Effects on Vulvar and Vaginal Atrophy

Two controlled studies have demonstrated the efficacy of ESTRING (estradiol vaginal system) in the treatment of postmenopausal urogenital symptoms due to estrogen deficiency.

In a U.S. study where ESTRING was compared with conjugated estrogens vaginal cream, no difference in efficacy between the treatment groups was found with respect to improvement in the physician's global assessment of vaginal symptoms (83 percent and 82 percent of patients receiving ESTRING and cream, respectively) and in the patient's global assessment of vaginal symptoms (83 percent and 82 percent of patients receiving ESTRING and cream, respectively) after 12 weeks of treatment. In an Australian study, ESTRING was also compared with conjugated estrogens vaginal cream and no difference in the physician's assessment of improvement of vaginal mucosal atrophy (79 percent and 75 percent for ESTRING and cream, respectively) or in the patient's assessment of improvement in vaginal dryness (82 percent and 76 percent for ESTRING and cream, respectively) after 12 weeks of treatment.

In the U.S. study, symptoms of dysuria and urinary urgency improved in 74 percent and 65 percent, respectively, of patients receiving ESTRING as assessed by the patient. In the Australian study, symptoms of dysuria and urinary urgency improved in 90 percent and 71 percent, respectively, of patients receiving ESTRING as assessed by the patient.

In both studies, ESTRING and conjugated estrogens vaginal cream had a similar ability to reduce vaginal pH levels and to mature the vaginal mucosa (as measured cytologically using the maturation index and/or the maturation value) after 12 weeks of treatment. In supportive studies, ESTRING was also shown to have a similar significant treatment effect on the maturation of the urethral mucosa.

Endometrial overstimulation, as evaluated in non-hysterectomized patients participating in the U.S. study by the progestogen challenge test and pelvic sonogram, was reported for none of the 58 (0 percent) patients receiving ESTRING and 4 of the 35 patients (11 percent) receiving conjugated estrogens vaginal cream.

Of the U.S. women who completed 12 weeks of treatment, 95 percent rated product comfort for ESTRING as excellent or very good compared with 65 percent of patients receiving conjugated estrogens vaginal cream, 95 percent of ESTRING patients judged the product to be very easy or easy to use compared with 88 percent of cream patients, and 82 percent gave ESTRING an overall rating of excellent or very good compared with 58 percent for the cream.

Women's Health Initiative Trial with Oral Conjugated Estrogen

The Women’s Health Initiative (WHI) estrogen-alone trial enrolled predominantly healthy postmenopausal women to assess the risks and benefits of daily oral conjugated estrogen (CE) (0.625 mg)-alone 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, colorectal cancer, hip fracture, or death due to other cause.

The WHI oral CE-alone trial included 10,739 women (average 63 years of age, range 50 to 79; 75 percent White, 15 percent Black, 6 percent Hispanic, 4 other races), with an average follow-up of 7.1 years. The WHI oral CE-alone trial was stopped early because an increased risk of stroke was observed in the oral CE group. The stroke events were centrally adjudicated. The use of oral CE-alone, compared to placebo, increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.1

No overall difference for centrally adjudicated primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence were seen in women who received oral CE-alone compared to those who received placebo after an average follow-up of 7.1 years.1,2

The results of the WHI oral CE-alone trial are presented in Table 2.

Women's Health Initiative Memory Study with Oral Conjugated Estrogen

The Women’s Health Initiative Memory Study (WHIMS) estrogen-alone ancillary study of the WHI trial enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older to evaluate the effects of daily oral CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. In the WHIMS, 45% of the women were 65 to 69 years of age; 36% were 70 to 74 years of age; and 19% were 75 years of age and older. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type of dementia (having features of both AD and VaD). The most common classification of probable dementia in the treatment and placebo groups was AD.

In the WHIMS, after an average follow-up of 5.2 years, the relative risk of probable dementia for women in the oral CE-alone group versus the placebo group was 1.49 (95% CI, 0.83-2.66). The absolute risk of probable dementia for oral CE-alone group versus the placebo group was 37 versus 25 cases per 10,000 women-years.

Because WHIMS was conducted in women 65 to 79 years of age, it is unknown whether the findings in WHIMS apply to younger postmenopausal women.3