Breast cancer, progestins and natural progesterone
— is there a link?
by Dixie Mills, MD, FACS
Now more than at any other time in history, women of all ages are being exposed
to news about their bodies. The problem is, we are learning about some very complicated
systems in soundbites. The media — television, radio or print — wants
to get its message across very quickly and therefore often simplifies a scientific
report down to three sentences, while the researchers had to work in a laboratory
(ivory tower) for many years to produce the report — requiring at least ten
pages with charts and figures!
One minute we read that all hormone replacement therapy is risky and there is an
HRT–cancer link; the next we hear that HRT is okay for younger women; and
now we’re hearing that estrogen is not the only thing we have to worry about
— we should also be looking at the hormone progesterone and its role in the
body, particularly the breast. To top it off, we have the recent news that breast
cancer rates are going down as more women decline HRT.
What does all of this mean? The most recent research confirms that when synthetic
progestins (a lab-invented form of progesterone used in birth control pills and
HRT, among other medications) are combined with estrogen, there is increased risk
of breast cancer in menopausal women, especially when used continuously. This has
led to the assumption that natural forms of progesterone may have the same risks
— but in fact, natural progesterone, produced by the body or taken by mouth
or topically, has not been shown to increase the risk of breast cancer. Of course,
we need more research in this area, but we do know this:
progestins (synthetic or nonbioidentical) and progesterone
(natural or bioidentical) are different.
Their mechanisms are intricate and understudied — we simply don’t have
all the data yet. But we do have enough to answer the question we hear frequently
at Women to Women: Is topical progesterone cream safe? The simple
answer for the majority of women (with a few important exceptions) is yes; when
used as directed, bioidentical progesterone cream is safe. Let me explain why I
Update on the declining rates of breast cancer
The recent news about breast cancer rates decreasing sounded exciting and wonderful
— and it is — but it was actually rather old news being confirmed. The
report came from a 15–minute talk I attended at the San Antonio Breast Conference
(a large, 8000–attendee meeting). Called the SEER data, the results from nine representative centers are
very well-documented, and come from the year 2003 because the center wants to check
and double-check the numbers and it takes three years to do it! Results from 2004
will be announced in the spring of 2007.
The report found that the incidence of breast cancer, which had been slowly increasing
about 2% a year in the 1990’s then slowly decreasing about 1% a year in the
early 2000’s, suddenly dropped 7% in 2003. Looking at their data in subsets,
the researchers found the greatest decrease in women ages 50–69, and that
there was a 12% decrease in this age group of estrogen receptor–positive breast
The researchers examined all possible reasons and anomalies for this striking decline,
including the fact that women did not get as many mammograms
that year. In the end, they concluded that the cause of such a drop was that 50%
of women on HRT went off of it in 2002 after learning of the Women’s Health
Initiative study results. (The Women’s Health Initiative Study came out in
2002 with the news that Prempro — a combination of estrogen and progestins
— increased the risk of breast cancer).
The numbers actually fit quite well with the risk found in that study.
Since most breast cancer tumors take many years to manifest, one mechanism we could
infer from the rather sudden drop in breast cancer incidence noted in
the SEER data is that HRT may act like a Miracle-grow fertilizer on previously existing
cancer cells. What we don’t know is what the future will bring — will
the decline continue, plateau or bounce back up after time? Hopefully in our lifetime
we will have really striking news, like the rates have decreased by 50%, or even
Why the news media leaped on this one report is unclear. I suppose they saw it as
one glimmer of hope in an otherwise very scientific, rather dull meeting. (But what
I did find fascinating was a presentation about a mammary mouse virus being found
in over 30% of human breast tumors in the United States. With the recent link of
cervical cancer with the HPV virus, this sounded like something that deserved more
immediate attention. But I’m keeping my eye on this, so stay tuned!)
Ultimately, the easy message that was picked up by the media was this: going off
HRT leads to a decrease in breast cancer rates. As more women started dropping their
HRT medications, the drug companies — anxious about losing their market share
— responded by attacking natural bioidentical hormones, including progesterone
But natural progesterone is quite different from synthetic progestins, in a similar
way to how artificial sweeteners are different from natural sugars. One is cooked
up in a lab; the other is found in nature. Let’s look at the difference.
What is progesterone?
Progesterone, an active hormone in the female (and male) body, falls under the superclass
called progestogens, the term used to denote all progesterone formulas.
It is one of the many hormones made naturally from cholesterol in the body’s
and can be converted into estrogens (and testosterone) by specific enzymes and co-factors.
The effects of progesterone and estrogen are both necessary to orchestrate a woman’s
monthly cycle as well as other body functions.
In reproductive–age women, progesterone is primarily produced by the corpus
luteum — the empty shell of the egg follicle that ruptures during
a woman’s monthly ovulation. Progesterone levels rise following ovulation,
stimulating changes in vaginal mucus while also preparing the uterine lining for
implantation of the fertilized egg.
During pregnancy, progesterone is secreted in greater amounts from the placenta.
Without progesterone, an egg cannot attach and grow. The name progesterone itself
comes from the word “gestation,” for growth of an embryo, and “pro,”
meaning “for.” We had long assumed that assuring a healthy pregnancy
was its only purpose, but are now finding that men make progesterone too, and many
organs, like the brain, also have progesterone receptors. I’ve always wondered
why it seemed to be the neglected hormone — maybe because it was a longer
word. And because post-menopausal women were basically invisible and understudied
until about ten years ago, we have little documentation of what progesterone does
after the ovary stops releasing eggs.
Progesterone was discovered in the early 1930’s, but due to the fact that
it is poorly absorbed by the stomach in its natural state and also because it is
not water-soluble, changes had to be made in the laboratory to come up with a synthetic
version that would work in pill form. These synthetic formulas are called progestins.
What are progestins?
Like progesterone, progestins also fall under the superclass of progestogens, but
they are man-made in the laboratory and have been slightly biochemically altered
to mimic natural progesterone.
The first synthetic progestin, norethindrone, was invented in 1951 and
used in the first oral birth control pills. They continue to be used today to prevent
pregnancy. For example, a progestin is what is given in “mini pills”
and in intramuscular shots like Depo–Provera. The most common progestins —
medroxyprogesterone acetate (MPA, or Provera) and megestrol acetate
(Megace) — are given to treat abnormal bleeding, hot flashes, and even breast
In the early days of HRT, no one realized the relationship between estrogen and
progesterone or that progesterone was needed to suppress the proliferative effects
of estrogen on uterine tissue. In the 1970’s, when symptoms of menopause were
viewed solely as a result of a drop in estrogen levels, women were given estrogen–alone
(Premarin) pills to treat their discomfort. But this brought about unexpected results:
an increase in the incidence of uterine cancer.
To remedy this, an estrogen–progestin combination pill was developed to protect
women who wanted estrogen and still had a uterus. The most common variety of this
combination today is Prempro. The recommended doses have changed over time. Some
women on Provera (MPA alone) have been treated with a continuous low-dose regimen,
while others cycle on and off it.
Many women found and still find great relief through progestin–estrogen HRT
and Provera. For many years it was widely accepted, yet never far from controversy.
Meanwhile, scientists pursued a natural alternative to synthetic HRT.
Bioidentical progesterone and bioidentical hormone therapy
In 1998, an oral bioidentical progesterone (the brand name Prometrium) received
FDA approval. To make Prometrium, bioidentical progesterone is finely ground into
very small particles (micronized), then suspended in peanut oil so it that can be
When a hormone is described as bioidentical it means that its molecular
structure is identical to the form naturally produced in the human body. Since the
Women’s Health Initiative released their results on the
risks of synthetic HRT (actually horse-derived estrogens and a synthetic
progestin), there has been ongoing controversy as to whether or not bioidentical
hormone therapy (bHRT) poses the same risks for menopausal women.
We have been using bHRT successfully at Women to Women since its inception and prefer
it to the synthetic or nonbioidentical versions. At this point, bHRT has the advantage
to my mind because I prefer Mother Nature’s version of things. We also know
that there is a difference in the way natural progesterone behaves in the body compared
with synthetic progestins and can see how that plays out in breast tissue.
Natural progesterone and the breast
Progesterone’s role in the human breast is still under study; its molecular
mechanism of action and target cell proliferation and differentiation are not well
understood. A lot of interesting work is going on now with rat breasts or “tits”
or “teats,” which is provocative, but rats are very different from humans
— although we may share some of the same DNA. I think it is interesting that
rats’ teats are more like the human breast than they are like mice’s
teats because the rat forms lobules and the mouse doesn’t.
Everyone will agree that progesterone exerts powerful influences on breast physiology,
and it has been hypothesized to both reduce risk and to increase
risk of breast cancer. Until recently, progesterone was thought to be a sideline
player in the development of breast cancer. Most doctors thought it had a rather
innocuous role. After all, birth control pills contain many types of progestins
and there seems to be little risk as compared to the benefits. The presence of progestins
in HRT pills was even hoped by some to protect the breast like it did the uterus.
The late Dr. John Lee advocated progesterone as the forgotten cure and recommended
daily use of topical progesterone cream as a preventative and treatment for estrogen
dominance and breast cancer. Epidemiological studies are supportive of these theories,
in that women who underwent breast cancer surgery in their luteal phase
(after ovulation), when progesterone is highest, had a significantly better prognosis
than women who were in their follicular phase (first half of the cycle).
Additionally, breast tissue removed during breast reduction surgery did not show
increased cell proliferation after having been exposed to progesterone cream before
surgery. This was thought to be all good news for progesterone users, both synthetic
But then came the results of the WHI and the scales tipped dramatically once again.
In the laboratory Petri dish (a starkly different environment from the live human
breast), progestins are shown to cause more cell division (mitosis)
and proliferation, and therefore could induce genetic instability and possible cancer
mutations. There have been no similar studies on the effects of natural progesterone
on breast tissue, yet it has been tarred by the same brush.
Some progesterone experiments using very high doses of hormone combination over
ten years have been conducted on macaque monkeys. Though the results are hard to
quantify for humans, very few monkeys (1%) developed breast cancer. However, newer
work on biomarkers (fragments of DNA associated with disease) may be more
fruitful, but again, there does seem to be some unidentified difference between
monkeys and humans! Work on human breasts has been more difficult to come by as
breast tissue is not as accessible as the uterus or cervix.
Initially, I think some people thought that progesterone must work the same effect
on the breast as it does on the uterus, i.e., it should block estrogen stimulation
and cause cell differentiation. We do know that it does prepare the breast for lactation,
but the breast is not the uterus, nor does it have a period once a month and shed
its lining (thank heavens!). However, recent microscopic analysis of surgical breast
tissue does show that some cells in the luteal phase die off and are absorbed by
the body, rather than being released.
So we have to accept that there are wide gaps in our knowledge about the molecular
action of progesterone, but with recent technological advances we are discovering
more. We now realize that there are at least two isoforms of the progesterone receptor
(PR) and that progesterone interacts and cross-talks with many other growth factors
in and out of the cell. To date, no progesterone–receptor polymorphisms
(meaning variations in the form of a gene) have been conclusively identified as
associated with an increased or decreased risk of breast cancer, even in post menopausal
Although progesterone levels are difficult to measure and thus have not been widely
analyzed, to date the evidence does show that circulating levels of progesterone
in the blood are higher than circulating levels of estradiol (the major estrogen)
in post menopausal women. Even so, in the only large prospective study, no
association was observed between high circulating levels of progesterone and risk
of breast cancer.
However, the same cannot be said for progestins.
Progestins and the HRT–cancer link
In the Women’s Health Initiative, women who had undergone hysterectomy were
given Premarin (the estrogen-only arm of the study), and women who still had their
uterus were given Prempro (the estrogen-plus-progestin arm). The results of that
study to date apply only to the estrogen–plus-progestin (Prempro)
arm of the study.
European researchers are looking at their own use of estrogen, progestins, and progesterone.
Two studies from France are reassuring. They found sharp contrast between natural
progesterone and the use of progestins. In conjunction with a transdermal estradiol
gel, there was no increase in rates of breast cancer in the women using natural
progesterone. Additionally, a recent review of progestins, progesterone,
and breast cancer risk looked at over 100 references and found that only the synthetic
progestins, particularly when given continuously, increased breast cancer risk.
But this is not the final chapter in the story, either. From all these various findings,
new studies are being designed and conducted to determine whether it could have
been the regimen of continuously taking a progestin every day without a break, the
oral delivery method, or the type of progestin that caused the increase in risk
seen in the WHI.
The metabolites of progestins (what’s left after they’re metabolized
by the body) could also be the cause of an increased breast cancer risk. These substances
may be more androgenic (male hormone-like), or they may decrease insulin
sensitivity, both of which could augment the effects of estrogen in a negative fashion
and increase breast cancer risk. Another group of researchers
has identified a certain subset of women who seem to have a variation, or SNP (single-nucleotide
polymorphism) in the genetic material controlling the breakdown of progestogens
(all progesterone formulas), and some of these metabolites are more worrisome than
So, in thinking about progestins and your risk, the story continues to unfold, and
it’s useful to keep in mind that the type of progestin, how it is used, how
it interacts with your unique physiology, and how long you plan to use it all factor
into the equation.
What I find interesting is that birth control pills and the “morning-after”
pill both contain high levels of synthetic progestins and do not appear to have
a deleterious result for most women. However, the risk analysis is not altogether
equivalent here — perhaps because the women involved are younger, go on and
off them, get pregnant, or change brands; or it may perhaps be because many brands
do not contain the same dose of the progestin for the entire month. However, the
use of progestins for birth control generally employs a more cyclical approach (closer
to our natural cycles), rather than a continuous dose.
Certain types of hormonal birth control do affect certain subsets of women poorly,
with the progestins causing increased cell proliferation in the breast tissue; but
again, when the women have their periods, the breast swelling
and tenderness generally go away. Women often have other symptoms associated
with forms of hormonal birth control they don’t tolerate well. Family history
and personal biochemistry may come into play here. Women who don’t react well
to any kind of progesterone use (as evidenced by sore breasts or onset of irregular
bleeding or spotting) may need to investigate other natural treatment options, such
Which is safer: a progestin or natural progesterone?
In my practice, I try to give my patients the least intrusive and most natural options
first and build from there. Women often feel significantly better when using natural
bioidentical progesterone, and to my mind the Mother Nature–matched form is
much safer than the synthetic, mimicking adaptations. But it is always good to discuss
where you are in your life and weigh your individual benefits and risks with your
own healthcare provider. It’s clear that the older a woman becomes (along
with any complicating factors in her history), the more controversial her use of
any kind of hormones will be.
For now, the bottom line is that the jury is hung when it comes to progestins
and breast cancer. I wish it were clearer. Age, usage, and biochemistry are all
factors, with proponents and opponents still working hard to prove their points.
But the image is less fuzzy when it comes to natural progesterone.
The natural forms appear to have little influence on breast tissue, neither decreasing
nor increasing risk unless a woman has a genetic variation, as
mentioned above, that makes her vulnerable to all progesterone forms. To date, no
full-blown comprehensive study comparing the effects of progesterone with progestins
has yet to be funded. There is always hope that the future will deliver more definitive
answers. In the meantime, I think it is fair to say that bioidentical progesterone
creams can provide a suitable natural alternative to synthetic HRT for some women.
Who can use natural progesterone cream?
The natural progesterone supplementation we sometimes recommend to patients is in
an extremely low-dose (2%), USP (United States Pharmacopœia), topical cream
form. Keep in mind when choosing a topical progesterone cream that it is important
for “USP progesterone” to be listed in the ingredients. Many formulas
use wild yam without converting it first to progesterone, and these formulations
cannot be metabolized into progesterone within our bodies.
Bioidentical progesterone is safe for women when used as directed (three weeks on,
one week off; or two weeks on, two weeks off). Because there doesn’t seem
to be a risk associated with naturally occurring high blood levels of progesterone
following ovulation, we feel it is safe to use cream in this fashion. However, the
female breast is programmed to take a break from progesterone every month after
a period, and we feel it wise to emulate this cycle while your ovaries are still
Over the years, I have monitored many healthy patients in perimenopause and menopause
who used progesterone cream and have seen no direct correlation with an elevated
risk of breast cancer, even in women with a family history of breast cancer. I do
recommend, however, that any woman using hormones be monitored regularly by her
Who should not use natural progesterone cream?
Women with breast cancer or a past history of breast cancer:
This is the only group of women at any age that I advise to avoid using even low
doses of transdermal progesterone or Prometrium capsules without consulting with
their oncologist beforehand. We simply don’t know enough about the outcome
either way. It’s quite possible that certain tumors may not be affected, but
until we know more, I think it is clear that the possible risks could outweigh the
Women who note adverse effects with use of natural progesterone:
Some women will metabolize extra progesterone into estrogen — we call these
women “highly estrogenic.” They tend to respond quickly to supplemental
progesterone with increased breast tenderness (particularly during ovulation) and
irregular spotting or bleeding. The closer this kind of woman is to menopause, the
more cautious she should be with any form of progesterone. With the right medical
practitioner and a deep understanding of her whole health picture, it can be possible
for such a woman to actually change the way she metabolizes progesterone to make
it safe to supplement with bioidentical forms.
Post menopausal women:
Out of an abundance of caution, it is best not to use any form of progestogen, including
progesterone, if a woman is more than two years beyond her last period, unless she
is on estrogen.
It would also seem most prudent (at this stage of scientific knowledge) for a woman
to not take additional hormones, including progesterone, for more than a total of
five years. In this case, the reason for avoiding progesterone has more to do with
the natural evolution of hormones in the body than with any identifiably increased
risk. After menopause, it is natural for your body’s estrogen levels to taper
off — so, fittingly, should your progesterone levels.
If, however, you are using estrogen and have a uterus, you must also use some form
of progestogen to counter the effects of the estrogen on the uterine cells. The
use of (bioidentical) Prometrium is recommended for this circumstance, as studies
using progesterone cream are conflicting and very few. As with estrogen supplementation,
our recommendation is that it be used for a short period and no longer than five
years, at least until more information is available.
There has been some encouraging news on the breast
cancer front, and certainly more will be coming down the road. The greater
our understanding, the closer, perhaps, we can get to the day when no one will need
Unfortunately, there’s no magic pill to protect your breasts, and no clearly
defined yes-or-no answers when it comes to hormone therapy and safety. But at the
same time, there’s no reason for you to fear using natural progesterone cream
if it relieves your symptoms and makes you feel better. Every woman just has to
trust her own gut about her health, and do what seems to work for her and what she
feels good about. Just remember that building your core foundation of health by
exercising regularly, eating an optimal diet, and enjoying a healthy lifestyle is
truly the best cancer prevention strategy there is!
Our Personal Program is a great place to start
The Personal Program promotes natural hormonal balance with nutritional supplements,
our exclusive endocrine support formula, dietary and lifestyle guidance, and optional
phone consultations with our Nurse–Educators. It is a convenient, at-home
version of what we recommend to all our patients at the clinic.
If you have questions, don't hesitate to call us toll-free at
1-800-798-7902. We're here to listen and help.
Related to this article:
References & further reading
on breast cancer and progestins
Principal Author: Dixie Mills, MD