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

It is of considerable interest that the recommended dose of estradiol has been decreasing steadily. In 2001, Cohen suggested 0.5 mg was an adequate dose for many postmenopausal women, rather than the normally recommended dose of 1-2 mg/day. (21) In 2003, Prestwood et al demonstrated beneficial effects on bone density at a daily oral estradiol dose of 0.25 mg. (22) In 2004, an ultra-low dose transdermal estradiol formulation delivering 14 mcg/day, and demonstrating favorable impact on bone density, was introduced. (23) A similar pattern is evident in the recommended dose of conjugated equine estrogens. Initial recommended doses were 1.25 mg/day. (21) Subsequently, the recommended dose was lowered to 0.625 mg/day, and recently the U.S. Food and Drug Administration approved a 0.3-mg formulation. (21)

Estradiol replacement therapy at oral doses of 1-2 mg/day results in serum and urine estrone concentrations resembling those seen in pregnancy. However, there is an important difference between the estrogens present with estradiol replacement and those during pregnancy--estriol concentrations are much higher during pregnancy than during estradiol replacement. (24) Experimental and epidemiological studies suggest a high concentration of estriol may be necessary to modulate the impact of the high concentrations of estradiol and estrone seen in pregnancy. (24, 25)

Estrogen dose is only one important variable in determining the risk-benefit profile for hormone replacement therapy. By far, the strongest association between estrogen replacement therapy and breast cancer occurs when it is co-administered with the synthetic progestin medroxyprogesterone. (26, 27) The added risk of breast cancer when estrogens can be taken without a synthetic progestin is much less in some studies, and non-existent in others. We propose one important reason for the current uncertainty about the safety of estrogen-only replacement therapy is that estrogen doses have varied from study to study, and the preferred doses have been decreasing over time. Long-term retrospective studies, such as the Million Women Study, may be biased against estrogen replacement, because many patients received estrogen dosages that, in hindsight, were clearly excessive. Based on the data presented here, an oral estradiol dose of 0.25 mg/day or less should result in serum and urinary estrone concentrations within or slightly above the premenopausal reference range. This seems to be a prudent dose ceiling given our present level of knowledge.

Table 1. Reference Ranges for Urinary Estrogen Excretion

Phase            Estrone (mcg/24 hours)   Estradiol (mcg/24 hours)

Luteal                    3-52                      1-27
Follicular                2-39                      1-23
Mid-cycle                11-46                      4-45
Postmenopausal            1-7                       0-4

Table 2. Estrone Concentrations in Pre- and
Postmenopousal Women, Pregnancy, and with Estradiol

Patient Status               Serum Estrone (pg/mL)

Postmenopausal                      14-103
Follicular phase                    37-138
Luteal phase                        50-114
Peri-ovulatory                      60-229
Estradiol 1.0 mg/day               159-997
1 st Trimester pregnancy            62-715
2nd Trimester pregnancy            167-1862
3rd Trimester pregnancy           1039-3210