hazard Ratio = 2.13 (1.39-3.25) Writing Group WHI. JAMA 2002 30

Risk of VTE: Is Transdermal Estrogen Safer than Oral? No randomized trial data comparing benefits and risks 7 observational studies: VTE risk increased with oral, but not with transdermal ET Given consistency and biologic plausibility of observational data, reasonable to counsel patients that transdermal estrogen safer re risk of VTE Transdermal route particularly appropriate when obesity or other risk factors for VTE present Appropriate also for women with hypertriglyceridemia 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

Start HT using standard dose of estrogen Initiating HT in Symptomatic Young/Recently Menopausal women: One Clinician’s Approach (I) Start HT using standard dose of estrogen Oral estradiol (E2) 1 mg; Oral conjugated equine estrogen (CE) 0.625 mg Transdermal (TD) E2 0.05 mg patch For overweight/obese women, smokers and other women with ↑ risk VTE/CVD, consider TDE2 After VMS have resolved for several years on initial dose of estrogen, encourage trial of lower dose If VMS or loss of sense of wellbeing occur on the lower dose, patients can resume prior higher dose without an office visit AM Kaunitz. Menopause June 2014.

One Clinician’s Approach (II) When patient has been using HT with a low dose of estrogen (0.5 mg oral E2, 0.3-0.45 mg CEE, 0.0375, 0.025 mg TDE2) for several years, and reports no recent VMS: If patient not at elevated risk for osteoporosis, encourage discontinuing systemic HT Patient can restart HT if bothersome VMS or loss of sense of wellbeing recur Lowering the dose of or stopping systemic HT can result in symptomatic VVA/GSM; start vaginal ET if appropriate AM Kaunitz. Menopause June 2014.

One Clinician’s Approach (III) If patient at ↑ risk for osteoporosis (e.g. low BMI), discuss pros/cons of long-term/indefinite use of low dose ET with continuous or intermittent P endometrial suppression If progestin used intermittently, proactive endometrial surveillance appropriate Regular vaginal ultrasound assessment of endometrial thickness Prompt assessment of any spotting/bleeding appropriate in all menopausal women AM Kaunitz. Menopause June 2014.

Case: When is Extended Use of HT Appropriate? 62 yo woman, BMI 21, returns for well woman visit Prior hysterectomy, age 42 for uterine fibroids Due to bothersome VMS, began oral estrogen therapy in her early 50s Maternal history of hip fracture (age 76 years) Recently took 3-week cruise, leaving estrogen tablets at home Noted no hot flashes off estrogen

She asks: Should she continue ET? VMS no longer a concern for this 62 yo woman. However…

Her Risk For Osteoporosis is Elevated Low BMI; Maternal hip fx Estrogen effective in preventing osteoporosis and fractures Most estrogen formulations/doses FDA- approved for prevention of osteoporosis Standard and low doses effective NAMS. HT Position Statement. Menopause 2017. Kaunitz AM. Clinical Obstet Gynecol 2018

Osteoporosis Often Not Viewed as Preventable… Many women would prefer to avoid a diagnosis of osteoporosis, entailing long- term treatment with bisphosphonates or other bone agents Once VMS resolved, main indication for systemic HT is prevention of osteoporosis Kaunitz AM. Clinical Obstet Gynecol 2018

Use of HT to Prevent Osteoporosis: Clinical Considerations Use of HT for this indication more appropriate in higher-risk women (e.g. low BMI, +FH) If osteoporosis prevention the only indication for use, lower than standard dose HT appropriate Faster loss of BMD after stopping HT than with bisphosphonates Given EPT’s less favorable safety profile, long-term use of ET to prevent osteoporosis more appropriate than EPT; likewise, transdermal preferred when HT used in older menopausal women NAMS. HT Position Statement. Menopause 2017 Kaunitz AM. Clinical Obstet Gynecol 2018

She chooses to continue low dose transdermal ET… Follow-up of Case After her cruise (age 62), she chose to continue ET for skeletal health reasons, switching to 0.025 mg estradiol patch DXA at age 65: Lumbar Spine: T= -0.8 Femoral neck: T= -0.2 She is now age 71 BMI now 22; BMD remains normal She chooses to continue low dose transdermal ET…

Notice Received From Insurance Company (72 yo patient on 0 Notice Received From Insurance Company (72 yo patient on 0.025 mg estradiol patch) “Your patient is at least 65 years old and has evidence for either an estrogen containing preparation. Estrogen containing preparations should be avoided in older women …“ Insurance companies interpret American Geriatric Society ‘Beers List’ as indicating they should not reimburse for any systemic HT in women age 65+ years American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults: The American Geriatrics Society 2012 Beers Criteria Update Expert Panel 2012 J Am Geriatr Soc 2012; 60 (4): 616-631.

Use of HT in Older Menopausal Women: ACOG and NAMS Guidance “…ACOG recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of HT and estrogen therapy should be individualized based on each woman’s risk–benefit ratio and clinical presentation.” NAMS 2017 HT Position Statement: “The recommendation to use the Beers criteria to routinely discontinue systemic hormone therapy after age 65 is not supported by data” ACOG. Practice Bulletin 141. Obstet Gynecol January, 2014. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728-753. Available at no charge: menopause.org

Systemic HT: appropriate to initiate for In summary, regarding evidence on HT, the pendulum is swinging… Well informed OB/GYNs can change the conversation, removing fear from discussions re HT, and help women 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

Clinical Expert Series Additional Information Clinical Expert Series Management of Menopausal Symptoms Andrew M. Kaunitz, MD, and JoAnn E. Manson, MD, DrPH Obstet Gynecol October 2015; 126: 859–-876 The 2017 Hormone Therapy Position Statement of the North American Menopause Society. Available at no charge: Menopause.org Menopause 2017: Jul;24:728-753 Thank you!