Estrogen Metabolite Ratios: Time for us to let go….

Jacob Schor, ND, FABNO

October 5, 2012


The rabbits are gone.  City Park had a major spike in its rabbit population this past summer; instead of the lone rabbit who hid out at the southwest corner of the museum, there were bunches of them, [oh what’s the right word for a group of rabbits?  There are a number, bury, colony, down, drove, husk, leash, nest, trace trip, warren or wrack] sitting by the artificial stream that drains into the lily ponds.  Walking a dog Poppy’s size teaches one to keep their eyes open for animals like rabbits.  As calm and mild mannered as Poppy is at the office, she has the capacity to shift into four-wheel drive and initiate a turbo-charged pursuit if a rabbit starts hopping.


Anyway, the rabbits have quietly disappeared.  It shouldn’t have surprised me that we saw a coyote watching our progress last week through the tall grasses.  Perhaps the proper term for a colony of rabbits, at least from a coyote’s perspective, is a ‘larder of rabbits.’


Things change. 


I’ve had complaints from my dear wife about some recent newsletters; she has trouble following my transitions from one thought to the next.  So the topic of this newsletter is that ‘Things Change.’  While that is always the case, I am going to write about one specific theory that has been popular in alternative medicine, in particular cancer, over recent years that we may have been wrong about. 


This is the theory that the breakdown products of estrogen contribute to cancer risk to varying degrees.  The thinking has been that some of these estrogen metabolites are protective against cancer while others increase risk of cancer.  So looking at relative amounts of each estrogen breakdown product, or their ratio, could in theory be predictive of risk of estrogen dependent cancers.  This theory is known as the Estrogen Metabolite Ratio (EMR). 


The popular website Natural News sums it up like this:

“….the estrogen compounds called 2-hydroxyestrone and 16-alpha-hydroxyestrone are by far the most important for breast health. 2-hydroxyestrone is considered 'The Good Estrogen' because its presence doesn't seem to increase breast cancer risks, and MAY even be protective against it. However, 16-alpha-hydroxyestrone is considered 'The Bad Estrogen' because its presence seems to INCREASE breast cancer risk and has even been called a cancer CAUSING agent! All women have both estrogens, but each woman has a different RATIO, and this ratio is more important to health than the total AMOUNTS of the estrogens.


[When I mail these emails out, the software we use only sends the words and doesn’t preserve font size or other characteristics.  So let me point out that on the Natural News website the words that are capitalized in the above paragraph are also in bold letters.]


There’s a problem with this.  This entire theory may not be true. 


In August 2012, a study by Mackey et al brought what has been a long simmering doubt to my attention. They had conducted a prospective case-controlled study nested within the women's Health Initiative Hormone Trials (WHI-HT).  From this large cohort, 845 women with confirmed breast cancer cases were matched to controls by age and ethnicity. Stored blood was tested for these estrogen metabolites. 


In women using estrogen and progesterone together, 16alpha-hydroxyestrone levels increased slightly more than in women using estrogen alone (55.5 vs. 43.5 pg/ml). Both groups of women had significant increases,  ~300 pg/ml, in 2-hydroxyestrone levels. There was a modest association between higher baseline levels of 2-hydroxyestrone and larger 2:16 ratio with breast cancer risk.   Those diagnosed with estrogen receptor+/progesterone+ breast cancer, had higher baseline 16alpha-hydroxyestrone levels.   For those randomized to treatment with hormone replacement therapy, breast cancer risk was associated with greater increases in 2-hydroxyestrone and larger 2:16 ratio, but associations were not significant.  Increasing amounts of 16alpha-hydroxyestrone that resulted from hormone replacement therapy were not associated with breast cancer.


Go back up to the Natural News blurb up above.  The 16 alpha hydroxyextrone is supposed to be bad and the 2 hydroxyestrone good.  These recent results are backwards.


This Mackey study isn’t the only one that hasn’t  come out the way it is supposed to.


A paper published in October 2011 in the British Journal of Cancer also deserves our attention.  Zeleniuch-Jacquotte et al tested this “2 is good and 16alpha is bad” hypothesis as it relates to endometrial cancer and found no support.  They conducted a case-controlled study of 179 cases and 336 controls. Levels of 2 and 16-alpha-hydroxyestrone were measured. Risk of endometrial cancer was calculated and compared to these levels. No significant association was observed for the 2 versus16-alpha ratio.  Their results did not support the hypothesis that “… greater metabolism of estrogen through the 2-hydroxy pathway, relative to the 16-alpha-hydroxy pathway, protects against endometrial cancer.” 


A February 2011 a meta-analysis by Obe et al asked whether estrogen metabolite ratios change breast cancer risk.  Data from nine prior studies comprising 682 premenopausal cases and 1189 postmenopausal breast cancer cases was combined.  In comparing the “… highest compared with the lowest quantile of urinary EMR [estrogen metabolite ratio], nonsignificant associations suggested at best a weak protective effect in premenopausal but not in postmenopausal breast cancer (range of odds ratios: 0.50-0.75 for premenopausal and 0.71-1.31 for postmenopausal)….. Circulating serum/plasma EMR was not associated with breast cancer risk. …. Results of the prospective studies do not support the hypothesis that EMR can be used as a predictive marker for breast cancer risk.”


Return to the August 29 abstract featured in this review. A modest increase in risk for breast cancer was found in those women with a higher 2-hyrdroxyestrone level at baseline. Increased 16-alpha-hydroxyestrone was not associated with greater risk.  Read that over if.  This is backwards of what the EMR theory predicts.  


A 2008 paper is also worth mention. Heather Eliassen and colleagues at Harvard’s Channing Laboratory reported on their own attempt to sort out the impact of these estrogen metabolites.


They conducted a prospective case-control study using data and blood samples from the Nurses' Health Study. They tested for 2-hydroxyestrone and 16-alpha-hydroxyestrone in blood samples collected between 1989 and 1990 and compared levels in 340 cases of breast cancer with 677 matched controls. Neither estrogen metabolite appeared to change breast cancer risk.  Nor did the ratio between the two metabolites make a significant difference.


There was however a significant positive association observed for the 2-hydroxyestrone and the 2:16 ratio among women with ER-negative/PR-negative tumors. High numbers for either was associated with triple the relative risk for this small subgroup of breast cancer patients.  Again these results are backwards from what the theory predicts.


While these results don’t support the basic hypothesis that 2-hydroxyestrone lowers breast cancer risk nor that the 2 versus 16-alpha ratio is predictive of risk, the significant link found with hormone receptor negative breast cancer is worth noting.   This unexpected observation might argue in favor of aromatase inhibition even in hormone receptor negative breast cancer patients.


There is some evidence that 16-alpha-hydroxyestrone is protective in other ways. A 2009 study in the American Journal of Hypertension reported that there is an inverse association between 16-alpha-hydroxyestrone and systolic blood pressure in women, that is, the higher the 16-alpha levels, the lower their blood pressure.    Most would consider this a good, not bad, association.


We naturopathic physicians, are often ahead of the curve in translating new theories published in the scientific literature into clinical protocols for use with our patients.  This ‘early adopter’ tendency has its merits.  We sometimes find ways to help our patients when ‘regular’ medicine has yet to develop a treatment.  Because we limit our interventions to relatively non-toxic, low-risk therapies, we set a relatively low requirement of proof before experimenting with new ideas. We can justify our experimentation with a ‘might help and won’t hurt’ summation of risk analysis.  If we were using more dangerous therapies, we would surely raise the bar, asking for stronger evidence before we trying a new idea.


Being an early adopter does come with responsibility; if a new idea, doesn’t pan out, we need to abandon it and we need to let others know. 


It’s easier for us to take on new ideas than it is to let go of them In the case of estrogen metabolites, the theory that the 2-hydroxy form is good for women and the 16 alpha-hydroxy form bad, is not holding up.  Growing evidence suggests that there is little correlation between these hormones and cancer risk; the situation is more complex than we first thought.


It may be time that we let this idea go.  Things change.  In this case the science does not support what was once considered a promising theory and a potential avenue of treatment for estrogen sensitive cancers. 


Not exactly the same as rabbits disappearing, but hopefully you can see the tie-in.

Mackey RH, Fanelli TJ, Modugno F, Cauley JA, McTigue KM, Brooks MM, Chlebowski RT, et al. Hormone Therapy, Estrogen Metabolism, and Risk of Breast Cancer in the Women's Health Initiative Hormone Therapy Trial. Cancer Epidemiol Biomarkers Prev. 2012 Aug 29.


Zeleniuch-Jacquotte A, Shore RE, Afanasyeva Y, Lukanova A, Sieri S, Koenig KL, Idahl A, Krogh V, et al. Postmenopausal circulating levels of 2- and 16α-hydroxyestrone and risk of endometrial cancer. Br J Cancer. 2011 Oct 25;105(9):1458-64. doi: 10.1038/bjc.2011.381. Epub 2011 Sep 27.

Obi N, Vrieling A, Heinz J, Chang-Claude J. Estrogen metabolite ratio: Is the 2-hydroxyestrone to 16α-hydroxyestrone ratio predictive for breast cancer? Int J Womens Health. 2011 Feb 8;3:37-51.

Mackey RH, Fanelli TJ, Modugno F, Cauley JA, McTigue KM, Brooks MM, Chlebowski RT, et al. Hormone Therapy, Estrogen Metabolism, and Risk of Breast Cancer in the Women's Health Initiative Hormone Therapy Trial.  Cancer Epidemiol Biomarkers Prev. 2012 Aug 29. [Epub ahead of print]


Eliassen AH, Missmer SA, Tworoger SS, Hankinson SE. Circulating 2-hydroxy- and 16alpha-hydroxy estrone levels and risk of breast cancer among postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2008 Aug;17(8):2029-35.


Masi CM, Hawkley LC, Xu X, Veenstra TD, Cacioppo JT. Serum estrogen metabolites and systolic blood pressure among middle-aged and older women and men.  Am J Hypertens. 2009 Nov;22(11):1148-53.