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, the 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 hundreds 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 premenopause women (much more prevalent in peri-menopausal woman) have also been associated with increased breast cancer risk (Micheli et al Int J Cancer 112, 312-318, 2004).
Oral progesterone is mostly destroyed in the gastrointestinal tract before it enters the blood circulation 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 an anecdote, their use of topical progesterone in physiological amounts deserves more attention by the medical establishment.
Posted by David Zava, PhD at 10:39 AM