Transdermal estradiol gel for the treatment of symptomatic postmenopausal women.

OBJECTIVE: The aim of this study was to determine the efficacy, safety, and lowest practical dose of a transdermal estradiol gel in the treatment of symptomatic postmenopausal women. METHODS: Healthy postmenopausal women with seven or more moderate to severe hot flushes per day or 50 to 60 or more per week were randomized to transdermal gel containing 1.5 mg (n = 73) or 0.75 mg (n = 75) estradiol (EstroGel 0.06%) or placebo (n = 73) in a phase 3 study, or to 0.375 mg (n = 119) or 0.27 mg (n = 118) estradiol (0.03% gel) or placebo (n = 114) in a phase 4 study. RESULTS: The frequency of moderate to severe hot flushes and severity of all hot flushes significantly decreased versus placebo at weeks 4 and 12 with 1.5, 0.75, and 0.375 mg estradiol. Overall participant responder rates were generally lower in the phase 4 study than those in the phase 3 study with the approved 0.75-mg estradiol dose. Vaginal maturation index (VMI) shifts from baseline to week 12 were significant (P < 0.001) with 0.75 and 1.5 mg estradiol versus placebo; VMI improved (P < 0.001), superficial cells increased (P = 0.005), and parabasal cells decreased (P = 0.002) with 0.375 mg estradiol vs placebo but not with 0.27 mg estradiol. The most frequently reported treatment-emergent adverse events, although not necessarily treatment related, were headache, infection, breast pain, and nausea (phase 3 study) and insomnia and headache (phase 4 study). No serious adverse events were related to treatment; no deaths occurred. CONCLUSION: A transdermal gel with 0.75 mg estradiol was the lowest practical dose that effectively reduced the frequency and severity of moderate to severe hot flushes, improved VMI, and was well tolerated.