Editor’s Note: After the publication of Dr. David Zava’s last Health Watchers News and Views post, Hormone and Breast Cancer: the Latest Findings from the WHI, he received an attacking comment from a doctor who has been making claims for years that natural progesterone has the same effects as the synthetic progestins. Although, as an editor, I do not publish comments that attack, Dr. Zava wrote an eloquent, if technical response which adds to the dialogue about progestins, progesterone and breast cancer. We share it here for the reading pleasure of hormone biochemistry geeks everywhere!
I very much disagree with the comment that “Progestins cause more breast cancer than estrogens because they act like progesterone.” Yes, synthetic progestins increase breast cancer, but there is no evidence that progesterone does the same. Quite the contrary. Below is my argument in favor of natural progesterone as a preventive 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 what I mean by a progestogen; it is any molecule with a structure like progesterone that binds to and activates intracellular progesterone receptors, which would include all forms of synthetic progestins in addition to natural progesterone. Overall, what Fournier and colleagues found is that of all the progestogens studied, natural progesterone had the lowest risk, which was lower than no treatment.
Fournier et.al. then did a second study in the same patient population as above (80,391 postmenopausal women), but looked not only at the different types of hormones that were used (estrogens and progestogens), but risk in relationship to the type of tumor (ductal or lobular). They also looked at whether or not the tumors contained receptors for estrogen or progestogens. There are four categories for tumors with estrogen and progestogen receptors: 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-). For the record, I helped develop this technology in the 1970s, ran three different breast cancer testing laboratories that did this type of testing for many years (mid 1970s to mid 1990s), and published in this area extensively using breast cancer cell lines and human clinical samples post surgery for breast cancer.
What Fournier and group found in the second study (J Clin Oncol 26 (8): 1260-1268, 2008) is that the combination of estrogens and progestogens for more than 5 years is associated with increased risk of breast cancer. When this is broken down into ductal vs lobular cancers, the use of estrogens plus progestogen (including natural progesterone) is associated with an increased risk for breast cancer. What Dr. Grant fails to mention is that 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 also important to keep in mind that the Fournier studies did not compare the effects of oral vs topical progesterone. 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 does the oral route. Luteal tissue levels of progesterone need to be achieved for progesterone to act as an estrogen antagonist to prevent estrogen from excessively stimulating breast cell proliferation, which can increase breast cancer risk. Women who have an excess of estrogen relative to progesterone (low progesterone/estradiol ratio), are more likely going 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 premenopausal women (much more prevalent in peri-menopausal women) 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 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 (20-50 mg) administered topically deliver physiological amounts of progesterone to the breast tissue and suppress estrogen-stimulated cell proliferation (Chang KJ et.al. Fert Sterility 63: 785-791, 1995 and De Boever J 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. And the actual estrogen levels relative to progesterone are not evaluated in these studies. The study by Fournier mentioned above looks at oral, not topical, progesterone. Based on saliva, 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 Prev 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 biology behind progesterone delivered topically (protective).
When I talk to very high level 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 it doesn’t increase serum levels. This is true, as it is for all topically delivered hormones, but it does increase saliva, capillary blood, and tissue levels of progesterone. With this data in hand, it doesn’t take a genius to figure out something is wrong with serum testing when hormones are delivered topically.
Hopefully one day the medical establishment will finally wake up and listen to what women have been telling them for years—topical progesterone works. Then they might discover what has been right under their noses (the scientific articles supporting the utility and effectiveness of topical progesterone) for too many years.