Managing Poor Response to Hormone Therapy
September 1, 2006 5 minutes read
Managing Poor Response to Hormone Therapy
Special Report
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Hormone therapy is highly effective for relieving symptoms associated with menopause and for preventing postmenopausal osteoporosis. Some women, however, respond unsatisfactorily to standard doses of hormone therapy. When hormone therapy is administered to control menopausal symptoms, response is assessed by the patient's report of symptom relief, but the subjective nature of this response makes it difficult to measure the efficacy of the treatment. Assessing true efficacy requires an objective measurement, such as bone mineral density. Evidence indicates that from 5% to 15% of post menopausal women on hormone therapy continue to lose bone and experience fractures.1-3
Is Bone Poor Response Real?
Analysis of data from randomized trials evaluating raloxifene and alendronate for osteoporosis treatment revealed that many women whose bone density decreased after the first year of active treatment subsequently gained bone density in the second year of therapy.4 Extreme results with any laboratory measurement are often due to random error, and subsequent results return to the normal range—a phenomenon known as regression to the mean. Thus, it was argued that bone treatments should not be discontinued when measurements after one year indicate loss of bone density. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, true bone loss was rarely documented in women who had repeated bone density measurements.5
Extrapolation of these conclusions to the clinical practice setting must consider the differences between clinical trial participants and real-world patients. Adherence to treatment is far better among clinical trial participants than among nonstudy patients. In addition, clinical trial participants represent a very homogeneous group of individuals because of highly selective inclusion and exclusion criteria. There is good reason to suspect that poor response reflects the considerable variation from individual to individual in metabolism and clearance of administered estrogen, and that there exists a considerable group of women who metabolize and clear estrogen at a greater rate, thus requiring a higher dose.
The prevalence of poor response is supported by the two-year Women's Health, Osteoporosis, Progestin, Estrogen (HOPE) trial.6 This trial demonstrated that lower doses of estrogen are effective for preventing bone loss, but there is a dose-response relationship between bone density and estrogen dose. The percentage of women who experienced more than 2% bone loss at the hip increased from 8.7% with a dose of 0.625 mg conjugated estrogens to 13.8% with a dose of 0.3 mg. Considering the current emphasis on lower-dose estrogen therapy, it is appropriate to be concerned whether each individual woman is experiencing an adequate response.
Management of Poor Response
Patients who are losing bone density despite hormone therapy require evaluation. Other causes of bone loss must be ruled out. Patients being treated for hypothyroidism should have TSH measurements at least annually to assess whether the current dose of thyroid supplementation is appropriate. Calcium and vitamin D intake must be adequate in order for any antiresorptive agent to be fully effective in protecting against bone loss. I recommend the measurement 25-hydroxy vitamin D aiming to maintain a level greater than 30 ng/mL.
Rapid estrogen metabolism and clearance leading to low circulating estrogen levels are probably far more prevalent as a cause of poor response to standard estrogen therapy than is recognized. One practical approach is to titer the dose of estrogen utilizing the blood concentration of estradiol. This approach is supported by a study in Finland in which 11% of women were losing spinal bone and 26% were losing bone at the hip despite hormonal treatment.7 Evaluation of these women revealed the uniform characteristic of a low blood estradiol levels.
Adjusting the Estrogen Dose
Measuring estradiol levels in postmenopausal women is complicated by the fact that standard laboratory estrogen assays are designed for higher blood levels than those encountered after menopause. Clinicians must establish the sensitivity of the assay performed in their laboratories and learn what range of results can be reliably measured in post-menopausal women. With a sensitive assay, estrogen therapy can be titered, aiming at levels between 50 and 100 pg/mL.
An acidic vaginal pH (less than 4.5) correlates well with adequate systemic estrogen levels, and this simple method has been advocated as a means to assess the efficacy of estrogen therapy.8,9 The validity of this approach, however, has not been established in a carefully designed clinical trial.
Conclusion
As clinicians and the pharmaceutical industry promote lower doses of estrogen, a greater rate of poor response as measured by bone density can be expected. Women who are losing bone despite treatment deserve evaluation, but once other causes of bone loss are ruled out and adequate calcium and vitamin D intake is established, consideration should be given to identifying women who might benefit from a simple adjustment of the estrogen dose.
References
- The Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;276:1389-1396.
- Nelson HD, et al. Osteoporosis and fractures in postmenopausal women using estrogens. Arch Intern Med. 2002;162:2278-2284.
- Hillard TC, et al. Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss. Osteoporos Int. 1994;4:341-348.
- Cummings SR, et al. Monitoring osteoporosis therapy with bone densitometry: misleading changes and regression to the mean. Fracture Intervention Trial Research Group. JAMA. 2000;283:1318-1321.
- Greendale GA, et al. How many women lose bone mineral density while taking hormone replacement therapy? Results from the Postmenopausal Estrogen/Progestin Interventions Trial. Arch Intern Med. 2000;160:3065-3071.
- Lindsay R, et al. Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women. Osteoporos Int. 2005;16:372-379.
- Komulainen M, et al. Identification of early postmenopausal women with no bone response to HRT: results of a five-year clinical trial. Osteoporos Int. 2000;11:211-218.
- Roy S, et al. Vaginal pH is similar to follicle-stimulating hormone for menopause diagnosis. Am J Obstet Gynecol. 2004;190:1272-1277.
- Notelovitz M. Estrogen therapy in management of problems associated with urogenital aging: a simple diagnostic test and the effect of the route of hormone administration. Maturitas. 1995;22(Suppl):S31-S33.
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