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Low-Dose Transdermal Estradiol Cools Down Hot Flushes: Presented at NAMS

By Carole Bullock

DALLAS, TX -- October 9, 2007 -- For the relief of hot-flushes, transdermal estradiol (E2) gel 0.1% offers women a low-dose estrogen alternative to conventional hormone replacement therapy, according to a report presented at the North American Menopause Society (NAMS) 18th annual meeting.

"Even though hormone therapy is the most effective treatment for menopausal symptoms, many women discontinue hormone therapy due to postmenopausal bleeding or breast tenderness," noted Ronald Ackerman, MD, Chief Executive Officer and Medical Director of Comprehensive Clinical Trials, West Palm Beach, Florida.

"So the treatment goal is to provide the least amount of estrogen over the least amount of time which can be effective for the individual patient. Transdermal is a growing trend owing to its ability to bypass the liver and be given at lower doses," he said at this presentation, given on October 4.

Used primarily for treating vasomotor symptoms associated with menopause, the once-a day transdermal gel was developed from sunflower seeds.

In a double-blind, 12-week randomization, 488 postmenopausal women who had amenorrhea (for 12 months or more), bilateral oophorectomy with or without hysterectomy, and more than 50 moderate to severe hot flushes per week were given one of three doses. The study included women between the ages of 18 to 65 years; 89% were white, 9% black, and 2% Asian.

Estradiol and a placebo gel were supplied in single-use packets and applied on each thigh daily in an alternating pattern to prevent skin irritation.

The safety and efficacy of transdermal estradiol gel 0.1% in the treatment of menopausal symptoms were measured at doses of 0.25, 0.5, and 1.0 g/d.

At the start of the study, all subjects had normal or atypical pap smears, normal mammograms, and satisfactory transvaginal ultrasound examinations. Safety analyses included the incidence of adverse events and clinical laboratory evaluations, including plasma levels of sex hormone-binding globulin (SHBG). Application site tolerability was assessed using the Draize scale.

Median estradiol concentrations increased proportionally to the dose of estradiol gel 0.1% at weeks 4, 8, and 12.

All doses of estradiol gel 0.1% produced physiologic E2:E1 ratios similar to those seen in premenopausal women.

E2:E1 ratios increased from a baseline mean of 0.17 to 0.49, 0.69, and 0.95 with the 0.25, 0.5, and 1.0 g/d doses, respectively, of estradiol gel 0.1%.

Mean Draize scale scores after 4, 8, and 12 weeks of treatment were 0.0 for all treatment groups except for a mean value, after 4 weeks of treatment, of 0.1 ± 0.34 for the group receiving the 0.5-g/d dose.

The most frequent complaints were breast tenderness and postmenopausal bleeding, which appeared to be dose-related and would be expected with increased circulating estrogen concentrations, Dr. Ackerman noted.

Adverse events were reported in 278 women (56%); most events (92%) were reported as being mild or moderate and occurred more frequently with the higher doses.

No clinically relevant changes of the skin at the application site compared to baseline were observed, and no cases of hyperplasia or carcinoma were found in any of the treatment groups. Nor were there any remarkable changes in hematology; blood chemistry; urinalysis; and lipid, coagulation, or carbohydrate values following treatment with estradiol gel 0.1%. SHBG levels remained unchanged after 12 weeks of treatment at all doses.

"The vast majority of patients had no evidence of skin irritation throughout the treatment period," Dr. Ackerman said.

[Presentation title: Safety and Tolerability of 3 Doses of Estradiol Gel 0.1% in the Treatment of Menopausal Symptoms. Abstract P-12.]

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