1. WHI Trial of Estrogen plus Progestin: Reviewer’s Comments Endocrinologic and Metabolic Drugs Advisory Committee Meeting Rockville, Maryland - 7 October 2003 Bruce V. Stadel, MD, MPH Division of Metabolic and Endocrine Drug Products Center for Drug Evaluation and Research

2. 2 FDA-Approved Estrogen Plus Progestin Products for Prevention of Postmenopausal Osteoporosis Product Active IngredientsDoses (mg) Prempro TM Premphase  conjugated estrogens/ medroxyprogesterone 0.625/2.5, 0.625/5.0, 0.45/1.5, 0.3/1.5 0.625 x 14 days + 0.625/5.0 x 14 days Activella  estradiol/ norethindrone 1.0/0.5 Femhrt  ethinyl estradiol/ norethindrone 0.005/1.0 Ortho- Prefest TM estradiol/ norgestimate 1.0/0.09

3. 3 FDA-Approved Estrogen Products for Prevention of Postmenopausal Osteoporosis ProductActive IngredientsDoses (mg) Premarin  conjugated estrogens 0.3, 0.45, 0.625, 0.9, 1.25, 2.5 Estrace  estradiol0.5, 1.0, 2.0 Climara  (transdermal)estradiol0.025, 0.05, 0.075, 0.1 Ogen  estropipate0.75, 1.5, 3.0 Ortho-Est  estropipate0.75 Vivelle-Dot  (transdermal)estradiol0.025, 0.0375, 0.05, 0.075, 0.1

4. 4 IMS Health, National Prescription Audit Plus™, 1995 – July 2003, extracted August 2003.

5. 5 WHI Trial of Estrogen plus Progestin Invasive Breast Cancer by Prior Menopausal Hormone Use N diagnosed/N randomized (%) Prior Use Estrogen plus progestin 58/2225 (2.61%) Placebo 29/2079 (1.39%) Difference 1.22% (95% confidence interval) (+0.38% to +2.08%) No Prior Use Estrogen plus progestin 141/6277 (2.25%) Placebo 121/6020 (2.01%) Difference 0.24% (95% confidence interval) (–0.28% to +0.75%) Derived from: Chlebowski et al. JAMA. 2003;289:3243-3253

6. 6 Relative Risk of Breast Cancer for Users of Hormone Replacement Therapy in the Million Women Study From: Million Women Study Collaborators. Lancet. 2003;362:419-427.

7. 7 Relative Risk of Breast Cancer for Users of Hormone Replacement Therapy in the Million Women Study From: Million Women Study Collaborators. Lancet. 2003;362:419-427.

8. 8 Major Path of Estrogen Production in Postmenopausal Women Androstenedione, mostly from the adrenal glands, is aromatized to estrone in adipose tissue

9. 9 Can Measuring Endogenous Estrogens Predict Response To Treatment? Osteoporosis 1. Cummings SR, Browner WS, Bauer D, et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med. 1998;339:733-738. “Postmenopausal women with undetectable serum estradiol concentrations and high serum concentrations of sex hormone globulin have an increased risk of hip and vertebral fracture.” Breast Cancer 2. Endogenous Hormones and Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95:1218-1226. “The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the the result of the associated increase in estrogens, particularly bioavailable estradiol.”