Benton Franklin County Medical Society 31st Annual CME Seminar

Management of Current HT/ET and SERM Recommendations Benton Franklin County Medical Society 31st Annual CME Seminar February 21, 2015 Kennewick, Washington Spokane steoporosis Dr. Lynn Kohlmeier Lynn Kohlmeier, MD Endocrinologist Spokane, WA

Management of Current HT/ET and SERM Recommendations Lynn Kohlmeier, MD Impact and Consequences of Estrogen Loss History of Estrogen + Progesterone (EPT or HT) and Estrogen alone (ET) WHI Affect Safety Post-WHI Cardiac/Vascular Breast Endometrium Bone Selective Estrogen Receptor Modulator (SERM) SuperSERM or Tissue Selective Estrogen (TSE) 2

Management of Current HT/ET (Consequences of Estrogen Loss) Skin dryness and Aging Vasomotor symptoms Hot flashes Sleep disturbance Cardiovascular disease Urogenital atrophy Osteoporosis

History of Hormone Therapy (Pro-Estrogen and Anti-Estrogen Camps) 1896 1927 1932 1940s 1966 1970s First published paper on treating severe climacteric symptoms Preventing climacteric syndrome with estrogen first mentioned Wilson s Feminine forever published; increased endometrial cancer First commercial estrogen preparations become available CE introduced as a treatment for hot flushes and sleep disturbances Progestins added to protect the endometrium van Keep PA. Maturitas. 1990;12:163-170. Kopera H, et al. Intl J Clin Pharmacol, Ther Toxicol. 1991;29(10):412-417. slide compliments of Risa Kagan, M 4

Management of Current HT/ET Recommendations PRE-WHI MIRACLE DRUG CURES Hot Flashes Reduces Osteoporosis Reduces Heart Disease Decreases Wrinkles Improves Cognition Enhances Well-Being slide compliments of Risa Kagan, MD 5

*from primate Slide atherosclerosis compliments studies of Brad Hurst, MD Management of Current HT/ET Recommendations Estrogen before plaque >>> prevents plaque* Estrogen after plaque >>> accelerates plaque*

Management of Current HT/ET and SERM Recommendations Spokane steoporosis Dr. Lynn Kohlmeier

FDA- Approved Angeliq (drospirenone and estradiol) Alora (estradiol transdermal system) Climara (estradiol transdermal system) Climara Pro (estradiol/levonorgestrel transdermal system) Combipatch (estradiol; norethindrone acetate transdermal system) Delestrogen (estradiol valerate injection) Duavee (basodoxifene/cee, SuperSERM/TSE) Enjuvia (synthetic conjugated estrogens; B) Estraderm (estradiol transdermal system) Estrasorb (estradiol topical emulsion) Evista (raloxifene, SERM) Femhrt (norethindrone acetate/ethinyl estradiol tablets) Femring (estradiol acetate vaginal ring) Prefest (estradiol/norgestimate) Tablets Premarin (conjugated estrogens tablets) Premarin Intravenous (conjugated estrogens, USP for injection) Vivelle (estradiol transdermal system) Vivelle-Dot (estradiol transdermal system) Premarin Vaginal Cream (conjugated estrogens) PREMPRO/PREMPHASE (conjugated estrogens/ medroxyprogesterone acetate tablets) 8 Spokane steoporosis Dr. Lynn Kohlmeier

History of Hormone Therapy (Disease Prevention) 1991 WHI Established 2002 WHI E+P (HT) Arm Halted 2004 FDA Treatment Recommendations WHI E-Only Arm Ended WHI Trial: 3 Components Randomized Clinical Trial Observational Study Community Prevention Study slide compliments of Risa Kagan, MD

History of Hormone Therapy (WHI Trial Design) YES N= 10,739 Hysterectomy NO N= 16,608 Conjugated equine estrogen (CEE) 0.625 mg/d (E alone) Placebo CEE 0.625 mg/d + medroxyprogesterone acetate (MDA) 2.5mg/d (E + P or HT) Placebo slide compliments of Risa Kagan, MD 10

Management of Current HT/ET Recommendations POST-WHI DANGER DRUG CURES Hot Flashes Reduces Osteoporosis Enhances Well-Being Reduces Colon Cancer?? Heart Disease?? Breast Disease slide compliments of Risa Kagan, MD 11

WHI Outcomes with HT/Prempro Overall Outcomes With PREMPRO Reported From the WHI - Annualized Attributable Risk per 1,000 Women Change in Annual Events per 1,000 Women 1.8 1.5 1.2 0.9 0.6 0.3 0-0.3-0.6 * 0.8 0.8 Invasive Breast Cancer 1 * Stroke 2 1.8 VTE 3 0.7 CHD2-0.1 Endometrial Cancer 4 NS = statistically nonsignificant change; VTE = venous thromboembolism, CHD = coronary heart disease *Nominal confidence intervals significant (adjusted confidence intervals not shown). No adjudicated data available. 1. Anderson GL, et al. Maturitas. 2006;55:103-115. 2. Rossouw JE, et al. JAMA. 2007;297:1465-1477. 3. Cushman M, et al. JAMA. 2004;292:1573-1580. 4. Anderson GL, et al. JAMA. 2003;290:1739-1748. * NS NS -0.6 * Colorectal Cancer 5-0.5 * Hip Fractures 6-0.6 * Vertebral Fractures 6 12

WHI Outcomes with HT/Prempro WHI E+P Substudy Risk by Age Attributable risk per 1,000 women Number of Events 5 3 1-1 -3 0.5 0.5 0.5 1 CHD 1 Stroke Colorectal cancer 1.1 4 Invasive breast cancer 3 VTE 5 Hip fracture 3.5 * 2.4 0.8 1 1.6 1.3 1.1 0-0.1-0.2-0.2-0.9-1.4-1.5 2 Placebo (Baseline Risk) -5 Age 50-59 Age 60-69 Age 70-79 *Significance by hazard ratio and 95% confidence interval compared with placebo. Significance by hazard ratio and 95% confidence interval compared with 50-59 year old women taking placebo. 1. Rossouw JE, et al. JAMA. 2007;297:1465-1477. 2. Chlebowski RT, et al. JAMA. 2003;289:3243-3253. 3. Cushman M, et al. JAMA. 2004;292:1573-1580. 4. Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004. 5. Cauley JA, et al. JAMA. 2003;290:1729-1738. - 4 13

WHI Outcomes with ET/Premarin Overall Risks With PREMARIN Reported From the WHI: Annualized Attributable Risk per 1,000 Women Change in Annual Events per 1,000 Women 1.2 0.9 0.6 0.3 0-0.3-0.6-0.9 NS -0.6 Invasive Breast Cancer 1 * 1.2 0.8 NS NS -0.3 Stroke 2 VTE 3 CHD 2 0.1 NS Colorectal Cancer 4-0.7-0.7 * Hip Fractures 5 * Vertebral Fractures 5 Placebo (Baseline Risk) NS = statistically nonsignificant change; VTE = venous thromboembolism; CHD = coronary heart disease. *Nominal P<0.05 vs. placebo (adjusted confidence intervals not shown). The risk of VTE (deep vein thrombosis [DVT] and pulmonary embolism) was reported to be increased for women receiving daily CE compared with placebo, although only the increased risk of DVT reached statistical significance. The increase in VTE risk was demonstrated during the first 2 years. 1. Stefanick ML, et al. JAMA. 2006;295:1647-1657. 2. Rossouw JE, et al. JAMA. 2007;297:1465-1477. 3. Curb JD, et al. Arch Intern Med. 2006;166:772-780. 4. Ritenbaugh C, et al. Cancer Epidemiol Biomarkers Prev. 2008;17:2609-2618. 14

WHI Outcomes with ET/Premarin WHI E-Alone Substudy Risk by Age Attributable risk per 1,000 women 5 1 CHD 1 Stroke Colorectal cancer 2 Invasive breast cancer 3 VTE 4 Hip fracture 2 Number of Events 3 1-1 -3-5 -1-0.2-0.8 0.4 0.3 2* 0.7-0.5-0.4-0.3-0.7-1 Age 50-59 Age 60-69 Age 70-79 *Significance by hazard ratio and 95% confidence interval compared with placebo. Significance by hazard ratio and 95% confidence interval compared with 50-59 year old women taking placebo. 1-0.2 1.7 1.1 1.7 * -2.1 * Placebo (Baseline Risk) No significant age interaction for VTE. 1. Rossouw JE, et al. JAMA. 2007;297:1465-1477. 2. Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-1712. 3. Curb JD, et al. Arch Intern Med. 2006;166:772-780. 4. Jackson RD, et al. J Bone Miner Res. 2006;21:817-828. - 2-15

Post WHI: Challenges of ET/HT Clinician Time Constraints Buzz about Bioidenticals & Alternatives Women Need Individualized Treatment Media Impact Public s Understanding of HT Risks & Benefits slide compliments of Risa Kagan, MD 16

Management of Current HT/ET Recommendations A Decade After The Women s Health Initiative The Experts Do Agree Statement was published in North American Menopause Society (Menopause), American Society for Reproductive Medicine (Fertility and Sterility), and Endocrine Society (Journal of Clinical Endocrinology and Metabolism) 17 slide compliments of Risa Kagan, MD

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Vasomotor Symptoms ET with or without progestogen is most effective treatment of menopause-related vasomotor symptoms Almost all systemic HT products are approved for vasomotor symptom relief Vaginal Symptoms ET is most effective treatment of moderate to severe symptoms of vulvar and vaginal atrophy Many systemic HT and local vaginal ET products available for treating these symptoms 18

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Sexual Function Low-dose local ET may improve sexual function by improving lubrication and increasing blood flow HT is not recommended as sole treatment of other sexual function problems (eg, diminished libido) Urinary Tract Health Local ET benefit women with overactive bladder Only vaginal ET effective for urinary tract infection Systemic ET may worsen or provoke stress incontinence Ultralow-dose transdermal ET has no effect on incontinence 19

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Osteoporosis HT reduced the risk for fracture (eg, hip, spine, nonspine) in postmenopausal women in the Women s Health Initiative (WHI) who were not selected on basis of osteoporosis Many systemic HT products are approved for preventing postmenopausal osteoporosis No HT product is approved for treating osteoporosis Extended use of HT is option for women at high risk of osteoporotic fracture when alternate therapies aren t appropriate Risks of long-term HT use should be considered Benefits of HT on bone mass dissipate quickly after discontinuation 20

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Coronary Heart Disease ET may reduce CHD and coronary artery risk when initiated in younger and more recently postmenopausal women without a uterus HT is currently not recommended for coronary protection in women of any age Stroke Both ET and HT appear to increase ischemic stroke risk and have no effect on hemorrhagic stroke risk 21

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Venous Thromboembolism Oral HT increases the risk of VTE in postmenopausal women VTE risk emerges soon after HT initiation (1-2 y) and decreases over time Lower VTE risk with either EPT or ET in women before age 60 Possible lower VTE risk with transdermal and lower oral HT doses. No RCT evidence 22

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Endometrial Cancer Unopposed systemic ET in postmenopausal women with an intact uterus is associated with increased endometrial cancer related to dose/duration of use HT not recommended with history of endometrial cancer history Breast Cancer Diagnosis of breast cancer increases with HT use beyond 3-5 years Unclear whether HT risk differs between continuous and sequential progestogen HT and to a lesser extent ET increase breast cell proliferation, breast pain, and mammographic density 23

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Breast Cancer HT may impede diagnostic interpretation of mammograms Breast cancer diagnosis dissipated 3 years post HT cessation Breast cancer mortality higher in women assigned to HT compared to placebo Women starting HT shortly after menopause experience increased breast cancer risk, but those with a gap time greater than 5 years do not ET arm of WHI showed no increased cancer risk after mean 7.1 years on study ET and HT use in breast cancer survivors may increase recurrence risk

Management of Current HT/ET Benefits & Risks Mood and Depression NAMS position statement. Menopause 2012 Evidence is mixed on effect of HT on mood when no clinical depression Progestogens in EPT may worsen mood when history of PMS, PMDD, or clinical depression HT should not be recommended as an antidepressant Cognitive Aging/Dementia Evidence is mixed on effect of HT on cognition at time of menopause with no effect on episodic memory or executive function with ET at time of menopause WHI Memory Study in HT use ages 65-79 an increase in dementia was reported

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Premature Menopause/ Premature Ovarian Insufficiency Data regarding HT in women over age 50 should not be extrapolated to younger postmenopausal women Likely risks attributable to HT are smaller and benefits greater in younger women Use of HT or OCPs until median age of menopause is recommended at which time decision reevaluated Total Mortality HT may reduce total mortality when initiated soon after menopause ET and HT may reduce total mortality by 30% when initiated in women younger than age 60

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Practical Therapeutic Issues Well-tested, government-approved, brand-name HT/ET products contain hormones chemically identical to those made by ovaries Bioidentical Hormone Therapy BHT usually refers to custom-compounded formulations marketed as more natural or bioidentical BHT should include package inserts explaining benefits & risks just like government-approved HT/ET products

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Dose & Route of Administration Therapeutic goal is lowest effective estrogen dose consistent with individual treatment goals, benefits, and risks, plus progestogen for women with a uterus Lower doses have fewer side effects and may have more favorable benefit-risk ratio than standard doses but lower doses not been tested in long-term trials All routes of administration effectively treat symptoms Non-oral routes may offer both advantages and disadvantages compared with oral route (no RCTs) Transdermal ET may be associated with lower risk of DVT, stroke, and MI

Management of Current HT/ET Benefits & Risks NAMS position statement. Menopause 2012 Bioidentical Hormone Therapy (BHT) Custom BHT may combine several hormones and use nonstandard routes of administration Use of compounded BHT and salivary hormone testing are not recommended BHT is not tested for efficacy, safety, batch standardization, or purity FDA says compounding pharmacies make false and misleading claims about safety/effectiveness of BHT Compounded HT should only be used by women allergic to ingredients in approved products

Management of Current HT/ET Treatment Duration of Use HT increases risk of breast cancer incidence and mortality with 3-5 years of use ET poses no increase of breast cancer with early postmenopausal use; decrease found after hiatus in estrogen exposure With ET, potential CAD/CHD benefits with early use Initial increase in CHD risk when HT is initiated further from menopause Extending HT acceptable for: NAMS position statement. Menopause 2012 Women who request it and well aware of potential risks/benefits Prevention of further osteoporosis-related fracture and bone loss when alternate therapies are not appropriate or cause unacceptable adverse effects

Management of Current HT/ET Treatment NAMS position statement. Menopause 2012 Discontinuation All-cause mortality neutral for both Symptom recurrence similar whether tapered or abruptly discontinued After 3 years of ET discontinuation: - No increase in CHD, DVT, stroke, hip fracture, colorectal cancer, or total mortality - Decrease in breast cancer persisted After 3 years of HT discontinuation: - Rate of cardiovascular events, fractures, and colon cancer same as placebo group - Increase in rate of all cancers and mortality from breast cancer

Management of Current HT/ET Treatment NAMS position statement. Menopause 2012 Conclusions & Recommendations Individualization is key in decision to use HT and should incorporate the woman s health and QOL priorities as well as her personal risk factors for VTE, CHD, stroke, and breast cancer Duration recommendations differ for HT and ET: Use of HT is limited by risk of breast cancer and breast cancer mortality after 3-5 years Use of ET is more favorable with benefit-risk profile during mean of 7 years of use and 4 years of followup allowing more flexibility in duration of use

Management of Current HT/ET Treatment NAMS position statement. Menopause 2012 Conclusions & Recommendations ET is most effective for vulvar and vaginal atrophy Low-dose local vaginal ET advised for vaginal sxs Women with premature/early menopause can use HT until median age of menopause (51 y); longer duration can be considered for symptoms Although ET did not increase breast cancer risk in WHI, no safety data for breast cancer survivors, and RCT reported higher increase in recurrence Both transdermal and low-dose oral estrogen associated with lower risks of VTE and stroke but RCT evidence not yet available

SERM, Selective Estrogen Receptor Modulator, Raloxifene (Evista) Reduces bone resorption/turnover 60 mg oral daily now generic 30% in biochemical marker Approved for both prevention and treatment 2-3% BMD increases at hip & spine @ 3yrs Decreased incidence of vertebral fractures (30-50%) in women w preexisting vertebral fractures or low bone mass No effect on nonvertebral or hip fractures observed Adverse effects: Hot flashes, venous thrombosis, leg cramps Extra-skeletal effects: Reduction in invasive breast cancer No increase in stroke, MI or death Reduction in LDL Ettinger B, et al. JAMA. 1999;282:637-45.

First SuperSERM/TSE Benefits & Risks Duavee Approved Oct 2013 by the FDA pairs estrogen with a SERM rather than progestin, which helps prevent uterine lining thickening that can result from treatment with only estrogen CONJUGATED ESTROGEN (which help provide significant relief from moderate-to-severe hot flashes due to menopause and prevent bone loss) BAZEDOXIFENE (an estrogen agonist/antagonist, also known as a selective estrogen receptor modulator or SERM, which helps protect the uterine lining from the thickening that may occur in women who take estrogens alone) 35

First SuperSERM/TSE Benefits & Risks 36

First SuperSERM/TSE Skeletal Health Bazedoxifene, raloxifene (Evista), or placebo studied in 2-year randomized trial in 1583 postmenopausal women with low bone mass, T-score -1.0 to -2.5 Bazedoxifene or raloxifene similarly maintained spine and hip BMD, whereas women in the placebo group had significant bone loss at both sites (between group differences were 1.5 and 1.6%, respectively) Bazedoxifene (20 or 40 mg daily) or raloxifene (60 mg daily) in 3-year randomized trial in 6847 postmenopausal women with osteoporosis, T-score -2.5 or lower showed significant reductions in cumulative incidence of new vertebral fractures compared to placebo (fracture rates of 2.3, 2.5, 2.3 versus 4.1%) Risk of nonvertebral fractures were not decreased however in the raloxifene or bazedoxifene groups compared with controls

First SuperSERM/TSE Skeletal Health Duavee, BZA/CE, raloxifene, or placebo was studied in 3397 postmenopausal women with low bone density Lowest dose BZA (10 mg) combined with highest dose CE (0.625 mg) resulted in greatest increase in BMD In women > 5 years post menopause, formulations of BZA/CE containing BZA 10 or 20 mg with CE 0.45 or 0.625 mg resulted in greater increases in spine BMD than raloxifene (between group difference 1.2 to 1.6%)

Management of Current HT/ET and SERM Recommendations A free mobile app for menopause symptom management from The North American Menopause Society Clinical decision-support tool Available for iphones and ipads Dual mode for Clinicians and Women/Patients Learn more at: Menopause 2015; 22(3):[e-pub 10/13/14] or at www.menopause.org

Management of Current HT/ET and Spokane SERM Recommendations steoporosis Dr. Lynn Kohlmeier Risk/Benefit Analysis: Risk of a therapeutic intervention vs. Risk of not treating, balanced against the possible benefit of a therapy Thank You For Your Attention! www.menopause.org Risk Benefit