Assessing Blood Estradiol Levels

Abstract & Commentary

Synopsis: Topical estradiol application can be associated with falsely high blood estradiol measurements.

Source: Vihtamaki T, et al. Maturitas. 2004;48: 347-353.

Vihtamaki and colleagues from Finland measured the circulating levels of estradiol 12 hours after the topical, percutaneous, evening administration of 1.5 mg estradiol (EstroGel) in 10 women who had been using this method of hormone therapy for at least 2 years. The gel was applied with a plastic gloved hand to an area as large as possible (per standard directions for use) on the thigh for 2 weeks followed by application on the arm for 2 weeks. This was followed by the same schedule but this time using a bare right hand for the application. The blood samples were collected from both cubital veins. The major finding was remarkably higher estradiol concentrations when the gel was applied to the left arm or the thigh with a bare right hand. Therefore, skin contamination by topical estradiol can distort blood estradiol measurements.

Comment by Leon Speroff, MD

Estradiol delivery can be accomplished by the daily application of a gel (EstroGel, Estreva) or a lotion (Estrasorb) to the skin, usually over the upper arms and shoulders or the abdomen and thighs.1,2 The gel preparation produces blood levels of estradiol of approximately 95-125 pg/mL, levels that are both higher and more variable than the standard oral regimens.3,4 EstroGel and Estreve are supplied in a pump that delivers 0.75 mg estradiol with each dose of EstroGel and 0.5 mg with Estreva. Estrasorb is packaged in foil pouches; the contents of 2 pouches applied daily produce systemic levels similar to those achieved with a 50 mg gestradiol patch method.

Studies with topical estradiol have indicated that blood estradiol measurements vary from individual to individual. The differences between individuals reflect differences in percutaneous absorption, variations in estradiol metabolism, retention time in the skin, and surface area of the application. Because of these differences, the same dose will not have the same clinical efficacy in all individuals. Within one individual, the blood levels are relatively constant; and for this reason, monitoring the estradiol level when clinically indicated is worthwhile. When a topical estradiol method is being used, care must be taken to obtain the blood sample from an arm that has not received estrogen application and that is opposite to the drug-applying hand. Unfortunately with the percutaneous method, accuracy requires the use of a gloved hand and leaving one arm untouched for 2 weeks.

Why measure the blood estradiol at all? Because of the variability from individual to individual in metabolism, it makes sense that the same dose will not provide clinical efficacy in all patients. The problem is that we are limited by having only one objective assessment of efficacy: bone density measurements. For this reason, it is worthwhile to measure the bone density in treated women when they are in their late 60s to detect poor responders. On the average, about 10-15% of women lose bone despite being prescribed hormone therapy. A Finnish 5-year clinical trial reported a prevalence of poor response based on bone density of 11% for spinal bone and 26% for the hip.5 As expected, smoking and low body weight were common findings among the poor responders, but the most impressive characteristics were lower estradiol and higher FSH levels. It is only logical that there exists a group of women who metabolize and clear administered estrogens at a greater rate, and thus require a higher dose to sustain a protective effect on bone. Indeed, considerable variation in estradiol levels has been documented in individuals receiving both oral and transdermal hormone therapy.6,7 Marketing presentations by the pharmaceutical companies provide mean levels, suggesting stable and smooth maintenance of blood levels; however, the ranges, which are wide, are not revealed. An aim of individualizing hormone therapy is to determine the appropriate dose for the intended objective; in the case of bone, the minimal estradiol level should be 40-60 pg/mL, and a practical range for a blood sample derived during office hours from a patient taking her medication at night is 50-100 pg/mL.

Monitoring the estradiol blood level in postmenopausal women receiving hormone therapy is not as straightforward as it would seem. There are 2 primary difficulties. First, the clinical assays available differ considerably in their technique and quality (laboratory and antibody variations). Second, the various commercial products represent a diverse collection of estrogenic compounds, ranging from estradiol to unique equine estrogens. Although the body interconverts various estrogens into estrone and estradiol, is this process relatively consistent within and between individuals? For example, a highly specific assay for estradiol will detect very low levels of estradiol in women receiving 0.625 mg conjugated equine estrogens; nevertheless, most clinical assays will report a level of 40-100 pg/mL in these women. I find measurement of blood estradiol levels very useful in selected patients, such as the patient who requests ever-increasing doses of estrogen for the treatment of symptoms, which in the presence of very high blood levels of estradiol can be confidently diagnosed as psychosomatic. What each clinician must do is learn what blood level of estradiol as performed by the local laboratory is associated with the standard doses of hormone therapy (0.625 conjugated estrogens, 1 mg estradiol, 50 mg transdermal estradiol) and consistently use the same laboratory. In our laboratory this range is 40-100 pg/mL estradiol when the estrogen is taken the evening before the office visit (with transdermal administration, blood sampling should be obtained the day before new patch placement); the range reflects individual variation including the variability from peak to nadir values. Remember that because FSH is regulated by a factor other than estrogen (ie, inhibin), FSH levels cannot be used to monitor estrogen dosage. Postmenopausal hormone therapy will produce only a 10-20% decrease in FSH and LH, and there is great individual variability in the responses.8

Products containing ethinyl estradiol will not affect the circulating estradiol level. Ethinyl estradiol circulates without being changed, and the antibodies in the immunoassays for estradiol will not recognize it. It is for this reason that women on oral contraceptives have very low measurements of estradiol. This problem for the postmenopausal use of ethinyl estradiol is not a major handicap because ethinyl estradiol is slowly metabolized, and blood levels are relatively stable with less variation from individual to individual compared with the other estrogen formulations.

As clinicians and the pharmaceutical industry promote lower doses of estrogen with the attractive notion that less is safer, a greater rate of poor response as measured by bone density can be expected. In my view, once a poor responder is detected by measurement of bone density, titering of estrogen dose is indicated, using the blood concentration of estradiol. I would further emphasize that appropriate detection and investigation will confirm that a relatively low blood estradiol level is the cause of most cases of poor bone response (in the presence of appropriate calcium and vitamin D supplementation). Measurement of vaginal pH from the lateral vaginal wall is very simple and inexpensive. It has been impressive in our experience and that of others how an acidic pH (less than 4.5) correlates with estrogen administration.9,10 This may be the best method to assess the adequacy of estrogen therapy. Assessing vaginal cytology is not useful. The vaginal mucosa is too sensitive to estrogen to allow dose-response titering.

References

1. Archer DF, et al. Menopause. 2003;10:516-521.

2. Food and Drug Administration. FDA approves Estrasorb for treatment of menopausal hot flashes. http://www.fda.gov/bbs/topics/ANSWERS/2003ANS01255.html 2003.

3. Dupont A, et al. Maturitas. 1991;13:297.

4. Walters KA, et al. Maturitas. 1998;29:189-95.

5. Komulainen M, et al. Osteoporos Int. 2000;11:211-218.

6. Gavaler JS. J Women’s Health. 2003;12:757-768.

7. Kraemer GR, et al. Fertil Steril. 2003;79:534-542.

8. Castelo-Blance C, et al. Maturitas. 1993;17:101-111.

9. Notelovitz M. Maturitas. 1995;22(Suppl): S31-S33.

10. Roy S, et al. Am J Obstet Gynecol. 2004;190:1272-1277.

Leon Speroff, MD, Professor of Obstetrics and Gynecology, Oregon Health Sciences University,Portland is Editor for OB/GYN Clinical Alert.