Lowest-Dose Estradiol Gel for Menopausal Hot Flashes

Since the initial publication of the Women's Health Initiative (WHI) study in 2000, the use of hormone therapies during menopause has shifted to focus almost exclusively on low-dose options. In accordance with the WHI results, the North American Menopause Society (NAMS) now recommends that women who take estrogen therapy for the vasomotor symptoms of menopause use the lowest possible dose, and for the shortest amount of time.

The most recent addition to these options is the newly approved transdermal estradiol gel 0.1% (Divigel; Upsher-Smith Laboratories), which contains the lowest FDA-approved dose of estradiol for the treatment of moderate-to-severe hot flashes in menopausal or postmenopausal women. Thus, Divigel fits in well with the current guidelines from NAMS, as well as with what has become common practice for most physicians prescribing hormone therapies today.

"From a physician's standpoint, you have the lowest approved dose?, a steady dose that bypasses the liver, and it's very easy to teach the patient how to correctly use the medication," says Richard E. Hedrick, Jr, MD. "From a consumer's standpoint, it's very convenient for busy businesswomen. You can travel with it. And it's a premeasured dose, so you don't have to be afraid that you're going to give yourself the wrong dose or too much of a dose."

A variety of low-dose transdermal treatments are currently available (Table 1). Divigel is the only topical treatment that offers 3 dose options. A major advantage of the gel is, "You get a very steady dose versus what you often see with some of the oral agents and sometimes with patches," says Dr Hedrick, one of the Divigel trial investigators who is currently in private practice in Winston-Salem, NC. "And for many women who are very active, as far as recreational sports and working out, it's not going to be like a patch that may not stay on your skin and potentially cause a variable absorption."

The Low-Dose Advantage

Am J Med.

Low-dose estrogen reduces the frequency of moderate-to-severe hot flashes by about 65%. This compares favorably with the 75% to 80% reduction provided by standard doses ( 2005;118[suppl 12B]:74S-78S). Although it takes longer for the full effects of the drug to be appreciated (8-12 weeks vs 4 weeks with standard doses), the lower doses are much less likely to cause bothersome adverse effects, such as irregular or heavy bleeding and breast tenderness.

So why do most physicians continue to prescribe standard doses? As a practicing physician, Dr Hedrick finds that patients are often hesitant to change to a lower dose when they are doing well on a standard dose. "Physicians need to take the time to explain the rationale and also reassure patients that a lower dosage can be a trial. If it doesn't help, you can always go back to the other dose."

Efficacy, Contraindications

Divigel was investigated in a phase 3 randomized, double-blind, placebo-controlled trial that included 495 postmenopausal women who had at least 50 hot flashes weekly of moderate-to-severe intensity when the study began.

Participants were randomized to 1 of 3 doses of the gel—0.25 g (0.25 mg estradiol), 0.5 g (0.5 mg estradiol), or 1.0 g (1.0 mg estradiol)—or to placebo. All the study medications were applied once daily to the thigh.

After 4 weeks of treatment, the 2 higher doses of Divigel were significantly more effective than the placebo in reducing the daily frequency, as well as the severity of hot flashes. Starting at week 7 and through week 12, all 3 doses showed significantly better efficacy than the placebo (ONLINE EXTRA: Table 2).

Divigel was well tolerated, with fewer than 1% of patients reporting skin irritation—one of the main complaints among women using hormonal patches.

Contraindications to Divigel are the same as with any estrogen product; these include:

• Abnormal genital bleeding
• History of breast cancer or estrogen-dependent neoplasia
• History of thromboembolism, stroke, or myocardial infarction within the past year
• Liver dysfunction
• Known or suspected pregnancy.

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

Advising Your Patients

Dr Hedrick recommends physicians consider transdermal formulations for any woman who seeks medical attention for moderate-to-severe hot flashes that are affecting her quality of life and personal relationships. "In general, with the safety parameters and the good tolerability of the skin, and with bypassing the liver, Divigel is my first choice to consider."

And as with the other hormonal options used for this patient population, although no hyperplasia was reported in clinical trials of Divigel, "If a woman has an intact uterus, it should be combined with progesterone to prevent the lining of the uterus from thickening and potentially creating hyperplasia," says Dr Hedrick. He usually prescribes micronized progesterone (Prometrium), either 200 mg for 12 days/month or 100 mg/day.

Dr Hedrick emphasizes the need for educating menopausal women about what has changed since the original information from the WHI study became available.

It now appears that there is a difference when hormonal therapy is started during the first 10 years after menopause compared with starting it later. "And that seems to apply to cardiovascular risk, and it may even apply to some of the studies we're seeing on dementia. I hope that patients will continue to look at how this information evolves and educate themselves so that they know what their options are." (ONLINE EXTRA: See Table 3 for low-dose oral hormone therapy options)