Estradiol gel: A new option in hormone replacement therapy

Minimum level of protection achieved. Following a comparison of oral and percutaneous estradiol, Reginster et al²⁷ suggested that a minimum estradiol level of 60 pg/mL is necessary to prevent postmenopausal bone loss. Mean serum estradiol levels in women receiving 1.5 mg/day estradiol gel were 75.7 pg/mL and 78.4 pg/mL at 24 and 36 months, respectively, in a study by Palacios et al,¹⁰ and 85.8 pg/mL in a study by Devogelaer and colleagues.²⁴ In these trials, BMD increased, and it remained steady in other investigations.^28,29

More recent trials suggest that lower serum estradiol levels secondary to smaller estrogen doses have the capacity to maintain BMD.^30,31 A 1.9% mean increase of BMD at the lumbar spine was reported in women with a mean serum concentration of 17 pg/mL in a 2-year study³⁰ of a transdermal estradiol delivery system. The percutaneous route does not appear to limit these beneficial effects.

How are metabolic factors affected?

In general, oral estrogens produce beneficial changes in lipid metabolism, particularly higher levels of high-density lipoprotein (HDL) cholesterol. However, they also elevate triglyceride and glucose levels. How this plays out clinically is unclear. Both the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study (HERS) found no cardioprotective effects of oral estrogen despite increases in HDL and decreases in low-density lipoprotein (LDL) levels.^1,32

Oral versus percutaneous estradiol. No long-term studies of this magnitude have investigated the effect of percutaneous estradiol on coronary artery disease, although numerous clinical trials have shown that the route of estrogen delivery affects many of the metabolic variables used to estimate the risk of negative cardiac outcomes. It remains to be determined whether percutaneous estradiol affects these metabolic factors in ways that influence morbidity and mortality.

In 1 trial,³³ oral conjugated estrogen led to the following significant changes in lipids:

• increase in very low density lipoprotein (VLDL) cholesterol,
  
• decrease in LDL cholesterol (but not the LDL apoprotein B),
  
• increase in HDL and apoprotein A1, and
  
• significant increase in HDL2 cholesterol.
  

In a separate study,⁹ oral conjugated estrogen had a 2.5-fold increase in serum angiotensin, and percutaneous estradiol gel, no effect.

Same effects when progestin is added. Beneficial effects were not diminished when oral micronized progesterone was added to percutaneous estradiol.³⁴ Estradiol gel significantly reduced total serum cholesterol and LDL cholesterol in the first year of treatment, compared with placebo.

Coagulation effects. Percutaneous estradiol has fewer negative effects on coagulation factors than its oral counterpart. One study³⁵ investigating combination therapy with micronized progesterone compared the effects of percutaneous estradiol and oral estradiol valerate. The group receiving percutaneous estradiol gel/micronized progesterone had no significant changes in plasminogen activator inhibitor, tissue-type plasminogen concentration, and global fibrinolytic capacity. The other group had a significant decrease in mean tissue-type plasminogen concentration and plasminogen activator inhibitor activity and a significant rise in global fibrinolytic capacity.

The oral estradiol—but not the percutaneous formulation—significantly increased the mean value of prothrombin activation peptide and decreased mean antithrombin activity compared with no treatment.

Poor glycemic control may increase the risk of cardiovascular disease, but oral and percutaneous estradiol appear to have similar glycemic effects. A comparative trial³⁶ of oral estradiol valerate 2 mg/day and percutaneous estradiol 1 mg/day found no differences in glycosylated hemoglobin A1c levels (declined in both groups) or in fasting and 2-hour post-prandial blood glucose levels (constant in both groups) or insulin sensitivity.

Treatment duration may also influence how percutaneous estradiol affects metabolic factors. An open-label longitudinal prospective study³⁷ of 30 women receiving estradiol gel 1.5 mg/day for 6 months found a significant decrease in lipoprotein (a), apoprotein A-I, apoprotein B, HDL cholesterol, and HDL3 cholesterol. At 1 year, however, these changes were not significant.

No association with venous thromboembolism. Transdermal estradiol administered as a patch or percutaneous gel had no effect on the risk of venous thromboembolism in a multicenter case-control investigation.³⁸

In contrast, a recent retrospective study found a risk of venous thromboembolism that was at least 4 times greater with oral estrogen than with transdermal estradiol.³⁸

Use a progestogen to prevent endometrial hyperplasia

Like other forms of estrogen, percutaneous estradiol stimulates the endometrium. For this reason, women who have an intact uterus should use a progestogen in an adequate dose to prevent hyperplastic changes.³⁹ Although numerous regimens appear to be effective, the optimal route, dose, and duration of progestin in women using percutaneous estrogen remain to be determined.

Percutaneous estradiol versus other routes of administration. Endometrial thickness and amenorrhea rates over 6 months were not statistically different among 54 women treated with estradiol gel 1.5 mg/day, transdermal estradiol 50 μg/day, or oral estradiol valerate 2 mg/day—all in combination with nomegestrol acetate 2.5 mg/day.⁴⁰ The overall rates of no bleeding or spotting over 6 cycles of treatment were 78% in the percutaneous estradiol group, 48% in the transdermal group, and 60% in the oral group.