Estriol, an estrogen that has virtually been ignored by the
mainstream medical community, is one of the three principal
estrogens produced by the body. Estriol was originally thought to
have little significance due to its weak estrogenic activity when
compared with estrone and estradiol. Nonetheless, research has
found that its weakness may very well be its strength.
Studies suggest that when the lower-potency estrogen, estriol, is
administered topically, it does not increase the risk of
hormone-dependent cancers of the breast or endometrium (uterine
lining).1-3However, having weaker estrogenic effects does not mean
that estriol has none of the benefits that come with more potent
Studies suggest that estriol reduces symptoms of menopause, such as
hot flashes and vaginal dryness, but with a better safety profile
compared with more potent estrogens.This makes estriol a better
choice for bioidentical hormone-replacement treatment regimes.
That is not all this 'weak' hormone is good for! Research suggests
that estriol has benefits for bone density, heart health, multiple
sclerosis, and postmenopausal urinary tract health.6-12 In this
article, we will review the attributes of this 'weaker' estrogen,
and why this estrogen is currently in the news.
Estriol and Hormone Replacement Therapy
If you are on hormone-replacement therapy (HRT) and have never
heard of estriol, you might be wondering why not? Before the 1970s,
estriol was thought to have significance only during pregnancy.
Levels of estriol are elevated in pregnancy up to 1,000 times
compared with normal non-pregnant levels.
In the 1960s, we saw the beginning of hormone-replacement therapy
with patented equine estrogens such as Premarin® and synthetic
progestins as found in Provera®.
By the 1990s, one-third of menopausal women were taking Premarin®.
Research uncovered the increased incidence of breast cancer,
increased risk of blood clotting, and increased cardiovascular risk
associated with the use of these horse-derived and synthetic
hormones (used in combination in the patented medication Prempro®).
The medical community began to wonder if using hormones from
pregnant horses was such a good idea.
In an effort to find a safer alternative, many patients and
practitioners began looking into 'natural' hormone-replacement
treatment using bioidentical hormones, which are identical to those
produced naturally within the body. Bioidentical-hormone
replacement was pioneered in the 1980s as a treatment for menopause
by Dr. Jonathan Wright in Washington state.
Interest in estriol increased as it was discovered that estriol was
safer than horse-derived and synthetic hormones in relation to
cardiovascular health and potentially cancer risk. Unfortunately,
many doctors have not adopted its use, and many bioidentical
hormone-replacement regimes use only estradiol, a more potent
estrogen with increased associated risks.
The benefits of estriol may, in part, be explained by the mixed
pro-estrogenic and anti-estrogenic effects of this interesting
estrogen hormone. Scientists Melamed et al. investigated the
mixture of stimulating and non-stimulating effects posed by estriol
upon estrogen receptors. When estriol is given together with
estradiol, the estradiol-specific stimulation to cells is
This little-appreciated scientific fact helps to explain how
estriol can reduce pro-carcinogenic effects of more powerful
estrogens like estradiol. However, when estriol is given alone over
a long period of time, it can produce a more complete
pro-estrogenic effect, explaining why symptom relief is achieved
when menopausal women take estriol.2 Experimental studies suggest
that both estriol and tamoxifen (a synthetic anti-estrogen) have
protective effects against radiation-induced cancer of the breast.
In a prospective study funded by the US Army and performed at the
Public Health Institute, Berkeley, California, researchers compared
estriol levels during pregnancy with breast cancer incidence 40
years later. Results revealed that of the 15,000 women entered in
the study, those with the highest levels of estriol relative to
other estrogens during pregnancy had the lowest cancer risk.
In other words, as the relative level of estriol increased during
pregnancy, risk of breast cancer decreased 40 years later. In fact,
women with the highest level of estriol during pregnancy had 58%
lower risk for breast cancer compared with women who had the lowest
serum estriol levels. The authors also noted that Asian and
Hispanic women had higher estriol levels compared with other racial
groups. Interestingly, Asian and Hispanic women have the lowest
breast cancer rates.
The authors concluded, "If confirmed, these results could lead to
breast cancer prevention or treatment regimens that seek to block
estradiol estrogen action using estriol, similar to treatment based
on the synthetic anti-estrogen tamoxifen."
In another study, Takahashi et al. studied the safety of estriol
treatment for menopausal symptoms. Fifty-three women with either
surgically induced or natural menopause were given 2 mg of oral
estriol/day for 12 months.
Endometrial and breast assessments done with endometrial biopsy and
breast ultrasound, respectively, found normal results in all women.
The authors concluded that over a 12-month period, "estriol
appeared to be safe and effective in relieving symptoms of
In one investigation, 52 postmenopausal women were given 2 mg, 4
mg, 6 mg, or 8 mg/day of oral estriol for six months. In all
patients, vasomotor symptoms of menopause (such as hot flashes)
were decreased. The most improvement was experienced by women
taking the highest dose of 8 mg. There were no signs of endometrial
hyperplasia confirmed by endometrial biopsy over the six-month
treatment period. Mammograms were obtained on six of the patients
who had mammary hyperplasia at the study's outset, and no further
changes were seen.
Although the oral route of administration of estriol appears
relatively safe over the short-term, the transdermal route is
preferred for long-term use. For example, Weiderpass et al. found
an increased risk of endometrial atypical hyperplasia and
endometrial cancer with oral use of estriol, but not with
transdermal estriol over at least a five-year period. Compared with
no use of estriol, those who took oral estriol for at least five
years had a significantly greater risk, compared with individuals
who did not take any estriol.
Women using topical estriol for at least five years did not have
any increased risk. As you will read in the "Safety" box, several
studies suggest that the use of topical natural progesterone cream
may further reduce the risk to the endometrium.
Henry Lemon, MD, a women's cancer specialist, took this research
one step further and developed the concept of the estrogen
quotient—the ratio of estriol to the sum of estradiol and estrone
(estriol/estrone+estradiol). By looking at this ratio of 'good'
estrogen to 'bad' estrogen, a physician can evaluate breast cancer
risk and prescribe estrogen replacement better tailored to the
individual to reduce cancer risk. The estrogen quotient can be
evaluated from a 24-hour urine hormone panel.
Estriol Reduces Markers of Cardiovascular Risk
Growing evidence suggests that estriol may offer protective
benefits for the cardiovascular system. For instance, Takahashi et
al. found that some women with natural menopause given 2 mg/day
oral estriol for 12 months had a significant decrease in both
systolic and diastolic blood pressure.
Another study compared the use of oral estriol at a dose of 2
mg/day for 10 months in 20 postmenopausal and 29 elderly women.
Some of the elderly women had decreases in total cholesterol and
triglycerides and an increase in beneficial high-density
Estriol Improves Bone Mineral Status in Women With Osteoporosis
A Japanese study involving 75 postmenopausal women found that after
50 weeks of treatment with 2 mg/day of oral estriol cyclically and
800 mg/day of calcium lactate, women had an increase in bone
mineral density, a decrease in menopausal symptoms, and no
increased risk of endometrial hyperplasia (tissue overgrowth that
may precede cancer).
Similarly, Nishibe et al. investigated treatment of postmenopausal
and elderly women with 2 mg/day of oral estriol and 1,000 mg/day of
calcium lactate versus 1,000 mg/day calcium lactate alone. The bone
mineral density significantly increased in women who received
estriol, whereas the women who did not take estriol experienced a
decrease in bone mineral density.
Estriol Reduces Brain Lesions of Multiple Sclerosis
The high levels of estriol during pregnancy have been known to
alleviate some autoimmune conditions due to its ability to shift
immune response.9 For instance, Sicotte et al. at the Reed
Neurological Research Center in Los Angeles investigated the
effects of pregnancy-level doses of estriol (8 mg/day) in
non-pregnant women with multiple sclerosis (MS).
Cerebral MRI images showed a significant reduction of
gadolinium-enhancing cerebral lesions from multiple sclerosis.
These lesions increased when treatment stopped and decreased when
treatment was restarted.28 Gadolinium is a contrast agent used in
certain MRI studies; gadolinium-enhancing lesions are associated
with an increased inflammatory response marking disease progression
in patients with MS. Lowered amount of these lesions seen on MRI
with gadolinium contrast would equate to a decrease in disease
This effect may also apply to men with autoimmune conditions.
Another team of researchers from the Reed Neurological Research
Center in Los Angeles found that estriol treatment ameliorates
experimental autoimmune encephalomyelitis (EAE) in males, compared
with placebo treatment.29EAE is an experimental demyelinating
inflammatory disease that shares numerous characteristics with MS.
Estriol treatment also resulted in a decrease of proinflammatory
immune markers. This is very promising news for patients and their
doctors who are struggling to treat challenging neurological
conditions associated with inflammation.
Estriol Protects Urinary Health in Postmenopausal Women
Postmenopausal women who suffer from incontinence or recurrent
urinary tract infections will be pleased to know that estriol
offers benefit in the context of these troublesome conditions. In a
prospective, randomized, placebo-controlled study, 88 women were
given 2 mg intravaginal estriol suppositories (once daily for two
weeks, then twice weekly for six months) or placebo. Of the women
in the estriol group, 68% reported improvement in symptoms of
incontinence. In addition, measurements of mean maximal urethral
pressure and mean urethral closure pressure were significantly
In another randomized, double-blind, placebo-controlled trial,
women with recurrent urinary tract infections (UTI) were given
either intravaginal estriol cream (containing 0.5 mg estriol, once
daily for two weeks, then twice weekly for eight months) or
placebo. The incidence of urinary tract infection was dramatically
reduced in the estriol group compared with placebo (0.5 versus 5.9
episodes per year).
Measurement of Estriol
Hormones produced by the body are secreted in pulses, while
hormones taken transdermally or orally will initially be very high
and slowly decline over the course of the day. This scientific
reality makes testing for estriol at a single point in time—as
would be the case for saliva or serum testing—very inaccurate.
There are too many variables: When did your body last put out a
pulse of the hormone under investigation? When did you take your
hormone-replacement therapy? Estriol in particular does not last
very long in the blood. In fact, the half-life of estriol has been
shown to be between 3.6 and 64 minutes.
The more accurate way to assess estriol is by collecting what is
excreted during a 24-hour urine collection. This form of testing
ensures that we have an accurate value that is not affected by the
fluctuations of the day, because we are measuring 24 hours' worth
of hormone production.
Estriol in the News
Recently, the FDA made claims that estriol—a hormone naturally
produced by women's bodies—is not safe, even though the FDA did
admit at a press conference that no adverse effects from estriol
have ever been reported. After reading about the benefits of
estriol that research has uncovered, it is hard to understand why
the FDA would want to take this more protective estrogen off the
market and out of reach of the many thousands of women seeking
relief from menopausal and postmenopausal symptoms.
This recent attack on estriol also includes all bioidentical
hormones produced by compounding pharmacies. Why are these
substances such a threat? This is not the first time the FDA has
made attacks on unpatented natural substances. Bioidentical and
therefore unpatentable hormones are a threat to the income of big
drug companies. The fees paid by these big drug companies are a
large portion of FDA income. Would you not say that there is a
conflict of interest here? Why would any woman want to take horse
estrogen or chemically imprecise, yet patentable estrogen rather
than estrogen that is identical to that produced by women's own
bodies? This is even more questionable in the light of all the
negative research showing increased health risks from these
FDA-approved substances. And is it not the job of the FDA to make
sure that women get safe and effective medicine? It seems the FDA
has largely lost sight of its original goals. For more information
on this and to take action, please visit the HOME (Hands Off My
Estrogen!) Coalition website at www.homecoalition.org.
Estriol, once thought of as insignificant and weak, actually has
protective effects against stronger estrogens. For this reason, it
is a relatively safer choice for bioidentical hormone-replacement
therapy. We have learned that safety is also increased by using
topical administration instead of oral administration, and by
balancing estrogen with progesterone.
Estriol has benefits beyond treating typical postmenopausal
symptoms. Estriol offers potential benefit for people with MS,
postmenopausal women prone to urinary tract infection or
incontinence, and menopausal/ postmenopausal women with
osteoporosis. It would be a great shame to lose this wonderful tool
before it was ever fully utilized.