Does Progesterone Increase Breast Cancer Risk?

There appears to be some controversy brewing about progesterone possibly increasing the risk of breast cancer. This is based on a secondary follow-up of a French study (Fournier et al J Clin Oncol 26 (8):1260-1268, 2008) investigating breast cancer incidence in approximately 80 thousand women who had used various forms of estrogens and progestogens for hormone replacement therapy. It is being suggested that progesterone increases breast cancer risk, contrary to popular thinking that this hormone is safe and helps prevent breast cancer. The following is my argument in favor of natural progesterone as a preventative for breast cancer, with reference to the Fournier studies that address this issue.

Fournier and colleagues (Breast Cancer Res Treat 107: 103-111, 2008) originally published their clinical study looking at the relationship of different progestogens, in combination with estrogen, on the risk of developing breast cancer. First, I think it important to define a progestogen; it is any molecule with a structure similar to the natural hormone progesterone that binds to and activates intracellular progesterone receptors. This would include all forms of synthetic progestins in addition to natural progesterone. What Fournier and colleagues found in the first study is that of all the progestogens studied, natural progesterone had the lowest risk, which was actually lower than no treatment at all.

Fournier and colleagues then did a second follow-up study (J Clin Oncol 26 (8): 1260-1268, 2008) in the same patient population as the first study (80,391 postmenopausal women), but looked not only at the different types of hormones that were used (estrogens and progestogens), but breast cancer risk in relationship to the type of tumors (ductal or lobular) that occurred in some of these women. They also looked at whether or not the tumors contained receptors for estrogen or progestogens, which includes four categories: ER+/PR+, ER+/PR-, ER-/PR+, and ER-/PR-. Most breast cancers (60-70%) present with receptors for both estrogens and progestogens (ER+/PR+), and about 20-30% fall into the other categories (about 10-15% are ER-/PR-). This is an area I would consider myself somewhat of an expert in as I helped develop the technology for detecting ER and PR in breast cancers in the late 1970's, ran three different breast cancer testing laboratories that did this type of testing (from the mid 1970s to mid 1990s), and am published extensively using breast cancer cell lines and human clinical samples post breast cancer surgery.

What Fournier and group found is that the combination of estrogens and progestogens for more than 5 years is associated with increased risk of breast cancer. Broken down in ductal vs lobular cancers, the use of estrogens plus progestogen (including natural progesterone) was associated with an increased risk for breast cancer. While this could be interpreted to indicate that natural progesterone increases breast cancer risk, it should be kept in mind that the data shows it's the combination of estrogen and natural progesterone that increases risk. In fact, risk with estrogen plus progesterone is actually less than the risk of estrogen alone (1.7 vs 2.1, respectively), and that of all the progestogens, natural progesterone has the lowest risk. So there is a different way of looking at this data. It is important to keep in mind that this study did NOT look at natural progesterone by itself, only estrogen plus progesterone. Another way of interpreting this data is that natural progesterone decreased the risk of breast cancer caused by long term use of estrogens (i.e. risk 2.1 to 1.7).

It is important to also keep in mind that the Fournier studies did NOT look at the effect of progesterone alone, or compare the effects of oral vs topical progesterone. Most of these studies are based on oral progesterone use.

Based on what we have seen in hundereds of thousands of salivary and capillary blood progesterone levels following different routes of progesterone administration, the topical route of administration delivers much more progesterone to tissues than the oral route. Oral progesterone therapy only raises progesterone to subluteal levels (1-5ng/ml) (Nahool and Levits references) and this is also reflected in lower salivary and capillary whole blood progesterone levels. Luteal levels of progesterone (>10ng/ml) need to be achieved for progesterone to act as an estrogen antagonist to prevent estrogen from excessively stimulating breast cell proliferation. Women who have an excess of estrogen relative to progesterone (low progesterone/estradiol ratio), are more likely to have atypical benign breast disease that is at increased risk of developing into breast cancer (Sitruk-Ware et al J Clin Endocrinol Metab 44, 771, 1977). Low endogenous luteal progesterone levels in premenopuase women (much more prevalent in peri-menopausal woman) have also been associated with increase breast cancer risk (Micheli et al Int J Cancer 112, 312-318, 2004).

Oral progesterone is mostly destroyed in the gastrointestinal track before it enters the blood circluation and delivered to the tissues. Based on saliva and capillary blood progesterone levels, topically delivered progesterone is 20-100 times more efficiently delivered to tissues. Studies in humans have shown that physiological amounts of progesterone (20-50mg) administered topically deliver physiological amounts progesterone to the breast tissue and suppress estrogen-stimulated cell proliferation (Chank KJ et al Fert Sterility 63: 785-791, 1995 and De Boever et al Endocrinol of Cystic Breast Disease, 1983). My concern is that women using estrogens and ORAL progesterone as hormone replacement may not be getting enough progesterone to tissues to counter the growth-promoting effects of the estrogens. Unfortunately, the estradiol level, relative to progesterone (i.e. progesterone/estradiol ratio), was not evaluated in these studies. In vivo, during the luteal phase of the menstrual cycle, the level of progesterone is approximately 100-200 times higher than estradiol in all body fluids that have been studied (serum, capillary whole blood, saliva, urine). Lower levels are associated with increased risk for benign breast disease, higher proliferative rates, and increased breast cancer risk (Sitruk-Ware et al J Clin Endocrino Metab 44, 771, 1977; Micheli et al Int J Cancer 112, 313-318, 2004).

The Fournier studies referenced above looked at ORAL, not topical, progesterone. Based on salivary, capillary blood, and tissue progesterone levels from the studies mentioned above, topical progesterone is far more effective in delivering a physiological amount of progesterone to the breast and controlling estrogen-stimulated cell proliferation.

It is unfortunate that in spite of all the science and clinical studies behind it, only one small study (Plu-Bureau G et al Cancer Detect Preve 23(4), 290-296, 1999) that I am aware of looked at the risk of breast cancer with TOPICAL progesterone in a manner similar to what Dr. John Lee recommended for progesterone use (10-30 mg topical progesterone daily). In that study, they showed the risk to be reduced by half (0.5) in those using topical progesterone for 3 years or more. This is entirely consistent with the notion that when progesterone is delivered topically at a physiological level, it is protective.

When I talk to very high levels of people about why they should at least study the relationship of topically delivered progesterone to breast cancer risk, I am told they don't think it could possibly be effective because topical progesterone doesn't increase serum levels. This is true for all nonpolar sex-steroid hormones used clinically as replacement therapies, including estradiol, progesterone, and testosterone. While topical delivery of these hormones does not increase serum levels significantly, this route of administration does result in marked increase in levels of these hormones in saliva, capillary blood, and tissue.

When it is finally realized that topical hormone deliver of progesterone is a very efficient way to deliver progesterone to tissues, and that serum is not reflective of this delivery, progress will be made in avoidance of over-treatment (often occurs with topical delivery as a result of tracking success with serum levels that do not increase significantly), and delivery of a physiological amount of progesterone to tissues that is breast protective. Dr. John Lee, and many of those who follow his protocols for physiological delivery of topical progesterone, have reported very few breast cancer cases in their clinical practice. While this is anecdote, their use of topical progesterone in physiological amounts deserves more attention by the medical establishment.

Hormone Therapy and Breast Cancer: Latest WHI Findings as Reported in JAMA

I was sent a link to the Today Show, broadcast on October 20th which featured an interview with Dr. Nancy Snyderman, discussing further findings from the Women's Health Initiative Study (WHI), published in the Journal of the American Medical Association (JAMA) this week. This news may confuse your patients and I wanted to take this opportunity to explain the study and assure you this study does not include natural hormones, but refers to the combination of Premarin and Provera.

The experts stated that there is an increase in risk of death from breast cancer when you are taking the combination of estrogen and progestin. In this case, the drugs that were used were Premarin and Provera. Premarin is known as conjugated equine estrogens and is horse estrogen which has some similarities to human estrogen but is not the same. Provera is a progestin known as medroxyprogesterone acetate and is very different in function from natural progesterone.

"Experts" who are saying that synthetic progestins increase breast cancer risk are right, but, we've known that since 2002. Unfortunately, these same "experts" are now claiming an association of natural progesterone with breast cancer by default. They espouse that there is no clinical evidence to show natural progesterone is any safer than synthetic progestins. Unfortunately, this is an incorrect assumption and they have not done their homework. Natural progesterone has a much safer profile than all forms of synthetic progestins, not only for the breasts, but for nearly all tissues of the body, including the reproductive tissues, the cardiovascular systems, and the brain. There is a plethora of published literature on this subject.

For those who are unsure about the striking differences in safety profiles of synthetic progestins versus natural progesterone as regards breast cancer risk, several clinical trials have clearly shown the superiority of natural progesterone.

In a 2005 review of clinical studies comparing synthetic progestins to natural progesterone, Campagnoli and coauthors (J Steriod Biochem Mol Biol 96, 95-108) concluded that: "The balance of the in vivo evidence is that progesterone does not have a cancer-promoting effect on breast tissue. .....We therefore suggest that when HRT is indicated, preparations containing progesterone and not a synthetic progestin should be used, according to a sequential or cyclic-combined regimen. In this way the risk of endometrial cancer is minimized without increasing the risk of BC."

In another 2005 clinical trial comparing synthetic progestins to the natural progesterone, Fournier and coworkers (Int J Cancer 114, 448-454) found that: "The risk was significantly greater than p0.001 with HRT containing synthetic progestins than with HRT containing micronized progesterone, the relative risk being 1.4 and 0.9, respectively." Yes, that's right; progesterone users had a lower risk.

So why are the news media confusing synthetic progestins with natural progesterone? Too often information such as this is streamlined in mainstream media by those who have power, money and the ability to shout through the megaphone the loudest. We know all too often that large pharmaceutical companies have a strangle hold on funding for universities, who gets grants, what gets published, whose opinions get press, the success of women's health organizations and journals they represent. Unfortunately, because of this ability to present one-sided research in such a commanding way, it is not unusual that the news media doesn't spend much time researching the science and the evidence based data and studies that are available; and in this case, available about the difference between progestins and natural progesterone as well as the benefits of natural progesterone.

The decision on natural hormone therapy is one between a patient and physician; you cannot extrapolate what happens in the body using Premarin and Provera to discuss what happens in the body with its own natural hormones. Natural hormones, when properly balanced, allow the body to function at its optimal level.

Thank goodness for women's intuition that senses right from wrong.

Additional information: The Bioidentical Hormone Debate: Are Bioidentical Hormones (estradiol, estriol, and progesterone) Safer or More Efficacious than Commonly Used Synthetic Versions in Hormone Replacement Therapy?

Testosterone: Elixir or Dangerous Drug?

A recent study published in the prestigious New England Journal of Medicine (NEJM) (1) casts a shadow on the common use of testosterone therapy in older men for boosting their energy and vitality. An FDA-approved testosterone gel was shown to significantly increase risk for adverse cardiovascular, respiratory, and dermatological events in men 65 or older who had impaired mobility and increased health risks.

These unexpected negative results fly in the face of decades of good research on testosterone therapy in older men showing it to be beneficial to the cardiovascular system, and improve sexual function, mood, energy level, and muscle and bone mass and strength (2,3,4,5).

What went wrong? Why were the results so different from hundreds of other publications painting testosterone as the elixir of youth and vitality? Was it the dose of testosterone these men were using, or the way it was delivered as a gel through the skin?

In the NEJM study the testosterone treated men had mean venous serum testosterone levels of 574+/- 403 ng/dL, compared with 292+/- 160 ng/dL in the placebo group. The Endocrine Society Clinical Practice Guidelines suggests that testosterone should be dosed to achieve serum levels about mid-range for a healthy young male (5). The 50-150 mg topical testosterone gel put the testosterone-treated men well within the expected mid-physiological range seen in healthy young men (about 500-1000 ng/dL). So based on conventional serum testing one would conclude that overdosing would not likely be responsible for the adverse reactions these men had to testosterone. Or was it?

Let’s look at some assumptions made about using conventional venous serum to monitor how much testosterone is entering the body following topical testosterone therapy. It is “assumed” that when testosterone is delivered as a topical gel only 10% is absorbed and utilized by the body. This is based on measuring the total amount of testosterone that can be detected in venous serum over a specific time frame, usually about 12-24 hours, after the testosterone has been applied to the skin. With this conventional wisdom of 10% absorption, topical testosterone gel has been FDA-approved at a pharmacological dose about 10 times higher (50-100 mg) than the amount a healthy young male’s testes will manufacture in a day, which is about 5-10 mg of testosterone.

The NEJM study (1), and many others preceding it (4,5), confirmed that the daily topical dosage of 50-150 mg testosterone results in a level of serum testosterone (mean 574 ng/dL) that would be considered healthy in young men. So why was this dose of topical testosterone not healthy for the older men?

It is “assumed” that when testosterone is delivered into the body using a topical gel that serum testosterone measurements, derived from a venous blood draw, actually reflect how much testosterone is entering tissues throughout the body.

What evidence do we have that the pharmacological dose (50-150 mg) of topical testosterone used in the NEJM study was actually “delivering” a physiological dose of testosterone into the tissues of these older men? The correct answer is none. This would require measuring the levels of testosterone in different tissue biopsies, which for obvious reasons is not practical and such studies would not likely find many volunteers.

However, there are other means to look a little closer at “tissue” exposure to testosterone, which is to measure the level in the fluid of tissues bathed by capillary beds (blood flowing to tissues and delivering nutrients and hormones) as opposed to blood flowing away from tissues (i.e. venous blood). Capillary blood and saliva provide the next-best alternative as they are easily accessible body fluids that are more representative of the direct interaction of capillary beds with tissues (6,7).

Over the past 10 years ZRT Laboratory has measured the levels of steroid hormones (estradiol, progesterone, testosterone, DHEAS, cortisol) in saliva and capillary blood (finger stick) from men and women who have used a plethora of different hormone doses and delivery systems (topical creams and alcoholic gels, oral, im-injections, sc-pellets, sublingual drops, and troches). Information on hormone type, dosage, delivery, and timing on well over a million people has been recorded in our database.

In mining this extensive database, we find that when steroid hormones are produced endogenously by the ovaries and testes and released into the bloodstream the levels in venous blood serum are quantitatively equivalent to whole capillary blood drawn from the finger (7). Under the same conditions, salivary hormones are about 2-3% of venous serum or capillary blood hormone levels, as reported extensively in the literature (6).

In contrast to what we see with endogenously produced hormones, when testosterone, or any other steroid hormone, is applied topically as a cream, gel, or spray, levels in capillary blood (finger) are remarkably higher, by 10-20 fold, than venous blood levels. Moreover, salivary hormones are often >100% of venous serum levels, which ordinarily are only 2-3%. This remarkable increase in capillary blood and salivary testosterone is NOT seen when it, or other hormones, are delivered orally, or as im-injections or sc-pellet implants. With these delivery systems capillary blood and venous serum levels are about the same.

This discrepancy in venous serum vs capillary blood and salivary hormone levels following topical hormone delivery has created enormous confusion among physicians attempting to interpret hormone test results. Those using venous serum are often frustrated that pharmacological dosing, as seen in the NEJM article, only leads to lower to mid-physiological serum testosterone levels, but side effects such as excessive buildup of red blood cells associated with pharmacological dosing. On the other side, those using saliva and capillary blood testing are shocked to see that pharmacological dosing leads to pharmacological levels much higher than expected.

Specifically, with reference to the use of topical testosterone gels in men at the 50-150 mg dosage, we find mean capillary (finger tip) blood levels of testosterone to be about 5000 ng/dL, approximately 10 x higher than the venipuncture serum blood levels reported in the NEJM study (574 +/- 403 ng/dL).

Of further relevance to the NEJM study, we find that men using the higher pharmacological topical testosterone gel have capillary blood levels of estradiol that usually exceed 100 pg/ml, which is very high for males. While physiological levels of estrogens are beneficial to the male cardiovascular system, higher levels can be harmful (8). Unfortunately, estrogens were not monitored in the NEJM study so it is not possible to know if levels, even in venous serum, were higher than physiological range. It is very possible that some of the cardiovascular events observed in the older high risk men participating in the NEJM study were precipitated by excess estrogens derived from excess testosterone.

We believe these differences in conventional venipuncture serum vs capillary blood and saliva testosterone provide a rational explanation for the unexpected adverse clinical events seen in the NEJM study.

Based on the exceptionally high testosterone and estradiol levels we have documented in capillary blood and saliva following use of topical testosterone gels in the 50-150 mg range, we suggest that dosage for topical delivery of testosterone, or any steroid hormone, should not be determined by venipuncture serum levels as this will result in over dosage and potential for toxicity, as seen in the men participating in the NEJM study.

Perhaps a lesson is learned from The Swiss alchemist, Paracelsus, who noted some 500 years ago: "All things are poison and nothing is without poison. Only the dose permits something not to be poisonous."

Hormones are no different. A physiological level of testosterone is unquestionably life-enhancing in men of all ages and health conditions who suffer from testosterone deficiency. However, at a high enough dose testosterone, like all hormones, has the potential to transition from an elixir to a dangerous drug.

References:
(1) Basaria S et.al. N Eng J Med June 30, 2010. Adverse Events Associated with Testosterone Administration
(2) Bhasin S, et. al. J Clin Endocrinol Metab 90: 678-688, 2005. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on skeletal muscle.
(3) Wu FCW et. al. N Engl J Med 363: 123-35, 2010. Identification of late-onset hypogonadism in middle-aged and elderly men.
(4) Fernandez-Balsells et. al. J Clin Endocrinol Metab 95: 2560-2010, 2010. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.
(5) Bhasin S et.al. J Clin Endocrinol Metab 95: 2536-2559, 2010. Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline.
(6) Vining RF, McGinley RA. J Steroid Biochem 27: 81-94, 1987. The measurement of hormones in saliva: possibilities and pitfalls.
(7) Edelman et.al. Fert steril 88(5): 1404-7, 2007. A comparison of blood spot vs plasma analysis of gonadotrophin and ovarian steroid hormone levels in reproductive age women.
(8) Sudhir K, Komesaroff PA. J Clin Endocrinol Metab 84, 3411-3415, 1999. Cardiovascular actions of estrogens in men.

Ask Dr. Zava - Premarin and Breast Cancer

Dear Dr. Zava,

Does Premarin increase the risk of Breast Cancer and can we prove it? (I know the WHI study showed that the combo of CEE and MPA caused an increase in heart attack and breast cancer, but the 2nd arm of the study that related only to CEE showed only an increase in stroke).

DTZ: The evidence here is that Premarin alone actually decreases breast cancer risk, which is the conclusion of the WHI. My thoughts are that Premarin contains many estrogen conjugates that may have benefit to decrease cell proliferation of breast cells, both normal and cancerous. In most cases, Premarin at the lower dosing (0.325-0.625) results in a very physiological level of estradiol in saliva and blood (ZRT database of thousands of women using Premarin). John Lee, MD used low dose Premarin (0.325) in conjunction with natural TOPICAL progesterone throughout his 30 years of clinical practice and had excellent results - low cancer incidence, his patients were compliant and felt great. This is limited by anecdote. Those who argue that horse estrogens cause cancer are going to lose that battle. Those who argue that oral estrogens alone, in any form, are more harmful to the cardiovascular system (increased strokes) and brain (shrinks the brain-new study) will win that battle. We need to be looking at the overall risk of any hormone. If the hormone has ANY risk to any of the major systems of the body, it should NOT be used if the bioidentical shows little or no risk (which it does). I think the argument about Premarin and breast cancer is a moot point as it doesn’t appear to cause harm to the breast, but does cause harm to other systems in the body.

Ask Dr. Zava - estrogen excess

Dear Dr. Zava,

I am a 63 year-old woman who had a total hysterectomy at age 42. I am osteopenic and want to take bioidentical progesterone. I love the feeling I get from taking it, but I get a lot of breast tenderness. I even decreased the dosage to 5 mg and still got the breast soreness. I also have fibrocystic breasts and low thyroid. I was taking Synthroid and recently changed to porcine thyroid.

I have had fatigue issues for years and the natural hormones made me feel so much better. I would really like to take the progesterone but am worried about the breast reaction. I also got the DHEA, and testosterone cream. These were very low dose preparations as well, but I had to quit taking them due to the breast problem.

I had a blood test years ago and was very deficient in all hormones. I eventually decided that I must be converting everything to estrogen and maybe I could not process the hormones. I have also been thinking I have adrenal fatigue as well. I am taking some adrenal support capsules that have some adrenal tissue in them. I am really trying to find a solution and wonder if you have ever encountered this problem in your experience.

I thank you in advance for any insight you might have. –Nancy


Dear Nancy,

It would seem that your breast tissue is very sensitive to hormones, including progesterone.
If you have not tested your hormones during hormone therapy it’s not possible to know if they are in excess, or the breast tissue is just extra sensitive to normal levels of hormones, or both. Women who have had a total hysterectomy usually have very low levels of hormones. However, you do complain of fibrocystic breasts, which is usually due to estrogen dominance, but some also say an iodine deficiency. You are probably right in saying that you convert hormone precursors to estrogens, which is probably why androgens like testosterone and DHEA (estrogen precursors) cause the same problem.

In some women with estrogen excess, progesterone therapy, when first used, can cause breast soreness. At the cellular level, progesterone works in synergy with estrogen to stimulate normal breast cell proliferation and differentiation, and then inhibits proliferation. This is how progesterone works in synergy with estrogens to allow the tissue to specialize and stop dividing. However, if estrogen is in excess for a prolonged period of time it is more difficult for progesterone to be growth-inhibitory. The growth-inhibitory properties of progesterone may also depend on the cellular levels of progesterone receptors, which can vary from one person to another.

My guess is that your breast cells have just seen too much estrogen for too long, and that when you first use the progesterone it has more of the growth-promoting actions, which cause the soreness.
Some have suggested that breast tenderness can be due also to iodine deficiency. Normal breast tissue is iodine dependent and when levels are low, the tissue is hypersensitive to estrogens. So part of your problem might be due to iodine deficiency.

Vitamin D is also important for normal breast function, so this may also be an issue for you. You should check your Vitamin D level and consider supplementation if low.

Many of the physicians I have worked with have said they find that in women with estrogen dominance it is best to lower the estrogen burden first before using natural progesterone. Otherwise, progesterone can cause the problems you mention.

All this said you need to discuss this with your doctor and consider means to lower the apparent estrogen burden in your breast tissue. I say apparent because we don’t know for sure if you have excess estrogen in your bloodstream, or in your breast tissue. There are many natural ways to lower your estrogen burden, including weight loss, exercise, and more fiber in the diet. You can find out more about this in What Your Dr May Not Tell You about Breast Cancer.

I would also suggest you look at your hormone levels, particularly estradiol, progesterone, testosterone, DHEA(S), and cortisol before you begin any hormone therapy.