CLINICAL STUDIES
Effects on the Endometrium
In a 3-year, double-blind, placebo-controlled study of 356 nonhysterectomized, postmenopausal women between 45 and 64 years of age randomized to receive placebo (n=119), 0.625 mg conjugated estrogen only (n=119), or 0.625 mg conjugated estrogen plus cyclic PROVERA (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg PROVERA plus 0.625 mg conjugated estrogens compared to the group receiving 0.625 mg conjugated estrogens only. See Table 2.
| Histological Results | Placebo (n=119) | CEE † (n=119) | PROVERA ‡ + CEE (n=118) |
|---|---|---|---|
| Normal/No hyperplasia (%) | 116 (97) | 45 (38) | 112 (95) |
| Simple (cystic) hyperplasia (%) | 1 (1) | 33 (28) | 4 (3) |
| Complex (adenomatous) hyperplasia (%) | 1 (1) | 27 (22) | 2 (2) |
| Atypia (%) | 0 | 14 (12) | 0 |
| Adenocarcinoma (%) | 1 (1) | 0 | 0 |
In a second 1-year study, 832 postmenopausal women between 45 and 65 years of age were treated with daily 0.625 mg conjugated estrogen (days 1–28), plus either 5 mg cyclic PROVERA or 10 mg cyclic PROVERA (days 15–28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic PROVERA (days 15–28) plus daily conjugated estrogens showed a significantly lower rate of hyperplasia as compared to the conjugated estrogens only group. See Table 3.
| CEE * | MPA † + CEE * | ||
|---|---|---|---|
| (n=283) | MPA 5 mg (n=277) | MPA 10 mg (n=272) | |
| Cystic hyperplasia (%) | 55 (19) | 3 (1) | 0 |
| Adenomatous hyperplasia without atypia | 2 (1) | 0 | 0 |
Women's Health Initiative Studies
The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years.
For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
| Event | Relative Risk CE/MPA vs placebo (95%nCI ‡) | CE/MPA n = 8,506 | Placebo n = 8,102 |
|---|---|---|---|
| Absolute Risk per 10,000 Women-Years | |||
| |||
| CHD events | 1.23 (0.99–1.53) | 41 | 34 |
| Non-fatal MI | 1.28 (1.00–1.63) | 31 | 25 |
| CHD death | 1.10 (0.70–1.75) | 8 | 8 |
| All strokes | 1.31 (1.03–1.68) | 33 | 25 |
| Ischemic stroke | 1.44 (1.09–1.90) | 26 | 18 |
| Deep vein thrombosis§ | 1.95 (1.43–2.67) | 26 | 13 |
| Pulmonary embolism | 2.13 (1.45–3.11) | 18 | 8 |
| Invasive breast cancer¶ | 1.24 (1.01–1.54) | 41 | 33 |
| Colorectal cancer | 0.61 (0.42–0.87) | 10 | 16 |
| Endometrial cancer§ | 0.81 (0.48–1.36) | 6 | 7 |
| Cervical cancer§ | 1.44 (0.47–4.42) | 2 | 1 |
| Hip fracture | 0.67 (0.47–0.96) | 11 | 16 |
| Vertebral fractures§ | 0.65 (0.46–0.92) | 11 | 17 |
| Lower arm/wrist fractures§ | 0.71 (0.59–0.85) | 44 | 62 |
| Total fractures§ | 0.76 (0.69–0.83) | 152 | 199 |
| Overall mortality# | 1.00 (0.83–1.19) | 52 | 52 |
| Global IndexÞ | 1.13 (1.02–1.25) | 184 | 165 |
Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk in overall mortality [hazard ration (HR) 0.69 (95 percent CI, 0.44–1.07)].
Women's Health Initiative Memory Study
The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 33 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use).