Bioidentical Hormones for Menopausal Therapy

Cynthia K Sites

Disclosures

Women's Health. 2008;4(2):163-171. 

In This Article

Evidence for Relief of Hot Flashes & Vaginal Dryness with Very Low-dose Estradiol

Since the findings of the Women"s Health Initiative and HERS were published, patients and pharmaceutical companies have worked to find alternatives for menopause symptom relief. With the recommendation to use the smallest dose of estrogen for the shortest amount of time needed to relieve hot flashes and vaginal dryness,[22] various formulations of transdermal estradiol therapy have emerged. The first generation of transdermal estradiol skin patches (reservoir or imbedded types) deliver estradiol in a constant fashion with application once or twice weekly, but 15% of patients note skin irritation caused by the adhesive.[23] Several new estradiol gel products have been developed and are approved by the US FDA for hot flash symptoms, including Divigel®, Estrogel® and Elestrin™. Gels have an advantage over patches in that there is no adhesive necessary, which markedly reduces skin sensitivity side effects.

With gels, estradiol is stored in the skin as a reservoir rather than in a pouch or matrix reservoir of a patch. It appears that the skin releases estradiol in a consistent fashion, with the pharmacokinetics of Estrogel and Elestrin both reporting that steady state is reached after 3 days of a once-daily application on the upper outer arm.[23,24] Pharmacokinetics for Elestrin, Estrogel and Divigel[53] are noted in Table 1 based on information submitted to the FDA.

Elestrin and Divigel are currently the lowest dose transdermal estradiol gels approved for the relief of hot flashes. The lowest dose of Elestrin tested in the Phase III clinical trial, 0.87 g delivering 0.52 mg estradiol per day, was effective in significantly relieving both the frequency and severity of hot flashes significantly by 50% at 4 and 12 weeks of treatment compared with placebo. Blood estradiol levels and safety profiles on this lowest dose of Elestrin were similar to placebo, with effectiveness noted at 12.5 µg/day of estradiol. Similarly, for Divigel, 0.5 mg estradiol per day delivered by gel significantly relieved hot flashes by 4 and 12 weeks.[53] A recent randomized, controlled trial also reported that a transdermal patch releasing 14 µg/day of estradiol significantly relieved hot flashes in 41% of participants, confirming the efficacy of transdermal microdose preparations.[25] Thus, FDA-approved transdermal gel preparations delivering approximately 0.5 mg/day estradiol, producing mean serum estradiol levels of 15.4-21 pg/ml, are adequate to significantly reduce the frequency and severity of hot flashes in postmenopausal women.

Low-dose transdermal estradiol products have also been found to improve vulvovaginal atrophy symptoms in postmenopausal women, but may promote endometrial proliferation.[26,27] In a randomized, placebo-controlled trial, Estrogel 0.87 g/day was found to reduce the baseline severity in the most bothersome moderate-to-severe vulvovaginal atrophy symptoms significantly by week 12. Similarly, vaginal pH levels decreased and vaginal maturation index increased by week 12.[26] In a 2-year randomized, double-blind, placebo-controlled trial of a transdermal patch releasing 14 µg estradiol per day in older postmenopausal women, vaginal epithelial cells showed a pattern of greater maturation in the estradiol group compared with the placebo group.[27] In addition, 2 years of ultralow-dose estradiol did not increase the rates of endometrial hyperplasia and was associated with minimal proliferative effect on the endometrium.[27] It is not known what effect long-term transdermal Biest will have on endometrial proliferation. If transdermal Biest is shown to increase endometrial proliferation, long-term studies should be performed to determine if bioidentical progesterone or commercial progestins reverse the proliferative changes caused by Biest. It is important to note that bioequivalence can not be claimed by "bioidentical" compounded products that use different routes, carriers and doses of administration.

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