Menopause Hormone Research Benefits/Risks Essentials April IWH 2015

Menopause Hormone Research Benefits/Risks Essentials April IWH 2015 Tori Hudson, N.D. Professor, NCNM/Bastyr U Medical Director, A Woman s Time Program Director, Institute of Women s Health and Integrative Medicine www.drtorihudson.com www.instituteofwomenshealth.com

Disclosures Director of research/education Vitanica Scientific Advisory Boards: Gaia Professional Solutions Nordic Naturals Natural Health International Integrative Therapeutics Nutritional Fundamentals for Health Pharmaca Integrative Pharmacies

Objectives Review of key research studies in menopause and hormone therapy Review of evidence based benefits and risks Ability to address controversial issues in HRT prescribing

Fundamental Goals of Intervention Symptom relief -with minimal impact on increasing risks of other diseases Disease Prevention and Treatment Opportunity for changes in life Education about health

Individualized Approach and Risk Assessment Symptom severity, duration, nature Risk for osteoporosis Risk for Cardiovascular Disease Risk for Alzheimer s dementia Other- colon cancer, breast cancer, macular degeneration, DM, gallstones Patient priorities, values, fears, concerns

Terminology (it s not replacement anymore) ET- estrogen therapy EPT-estrogen and progestogen therapy HT-hormone therapy (covers ET and EPT) Progestogen- class includes progesterone and progestins CC-EPT-continuous combined EPT means daily dosing of both estrogen and progestogen CS-EPT- continuous/sequential EPT= daily estrogen and cyclic progestogen (14 days a month or on 3 days off 3 days {ortho prefest}) MHT (menopausal hormone therapy

Key Points NAMS 2012 Hormone Therapy Position Statement NAMS position statement. Menopause 2012.

Objective To further distinguish the differences in the therapeutic benefit-risk ratio between estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) at various ages and time intervals since menopause onset 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 NAMS position statement. Menopause 2012.

Conclusions & Recommendations (cont d Duration of use recommendations differ for EPT and ET: For EPT, duration is limited by the increased risk of breast cancer and breast cancer mortality associated with 3-5 years of use For ET, more favorable benefit-risk profile during mean of 7 years of use and 4 years of follow-up, a finding that allows more flexibility in duration of use NAMS position statement. Menopause 2012.

Conclusions & Recommendations (cont d) ET is most effective treatment for vulvar and vaginal atrophy; low-dose local vaginal ET advised when only vaginal symptoms are present NAMS position statement. Menopause 2012.

Symptomatic Vulvovaginal Atrophy 2013 NAMS position statement First line therapies: nonhormonal lubricants or consider regular use of long acting vaginal moisturizers Moderate to severe symptomatic VVA and milder VVA who do not respond to lubricants and moisturizers: ET either vaginally at low dose or systemically Low dose vaginal estrogen is preferred with VVA is the only menopausal sx. Consider Ospemifene for dyspareunia History of breast or endometrial cancer: management depends on preference, need, understanding of potential risks and consultation with her oncologist. ET carries a class effect risk of VTE. Low dose vaginal estrogen carry a very low risk A progestogen is generally not indicated when low dose vaginal estrogen is administered for symptomatic VVA. No endometrial safety data if > 1 yr. If high risk of endometrial cancer or is using a higher dose of vaginal ET: transvaginal US or intermittent progestogen therapy. Spotting or bleeding in a postmenopausal woman with uterus: thorough evaluation that may include transvaginal and/or endometrial biopsy.

Conclusions & Recommendations (cont d) Women with premature or early menopause can use HT until median age of menopause (51 y); longer duration can be considered for symptom management

Duration of Use (cont d) Extending EPT use is acceptable for: Women who request it and are well aware of potential risks and benefits Prevention of further osteoporosisrelated fracture and bone loss when alternate therapies are not appropriate or cause unacceptable adverse effects NAMS position statement. Menopause 2012.

NAMS 2012 Summary Hot flashes: women with a uterus take estrogen plus progestogen Low-dose vulvo/vaginal ET if local symptoms only Neither ET or EPT increases the risk of heart disease in healthy women under age 60 or within 10 years of menopause. The risk of stroke can be increased but is rare in the 50s If POF or early menopause- use HT until the average age of natural menopause (51). Longer duration of tx can be considered if needed. Lack of safety data supporting the use of HT in breast cancer survivors

NAMS 2012 Summary Both transdermal ET and low-dose oral ET is associated with lower risks of blood clots and stroke than standard doses of oral estrogen, but confirmation of benefits in RCT is not yet available

Discontinuation After 3 years of EPT discontinuation: Rate of cardiovascular events, fractures, and colon cancer same as placebo group Increase in rate of all cancers and mortality from breast cancer After 3 years of ET discontinuation: No increase in CHD, DVT, stroke, hip fracture, colorectal cancer, or total mortality Decrease in breast cancer persisted

Discontinuation (cont d) HRs for all-cause mortality neutral for both 50% chance of vasomotor symptoms recurring when HT discontinued Symptom recurrence similar whether tapered or abruptly discontinued Decision to continue HT should be individualized NAMS position statement. Menopause 2012.

Conclusions & Recommendations (cont Although ET did not increase breast cancer risk in WHI, there is lack of safety data for breast cancer survivors, and one RCT reported higher increase in recurrence rates Both transdermal and low-dose oral estrogen associated with lower risks of VTE and stroke but RCT evidence not yet available NAMS position statement. Menopause 2012.

Global Consensus Statement on Menopausal HRT Core Recommendations MHT (menopausal hormone therapy) MHT is most effective treatment for VMS associated with menopause at any age Benefits likely outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopause. MHT effective and appropriate for prevention of osteoporosis-related fractures in at risk women before age 60 or within 10 years after menopause

Global Consensus Statement on Menopausal HRT Core Recommendations Standard dose E alone may decrease CHD and all cause mortality in women < 60 and within 10 years of menopause. EPT in women < 60 or within 10 years of menopause show similar trend for mortality but in most RCT, no increase or decrease in CHD Local low-dose estrogen tx for with sx limited to vulvovaginal atrophywomen

Global Consensus Statement on Menopausal HRT Core Recommendations E alone in women with hysterectomy EPT in women with uterus MHT is individual decision - QOL - health priorities - personal risk factors such as age, time since menopause, risk of VTE, stroke, IHD, breast CA Risk of VTE and ischemic stroke increases with oral MHT but absolute risk is rare < 60 y.o. Lower risk of ischemic stroke with td

Global Consensus Statement on Menopausal HRT Core Recommendations Risk of breast cancer associated with MHT is primarily associated with addition of progestogen and duration. Risk is small and risk decreases after treatment is stopped Dose and duration of MHT determined by tx goals and safety issues; individualize POF: systemic MHT until 51 No MHT in breast cancer survivors

Long term MHT Initiate HT in healthy symptomatic women within 10 years of menopause or < 60 and who do not have CI to HT VMS persist for an average of 7.4 years and for > 10 years in many women Moderate to severe VMS in 42% of women aged 60-65; many after 65 Switch to td by age 65 Continue vs d/c is individualized Weigh benefits vs risks annually

Important Research to be Familiar With

Nurse s Health Study 30-55 y.o. 40%-50% reduction in the number of heart attacks

PEPI Trial Heart Disease Risk Factors The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. Objective:To assess pairwise differences between placebo, unopposed estrogen, and each of 5 regimens: 1) placebo; 2) CEE 0.625 mg per day; 3) CEE, 0.625 mg per day, taken with cyclic medroxyprogesterone acetate (MPA), 10 mg per day for 12 days a mo; 4) CEE, 0.625 mg per day, plus consecutive MPA, 2.5 mg per day; 5)CEE, 0.625 mg per day, plus cyclic micronized progesterone (OMP), 200 mg per day for 12 days a mo. Primary Endpoints: Four endpoints were chosen to represent four biological systems related to the risk of cardiovascular disease: 1) high-density lipoprotein cholesterol (HDL-C); 2) systolic blood pressure; 3) serum insulin; fibrinogen. Conclusions:Estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on insulin or blood pressure. Unopposed estrogen is the optimal regimen post-challenge for elevation of HDL-C, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, CEE with cyclic OMP has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia. JAMA 1995 Dec 6;274(21):1676

HERS Study No overall effect of 4.1 years of therapy with estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Within the overall null effect, a 50% increase in cardiovascular events was seen in the first year, followed by fewer events after 2 years of treatment in the hormone therapy group than in the placebo group. Ann Intern Med 1999 Sep 21;131(6):463-6.

EPAT Estrogen in the Prevention of Atherosclerosis Trial RDBPCT; 2 years, serial arterial imaging; healthy postmenopausal women without preexisting CVD Primary trial outcome: positive beneficial effect of unopposed ERT (17-beta estradiol) on the progression of subclinical atherosclerosis. Results P group: average rate of progression of subclinical atherosclerosis measured by carotid artery intima-media thickness was +0.0036 mm/year Results unopposed ERT group, subclinical atherosclerosis regressed at a rate of 0.0017 mm/year (P=0.046 for difference between treatment groups). In women who did not use lipid-lowering medication, the placebo-unopposed ERT difference (benefit) in the average rates of atherosclerosis progression was even greater. Conclusion: EPAT supports the growing body of data that indicate that the preexisting state of health of the vasculature and the timing (relative to menopause) of initiation of ERT determine whether atherosclerosis will respond beneficially to hormone therapy. Hodis H, et al. EPAT Ann Intern Med 2001;135:939-953

WELL-HART Women s Estrogen and Lipid Lowering Heart and Atherosclerosis Progression Trial 226 older postmenopausal women (mean 18 years after menopause) with established coronary-artery atherosclerosis Results: 17ß-estradiol either alone or with sequentially administered medroxyprogesterone acetate had no significant effect on the progression of atherosclerosis. Conclusion: Effect of HT on established atherosclerosis = null Hodis H, et al. NEJM 2003;349:535-545

WHI Review RISK vs Benefits HRT Placebo Difference Breast CA 3.8 3.0 +26% Heart Dx 3.7 3.0 +23% Stroke 2.9 2.1 +38% Clots 2.6 1.3 +100% Hip fx 1.0 1.5-33% Colon CA 1.0 1.6-37% JAMA 2002;288:321-333

Combination Oral EPT Increased risks - Venous thromboembolism (2.11) - Stroke ( 1.41) - CHD ( 1.29) - Breast Cancer ( 1.26) - Gall bladder disease WHI;JAMA 2002; 288:321-333

Post initial 2002 WHI publication Sales of oral HT dropped 32% in the first year Lack of cardiovascular harm in women who begin HT between the ages of 50 and 59 or within 10 years of menopause Observational studies suggest HT merely unmasked latent breast cancers 6.7% drop in breast cancer rates in 2003

Drop in Breast Cancer Incidence-2003 A significant 6.7% decline in breast cancer in U.S. women in 2003. Data from 2004 showed a leveling off with no real additional decrease. The decrease, which started in mid-2003, was seen only in women 50 years of age or older and was 2 to 3 times more evident in estrogen-receptor-positive cancers The decreases were similar for localized disease and more advanced disease, and were evident in primary breast cancers but not in contralateral second primary or late stage breast cancers Breast Cancer Res Treat 2006; 100: Suppl: S2, a abstract.

Estrogen Only:Hazard Ratios Coronary heart disease 0.91 Stroke 1.39 Pulmonary embolism 1.34 Deep vein thrombosis 1.47 Breast cancer 0.77 Colorectal cancer 1.08 Hip fracture 0.61 Vertebral fracture 0.62 Total fracture 0.70 Total mortality 1.01 JAMA 2004;291:1701-12

Million Women Study 1,084,110 women aged 50-64 in UK followed for up to mean of 4 years Results: - ET use RR= 1.3 (1.21-1.41) - EPT use RR= 2.0 (1.88-2.12) - No differences in dose, type of E or P, cyclic vs continuous (Did not include OMP) - Risks increased with total duration of use - Risk decreased with time since last use Million Women Study Collaborators, Lancet 2003

ET Only Increased risks - VTE ( 1.33) - Stroke (1.39) - Gall bladder disease Estrogen alone did not increase the risk for heart disease or VTE and was associated with a nonsignificant trend toward reduced risk for breast cancer WHI;JAMA 2004; 291:1701-1712

WHI and Global Cognition Women s Health Initiative Memory Study (WHIMS) An ancillary study of women 65 years and older from 39/40 centers within the WHI CEE/MPA trial; 4532 (92.6% enrolled) No improvement in cognitive function in HRT group Small increased risk of clinically relevant meaningful cognitive decline in HRT group Rapp et al. JAMA 2003;289(20)

WHI -Mild cognitive decline and Dementia; WHIMS WHIMS: RCT 4532 from WHI; CEE/MPA 40 (66%) postmenopausal women with dementia in HRT group 21 (34%) in placebo group Overall risk was twice that of women in placebo; risk began to appear within 1 year MCI: no statistical differences in risk; Shumaker et al. JAMA 2003;289(20) Shumaker et al. JAMA 2003;289(20)*

WHIMS-Dementia and Impaired Cognition PremPro Placebo CI Age 65-69 6 cases 2 cases 0.66-16.11 Age 70-74 12 cases 9 cases 0.62-3.49 Age > 75 22 10 1.11-4.94

HRT and GYN cancers 16,608 women in WHI; 5.6 years F/U - 111 women diagnosed with gyn cancers invasive ovarian=32 endometrial = 58 nonendometrial uterine=1 cervical = 13 other = 7 JAMA 2003;290

CEE/MPA and Gyn Cancers 20 cases of invasive ovarian cancer in EPT group vs 12 cases in placebo group; HR 1.58 (95% CI, 0.77-3.24) 27 cases of endometrial cancer in EPT group vs 31 cases placebo; 0.81 (95% CI, 0.48-1.36) No differences in tumor histology, stage, grade for either cancer 8 cases of cervical cancer in EPT group vs 5 cases in placebo; HR 1.44 (95% CI, 0.47-4.42)

HRT-Ovarian Ca Risk New study 2015 HRT was significantly associated with an increased risk for ovarian cancer in postmenopausal women Greatest risk in current users of HT and falls after use ceases, and varies by tumour type. 1 additional ovarian cancer for every 1000 users in HRT users for 5 years, starting near age 50. 1 extra death per 1700 users The more recent the therapy, the greater the risk Prospective studies: risk was greatest among women who were taking HRT when last asked. Elevated risk even among women who had been using HRT for less than 5 years at diagnosis. If stopped HRT but were within 5 years of last use at the time of their cancer diagnoses = 23% increased RR. The longer the time since last use of HRT, the lower the cancer risk. But, if used HRT for at least 5 years = still associated with 10% increased RR more than 5 years later. Increased risk was ERT only and EPT Lancet, online February 2015

Estrogen/Testosterone and Breast Cancer Risk Among women with natural menopause, the risk of breast cancer was nearly 2.5 fold greater among current users of estrogen plus testosterone therapies than among never users of postmenopausal hormone therapy. Risk of breast cancer associated with current use of estrogen and testosterone therapy was significantly greater compared with estrogen only therapy and marginally greater than estrogen and progestin therapy. Women receiving HT with testosterone had a 17.2% increased risk of breast cancer per year of use. Arch Intern Med 2006;166:1483-1489

HT and Breast Cancer Incidence and Mortality- 2010 CEE 0.625 mg/day and 2.5mg/day MPA on breast cancer incidence mortality after an average follow-up of 11 years Primary finding = 1 to 2 extra deaths from breast cancer per 10,000 women per year. This increase risk of breast cancer is similar to the increased risk of having menopause 5 years later than other women. Cancers more commonly lymph-node positive (81 vs 43), More deaths from all causes occurring after a breast cancer diagnosis (51 deaths in the Prempro group vs 31 deaths in the placebo group. the tumors were similar in histology and grade to breast cancers in the placebo group. In summary, use of conjugated equine estrogens and progestin increased the risk of breast cancer incidence after 11 years and the cancers were more commonly node-positive with a suggestion of increased mortality. JAMA 2010;304(15):1684-1692.

Uh oh: Breast Cancer Risk and HT initiation timing Breast cancer risk was greater in EPT users than in ET users, and greater risks when starting HT less than 5 years from menopause. Absolute increments of increase in breast cancer cases are small= 3.1 additional cases per 10,000 for current EPT users and 1.3 additional for ET. Beral V. J Natl Cancer Inst 2011

2010 Review: Estrogen Benefits Breast Cancer Risk Estrogen alone significantly lowered the risk of breast cancer by 32% in 8,500 women= no FH of breast cancer Among 7,600 women with no history of benign breast disease, those taking estrogen had a 43% lower risk of breast cancer. Ragaz M. Poster Session at San Antonio Breast Cancer Symposium 2010

Health outcomes after D/C ET 2011 CEE use was assoc with a decreased risk of invasive breast cancer and much more favorable results for CHD, all-cause mortality, and several outer outcomes in younger than in older women. Results: a significantly reduced risk of invasive breast cancer among women randomized to CEE vs placebo over the 10.7 years of f/u. In the overall study population, there was no significant effect of CEE on CHD, DVT, stroke, hip fx, colorectal cancer or total mortality. However, younger women (50-59 at enrollment) tended to have much more favorable outcomes on CEE than the older women for CHD, MI, colorectal cancer, all-cause mortality and the GI. Risks were 40% to 50% lower with CEE than placebo in women 50-59 but were higher with CEE than placebo in women ages 70-79. 50-59: for every 10,000 women taking CEE there were 12 less MIs, 13 less deaths, 18 less adverse events. 70-79: 16 extra MIs, 19 extra deaths, 48 extra adverse events JAMA 2011; 305:1305-1314

Timing of Hormone Therapy and Cardiovascular Risk- California Teachers Study Objective: effects of age at current HT use on CHD mortality. During the average f/u of 5-7 years, 18% of never users, 18% of former users, and 7% of current users of HT died. Compared with never use, current HT use was associated with a 16% lower risk for CHD-related death. This risk reduction was most pronounced in current HT users younger than 60 years of age, in whom a 62% risk reduction was noted. As the age of users increased, this apparent protection against fatal CHD attenuated. Results were similar with use of estrogen-alone or combination estrogen- progestin HT. Menopause 2011 Mar;18(3):253-61.

CHD and EPT Does the Increased Risk Disappear Estimate the effect of continuous estrogen plus progestin therapy on CHD risk over time and stratified by years since menopause Design: WHI RDBPCT CEE 0.625 mg + MPA 2.5 mg vs placebo Conclusion: No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use, including in women who initiated therapy within 10 years after menopause. A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use. Ann Intern Med 2010;152:211-217

HT and Coronary Heart Disease: Role of Time since Menopause and Age at HT Initiation Prospective examination of the relation of HT to CHD according to timing of hormone initiation relative to age and time since menopause. Results: Beginning HT near menopause had a significantly reduced risk of CHD E alone = RR.66 EP = RR.72 Benefits of HT, especially E alone, decreased when therapy was initiated long after menopause J Women s Health 2006;15(1)

The Timing Hypothesis ELITE trial preview This study aims to present methods and baseline data from the ELITE trial, the only clinical trial designed to specifically test the timing hypothesis of postmenopausal hormone therapy. RDBPCT. 643 healthy postmenopausal women wo/cardiovascular disease; randomized to oral estradiol or P for 6-7 years according to time since menopause (> 6 or > 10)

ET only and cardiovascular risk and all cause mortality In the RCT, CEE use was assoc with a decreased risk of invasive breast cancer and much more favorable results for CHD, all cause mortality and several other outcomes in younger than in older women. For every 10,000 women per year taking CEE, there were 12 fewer heart attacks, 13 fewer deaths and 18 fewer adverse events for women ages 50-59. in contrast, for every 10,000 women per year ages 70-79, there were 16 extra heart attacks, 19 extra deaths and 48 extra adverse events for women taking CEE LaCroix A. JAMA 2011;305

Danish CVDx Study Objective: Long term effect of HT on cardiovascular outcomes in recently postmenopausal women. Participants 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal FSH values. -502 women allocated to HT and 504 to receive no treatment - Women with hysterectomy were included if they were aged 45-52 and had postmenopausal FSH levels. Interventions: If uterus= estradiol and norethisterone acetate ; if hysterectomy = received 2 mg estradiol a day. Main outcome measure: Primary endpoint =composite of death, admission to hospital for heart failure, and myocardial infarction. Conclusions After 10 years of randomised treatment, women receiving HT after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke. This is the longest randomized trial with hard end points, and found a 50% reduction in cardiovascular end points for the women who took HRT, and there was no increased risk of cancer Schierbeck L, et al. BMJ 2012; 345

KEEPS Early Postmenopausal women 42-59 EPT started soon after menopause appears to be safe; relieves many sx of menopause, improves mood, bone density and several markers of cardiovascular risk Both HT groups: reduced VMI, increased BMI; sexual function revealed significant improvements in lubrication and decreased pain with intercourse in both HT groups. However, the t-e2 group had improved arousal and desire while the CEE group did not. CVD: carotid US studies showed similar rates of progression of arterial wall thickness in all three tx groups over the 4 years of the study; these changes were generally small; there was a trend toward less progression of CAC (carotid artery calcium) in the two HT groups. Neither CEE or t-e2 significantly affected systolic or diastolic BP. CEE was assoc with increase in HDL and decrease in LDL, but increased in TGs and CRP t-e2 improved glucose levels and insulin sensitivity; no effect on HDL, LDL, TGs No statistically significant differences in rates of breast cancer, endometrial cancer, MI, TIA, stroke or venous thromboembolic disease between the three groups. Cognitive study: oral CEE and t-e2 to recently menopausal women did not create any detectible adverse effects either on cognition. But no benefits either. CEE improved significantly on measures of depression/dejection and anxiety-tension. Trend towards less anger and memory recall. T-E2 had a trend toward adverse performance in memory of past events and their severity. Womens Health (Lond Engl) 2013 Jan;9(1):9-11

KEEPS Contradiction or Clarification? The new study didn't show significant differences in adverse events between women taking oral or transdermal estrogen with progesterone and those on placebo, including: Breast cancer Endometrial cancer Myocardial infarction Transient ischemic attack Stroke Venous thromboembolic disease

Hormone Therapy dose, formulation, route of delivery and CV events WHI Observational Study Compared different estrogen doses, routes of delivery, HT formulations in postmenopausal women and risk of CHD, stroke, CVD mortality,all cause mortality. The mean f/u was 10.4 years. Results: -Oral estradiol was associated with lower hazard ratios for stroke than oral CEE but statistical power was limited. -Transdermal estradiol was associated with moderate but nonsignificantly lower risk of CHD compared with oral CEE. -Slightly more favorable results for low dose oral CEE vs conventional oral dose of CEE but not statistically significant. -For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations or routes of delivery. Dose : low dose CEE = < 0.625 mg; conventional dose CEE = 0.625 mg; high dose CEE > 0.625 mg. Oral estrogen formulation categories included oral estradiol and oral CEE. Oral estrogen plus progestogen users included both oral CEE and oral estradiol with a progestin or progesterone. Transdermal estrogen categorization included all dose formulations, and concomitant oral progestin or progesterone in women with a uterus. Menopause 2014;21(3):260-266

Risks vs Benefits to be Familiar With

HT: Determining Risk vs Benefit 3 most important factors= 1. The age at initiation of hormone therapy (i.e. years since menopause), i.e. therapeutic window 2. Dose of estrogen 3. Route of administration

1. Therapeutic Window Benefits outweigh risks - initiate HT within 10 years to prevent: urogenital atrophy dementia possibly cardiovascular disease - initiate HT within 3-6 years to prevent or treat bone loss

2. Dose of Estrogen 0.3 mg dose of CEE (or = 0.5 mg oral estradiol) is effective for treating hot flashes and vaginal dryness and for the prevention of osteoporosis in menopausal women. This dose also affects cardiovascular risk. - 0.3 mg/day CEE = reduced risk of CHD and stroke compared with nonestrogen users- if before 10 years postmenopause - 0.625 mg/day was assoc with an increased risk of stroke. (oral estradiol less risk of stroke than oral CEE)

2. Dose of Estrogen WHI observational study: women using low dose estrogen- defined as < 0.625 mg/day as part of estrogen plus progestin therapy had a 71% lower risk of coronary heart disease and a 69% lower risk of VTE over an average f/u of 5.5 years compared with women using a conventional dose regimen. Among women using estrogen plus progestin, the risk of CHD was more than double in users of high-dose estrogen vs women receiving a standard dose. No relationship was observed between estrogen dose and cardiovascular events with estrogen alone.

3. Route of administration Transdermal avoids the hepatic first pass - lowers risk of thromboembolic effects - transdermal estrogen does not confer added risk of VTE or stroke

The Message on Estrogen Non-oral/transdermal Estrogen may be a preferred option to reduce risks of CVD, DVT, PE Oral estradiol safer than oral CEE for stroke/ DVT Non oral options: Patches, Creams, Gels Is Sublingual different than oral??? Provide adequate endometrial protection in those women with a uterus; or surveillance

ET/EPT Potential Contraindications Breast cancer Endometrial cancer within first 5 years Unexplained vaginal bleeding Active liver disease Chronic severe hepatic dysfunction (AST> twice normal) Recent vascular thrombosis Risk factors for CAD > 10 years postmenopausal or after D/C HRT and then wants to restart

ET/EPT Cautions Familial mixed hyperlipidemia or hypertriglyceridemia (TG> 300 mg/dl) History of endometriosis History of leiomyomas??? Atraumatic thrombophlebitis or history of thromboembolic event disorder History of gallbladder disease and no cholecystectomy Seizure disorders Migraine headaches First degree relative with history of ovarian cancer First degree relative with history of breast cancer

HT Clinical Recommendations Dosing Lower than standard doses of ET and EPT should be considered - may provide adequate symptom relief - preserve BMD - better tolerated r.e. mastalgia -Some women may need additional local therapy for persistent vaginal sx Lower doses may or may not have more positive safety profile than standard doses; no testing in long term trials.

Progestogen use The approved use for progestogens in menopause is for endometrial protection Women with a prior hysterectomy do not require progestogens. May be used for symptom relief. There are endometrial biopsy proven minimum standards for many forms of progestogens- Cannot safely use lesser amounts or unapproved formulations or progesterone {transdermal creams, troches, Mirena IUD, vaginal progesterone, longcyclic (q3 month) }without endometrial surveillance with biopsies or transvaginal ultrasounds

Controversial Progestogen Use The addition of a progestogen to ET in women without a uterus to better control menopausal vasomotor symptoms has been studied and is frequently prescribed It does not balance the estrogen, but may undo some of estrogen s actions. There are no completed studies on the endometrial protection by the Mirena IUD 1999 study showed 4% and 8% vaginal progesterone was effective for secondary amenorrhea withdrawal bleeding prevented hyperplasia Called Prochieve Long-cyclic use may not protect from hyperplasia as well as standard regimens, but is better than none. There are no studies on transdermal progestogerone and hyperplasia protection except the prochieve When using non-standard progestogens, consider transvaginal ultrasounds or endometrial biopsies.

Are all estrogens and progestogens the same?

Important Distinctions Botanicals - Phytoestrogens - Non phytoestrogens Bio Identical Hormones (compounded) Bio-Identical Hormones (pharmaceutical company) Non bio-identical hormones from natural substances Synthetic Hormones

Compounded bio-identical Hormones Estradiol Estriol Estrone Progesterone Testosterone DHEA (Pregnenolone)(Growth Hormone)(Thyroid) Capsules, creams,gels, sublingual, vaginal, injections, implanted pellets

Bio-identical Hormones (Compounded) Plant Derived (Soybeans or Mexican wild yam) Extract compounds from those plants Made into a hormone in the laboratory Biochemically identical to endogenous hormones Less nuisance effects; bio-identical metabolism/ footprint Unlimited dosing options Individualized Special situations Titrate doses

CEE and synthetics CEE and synthetics - exaggerated potency in the hepatic system - longer half life - more metabolites; different metabolic consequences

Conjugated Equine Estrogens 17B estradiol 17B-Dihydroequilin 17 B-Dihydroequilenin 17 alpha-dihydroequilin 17 alpha-estradiol Estrone 52.5%-61.5% Equilin 22.5%-30.5% 17alpha-Dihydroequilenin Equilenin Delta 8,9 Dehydroestrone Sulfate Equilenin

Progestins vs OMP Cardiovascular effects Progestins -More androgenic - Inhibits positive effects of estrogen on nitric oxide ( I.e. the vasodilation effects) - Diminishes positive effects of estrogen on HDL - Up regulates thrombin receptor on VSMC - Increases VTE, CVD OMP- less androgenic vasodilatory effects did not diminish HDL effects of estrogen more mineralcorticoid than glucocorticoid

Progestins vs OMP Breast Effects Progestins- greater proliferation of breast epithelium with E + P than with E alone; ex/ WHI Progesterone- less breast cell proliferation

Comparison of OMP vs MPA Women using OMP containing HRT experienced -significant improvement in vasomotor symptoms, somatic complaints, anxiety and depressive symptoms - less abnormal bleeding patterns - 80% satisfaction with OMP regimen Fitzpatrick et al. J Women s Health 2000;9(4)

Rationale for 17B E2 Identical to ovarian sex steroid production Tissue responsive specificity Shorter half life Bio-identical liver conjugation Bio-identical metabolic footprint Bio-identical metabolic consequences Decreases IMT Late menopause and 18% decrease CVD Decrease in 17BE2 and increase CVD

Estriol Placenta production Commercial source=diosgenin Estriol does not convert to estradiol Binds poorly to estrogen receptors Rapidly metabolized Rapidly inactivated; 1% to 2% enters circulation At the estrogen receptor: agonist and antagonist Binding is brief

Bio-Identical Progesterone Hot flashes and night sweats Abnormal bleeding; secondary amenorrhea Insomnia, Anxiety PMS, Acne Prevents fibrocystic breast changes and fluid Uterine sedative Protects against coronary vasospasm Endometrial protection with estrogen Better effect on HDL Less nuisance effects

Transdermal Progesterone and VMI, lipids, bone markers, moods, QOL Transdermal 32mg cream vs placebo No detectable change in VMI, mood characteristics, libido, blood lipids or metabolic markers Slight elevation of blood progesterone; inadequate for endometrial response Wren et al. Menopause 2003;10(1)

Transdermal Progesterone and Vasomotor Symptoms N=102 postmenopausal women Tx: Progesterone transdermal ¼ tsp (20 mg) daily vs. placebo Calcium 1200 mg 25/30 (83%) in tx group=improvement or resolution 5/26 (19%) in P group=improvement or resolution BMD no difference between two groups Leonetti, et al Ob/Gyn 1999

OMP for Vasomotor Symptoms Objective: compare OMP with placebo as therapy for postmenopausal hot flushes and night sweats. N=133 (OMP group = 75;placebo = 58); 1-10 years postmenopausal. RDBPCT of OMP 300 mg at bedtime vs placebo x 12wk Results: VMS score reduction of women taking OMP were better than placebo with a mean reductions of VS score of10.0 vs 4.4 Menopause 2012;19(8):886-893

Progesterone and Breast????? safety P deficiency associated with 5-fold increase in premenopausal breast cancer (Cowan 1981) Induces apoptosis via b53 and bcl-2 (Formby 1998) Long-term use (td) in women with benign breast disease didn t increase BrCa risk (Plu-Bureal 1999) No change in breast nodularity with P alone (Nappi) Women who develop breast CA do not have different blood levels of P (Helzlsouer) Progestins inhibit growth and stimulate differentiation (Kester)

Progesterone may increase breast cancer risk less than progestin The risk of breast cancer is slightly increased with a postmenopausal hormone therapy regimen consisting largely of transdermal estradiol combined with progestins, but not when combined with progesterone. Int J Cancer 2005;114:448-454.

Unequal risks for breast cancer associated with different HT Data from the French E3N cohort study 2,354 cases of invasive breast cancer among 80,377 postmenopausal women over 8 years. E alone 1.29 (1.02-1.65) E-Progesterone 1.00 (0.83-1.22) E-dydrogesterone 1.16 ( 0.94-1.43) E-other progestins 1.69 (1.50-1.91) Fournier, et al. Breast Cancer Res Treat 2007

Role of Progestogen Type in Breast Cancer Risk The type of progestogen and regimen used affect breast cancer risk Breast cancer cases (739)and matched controls (816)with no breast cancer history. OMP: breast cancer risk was not increased. The odds of breast cancer for users of progesterone derived progestogens progestins were 1.5 times higher than in controls and the odds for users of testosterone derived progestogens were 3.35 times higher than for controls. Women who used continuous combined regimens were at higher risk than those who used sequential regimens In addition, women who start HT early after the onset of menopasue were at higher risk of breast cancer than women who delayed treatemnet for 1 or more years. PLoS One 2013;8(11)::e78016

KEEPS again 1= 0.45 mg CEE + OMP 12 days/month; 2=.05 mg estradiol patch + OMP 12 days/month; 3=placebo + OMP 200 mg/day 12 days/month No statistically significant differences in rates of breast cancer, endometrial cancer, MI, TIA, stroke or venous thromboembolic disease between the three groups.

Progesterone Receptor and Breast Cancer Cell Proliferation Addition of progesterone had no effect on estradiol induced breast cancer cell proliferation Addition of MPA enhanced the estradiol effect i.e. overexpression of PGRMC1 sensitizes the proliferative response of the MCF-7 breast cancer cell line to estradiol Menopause 2011;18(8):845-850

Progesterone and Breast?????? Adverse In luteal phase fluid secretion peaks breast mitotic activity peaks Increased epithelial proliferation DNA production of nonglandular tissue and glandular epithelium peaks This cellular proliferation may accumulate genetic errors that lead to breast CA

Progesterone and Breast????? Adverse Tissue from mammoplasties- peak in mitotic activity during luteal phase Tissue near a benign or malignant lesionpeak in mitotic activity during luteal phase Higher proliferation in luteal phase correlated with higher serum progesterone levels Higher serum progesterone levels and increased mammographic density

Progesterone and Breast????? Adverse Increase in mammographic density with HRT, regardless of progestogen; no increase with E alone (Greendale 2003) WHI: CEE/MPA = 1.26 RR >4-5 yrs WHI: CEE/MPA= larger tumors, higher stage CEE alone= No increased risk; possible decrease Previous studies: CEE/MPA < CEE alone Recent studies: E/NE < E alone

Vaginal Estrogens Estriol suppositories or cream-(no change in serum E2 E3 1 mg supp. or E3 1mg/gm Estradiol ring (Estring)- no change in serum E2; delivers 0.006-0.009 mg estradiol/day for 3 months Estradiol tablets (Vagifem)- mixed elevated and not;. 025 mg tablet; 2x/wk CEE or E2 cream- more instances of increased E2 levels; Estradiol-0.1mg/gm; CEE- 0.625mg/gm compounded estradiol Crandall. J Women s Health 2002;11(10)

HRT Prescribing Concerns Oral bert with transdermal P in women with uterus Progesterone in women who have had a hysterectomy and are taking estrogen EPT in breast cancer survivors Progesterone in breast cancer survivors Estradiol/Estrone in breast cancer survivors Progesterone for BMD OMP to treat proliferative endometrim, hyperplasia or atypical hyperplasia

Bio-Identical Hormones What Do They Offer? Progesterone vs MPA - less androgenic - Some symptom relief- sleep, VMI - less nuisance effects - less attenuation of HDL effects from oral E - breast friendlier (3 French studies, KEEPs) - bio-identical metabolic footprint - If compounded: Diverse delivery systems and bases customized dosing; titrating doses

Bio-Identical Compounded Hormones What Do They Offer? Estradiol (oral) - Estrogen alone= no increased risk of breast cancer - More favorable than CEE r.e. stroke - bio-identical metabolic foot print - preferred effect on DNA? - Sometimes less nuisance effects - Anti-resorptive (similar to other estrogens) - Diverse delivery systems and bases - Customized dosing; titrating doses

Bio-Identical Compounded Hormones What Do They Offer? Estriol - Estriol receptors in vagina Stress Incontinence, atrophy, dryness, dyspareunia Dessole et aol. Menopause 2004;11(1) - Decreased UTIs - No detectable change in serum estradiol with vaginal estriol - Low doses may be breast friendly* - Offer menopause symptom relief - Customized delivery;doses; titrating - As bi-est/tri-est: able to use lower doses estradiol

Estriol and the Breast Induction of remission; arrest of growth of metastatic breast cancer Lemon. Cancer Res 1975;35 Lemon. Acta Endocrinol Suppl 1980;233 Japanese women excrete high levels of estriol unless they move to the West Dickinson et al. NEJM 1974;291 Tx with 2 mg Estriol= no breast tumors Takahashi et al. Hum Reprod 2000;15

Bio-Identical Compounded Hormones What don t they offer? Progesterone - Transdermal: No endometrial protection No osteoporosis protection Unclear breast safety Mixed symptom relief - OMP: No osteoporosis protection 4 observational studies only: breast safety Mixed symptom relief

Bio-Identical Compounded Hormones What don t they offer? Estradiol similar or different biological effects when compared to other estrogens?

Bio-identical Compounded Hormones What don t they offer Estriol - Incomplete assurance of breast safety - No significant anti-resorptive effects - No significant CVD adverse or pro events - 1-2 mg/day increased risk of endometrial CA and hyperplasia Weiderpass et al. Lancet 1999;353

Compounded Bio-Identical Hormones Summary Safest form of hormones available Can use lowest dose possible Variable delivery systems ( td- reduces clotting issues, does not increase CRP and TG) Intravaginal options Bi-est: allows for lower estradiol dose and possible breast protection of estriol Customized dosing and titrations up or down Bio-identical metabolic footprint and effects on genetic material

Summary Symptoms can recur when therapy is discontinued, independent of age and duration of ET/EPT use. Continued HT should be individualized- severity of symptoms, risk-benefit considerations Different compounds, dose and routes of delivery may have different outcomes- for now, results should be generalized to all agents within the same family Absolute risks of HT are small Benefits for bone and colon cancer risk small Individual risk profile essential Inform women of known risks and benefits

Summary Additions Effects of ET/EPT on risk of breast cancer, CHD, stroke, total CVD, and osteoporotic fracture in perimenopausal women with moderate to severe menopause symptoms have not been established in RCTs. Extrapolate data from other populations with caution. Ex/ WHI, HERS results should not be extrapolated to symptomatic menopausal women young than 50. WHI mean age 63; majority 10 years postmenopausal HERS mean age of 67 and known CAD Surgical menopause and premature menopause: riskbenefit ratio of HT more favorable

Dr. Tori Hudson Resources Women s Encyclopedia of Natural Medicine, 2008, second edition www.drtorihudson.com www.vitanicapro.com www.awomanstime.com www.instituteofwomenshealth.com www.naturopathicresidency.org