Breast health

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 think so.

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 cancers.

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 more!

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 creams.

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 metabolic cascade 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 cancer.

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 better absorbed.

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 and bioidentical.

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 women.

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 others.

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 as soy.

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 functioning.

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 healthcare provider.

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 benefits here.

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.

Stay tuned

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 pink ribbons.

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!

Related to this article:

References & further reading on breast cancer and progestins

 

Last Modified: 09/10/2012
Principal Author: Dixie Mills, MD