 | In nearly all the large scale studies that have examined the relationship between
estrogen replacement and cancer, the "estrogens" used have been estrone +
equilin (Premarin), estradiol, or ethinyl estradiol. |
| The results of many studies in laboratory animals and cell cultures have confirmed that
estrone, equilin, estradiol, and ethinyl estradiol can all cause cancer in endometrial and
breast tissue. |
| Some researchers think estriol - the major component of human estrogen - has virtually
no propensity to cause cancer, and that it reduces the carcinogenic activity of other
estrogens and other carcinogenic chemicals in breast tissue. Others, especially those
working with estriol in "unnatural" ways in experimental animals, believe
estriol may have carcinogenic potential. No large studies have been done in a human
population to examine the possible risk of cancer associated with estriol (or triple
estrogen, the combination of estriol, estradiol, and estrone in their natural proportions).
However, a large amount of clinical and laboratory evidence dating back to the mid-1960s
has been collected that addresses the issue of estriol and cancer. This research strongly
suggests that estriol has less cancer-causing potential than estrone, equilin, estradiol,
and ethinyl estradiol, and that estriol may actually inhibit the carcinogenic activity of
these other "estrogens." |
How Some "Estrogens" May Cause Cancer
One of estrogen's primary roles is the stimulation of growth and proliferation of cells
of the endometrial lining of the uterus and cells of the breasts in preparation for
pregnancy and lactation. Estrogens accomplish this by stimulating estrogen receptors
located on cells at these sites. In the endometrium, the tendency of "estrogens"
to induce proliferation is opposed by progesterone (or patentable "progestins."
In breast cells, the picture is much less clear. It appears possible that
"estrogen" stimulation of already cancerous breast cells is much less opposed by
progesterone (or "progestins") than "estrogen"-induced stimulation of
endometrial cells.
Built-in Cancer Protection
Unlike other "estrogenic" treatments, such as horse estrogens or 100%
estradiol, there is no evidence that estriol at reasonable doses stimulates excessive
proliferation of endometrial cells, which is a precursor to endometrial cancer. Estriol
actually may antagonize the proliferative activities of other estrogens, probably because
it competes for and benignly occupies estrogen receptor sites that would otherwise be
occupied by the other more proliferation-oriented estrogens1.
Thus, it appears that Nature may use estriol to partially block these powerful hormones
before they can do harm. Studies in experimental animals have shown that the proliferative
dose of estriol is at least twice as high as it is for horse estrogens (equilin + estrone)
and estradiol, and 60 to 75 times higher than that of the synthetic estrogen ethinyl
estradiol. This translates into a reduced or even negligible risk of endometrial cancer
from estriol. If Henry Lemon, MD, is correct, estriol may be Nature's own built-in cancer
protection. During the 1960s and 1970s, Dr. Lemon, a long-time physician, medical
researcher, and former head of the division of gynecologic oncology at the University of
Nebraska College of Medicine, studied the apparent ability of estriol to protect women
against breast cancer. Work published prior to Dr. Lemon's had already demonstrated that
estradiol and estrone were both capable of promoting abnormal cell proliferation,
including endometrial and breast cancer. It was also well-known that the body treats these
two hormones with extreme care, converting them to estriol rapidly and irreversibly.
Estriol, however, had no carcinogenic tendencies, as far as anyone knew.2
"Was it possible," asked Dr. Lemon, "that some women who develop breast
cancer have too little estriol relative to estradiol and estrone circulating in their
bodies?" While there had long been suspicion that estrogen was somehow related to
breast cancer, until Dr. Lemon came along, no one had thought to look at the levels of
each of the three primary estrogens separately to see how each one related to cancer.
To answer his question, Dr. Lemon ran a preliminary study in which he employed a
urinary estrogen quotient (Eq), which was simply a measure of the ratio of estriol
to the total of estradiol + estrone in the urine over a 24-hour period; the higher the
quotient, the more estriol there is relative to estradiol and estrone.3
In 34 women with no signs of breast cancer, Dr. Lemon found the Eq to be a
median of 1.3 before menopause and 1.2 afterward, with only 21% of the women below 1.0
less estriol than estrone plus estradiol). The picture was quite different in the 26 women
with breast cancer. Their median Eq was 0.5 before menopause and 0.8 afterward,
with 62% below 1.0. Thus, the women with breast cancer seemed to be making substantially
less estriol relative to the other estrogens than women without breast cancer.
Dr. Lemon's results raised many questions. Does this apparent hormone imbalance open
the door to breast cancer? Is it a reliable biologic marker of breast cancer risk? Could
it be used to predict which women were vulnerable to the disease but had not yet developed
it? And most importantly, could restoring the natural hormone balance prevent breast
cancer and perhaps even treat ongoing disease? These are intriguing questions that still
need good solid scientific answers.
Some researchers have published work disputing Dr. Lemon's findings, while others have
published research supporting him. The issue is complicated by the fact that a woman's
level of estriol when breast cancer becomes apparent may not be as important as a
deviation from the norm in her estriol levels as a young woman as a young woman.
One group of researchers found the levels of estrone and estradiol (the known
procarcinogenic estrogens) in the blood of 150 sisters and daughters of women with breast
cancer to be significantly higher than in a matched control group. They also found blood
levels of estrone and estradiol to be higher in 36 teenage daughters of women with breast
cancer. They noted studies showing that American women (who, as a group, have higher rates
of breast cancer) have lower levels of estriol than Asian women (who, as a group, have
lower levels of breast cancer), especially at the time the studies were done. The
researchers pointed out that Asian women in Hawaii - whose breast cancer levels were
midway between those of Asian women in Asia and American women - also had levels of
estriol midway between American women and Asian women in Asia. Clearly, much more
research, including large-scale, long-term human trials will be necessary to answer the
many unanswered questions regarding estriol's role in cancer.
Despite the absence of these large expensive clinical trials, much of the evidence that
is already available is encouraging. Dr. Lemon's preliminary results make sense in the
light of several findings reported by other researchers, as well as by Lemon himself:
| Laboratory animal studies totaling more than 500 rat-years have demonstrated that
estriol is the most active protective estrogen ever tested against cancers of the
breast induced by several potent carcinogenic agents,4
including radiation.5 |
| Few animal studies have shown estriol to have any significant carcinogenic activity -
unlike estrone and equilin, estradiol, ethinyl estradiol, DES, and other patentable
"estrogens," which are routinely found to be carcinogenic. Estriol, given in
high doses, given continuously (every day), or implanted under animals' skins in pellets
has been found to be carcinogenic. However, when estriol is given in pulses, or in
non-continuous doses (which approx-imates the natural pattern of estrogen secretion), it
was much less carcinogenic or not carcinogenic at all. |
| When estriol is given to rats and mice combined with estradiol and estrone, it inhibits
the ability of these other estrogens to stimulate uterine growth.6
|
| Estriol gives the immune system a boost by enhancing the activity of certain cells known
as phagocytes whose job it is to consume foreign invaders, such as bacteria and viruses,
and cancer cells. |
| In a group of premenopausal women with noncancerous breast diseases, including
fibroadenoma, sclerosing adenosis, and intraductal hyperplasia, estriol excretion was
found to be subnormal in 60%.7 |
| Dr. Lemon observed low estriol secretion in three women who had not yet developed cancer
but had precancerous changes of the breast.8 |
| During pregnancy, a woman's body increases its secretion of estriol by 1,000-fold. After
pregnancy, estriol levels drop but usually remain higher than they were prior to
pregnancy. This may help explain why women who have never given birth have a higher risk
of breast cancer than women who have borne a child.9 |
On balance, the evidence arising from modern scientific research favors estriol (when
used in physiologic doses according to natural timing patterns) as a noncarcinogenic,
anti-carcinogenic, or at worst, lowest risk estrogenic substance. When modern science
isn't crystal clear, it's always safest to mimic Nature as closely as possible, which is
why NHR employs the three human estrogens in exactly the patterns established in women's
bodies over tens of thousands of generations. This is undoubtably safer than using horse
hormones, other patentable estrogens, or incomplete, wrongly dosed, or poorly timed
natural estrogens, such as estradiol.
| Natural Hormone Replacement for Women Over 45,
published by Smart Publications, is available for $9.95 through LIFE Enhancement or your
local book store. |
Progesterone and Breast Cancer
Unlike synthetic "progestins," which have an uncertain influence on breast
cancer, two important studies employing natural progesterone have demonstrated a
clear protective benefit. In one publication, researchers at the Johns Hopkins University
Medical School reported on more than 1,000 women being treated for infertility who were
followed for more than 20 years. The women were divided into two groups, those whose
infertility was caused by a deficiency in progesterone and those whose progesterone level
was normal. With all other possible influences accounted for, the women who were
progesterone-deficient had a 5.4-fold greater risk of premenopausal breast cancer
compared with the women whose progesterone was normal. Even more startling was the finding
that the progesterone-deficient women had a 10-fold higher rate of death from cancers
of all kinds.10
The other study, conducted in Taiwan, focused on the proliferation of breast epithelial
cells removed from women who had undergone a lumpectomy for breast cancer. About 10 to 13
days prior to their surgery, the women were randomly assigned to apply a topical gel
containing either estradiol, progesterone, estradiol + progesterone, or a placebo each
day. When the researchers examined postsurgical breast tissue from around the lump, they
found increased proliferation of breast epithelial cells in the samples from the women who
had used the estradiol-only gel compared with placebo. By contrast, cell proliferation was
significantly reduced in the tissue samples from the women who had used either the
estradiol/progesterone gel or the progesterone-only gel.11
What about Ovarian Cancer?
The risk of developing ovarian cancer as a result of "hormone" replacement
has not been investigated nearly as intensively as breast or endometrial cancer. It should
be. A large, prospective study recently conducted by the Emory University School of Public
Health in Atlanta, Georgia, reported about more than 240,000 peri- and postmenopausal
women studied for seven years. The results indicate a significant risk associated with
"estrogen" replacement. During the course of the study, 436 of the women died
from ovarian cancer, and their risk of dying increased significantly with the length of
time they had been taking "estrogen" replacement. Women who had used
"estrogen" for six or more years but had stopped using it were found to be just
as much at risk as current users.12
Let's Remember...and Research the "Forgotten Estrogen"
In a 1978 editorial in the Journal of the American Medical Association titled,
"Estriol, the Forgotten Estrogen?" Alvin H. Follingstad, MD, bemoaned the lack
of large clinical trials on estriol that would earn it an FDA stamp of
"approval." Do we as clinicians have to wait the years necessary for the
completion of these trials before estriol becomes available to us?" he asked. "I
think not. Enough presumptive and scientific evidence has been accumulated that we may say
that orally administered estriol is safer than estrone and estradiol."
Two decades later, we are still waiting for those clinical trials, and what Dr.
Follingstad said then is even more true today. There's nothing to be gained by waiting. If
a woman is concerned about her risk of cancer from estrogen replacement (and who isn't?),
then the logical choice (considering both modern scientific research and hundreds of
thousands of years of human experience with producing and metabolizing estrogens) is
estrogen containing a majority of estriol, or in some cases, estriol alone.
*Premarin� isn't exactly the same as human estrogen, which is why I've
put the "estrogen" in ERT in quatation marks.
This is an extremely important point that I will come back to repeatedly.
References
1. Hisaw FI, Velardo JT, Goolsby CM. Interactions of estrogens on
uterine growth. J Clin Endocr. 954;14:1134-1143.
2. Hamilton, TH. Control of estrogen of genetic transcription and translation. Science.
1968; 161:649-661.
3. Lemon, HM, Wotiz, HH, Parsons, L, Mozden, PJ. Reduced estriol excretion in patients
with breast cancer prior to endocrine therapy. JAMA. 1966;196:112-120.
4. Lemon HM. Oestriol and prevention of breast cancer. The Lancet. March 10,1973:546-547.
5. Lemon HM, Heidel JW, Rodriguez-Sierra JF. Principles of breast cancer prevention. 1991;
Paper presented at Annual Meeting of the AACR.
6. Hisaw FI, Velardo JT, Goolsby CM. Interactions of estrogens on uterine growth. J Clin
Endocr. 1954;14:1134-1143.
7. Bacigalupo G, Schubert K. Untersuchungen uber die oestrogen auscheidung im urin bei
mastopathie. Klin Woschr. 1960;38:804-805.
8. Lemon, HM, Wotiz, HH, Parsons, L, Mozden, PJ. Reduced estriol excretion in patients
with breast cancer prior toendocrine therapy. JAMA. 1966;196:112-120.
9. Siitteri PK, MacDonald PC. The utilization of circulating dehydroepiandrosterone and
fate for estrogen synthesis during human pregnancy. 1963;2:713-730.
10. Cowan LD, Gordis JA, Tonascia JA, Jones GS. Breast cancer incidence in women with a
history of progesterone deficiency. J Epidemiol. 1981;114:209-217.
11. Chang KJ. Influences of percutaneous administration of estradiol and progesterone on
human breast epithelial cell cycle in vivo. Fertil Steril. 1995;63:785-791.
12.Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thun MJ, Heath CW. Estrogen
replacement therapy and fatal ovarian cancer. Am J Epidemiol. 1995;141:828-835.
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