Estradiol gel: A new option in hormone replacement therapy

Although the percutaneous estradiol group had a lower overall incidence of no bleeding or spotting than the other groups, the difference was not significant. Nor were there significant differences in the variation of endometrial thickness from baseline: A mean increase of 1.5 mm (±0.4 mm) was reported in the percutaneous group, compared with 1.5 mm (±0.7 mm) and 1.7 mm (±0.6 mm) in the transdermal and oral estrogen groups, respectively.

Estrogenic and progestogenic effects were similar for transdermal and percutaneous estradiol (with dydrogesterone 10 mg/day for days 1 to 12) after a baseline atropic endometrium was identified.³

Estradiol gel produces stable, physiologic serum estradiol levels and has a serum estrone to estradiol ratio close to 1.

The most effective progestogen dosage and duration are unknown, although many regimens have been studied:

• Percutaneous estradiol 1.5 mg/day for the first 24 days of the month in combination with nomegestrol acetate 5 mg/day for days 11 to 24: Over 6 months, researchers found a secretory pattern in the majority of women and no evidence of hyperplasia.¹⁸
  
• Percutaneous estradiol 3 mg/day for 3 of every 4 weeks in combination with nomegestrol acetate 5 mg/day for 10 days: No reduction in estrogenic endometrial effects.^41,42
  
• Estradiol gel 3 mg/day for 3 of every 4 weeks in combination with 200 mg or 300 mg oral micronized progesterone for the last 10 days of treatment: Dose was too low or treatment too short to produce a complete secretory transformation of the endometrium.⁴³ However, the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial⁴⁴ found no increased occurrence of hyperplasia in women using micronized progesterone 200 mg for 12 days of each cycle for more than 3 years in combination with oral conjugated estrogen 0.625 mg.
  
• Percutaneous estradiol 1.5 mg/day combined with micronized progesterone 100 mg daily (orally or vaginally) for the first 25 days of the month: Fully inhibited mitoses and induced amenorrhea in most of the women studied, with amenorrhea rates of 93.3% at 3 months and 91.6% at 6 months.⁴⁵
  
• Estradiol gel 1.5 mg/day with 100 mg vaginal micronized progesterone for 21 days per cycle: Stable endometrial thickness and no endometrial hyperplasia over 12 months.⁴⁶ However, breakthrough bleeding was reported in up to 30% of subjects, principally in the second 3 months of treatment.
  
• Percutaneous estradiol 1 mg/day for 3 months with oral medroxyprogesterone acetate 20 mg/day for the last 14 days, followed by a 7-day free interval: No reports of endometrial hyperplasia or suspect changes at 12 and 24 months.¹⁷
  
• Estradiol gel 2 mg/day for 21 days with 10 mg oral medroxyprogesterone acetate for the last 14 days, followed by a 7-day free interval: No endometrial hyperplasia or suspect changes at 12 and 24 months.¹⁷
  
• Estradiol gel 1 mg/day with medroxyprogesterone acetate 10 mg on days 1-12 every month or every 3 months: Endometrial hyperplasia was found in 1 woman (0.3%) in the group receiving the progestogen every 3 months. Endometrial histology did not differ between women taking medroxyprogesterone monthly and those taking it every 3 months.²¹
  
• Estradiol gel 3 mg/day with oral micronized progesterone 200 mg for 12 days of each cycle: Regular withdrawal bleeding in 70% of women.³⁴
  
• Percutaneous estradiol 1.5 mg/day in combination with a levonorgestrel-releasing intrauterine device: 80% of women were amenorrheic at 1 year, with a mean endometrial thickness 3 mm; at 5 years, 100% of women had epithelial atrophy.⁴⁷
  
• Estradiol gel 1.5 mg for 21 days with 200 mg oral progesterone for 14 days (126 women); 3 mg percutaneous estradiol for 21 days with 300 mg oral progesterone for 10 days (23 women); 1.5 mg estradiol gel with 300 mg oral progesterone (3 women); or 3 mg estradiol gel for 28 days with 200 mg progesterone for 14 days (5 women): No evidence of hyperplasia after 5 years of treatment.²