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Effects of Ultralow-Dose Transdermal Estradiol on Bone Mineral Density: A Randomized Clinical Trial

Ettinger, Bruce MD*; Ensrud, Kristine E. MD, MPH†; Wallace, Robert MD‡; Johnson, Karen C. MD, MPH§; Cummings, Steven R. MD¶; Yankov, Vladimir MD∥; Vittinghoff, Eric PhD, MPH*; Grady, Deborah MD, MPH*†‡§¶∥*

Obstetrics & Gynecology:
doi: 10.1097/01.AOG.0000137833.43248.79
Original Research

OBJECTIVE: Because small increments in levels of endogenous plasma estradiol are associated with higher postmenopausal bone mineral density, we investigated the safety and effectiveness in preventing bone loss of unopposed, very-low-dose transdermal estradiol for postmenopausal women.

METHODS: This was a randomized, placebo-controlled, double-blind trial with 2-year follow-up at 9 United States clinical centers. The study population comprised 417 postmenopausal women, aged 60–80 years, with intact uterus and bone mineral density z scores of –2.0 or higher, who were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). All participants received calcium and vitamin D supplementation. Lumbar spine and total hip bone mineral density change was measured by dual-energy X-ray absorptiometry; endometrial hyperplasia incidence was assessed by endometrial biopsy.

RESULTS: Median plasma estradiol level in the estradiol group increased from 4.8 pg/mL at baseline to 8.5 pg/mL at 1 year (P < .001 versus baseline) and to 8.6 pg/mL at 2 years (P < .001 versus baseline) and was unchanged in the placebo group. Lumbar spine bone mineral density increased 2.6% in the estradiol group and 0.6% in the placebo group (between-group difference 2.0%, P < .001). Mean total hip bone mineral density increased 0.4% in the estradiol group and decreased 0.8% in the placebo group (between-group difference 1.2%, P < .001). Osteocalcin levels and bone-specific alkaline phosphatase were lower in the estradiol group than the placebo group (P < .001 each). Endometrial hyperplasia developed in 1 woman in the estradiol group but in none of the placebo group (difference in 2-year rates 0.5%, 95% confidence interval 0–7.3%).

CONCLUSION: Postmenopausal treatment with low-dose, unopposed estradiol increased bone mineral density and decreased markers of bone turnover without causing endometrial hyperplasia.


In Brief

Treatment with low-dose, unopposed estradiol increased bone mineral density and decreased markers of bone turnover in postmenopausal women without causing endometrial hyperplasia.

Author Information

From the *Division of Research, Kaiser Permanente Medical Care Program, Oakland, California; †Epidemiology Clinical Research Center, University of Minnesota, and Veteran's Administration Medical Center, Minneapolis, Minnesota; ‡Department of Epidemiology, University of Iowa, Iowa City, Iowa; §Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis, Tennessee; ¶Department of Epidemiology and Biostatistics, University of California, and Clinical Research Division, California Pacific Medical Center Research Institute, San Francisco, California; ∥Ferring Pharmaceuticals, Inc, Suffern, New York; and **Department of Epidemiology and Biostatistics and Women's Health Clinical Research Center, Mount Zion Medical Center, University of California, San Francisco, California.

Received March 16, 2004. Received in revised form June 18, 2004. Accepted June 22, 2004.

Presented at the 52nd annual American College of Obstetricians and Gynecologists Clinical Meeting, Philadelphia, Pennsylvania, May 1–5, 2004, and published in abstract form as Ettinger B, Grady D, Foegh M, Hanes V. Osteoporosis prevention with unopposed ultralow-dose transdermal estradiol. Obstet Gynecol 2004;103 suppl 4:6S.

Presented at the 25th annual meeting of the American Society for Bone and Mineral Research, Minneapolis, Minnesota, September 19–23, 2003, and published in abstract form in the Journal of Bone and Mineral Research 2003;18 suppl 2:S53.

Financial Disclosure Grant support from Berlex Laboratories, Inc, Montville, New Jersey, was provided for research purposes only. Berlex also donated the transdermal patches. Vladimir Yankov, MD, was an employee of Berlex Laboratories when the research was conducted. Dr. Cummings holds a patent on Menostar. Dr. Grady received grant support from Berlex.

Address reprint requests to: Bruce Ettinger, MD, 156 Lombard Street, #13, San Francisco, CA 94111; e-mail:

© 2004 The American College of Obstetricians and Gynecologists