Clinical Review

Estradiol gel: A new option in hormone replacement therapy

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An expert profiles percutaneous gel: easy to use, well tolerated, and available in low doses.



  • Percutaneous estradiol gel can be prescribed at low doses.
  • Relief of menopausal symptoms can begin as early as 2 weeks after starting treatment.
  • Treatment with estradiol gel maintains or increases bone mineral density.
  • No large randomized, controlled trials have explored the effect of estradiol gel on coronary artery disease. It appears to have metabolic effects similar to those of oral estradiol.
  • Because percutaneous estradiol stimulates the endometrium, women with an intact uterus should also take a progestogen.

Although the Women’s Health Initiative1 discouraged many menopausal women from using oral estrogen, it failed to address the risks of treatment with other dosages or forms of estrogen and progestin.

Nor has any other trial of similar size and complexity taken up the issue. However, numerous smaller studies have been published.

This article summarizes findings on percutaneous delivery of estradiol gel (EstroGel), the most recently FDA-approved estrogen option for treatment of menopausal symptoms.

It describes the overall safety of estradiol gel, as well as its effectson:

  • menopausal symptoms,
  • bone,
  • metabolism, and
  • endometrium.

(In this article, “percutaneous delivery” refers to estradiol gel applied to the skin, and “transdermal estradiol” indicates delivery via a transdermal reservoir or matrix system, otherwise known as “the patch.” I have used an arbitrary definition to distinguish the gel from other methods of delivering estradiol across the skin. For example, Estrasorb is a liposomal formulation that is applied to the skin of the thigh. Although it is a percutaneous estradiol similar to the gel, this article focuses only on the latter option.)

Easy to apply, few skin reactions

Percutaneous estradiol gel formulations have been available for almost 30 years in Europe, where they are utilized by a majority of women on hormone therapy. In the United States, the hydroalcoholic gel is packaged in a pump that delivers 64 standardized 1.25-g doses, which contain 0.75 mg of 17ß-estradiol. Once it is applied, the gel is absorbed into an intradermal reservoir (FIGURE) and dries in 2 to 5 minutes, leaving no residue.

Patient selection. Estradiol gel is well-suited for patients who are concerned about the risks of oral estrogen (as portrayed in the mainstream press following the Women’s Health Initiative) and want to avoid that route of administration, as well as women who dislike or have difficulty swallowing pills. Percutaneous administration also is appropriate for physically active women who may have adhesion problems or skin irritation with the transdermal patch, or those who have had reactions to local adhesives in the past. The patient should be motivated to apply the gel on a daily basis.

Indications are moderate to severe vasomotor symptoms in menopausal women, and moderate to severe symptoms of vulvar and vaginal atrophy, although topical vaginal products should also be considered for the latter indication.

Contraindications are undiagnosed abnormal vaginal bleeding; history of breast cancer, other estrogen-dependent malignancy, stroke, heart attack, or liver disease or dysfunction; active thrombophlebitis or thromboembolic disorders (or a history of these); and known or suspected pregnancy.

Common side effects include headache, breast pain, irregular vaginal bleeding or spotting, stomach cramps or bloating, nausea and vomiting, and hair loss.

  • Skin reactions are infrequent, but should be taken into account when discussing per-cutaneous or transdermal delivery of any drug. However, estradiol gel appears to cause fewer skin reactions than the patch. In a study over more than 5 years, 0 of 157 women treated with percutaneous estradiol reported skin irritation.2 Other comparisons found similar outcomes.3,4
After the gel dries, other lotions or per-fumes can be applied to the site, if desired, and the woman can cover the site with clothing.

Onset of action is rapid, as it is with the transdermal patch.5 Dose variability is minimized when the gel is applied at the same time every day to a large area of skin, preferably the arm, although all application sites appear to produce similar results: abdomen, shoulders, arms, and inner thigh.6 The gel should not be applied to the breast or vagina.

Diminished effect with skin washing. In 1 trial, site washing 1/2 hour after application significantly decreased bioavailability and time to reach peak plasma concentrations.7 For this reason, the gel should be not applied before a bath, shower, or sauna.

Dosing options. The initial dose is 1.25 mg of gel, which is 1 pump of the bottle. The gel is collected in the palm of 1 hand and applied to the skin of the opposite arm from the wrist to the shoulder. The dose can be titrated by adding a second pump of the gel and applying it to the opposite arm. The dose can be lowered by using less than a full depression of the pump.


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