Diff. vs placebo
    P value†
5.17 (6.52)
-5.84 (4.52) 2.79 (3.70)
-7.55 (3.52)
1.71
0.043‡
1.76 (0.84)
-0.54 (0.84) 1.33 (0.97)
-1.03 (0.94)
0.49
<0.001‡
Effects on vulvar and vaginal atrophy
Results of the vaginal wall cytology showed a significant (P≤0.001) increase from baseline in the percent of superficial epithelial cells at Week 12 for 1.25 g EstroGel. In contrast, no significant change from baseline was observed in the placebo group.
Transdermal effects
In 2 controlled clinical trials, application site reactions were reported by 0.6% of patients who received 1.25 g of EstroGel. Other skin reactions, such as pruritus and rash, were also noted. (See Table 4.)
Women’s Health Initiative Studies
The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (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) (nonfatal myocardial infarction (MI), silent MI, and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE/MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These studies did not eva luate the effects of CE or CE/MPA on menopausal symptoms.
The 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 age of 63 years, range 50-79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 6.8 years are presented in Table 2.
TABLE 2 Relative and Absolute Risk Seen in the Estrogen Alone Substudy of WHI  *
Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
Not included in Global Index.
Results are based on an average follow-up of 6.8 years.
All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.
A subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 
Event Relative Risk
CE vs Placebo
(95% nCI*) Placebo
n = 5,429 CE
n = 5,310
  Absolute Risk per 10,000
Women-Years
CHD even