Estradiol (Estrogens) Disclosures /20/ :11:34 PM. Metabolism of Oral Estradiol 17β

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1 A Conversation About Hormone Therapy: Is There an Appropriate Dose, Route, and Duration of Use? Session 4Special Areas of Concern The Impact of Route of Administration (Oral, Transdermal, Vaginal) and Lower Delivered Doses on Risk-Benefit James A. Simon, MD, CCD, NCMP, IF, FACOG Clinical Professor Department of Ob/Gyn George Washington University Washington, DC Medical Director Women s Health & Research Consultants Washington, DC James A Simon, MD, Disclosures 216 Dr. James A. Simon has served (within the last year) or is currently serving as: Owner/Board of Directors: James A. Simon, MD, PC Advisory Board/Consultant: A consultant to or on the advisory boards of: AbbVie, Inc. (North Chicago, IL), AMAG Pharmaceuticals, Inc. (Waltham, MA), Amgen Inc. (Thousand Oaks, CA), Apotex, Inc. (Toronto, Canada), Ascend Therapeutics (Herndon, VA), JDS Therapeutics, LLC (Purchase, NY), Merck & Co., Inc. (Whitehouse Station, NJ), Noven Pharmaceuticals, Inc. (New York, NY), Novo Nordisk (Bagsvrerd, Denmark), Nuelle, Inc. (Mountain View, CA), Perrigo Company, PLC (Dublin, Ireland), Radius Health, Inc. (Waltham, MA), Regeneron Pharmaceuticals, Inc. (Tarrytown, NY), Roivant Sciences, Inc. (New York, NY), Sanofi S.A. (Paris, France), Sermonix Pharmaceuticals, Inc. (Columbus, OH), Shionogi Inc. (Florham Park, NJ), Sprout Pharmaceuticals (Raleigh, NC), Symbiotec Pharmalab (Indore, India), TherapeuticsMD (Boca Raton, FL). Speaker: On the speaker s bureaus of: Amgen Inc. (Thousand Oaks, CA), Eisai, Inc. (Woodcliff Lake, NJ), Merck (Whitehouse Station, NJ), Noven Pharmaceuticals, Inc. (New York, NY), Novo Nordisk (Bagsvrerd, Denmark), Shionogi Inc. (Florham Park, NJ). Grants/Research: Receiving grant/research support from: AbbVie, Inc. (North Chicago, IL), Actavis, PLC. (Dublin, Ireland), Agile Therapeutics (Princeton, NJ), Bayer Healthcare LLC., (Tarrytown, NY), New England Research Institute, Inc. (Watertown, MA), Novo Nordisk (Bagsvrerd, Denmark), Palatin Technologies (Cranbury, NJ), Symbio Research, Inc. (Port Jefferson, NY), TherapeuticsMD (Boca Raton, FL). Patent and Trademark Holder: U.S. Patent: 4,816,257, March 28, 1989: "Method for Producing an In Vivo Environment Suitable for Human Embryo Transplant.", U.S. Trademark: Reg. No. 3,446,895, Registered June 1, 28: You talk I ll Listen. We ll Plan Together., U.S. Trademark: Reg. No. 3,676,269, Registered September 1, 29: U.S. Trademark: Reg. No. 3,76,8, Registered March 16, 21: Women s Health & Research Consultants & Design, U.S. Trademark Serial No.:86-714,153. DR. SIMON SAYS Registered February 2, 216. Stock Shareholder and/or other Financial Support: Dr. Simon is a stockholder (direct purchase) in Sermonix Pharmaceuticals (Columbus, OH). Dr. Simon served as chief medical officer (CMO) of Sprout Pharmaceuticals until April 213. Estradiol (Estrogens) Metabolism of Oral Estradiol 17β Oral E 2 needs to be in a micronized or conjugated form in order to be efficiently absorbed by the gastric mucosa It is mostly conjugated as E 2 valerate, sulfate or acetate Greatest metabolism during first liver passage (~ 3% spanchnic extraction) Absolute bioavailability ~ 5-1% C18H24O2 Molar weight: g/mol (17β)-estra-1,3,5(1)-triene-3,17-diol Lobo RA, Cassidenti DL. J Reprod Med 1992;37:

2 Some Special Characteristics of Oral and Transdermal Estrogen Oral Estradiol and Estrone: E1 Predominates Levels Achieved Oral: conjugation or micronization to increase bioavailability; shellacing (Premarin) which affects pharmacodynamics Transdermal: Patch: alcohol vs matrix variable absorption, but less variability within a subject Gels: dermal reservoir, variable absorption but less within subject variability, transference a theoretical possibility E 2 needs to be in a micronized or conjugated form in order to be efficiently absorbed by the gastric mucosa Lobo RA, Cassidenti DL. J Reprod Med 1992;37: Anderson ABM. Br Med J 1978;1:14. Accumulated Levels of E1s (pool) with Oral, but not Transdermal E2 Alcohol Increases E2 Levels with The Patch Percent changes in serum E2 concentrations (mean ± SEM) before and after ethanol (solid circles) and carbohydrate-drink (open circles) ingestion. Estradiol patches remained in place throughout the study. *E2 significantly highter adter ethanol vs ethanol-drink ingestion, P =.38. ƚ E2 significantly higher after ethanol-drink ingestion vs baseline, P.1. ǂ Change in E2 after carbohydrate-drink ingestion not significant. Slater CC. Menopause 21;8:2-3. Ginsberg ES. JSGI 1995;2:

3 Excursion of E2 and E1 with Transdermal or Percutaneous E2 vs Oral First Pass Hepatic Effects of Estrogens Taken by Mouth E2 E1 Oral Estrogen Altered Estrogens Liver Decreased anti-clotting factors Increased clotting factors Increased C-reactive protein Increased HDL Cholesterol Systemic Circulation Skin Intestine Ovary Estradiol Patch Scott RT. Obstet Gynecol 1991;77: First Pass Effects (Stimulatory) Effects of Oral Estrogen Effects on globulins (SHBG, CBG, etc.), coagulation parameters (antithrombin-iii), inflamatory markers (CRP, etc.), lipids (HDL-C). Effects determined by dose and potency of estrogen and its bioavailability. Effects on lipids and inflammatory markers and insulin sensitivity to be reviewed. Oral versus Transdermal Estrogen on Lipids (Multitude of Studies) LDL-C, Lp(a), decrease similarly with both routes (unaffected by usual doses of added progesterone/progestogen). Triglycerides increase with oral, (attenuated somewhat with progesterone/progestogen addition); no change or some decrease with transdermals. HDL-C increase with orals (attenuated somewhat with progestogen addition); no change or very small increase with transdermals. Lobo RA, Cassidenti DL. J Reprod Med 1992;37:

4 Effects of Estrogen (Oral or Transdermal) on Inflammatory Markers Differences in Oral and Transdermal Estrogen on MMPs and Tissue Inhibitors in Normal Postmenopausal Women Estrogen generally decreases inflammation markers (CV protection) dependent on potency and dose of estrogen. ICAM-1, VCAM-1, MCP-1, E-selectin Exception: An increase occurs with oral dosing in CRP and MMP-9 (as well as others); not observied with transdermal administration. Decensi 22, Sumino 25, Lewandowski 26, Salpeter 26 Lewandowski KC, et al. J Clin Endocrinol Metab 26;91: HT and Plaque Rupture Susceptible Substrate HT MMP + Early Route of Administration: Coagulation and DVT HT MMP + Plaque Rupture Complicated Plaque Incitant Catalyst Substrate Reaction Slide courtesy of H. Hodis with modification 4

5 Excess incidence of potentially fatal events attributable to oral ERT (women aged 5-6 years) Trial Post Oral But Not Transdermal ET Impairs the Balance Between Procoagulant Factors Active Tx O (E2, 1 mg) T (E2, 5 g) Coagulation Markers Fibrinogen Factor VII F1&2 TAT VWF % change from baseline 7.7 (p <.5)* -5.5 (p <.5)* 6.8 (p <.5)* Zegura O (E2, 2 mg) T (E2, 5 g) 27.9 (p =.2) 11.6 (p =.7) Rabbani O (CE,.625 mg) T (E2,.1 mg) 22.7 (p =.3) Vehkavaara O (E2, 2 mg) T (E2, 5 g) 24.9 (p <.5) 16.9 (p <.5) Data from both Women s Health Initiative clinical trials. Olie V. Current Opinion in Hematology 21, 17: TAT = thrombin-antithrombin = not significant VWF = Von Willebrand factor antigen *vs placebo; vs baseline; between treatment groups after adjusting for baseline Post M et al. Am J Obstet Gyncol. 23;189: Rabbani L et al. J Am Coll Cardiol. 22;4: Zegura B et al. Athero. 23;168: Vehkavaara S et al. Thromb Haemost. 21;85: Trial Post Zegura Oral But Not Transdermal ET Impairs the Balance Between Anticoagulation Factors Rabbani Vehkavaara Active Tx O (E2, 1 mg) T (E2, 5 mg) O (E2, 2 mg) T (E2, 5 mg) O (CE,.625 mg) T (E2,.1 mg) O (E2, 2 mg) T (E2, 5 mg) Fibrinolysis Markers t-pa PAI-1 Antigen PAI-1 Activity PAP D-dimer % change from baseline 8.9 (p <.5)* 24.3 (p =.1) 25 (p =.5) 17.8 (p =.4) 18.3 (p <.1) 29.2 (p <.1)* 7.3 (p <.5) -25 (p <.5) 62.8 (p <.5) 66.7 (p <.1) t-pa tissue-type plasminogen activator PAI plasma plasminogen activator inhibitor = not significant. vs placebo; vs baseline; between treatment groups after adjusting for baseline. Post M et al. Am J Obstet Gyncol. 23;189: Rabbani L et al. J Am Coll Cardiol. 22;4: Zegura B et al. Athero. 23;168: Vehkavaara S et al. Thromb Haemost. 21;85: (p <.1) ESTHER Study: VTE Risk Factors Multicenter, hospital-based, case-controlled Postmenopausal women (45-7 y) with a first documented episode of idiopathic VTE VTE (n = 155) Pulmonary embolisms (n = 92) DVT (n = 63) Controls (n = 381) Assessed effect of oral vs TD route on thrombotic risk Oral and TD groups included patients using ET and EPT Both groups primarily treated with EPT Scarabin et al. Lancet. 23;362: ESTHER: EStrogen and THromboEmbolism Risk 5

6 VTE Risk: Oral vs TD (ESTHER Revisited) 1. Mutation Risk Factor Adjusted Odds ratio (95% CI) Nonusers.9 (.4-2.1) Transdermal estrogens 4.2 ( ) Oral estrogens Administration route Cases (n = 259) Canonico et al. Circulation. 27;115; Controls (n = 63) Adjusted odds ratio 95% CI Nonusers Transdermal (.4-2.1) estrogens Oral estrogens ( ) TD estrogens not associated with an increased risk of VTE Significant increase of VTE with oral estrogens *Adjusted for obesity status, family history of VTE, history of varicose veins, education, age at menopause, hysterectomy, and cigarette smoking. 9. Adjusted odds ratio 95% CI No mutation 1. Nonuser 1.2 Transdermal estrogen use 4.1 Oral estrogen use One of prothrombotic mutation* Dotted horizontal line indicates the OR of VTE associated with oral estrogen use in the whole population (OR, 4.3; 95% CI, ). Factor V Leiden or prothrombin G221A mutation 4.1 Nonuser 4. 4 Transdermal estrogen use Straczek et al. Circulation. 25;112: Oral estrogen use Obesity Risk Factor Differences in Body Composition with Oral and Transdermal Estrogen 1. Adjusted odds ratio 95% CI Nonuse BMI < BMI < 3 BMI 3 Transdermal estrogen use 5.9 Oral Estrogen use Nonuse Transdermal estrogen use Dotted horizontal line indicates the OR of VTE associated with oral estrogen use in the whole population (OR, 4.5; 95% CI: ) Canonico et al. J Thromb Haemost. 26;4: Oral estrogen use 4. Nonuse 5.4 Transdermal estrogen use 2.6 Oral estrogen use With oral, decrease in IGF-1, increase in GH, decrease in lipid oxidation: increase in fat mass and decrease in lean mass No appreciable change with transdermal trend to increase lean mass. 1-3 Untreated PM women gain abdominal fat with time, paralleled by increases in leptin; no changes observed with transdermal E O Sullivan AJ. J Clin Invest 1998;12: Ho KK. Ann Endocrinol 23;64: dos Reis CM. Maturitas 23;46: di Carlo C. Menopause 24;4:

7 What is the Effect of Hormones on Insulin Resistance/Sensitivity In Postmenopausal Women? Data are mixed influenced by status of women, type of regimen and length of treatment In general estrogen increases with insulin sensitivity, but is very dependent on dose and type of patient treated. Higher doses of estrogen decrease insulin sensitivity. Higher doses (or continuous) progestogens decrese insulin sensitivity. Oral versus Transdermal Estrogen on Insulin Sensitivity Overall HT increases sensitivity and decreases insulin resistance (IR) Attenuated by added progestogens (dose and type dependent) Effect of transdermal E2 is slightly less than with standard doses of oral estrogen; with larger doses of oral estrogen sensitivity decrease (more IR): bimodal effect 1. Lindheim and Lobo Fertil Steril 1993 & 1994, J Soc Gynecol Invest Transdermal estrogen and change in bodyweight or BMI One crossover study noted greater fat gain with oral vs. transdermal estrogen, results that are supported by clinical data. Santen RJ. Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement. JCEM.21:95,S1:S1-S66 Gallbladder Disease Use of transdermal estrogens are associated with a substantially lower risk of gallbladder disease than use of oral estrogens in a Prospective cohort study (Million Women Study). Over a five year period one cholecystectomy could be avoided for every 14 postmenopausal women of transdermal therapy rather than oral Liu B et al. Br Med J 28;337:a386. doi:1.1136/bmj.a386 45,984 (64.8%) of the participants in E3N Cohort were exposed to menopausal hormone therapy 2819 cholecystectomies were recorded between Menopausal hormone therapy was associated with an increased risk of cholecystectomy (HR=1.1, 95% CI ) compared with non users The association was restricted to unopposed oral estrogen therapy (adjusted HR 1.38, 95% CI ) Risk was significantly higher with oral estrogens than with transdermal estrogens (p =.3) Risk was significantly higher with oral unopposed estrogens than with oral estrogens combined with a progestagen (p =.3) Over 5 years, about 1 cholecystectomy in excess would be expected in every 15 women using oral estrogen therapy without progestogens, compared with non users Racine A, Bijon A, Fournier A, et al. CMAJ. 213 Apr 16;185(7): doi: 1.153/cmaj

8 Colorectal Cancer Risk: Oral Estradiol vs. TD Estradiol WHI suggested reduced risk of colorectal cancer, but data limited to oral CEE. 1 Large population based case-control study suggests protective effects potentially greater for TD estradiol than oral estradiol. 2 OE Use Only TDE Use Only 95% CI All Women Age- Case Control Adjusted (n=235) (n=171) OR Among women who had not had a sigmoidoscopy 3-5 yr prior Age- Case Control Adjusted 95% CI (n=216) (n=979) OR Limited by the small number of women with colorectal cancer who are exposed to TD estradiol, but if it is truly protective there will always be fewer exposed cases than control cases. Are there differences in Oral or Transdermal Estrogen Treatment in Women with Metabolic Syndrome? a Adjusted for age, race/ethnicity, cancer history, BMI, current statin use, estrogen daily dose, current progestin use, current smoking status, treated hypertension, treated diabetes mellitus, prevalent cardiovascular disease, and the number of GHC visits in the year before the index date. b Adjusted for age, race/ethnicity, BMI, current statin use, estrogen daily dose, current progestin use, current smoking status, treated hypertension, treated diabetes mellitus, prevalent cardiovascular disease, and the number of GHC visits in the year before the index date, as well as systolic blood pressure and total cholesterol level. 1. Writing group for WHI Investigators Csizmadi I, et al. Br J Cancer 24;9: Smith NL, et al. J Thromb Haemost. 26;4: Inflammation and Coagulation Markers with Oral and Transdermal Estrogen in Metabolic Syndrome Oral: CRP elevated but no significant increase MMP-9 increased TIMP decreased MMP-9/TIMP increased AT111 reduction Transdermal: No significant changes Route of Estrogen Administration: Sexual Function Chu & Lobo. 27 8

9 The Importance of Estrogen Therapy: Sexual Function Percent Increase in SHBG at 4 Months Healthy responsive genital tissues (eg, dryness, dyspareunia, vascular dilation) Impact on free and bioavailable testosterone (route of administration) Impact on bioavailable adrenal androgens % Change in SHBG from baseline % CE (.625 mg/d) n = 37 P <.1 45% Oral micronized estradiol (1 mg/d) n = 25 P <.1 12% Transdermal estradiol (5 µg/d) n = 24 Nachtigall et al. Menopause. 2;7(4): Changes in Binding Globulins With Oral Estrogen Replacement Therapy Age- and BMI-Adjusted Variables by Current Exogenous Estrogen Use in Postmenopausal Women Estrogen use SHBG 1-8 M Pre Post Menopausal * * * * Conjugated estrogens treatment (mg) CBG (binding capacity) g/1 ml 3 * 2 1 Pre Post Menopausal Conjugated estrogens treatment (mg) Nonusers Current Users (n = 676) (n = 31) Hormone (age, BMI-adjusted) Mean Mean P Value Dehydroepiandrosterone sulfate ( mol/l) <.1 Androstenedione (nmol/l) <.1 Testosterone (nmol/l) Free testosterone (nmol/l).4.3 <.1 Estradiol (pmol/l) <.1 Sex hormone binding globulin (x1-5 M) <.1 Adapted from Judd HL. Clin Obstet Gynecol. 1976;19: *P <.5 P <.1 Rancho Bernardo , ages 5-79 years. Tazuke, et al. Medicine. 1992;71:

10 Changes in Androgens and SHBG With Estrogen or Estrogen/Androgen Treatment Testosterone (total) SHBG Bioavailable testosterone (T/SHBG ratio) DHEAS Estrogen Estrogen Estrogen/Androgen (.625 mg) (1.25 mg) Half-strength Estrogen/Androgen Androstenedione SHBG = sex hormone binding globulin; T/SHBG = testosterone/sex hormone binding globulin ratio; DHEAS = dehydroepiandrosterone sulfate. All or represent statistically significant changes. KEEPS: Directions of Changes in CHD* Risk Factors Factor O CEE T E2 Systolic BP Neutral Neutral Diastolic BP Neutral Neutral LDL Cholesterol Favorable Neutral Triglycerides Adverse Neutral HDL Cholesterol Favorable Neutral Fasting Glucose Neutral Favorable HOMA IR* Neutral Favorable o CEE is Premarin.45mg/d t E2 is Climara.5 mcg/d *CHD: Coronary Heart Disease; HOMA IR: homeostasis model assessment estimated insulin resistance Simon et al. Menopause. 1999;6: Simon JA, Laliberté F, Duh MS, Pilon D, Kahler KH, Nyirady J, Davis PJ, Lefebvre P. Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. Menopause. 216 Jun;23(6):6-1. Methods Data Source: OptumHealth Reporting and Insights medical and pharmacy claims for more than 13 million privately-insured individuals from all census areas of the U.S. from January 21 through September 211 Study Population: Women 35 years of age newly initiated to either an ETS or oral ET agent and having 2 dispensings were selected Exclusion criteria: prior VTE or CVD diagnosis OR receipt of any other estrogen containing hormone therapy agents during the 18-day baseline period Study Design: a retrospective matched-cohort design was chosen to ensure that both groups were well balanced at baseline Women using ETS were matched 1:1 with women using oral ET based on both exact matching factors (e.g., baseline menopausal and post-menopausal disorders) and the propensity scores Page 4 1

11 Results Risk of VTE and CVD complications Overall, baseline characteristics and risk factors were well-balanced between cohorts A total of 718 ETS users developed VTE or CVD complications compared to 828 women in the oral ET cohort (P=.4) A total of 18 ETS users were hospitalized due to VTE or CVD complications compared to 177 women in the oral ET cohort (P<.1) Incidence Rate Frequency of Event Univariate Analysis (per 1 person-years) Outcome Unadjusted IRR ETS Oral ET ETS Oral ET P-value (95% CI) All Events VTE or CVD ( ).4 VTE ( ).375 CVD ( ).94 W/hospitalization VTE or CVD ( ) <.1 VTE ( ).675 CVD ( ).1 Page 41 Results Approach #2 Incremental Healthcare Cost Associated with Oral ET The adjusted all-cause healthcare cost difference was $56 per-patient per-month (PPPM) higher among oral ET users compared to transdermal users Adjusted incremental cost = $56 P- $6 Value=.26 Hospitalizations Incremental Cost PPPM Associated with Oral ET in US $211 $5 $4 $3 $2 $1 $ $7 $7 $3 $4 All-Cause Adjusted incremental cost = $24 P-value=.24 $23 VTE / CVD-related ER visits Outpatient visits Pharmacy Page 42 Conclusions Approach #1 CVD and stroke risks-particularly in women in their 5s-would be mitigated or eliminated by switching from CEE to transdermal estradiol (at 5mcg/24h or lower). BrCA risk would have been reduced to the risk in HT non-users if women had used MP instead of MPA. Physicians seeking to reduce VTE risk (the greatest risk of HT for early menopausal women) even in women with obesity or prothrombic mutations should use transdermal ET rather than oral ET or CEE. Estimates from three case-control VTE studies suggest a reduced number of VTE cases with transdermal HT versus oral HT. The consistency of the three study results provides even greater support for this conclusion. Conclusions (2)s Approach #2 Using a large matched-cohort study of over 15, women based on real-world data over a ten year period suggests that women receiving transdermal estrogens have a significantly lower incidence of VTE or CVD events compared to oral ET users This study also suggested that women treated with transdermal estrogens incur significantly lower all-cause and VTE/CVD-related healthcare costs compared to oral ET users Simon JA, Laliberté F, Duh MS, Pilon D, Kahler KH, Nyirady J, Davis PJ, Lefebvre P. Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. Menopause. 216 Jun;23(6):6-1. Simon JA, Laliberté F, Duh MS, Pilon D, Kahler KH, Nyirady J, Davis PJ, Lefebvre P. Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. Menopause. 216 Jun;23(6):

12 Progesterone (Progestogens) Metabolism of Oral Micronized Progesterone C21H3O2 Molar weight: g/mol pregn-4-ene-3,2-dione Potential Benefits of Oral Micronized Progesterone Relative Risks for Invasive Breast Cancer by Type of HT Progestogen (compared with HT never-users; E3N cohort study, n=8,377) E2 alone E2 + mic P4 E2 + DHG E2 + synth. Prog. E2: estradiol; mic P4: micronized progesterone; DHG: dydrogesterone; synt. Prog,: synthetic progestins (mainly nomegestrol acetate, promegestone, chlormadinone acetate, cyproterone acetate, medrogestone) Fournier A et al. Breast Cancer Res Treat 28; 17:

13 Testosterone (Androgens) C19H28O2 Molar weight: g/mol Δ 4 -Androsten-17β-ol-3-one Lipid Profiles Following 2 Years of Estrogen & Estrogen Plus Androgen Therapy in Postmenopausal Women Percent change from baseline Estrogen Estrogen plus androgen *P <.1 *P < HDL LDL Total cholesterol Triglycerides * Between group comparisons Adapted from Watts NB, et al. Comparison of oral estrogens and estrogens plus androgens on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol. 1995;85: Lipid Parameters Did Not Change with Transdermal T Administration Lipid Level (mg/dl) Shifren, et al. JCEM Baseline Placebo Total HDL LDL Triglycerides Cholesterol 15 g 3 g Oral vs Trandermal Testosterone Primary difference between oral and transdermal testosterone is that transdermal avoids first-pass metabolism Oral testosterone negative effect on lipoprotein profile 1, but this is outweighed by hepatotoxic adverse effects: Hepatocellular adenoma Cholestatic jaundice Hemorrhagic liver cysts Adverse events observed in males (female to male transsexuals) especially those with previous hepatic dysfuction, not women. 2 Transdermal testosterone has no related hepatotoxicity and therefore would be the safer option Braunstein GD, et al. Arch Intern Med 25;165: Bagatell CJ & Bremner WJ. N Engl J Med 1996;334: Basaria S & Dobs AS. J Clin Endocrinol Metab 26;91:

14 What if the WHI Had Used Transdermal Estradiol And Oral Progesterone Instead? 1 After the primary results of the WHI were published in 22 2 (HT), 24 3 (ET), many what if type questions were posed. Here we ask: 1) What if different estrogens and progestogens had been used? (estradiol and progesterone) 2) What if a different route of ET administration had been used? (transdermal vs. oral) If so, perhaps some or all of the adverse outcomes associated with CEE alone, or CEE with MPA, would have been avoided. 1) Simon JA. What if the Women s Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause. 214 Jul;21(7): ) Rossouw JE, et al. JAMA 22;288: (3) Anderson GL, et al. JAMA 24;291: ) Canonico M, et al. Stroke. 216;47: Ischemic Stroke (IS) Risk by Estrogen & Progestogen Administration Large Nested Case-Controlled Study of women who experienced IS was conducted to determine the risk of estrogens and progestogen type and dosage on IS. 1 Oral estrogens significantly increase IS risk in a dose dependent relationship while transdermal estrogens displayed no association. Cardiovascular risks were not affected by administration. Concomitant progestogens important determinate in IS outcome: Progesterone showed no adverse effects on the transdermal reduction in IS Pregnane derivatives, and nortestosterone derivatives showing no significant increase in IS risk Norpregnane derivatives increased IS risk. Odds ratios of IS according to estrogen dose by route of administration. Dotted lines represent overall OR for current users of oral (A) and transdermal (B) estrogens compared with nonusers. P for homogeneity between oral estrogen use and transdermal estrogen use is significant (p<.1). P for homogeneity between pharmacological classes of progestogens is significant (p=.3). *Adjusted for antidiabetic medication, antihypertensive medication, antidyslipidemia medication, and long-term chronic disease Ƚ85% of the subjects used nomegestrol acetate 1. Canonico M, et al. Stroke. 216;47: Estradiol (estrogen) Conclusions Just Imagine! Unique differences exist in E2 pharmacodynamics between oral and transdermal therapy. Differences exist in lipids, insulin resistance parameters, and inflammatory and coagulation markers. Data to date show lower CV effects with transdermal; including thrombosis, stroke (ischemic) and MI. In metabolic syndrome (MBS), and other high risk women transdermal therapy may be favored, based on surrogate marker data. The choice of therapy otherwise, remains an individual decision. 14

15 Selecting HT Based on Risks/Benefits in Symptomatic Individual Postmenopausal Women: Impact of Route of Administration Menopausal symptoms Breast cancer Osteoporosis Cardiovascular disease (including thrombosis and stroke) Potential benefits > Potential risks Woman with low CHD risk (eg, no CHD risk factors; no risk determinants of the metabolic syndrome; low CRP All others (eg, established CHD, diabetes, metabolic syndrome, obesity, atherogenic dyslipidemia, high CRP, thrombophilia, history of DVT, low sexual desire or sexual dysfunction ) Selection guided by patient s preferences Consider transdermal formulations 15