Life Extension Magazine®

Issue: Oct 1999

Estrogen Therapy

Estriol may offer myriad benefits for post-menopausal women-without the side effects.

Scientifically reviewed by: Dr. Gary Gonzalez, MD, on January 2021.


Estriol may offer myriad benefits for
post-menopausal women... without the side effects.

Life Extension magazine has previously suggested alternative approaches for women who are afraid of the cancer risks or side effects of long-term therapy with estrogen drugs approved by the Food and Drug Administration, such as Premarin. Here, we discuss an intriguing alternative called estriol, which is used extensively in Europe for estrogen replacement therapy in menopausal and post-menopausal women, but to date has rarely been used for that purpose in the United States.

Evidence suggests that estriol offers many of the benefits of more traditional estrogen-replacement therapies, but without the harsh side effects or longer-term dangers often encountered by other substances and trademarked products.

First, some background. The primary forms of estrogen include three substances-estrone, estradiol and estriol. Estrone sulphate is the form of estrogen found in Premarin, while 17-b estradiol is the form of estrogen found in the products Estrace and Estraderm. Estrone is the oxidized form of estradiol. Both of these substances, however, are the estrogens that significantly increase the risk of breast and ovarian cancer when taken for more than 10 years. According to the Merck Manual, conjugated estrogens are substances that even have been listed as known carcinogens.

Estriol, on the other hand, is a weak estrogen that provides the anti-aging benefits of estrogen replacement therapy, apparently without the risk of cancer. Consider this evidence of its benignity: during pregnancy, huge amounts of estriol are secreted by the placenta to protect the fetus. Urinary assay of estriol is used to assess the fetus' viability.

Since estriol is a weak estrogen, larger amounts must be used for estrogen replacement therapy. Estriol is used in doses of 2 to 8 mg per day. A dose of 2 to 4 mg of estriol is equivalent to, and as effective as, 0.6 to 1.25 mg of conjugated estrogens such as Premarin.

One of the most common side effects of standard estrogen therapy is endometrial hyperplasia, or hyper-proliferation of the cells of the uterine lining, a condition that often turns into uterine cancer. It can occur, for example, with the use of Premarin when used without a progestin, a natural or artificially produced hormone that enhances and protects the inner uterus. However, most investigators have found that the use of the alternative estriol therapy, even at the high dose of 8 mg per day, does not cause endometrial hyperplasia.

In one study by scientists at the Medical College of Georgia, in Augusta, 52 women with severe menopausal symptoms were given estriol succinate continuously for six months in doses of 2 to 8 mg per day. Significant improvements in symptoms were noted within one month of the start of the study, and they persisted as long as estriol therapy was continued. The degree of symptom improvement was directly related to the dose. Symptom relief was moderate at 2 mg per day, but marked at 8 mg per day.

Estriol therapy also reversed vaginal atrophy and improved the quality of cervical mucus. No breakthrough bleeding occurred in any of the subjects and biopsies of the inner mucous membrane of the uterus failed to show endometrial hyperplasia in any case, regardless of the dose of estriol used.

The scientists concluded, "Estriol therapy may be employed in dosages up to 8 mg/day continuously, especially in those patients in whom other estrogens induce undesired side effects such as nausea, breakthrough bleeding or endometrial hyperplasia, and the recurrence of hot flushes during cyclic therapy of more potent estrogens. . . Being a weak estrogen, it does not induce endometrial proliferation or breakthrough bleeding of any consequence, while modifying menopausal symptoms."

A longer-term and larger prospective study of estriol therapy for the symptoms of menopause was conducted by C. Lauritzen at the University of Ulm in Germany, and concluded, "Estriol therapy was successful in 92% of all cases. In 71%, hot flushes and sweating were completely eliminated, in 21% they were ameliorated, becoming weaker and occurring more seldom . . . Depressive moods were abolished in 24% of the cases, and in 33% they were ameliorated, so that an overall improvement occurred in 57%."

The study also found that forgetfulness, loss of concentration, irritability and heart palpitations were remarkably improved towards normal. Also, the number of patients suffering from migraine headaches decreased from 33 to 12, and atrophying of the vulva was completely eliminated in 44 of 61 cases, and showed improvement in 12 cases.

"Remarkably," the scientists added, "the quality of the skin improved according to the subjective impression of patients and physicians in a high percentage of cases. . . In no case did a deterioration of symptoms occur."

One of the major benefits of estrogen therapy is prevention of bone loss associated with osteoporosis. Postmenopausal women taking estrogen experience 50 percent fewer bone fractures than women of comparable age who have not taken estrogen. Although no studies have yet been conducted in the U.S. to determine if estriol therapy can prevent osteoporosis, a prospective double-blind study was conducted in 136 postmenopausal women at the Chinese Great Wall Hospital in Beijing, China, using nylestriol (CEE), a long-acting, estriol derivative.

The doctors found in the placebo group significantly greater loss of bone mass and higher low-density lipoprotein levels when compared with the treated group, and concluded, "CEE is an effective estrogen for preventing bone loss and lipid disorders in postmenopausal women, just as the most popular conjugated estrogen (Premarin), but is more convenient. Long-term CEE medication, its effects on endometrium and the regimen of progestin combination await further study."

There also is direct evidence from animal studies, and indirect evidence from human studies, that estriol can prevent breast cancer. Much of this work has been done by Dr. H.M. Lemon and associates of the department of internal medicine at the University of Nebraska Medical Center in Omaha. In one study, they induced mammary tumors by whole-body gamma radiation in female Sprague-Dawley rats. Among the control group, 75% developed tumors. However, among those animals receiving estriol, just 48% developed tumors after being subjected to radiation.

In another study by the Lemon team, estriol was shown to have "the most significant anti-mammary carcinogenic activity of 22 tested compounds [because] . . . estriol is less likely to induce proliferative changes in the target organs of cancer-prone women than estrone or estradiol."

Because of these anti-cancer effects of estriol in animals, Lemon looked at the question of whether estriol is related in any way to breast cancer in humans. He found that women with breast cancer have low levels of estriol relative to other forms of estrogen.

The evidence about estriol as a safe alternative estrogen therapy was summed up well by the Medical College of Georgia scientists, who concluded, "Estriol deserves a place in our therapeutic resources."