Estradiol (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.

14 CLINICAL STUDIES

14.1 Effects on Vasomotor Symptoms in Postmenopausal Women

A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of estradiol for vasomotor symptoms in 495 postmenopausal women (86.5 percent White; 10.1 percent Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2 week period prior to treatment). Women applied placebo, estradiol 0.25 grams (0.25 mg estradiol), estradiol 0.5 grams (0.5 mg estradiol) or estradiol 1.0 gram (1.0 mg estradiol) once daily to the thigh. Reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes were statistically significant for the 0.5 grams per day and the 1.0 gram per day estradiol doses when compared to placebo at week 4. Statistically significant reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes for the estradiol 0.25 grams per day dose when compared to placebo were delayed to week 7. There were statistically significant reductions in median daily frequency and severity of hot flushes for all three estradiol doses (0.25 grams per day, 0.5 grams per day and 1.0 gram per day) compared to placebo at week 12. See Table 3 for results.

Table 3: Summary of Change From Baseline in the Median Daily Frequency and Severity of Hot Flushes during Estradiol Treatment (ITT Population)

Estradiol Placebo
Evaluation 0.25 grams/day N=121 0.5 grams/day N=119 1.0 gram/day N=124 N=124
Frequency of Daily Hot Flushes
Baseline Median 9.72 9.24 9.64 9.32
Median Change: Week 4 p-value† -5.00 0.132 -5.73 0.011 -7.20 <0.001 -3.63
Median Change: Week 7 p-value† -6.62 <0.001 -7.14 <0.001 -7.71 <0.001 -4.37
Median Change: Week 12 p-value† -6.88 <0.001 -7.29 <0.001 -8.35 <0.001 -4.48
Severity of Daily Hot Flushes
Baseline Median 2.52 2.51 2.52 2.54
Median Change: Week 4 p-value† -0.07 0.283 -0.18 <0.001 -0.47 <0.001 -0.04
Median Change: Week 7 p-value† -0.24 <0.001 -0.46 <0.001 -1.06 <0.001 -0.06
Median Change: Week 12 p-value† -0.33 0.021 -0.56 0.002 -1.69 <0.001 -0.13

†p-values from the van Elteren’s test stratified by pooled center, comparison in median change was significant if p<0.05.

14.2 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 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-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years are presented in Table 4.

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For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the “global index” was a nonsignificant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. See Table 4.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36–1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–1.11)].

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 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 reductions 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 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

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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 for age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44–1.07)].

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