Estriol: A Kinder, Gentler Estrogen?
June 1999; Volume 1: 51-52
By Adriane Fugh-Berman, MD
In discussions about hormone replacement therapy (HRT), patients may ask about estriol or tri-estrogen formulations. Both of these are being promoted by some alternative medicine practitioners as safer forms of estrogen therapy than conjugated estrogens. Estriol has been touted as a "good" estrogen that does not increase the risk of breast cancer; claims are also made that it may reduce the risk of developing breast cancer. These claims are unsubstantiated.
Estriol is a weak, short-acting estrogen sometimes used to treat menopausal symptoms including hot flashes or urogenital atrophy;1 it has also been found beneficial in bone mineral density.2,3 It is not commonly used by conventional medical practitioners in the United States, but a number of alternative practitioners prescribe it.
Tri-estrogen is described in a publication distributed by Women's International Pharmacy (a compounding pharmacy in Madison, WI) as "a natural estrogen formula that attempts to minimize the risks of estrogen and maximizes its benefits. Tri-estrogen utilizes the benefits of all three naturally occurring estrogens: estrone (E1), estradiol (E2) and estriol (E3) in a safe and effective way." No evidence is presented for this claim; a MEDLINE search failed to turn up any clinical trials on tri-estrogen preparations.
Tri-estrogen preparations (also called "Tri-Est") are mixtures of estrone, estradiol, and estriol (typically in a 1:1:8 ratio). It is usually administered orally in doses of 2.5-5 mg/d (either continuously or 25 days a month). Although the hormones in Tri-Est are the same as endogenously produced hormones, this is no assurance of long-term safety. High levels of endogenous hormones are associated with increased breast cancer risk.4,5
Natural progesterone is often prescribed with this regimen. Topical forms of progesterone, however, may not achieve serum levels high enough to ensure endometrial protection. (See Alternative Therapies in Women's Health, April 1999, pp. 33-36.) Oral progestins are a better choice.
Claims that estriol does not cause endometrial stimulation are based on a 1978 study which found that estriol in a dose of 2-8 mg/d improved hot flashes and other symptoms in 52 symptomatic menopausal women (higher doses were more effective).6 Endometrial biopsy showed no evidence of endometrial hyperplasia after six months. However, six months is not enough time for hyperplasia production in women on any estrogen.
Two recent studies show that estriol does cause endometrial stimulation. Twenty-nine postmenopausal women scheduled for hysterectomies were treated with vaginal estriol (0.5 mg/d) or 17b-estradiol (0.05 mg/d).7 Biochemical and histological signs of estrogenic stimulation were found in the endometrium, myometrium, and vagina. Similar signs of estrogenic stimulation were found with both estradiol and estriol therapy. And a Swedish study of 1,110 women with postmenopausal bleeding found that endometrial hyperplasia (5-8 mm by transvaginal sonography) was significantly more common in women taking estriol than in women taking sequential estrogen and progestin therapy or with women not receiving HRT.8
Proponents also claim that estriol has anticancer effects. This claim is based on a handful of studies (almost all by the same researcher) done in the 1960s and 1970s. These old studies are often referenced as evidence of estriol’s benefits and are therefore worth discussing.
A study published in 1966 included 57 pre- and postmenopausal subjects with breast cancer and 41 without breast cancer. This study reports that women with breast cancer excreted 30-60% less estriol per 24 hours than did controls.9 However, these results were not statistically significant. The text states, "The differences between the group means for estriol excretion alone, or for the mean or median Eq values between the two groups did not attain the 5% confidence level by various parametrical and nonparametrical tests."
"Eq" stands for "estriol excretion quotient," a ratio of estriol to estrone and estradiol (an unusual test that apparently was invented by the authors). The authors’ entire basis for their conclusion is a higher number of "subnormal" Eq among breast cancer patients compared with controls in a subanalysis. "Subnormal" is not defined, and such results on an unvalidated test count for nothing.
Additionally, there is reason to suspect that a number of women in the control group may have had abnormal ovarian function that could have affected results: nine of 24 premenopausal women in the control group were infertile, two of 10 postmenopausal controls had "other cancers," and three had "polycystic ovaries or cortical fibrosis."
In a later article,10 the same author cites three studies (including the above study) as evidence for reduced estriol excretion in breast cancer and cites seven studies that found no difference. Although he notes that "initial reports of reduced estriol excretion in breast carcinoma have not been substantiated by others,"10 he continues to argue that estriol may be useful in breast cancer prevention.10,11 This is particularly notable given that by his own report six of 24 breast cancer patients treated with estriol (5-15 mg/d) experienced "increased growth of metastases," and two developed endometrial hyperplasia. Five others also experienced vaginal bleeding.10
Another oft-quoted citation contends that estriol arrests metastasis or causes remission of breast cancer in 37% of patients. This is based on a commentary by Follingstad that contains a reference to an unpublished study (by Lemon), in which an unspecified number of postmenopausal breast cancer patients received 2.5-15 mg of estriol for an unspecified amount of time.12 It is explicitly stated that the study was designed as a safety study and not designed to test efficacy.
In summary, there is evidence that estriol is estrogenic and when administered on a continuous basis can serve as hormone replacement therapy. However, there are few trials on this therapy. There is no reasonable scientific evidence that estriol has anticancer effects or that it is safer than estradiol or conjugated estrogens.
References
1. Cardozo L, et al. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: Second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol 1998;92:722-727.
2. Minaguchi H, et al. Effect of estriol on bone loss in postmenopausal Japanese women: A multicenter prospective open study. J Obstet Gynaecol Res 1996;22:259-265.
3. Itoi H, et al. Comparison of the long-term effects of oral estriol with the effects of conjugated estrogen, 1-alpha-hydroxyvitamin D3 and calcium lactate on vertebral bone loss in early menopausal women. Maturitas 1997;28:11-17.
4. Hankinson SE, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998;90:1292-1299.
5. Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 1998;90:814-823.
6. Tzingounis VA, et al. Estriol in the management of the menopause. JAMA 1978;239:1638-1641.
7. van Haaften M, et al. Biochemical and histological effects of vaginal estriol and estradiol applications on the endometrium, myometrium and vagina of postmenopausal women. Gynecol Endocrinol 1997;11: 175-185.
8. Granberg S, et al. Endometrial sonographic and histologic findings in women with and without hormonal replacement therapy suffering from postmenopausal bleeding. Maturitas 1997;27:35-40.
9. Lemon HM, et al. Reduced estriol excretion in patients with breast cancer prior to endocrine therapy. JAMA 1966;196:1128-1136.
10. Lemon HM. Pathophysiologic considerations in the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma. Acta Endocrinol Suppl (Copenh) 1980;233:17-27.
11. Lemon HM, et al. Inhibition of radiogenic mammary carcinoma in rats by estriol or tamoxifen. Cancer 1989;63:1685-1692.
12. Follingstad AH. Estriol, the forgotten estrogen? JAMA 1978;239:29-30.
27. Which of the following statements is true about estriol?
a. There is reasonable evidence that estriol prevents breast cancer.
b. There is reasonable evidence that estriol is effective in treating hot flashes and urogenital atrophy.
c. Estriol has all of the benefits of conjugated estrogens and none of the risks.
d. All of the above.
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