# Presentation: 713543

## 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**** **

## Slide 2

|             FDA-Approved Estrogen Plus Progestin Products
            for Prevention of Postmenopausal Osteoporosis  |  |  |  |
| --- | --- | --- | --- |
| Product |   Active Ingredients |  | Doses (mg)    |
| PremproTM

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-PrefestTM | estradiol/
norgestimate |  | 1.0/0.09 |
|  |  |  |  |

## Slide 3

|                         FDA-Approved Estrogen Products       
              for Prevention of Postmenopausal Osteoporosis |  |  |
| --- | --- | --- |
|    Product | Active Ingredients | Doses (mg) |
| Premarin | conjugated estrogens | 0.3, 0.45, 0.625,
0.9, 1.25, 2.5 |
| Estrace | estradiol | 0.5, 1.0, 2.0 |
| Climara (transdermal) | 
estradiol | 
0.025, 0.05, 0.075, 0.1 |
| Ogen | estropipate | 0.75, 1.5, 3.0 |
| Ortho-Est | estropipate | 0.75 |
| Vivelle-Dot (transdermal) | 
estradiol | 
0.025, 0.0375, 0.05, 0.075, 0.1 |

## IMS Health, National Prescription Audit PlusTM, 1995 – July 2003, extracted August 2003.

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

##              WHI Trial of Estrogen plus Progestin

-              **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

##                                           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.**

##                                           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.**

## Major Path of Estrogen Production in Postmenopausal Women

- Androstenedione,
- mostly from the adrenal glands,
- is aromatized to estrone
- in adipose tissue

##    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.”