Estradiol gel: A new option in hormone replacement therapy
An expert profiles percutaneous gel: easy to use, well tolerated, and available in low doses.
Stable, physiologic estrogen levels
Estradiol gel produces relatively stable serum estradiol levels, and therapeutic estradiol levels similar to those seen with other formulations, routes of administration, and dosages.
Percutaneous administration produces serum estrone to estradiol ratios close to 1, in contrast to higher ratios (5:1) with oral administration.8-11 The lower ratio approximates levels during the menstrual cycle of premenopausal women. (TABLE 1 gives estradiol and estrone levels from different studies following administration of estradiol as a gel, oral formulation, and transdermal patch.)
The percutaneous route also allows for delivery directly to the systemic circulation, avoiding gastrointestinal and first-pass hepatic metabolism and elimination. In contrast, oral micronized estradiol causes large fluctuations in serum estradiol and estrone levels due to absorption and metabolism.8
More stable serum levels than with the patch. One study12 comparing percutaneous and transdermal estradiol found similar interindividual variability but less stable serum levels in women using the transdermal system. A separate study13 also reported greater fluctuation of serum estradiol levels in women using a transdermal system than in those using the gel.
TABLE 1
Serum estradiol and estrone levels for various routes of estradiol
| AUTHOR | THERAPY | ESTRADIOL LEVEL (PG/ML) | ESTRONE LEVEL (PG/ML) |
|---|---|---|---|
| Scott et al8 | E2gel 3 mg/day | 102.9±39.9 | 120.0±50.5 |
| E2gel 1.5 mg/day | 68.1±27.4 | 90.6±45.7 | |
| Transdermal estradiol 50 μg/day | 41.1±13.5 | 45.0±15.9 | |
| Oral micronized estradiol 2 mg/day | 114.0±65.2 | 575.2±279.9 | |
| Palacios et al10 | E2gel 1.5 mg/day | 75.7±1.0 | 58.5±2.9 |
| Oral conjugated estrogen 0.625 mg/day | 39.6±4.6 | 126.0±7.6 | |
| Basdevant et al11 | E2gel 3 mg/day | 221.0±35.0 | 146.0±19.0 |
| Oral micronized estradiol 2 mg/day | 121.0±27.0 | 811.0±370.0 | |
| Archer15 | E2gel 0.75 mg/day | 33.5* | 49.0* |
| E2gel 1.5 mg/day | 65.0* | 58.0* | |
| Placebo | 5.0* | 23.0* | |
| *Median value | |||
| E2gel = percutaneous estradiol gel | |||
Studies compared relief of menopausal symptoms
Estradiol gel effectively relieved meno-pausal symptoms in randomized, double-blind studies, open label comparisons, and observational trials in postmenopausal women, with and without the addition of various progestins.
Symptom relief in comparison with baseline values is statistically significant as early as 2 weeks after initiating treatment. Relief of up to 2 years’ duration has been reported.3,14
Several studies have compared symptom relief achieved with estradiol gel, oral estrogen, transdermal delivery systems, and placebo3,9,14-18; findings are summarized in TABLE 2.
Same efficacy when progestogen is added. The following studies, and other studies,14 demonstrated that estradiol gel relieves menopausal symptoms whether it is administered alone or in combination with a progestogen, with efficacy similar to other estrogen formulations:
Climacteric symptoms decreased to the same extent when estradiol gel was combined with a levonorgestrel-releasing intrauterine device, oral micronized progesterone, or vaginal micronized progesterone.19
A study20 that added lynestrenol decreased the frequency of hot flushes and night sweats more than in women using estradiol gel alone. However, negative mood symptoms were more pronounced in the progestin-treated group.
Estradiol gel 1 mg/day in combination with monthly or quarterly oral medroxyprog-esterone acetate reduced the severity of hot flushes, sweating, and vaginal dryness, according to a 12-month trial.21
Symptoms decreased the same whether a levonorgestrel-releasing IUD or oral or vaginal progesterone was added.
Bone mineral density maintained or increased
Several randomized, controlled trials have documented the effects of estradiol gel on bone mineral density (BMD) and various markers of bone metabolism. In these studies, BMD remained steady22,23 or increased10,24,25 following treatment, and estradiol gel remained effective for up to 4 years.25 Estradiol gel maintained or increased BMD with or without addition of progestins.22,23,26
These investigations involved measurement of BMD at the lumbar spine, forearms, or hip, as well as biologic markers of bone turnover such as urinary hydroxyproline/creatinine ratio, serum alkaline phosphatase, and serum osteocalcin.
Serum estradiol and skeletal uptake of a bone-seeking agent also were determined. Estradiol gel regimens ranged from 0.75 mg/day to 3 mg/day, and populations included both surgical and natural menopausal subjects in several countries.
Effects comparable to oral estrogen. Compared with oral conjugated estrogen, which increased BMD at the lumbar spine by 4.3% (±3.2%), estradiol gel produced increases of 5.6% (±2.9%) at 24 months and 4.7% (±3.2%) at 36 months.10
The case. A 52-year-old woman with no menses for 8 months presents for management complaining of disabling hot flushes. Although she is moderately obese, with a body mass index of 29, she is normotensive without any other significant medical history except for hysterectomy at age 44 for excessive bleeding.
Counseling. During her 20s, the patient tried to use oral contraceptives on 3 separate occasions, but was unable to continue them because of nausea. Although she is interested in estrogen therapy for her vasomotor symptoms, she is concerned about the possibility of experiencing nausea again. You explain that one of the benefits of percutaneous estradiol is that it avoids the gastrointestinal tract.
Physical findings. Her physical examination is within normal limits, and gynecologic examination confirms no uterus and finds no palpable adnexal masses.
Outcome. After weighing the pros and cons, she elects to use estradiol gel. At her 3-month follow-up, she reports effective relief and good compliance.
