Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone

Alternative Medicine Review, March, 2005 by Patrick N. Friel, Christa Hinchcliffe, Jonathan V. Wright

Abstract

BACKGROUND: There is a lack of consensus about the safety of estrogen replacement therapy, especially with regard to its impact on a woman's risk for breast cancer. Elevated urinary or serum estrone and estradiol concentrations in postmenopausal women are associated with a moderately elevated risk of breast cancer. METHODS: Twenty-four-hour urinary steroid hormone profiles, including the measurement of estrone, estradiol, and estriol, were conducted for 35 postmenopausal women receiving oral estradiol at doses from 0.025-2.0 mg/day. RESULTS: Urinary excretion of estradiol exceeded premenopausal reference range values in women taking estradiol at doses greater than 0.5 mg/day. Urinary estrone excretion exceeded premenopausal reference range values in women taking estradiol doses of 0.25 mg/day or higher. Literature data indicate serum estrone concentrations also markedly exceed premenopausal reference ranges when estradiol is administered orally at a dose of 1 mg/day. CONCLUSIONS: The previously recommended oral dose of estradiol (1-2 mg/day) results in urinary excretion of estrone at values 5-10 times the upper limit of the reference range for premenopausal women. Retrospective studies associating oral estradiol with increased risk of breast cancer may reflect overdose conditions. Based on current knowledge, a prudent dose ceiling for oral estradiol replacement therapy of 0.25 mg/day is proposed.

(Altern Med Rev 2005;10(1):36-41)

Introduction

"The dose makes the poison."--Paracelsus (1493-1541)

Under laboratory conditions, estrogens are capable of both initiating and promoting malignancies. (1) A number of human breast cancer risk factors, such as early age at menarche and late age at menopause, reflect lifetime estrogen exposure. (2) Furthermore, epidemiological studies of estrogen concentrations in serum and urine demonstrate postmenopausal women with higher estrogen concentrations--especially in the case of estrone--are at elevated risk for developing breast cancer, compared to postmenopausal women with lower estrogen concentrations. (23) There is considerable evidence estrogens act as promoters of human breast cancer, although the evidence that estrogens act as breast cancer initiators is weaker. (4,5) Thus, while it seems reasonable to conclude estrogen replacement therapy for women during menopause results in an increase in breast cancer risk, the results of many retrospective and prospective studies of hormone replacement therapy (HRT) are inconsistent.

The Women's Health Initiative study found conjugated equine estrogens taken continuously at a dose of 0.625 mg/day, in combination with the synthetic progestin medroxyprogesterone, are associated with a modest but statistically significant increase in breast cancer risk. (6) But a study of the same conjugated equine estrogen regimen taken without a synthetic progestin, in women who had hysterectomies, found no increase in breast cancer risk.(7) However, the United Kingdom's "Million Women Study" of HRT found an elevated risk of breast cancer, even in women taking estrogens only (conjugated equine estrogens or estradiol orally), although the increase was not as great as for women taking estrogens combined with synthetic progestins. (8)

Studies of HRT in women with a history of breast cancer have also yielded conflicting results. A retrospective U.S. study found women with a history of breast cancer who received HRT (79% estrogen-only), had a 66-percent reduction in breast cancer mortality, compared to women with a history of breast cancer not receiving HRT. (9) A retrospective Australian study reached similar conclusions. (10) Two recent prospective studies of HRT in women with prior breast cancer found a large increase in breast cancer recurrence with HRT in one, but no increase in the other. (11) It is important to understand the reasons for such divergent results.

In the course of conducting comprehensive, 24-hour urinary steroid hormone profiles on hundreds of women receiving various formulations of HRT, the authors have recognized that women taking what were considered, until recently, standard HRT doses consistently excreted quantities of estrogens greatly in excess of those seen in healthy, non-pregnant, premenopausal women. This report presents data for women taking oral estradiol. The results suggest the dose of estrogen used may be an important determinant of adverse effects, including estrogen-related cancers.

Subjects

The data reported here were collected from the results of 24-hour urinary steroid hormone profiles conducted for clinical purposes on 35 women taking oral estradiol. Women submitted, along with urine specimens, a questionnaire on the use of hormones, other medications, and menopausal symptoms. The questionnaires were used as part of the laboratory quality assurance program, for review of test results, and for consultations with the physicians who ordered the tests. The women in this study represent 35 consecutive patients taking oral estradiol, with or without estriol, who submitted a questionnaire, and who took their prescribed estradiol dose on the day of collection. Data were collected over approximately one year.