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.
The effects of two different concentrations of a transdermal estradiol gel on hot flushes and vaginal cytology were evaluated in separate clinical trials. Reductions in hot flush frequency and severity, shifts to higher vaginal maturation value, and the percentage of participants having a response were significant with 0.06% estradiol applied daily to the arm.
From the 1Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, VA; 2Obstetrics and Gynecology, Columbia University Medical Center, New York, NY; and 3ASCEND Therapeutics, Herndon, VA.
Received July 29, 2011; revised and accepted October 4, 2011.
Funding/support: The conduct of the reported clinical studies was funded by Solvay Pharmaceuticals, Inc. ASCEND Therapeutics acquired the rights to EstroGel 0.06% (estradiol gel) in 2006 and provided support for statistical analysis and assistance in manuscript preparation to Steven Radecki, PhD and Kathleen Ohleth, PhD of Precise Publications, LLC, respectively.
Financial disclosure/conflicts of interest: Dr. Archer has been a consultant for Abbott Laboratories, Agile Therapeutics, Bayer Healthcare, CHEMO, Corcept, Merck (formerly Schering Plough, Organon), and Pfizer, Inc. (formerly Wyeth Laboratories); has received support for research activity from Bayer Healthcare, Duramed, Organon, Warner Chilcott, Watson Pharmaceutical, and Pfizer, Inc. (formerly Wyeth Laboratories); and has received lecture fees from Bayer Healthcare and Pfizer, Inc. (formerly Wyeth Laboratories). Dr. Pickar is a former employee of Wyeth Research and has consulted for Wyeth, Depomed, BHR Pharma, Bionovo, and ASCEND Therapeutics. Dr. MacAllister is an employee of ASCEND Therapeutics. Dr. Warren is a consultant for or advisory board member for Pfizer, Inc., QuatRx, and Yoplait and has received grants/research support from Ferring and Pfizer and is on the speaker’s bureau for Amgen, Upsher Smith, and Warner Chilcott.
Address correspondence to: David F. Archer, MD, Obstetrics and Gynecology, Clinical Research Center, Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507-1912. E-mail: firstname.lastname@example.org