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Hormones After Breast Cancer? A Reply to an Oncologist
by James Biddle MD

March, 2001

Letter to a local oncologist concerning a mutual patient with past history of breast cancer:

Dr. (Oncologist),

Thank you for your kind letter concerning this mutual patient with a distant past history of breast cancer. As you noted, she did have a 24-hour urinary sex hormone profile which showed low levels of testosterone and DHEA. However, her total estrogens were actually quite normal. The value that was of the most concern was the "Estrogen Quotient", which was low at 0.56, with a desired value of greater than 1.0.

I appreciate your professional concern and your hope that I am "not providing hormones to patients who have had breast cancer without strong consideration" of my actions. You noted that this patient is quite willing to work with the relative absence of these hormones "if there might be some deleterious effect should she take hormones." You have strongly urged her not to take any hormones due to the "worry of stimulating latent breast cancer cells."

I can appreciate your professional position and opinion concerning the issue of Hormone Replacement Therapy (HRT) in patients with a history of breast cancer. As I understand the situation, conventional wisdom and the current "standard of care" dictate that these women should not be given any HRT whatsoever because: 1.) Women given conventional HRT have a higher risk of breast cancer, and 2.) Breast cancer cells exposed to conventional HRT show increased growth in tissue culture.

I have great respect for these facts and personally would never give a patient in this situation conventional HRT. The NIH website at cancernet.nci.nih.gov is a bit more lenient, stating "Still another area of controversy centers on whether women who have had breast cancer can take HRT, especially since treatments for breast cancer can often lead to early menopause in younger women. Use of HRT in breast cancer survivors is widely discouraged because of the concern that exposure to the estrogen in HRT would increase their risk for recurrence. Some scientists question the validity of this concern, since the prognosis of women who took HRT before developing breast cancer seems to be better than that of women who did not do so. Women with a history of breast cancer should talk with their doctor about HRT so that they can make an informed decision."

Therefore, the NIH believes that it is the patient’s right to make their own informed decision concerning the use of HRT after breast cancer.

However, what if giving a woman no treatment is theoretically increasing her risk of breast cancer recurrence as compared to other available treatments? Should I not offer her treatments which have reasonable evidence to suggest that they will not only be harmless, but may actually decrease the risk of breast cancer? Within the directive of "Primum Non Nocere", or "First Do No Harm", the act of withholding treatment may actually be harmful.

When working with breast cancer patients, I am currently aware of three very important hormone ratios which can impact the growth of breast cells:

  • Progesterone : Estrogen.
  • Estriol : Estrone plus Estradiol (Eq = E3 / E1 + E2).
  • 2-OH-estrone : 16-alpha-estrone.

Regarding the ratio of progesterone to estrogen, a recent double-blind, placebo-controlled, randomized in vivo study found that estradiol stimulated increased proliferation and hyperplasia of breast duct epithelial cells (a reliable marker for risk of breast cancer), whereas natural progesterone prevented breast cell proliferation, thus protecting against the risk of breast cancer. (Chang KY et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertility and Sterility 1995;63:785-79.)

Regarding the Estrogen Quotient, it should be recalled that not all estrogens are equivalent in their actions on breast tissue. Estradiol is the most stimulating and estriol is the least, but they compete for the same receptors. Unfortunately, most women who are obese, postmenopausal, or taking conventional HRT have more strong estrogens than weak estrogens, reflected in an Eq < 1.0. It was published in JAMA that women with an Eq < 1 are much more likely to get breast cancer. In addition, women receiving endocrine therapy for breast cancer were more likely to go into remission if that therapy raised their Eq (Lemon HM et al. Reduced estriol excretion in patients with breast cancer prior to endocrine therapy. JAMA 1966; 196(13):112-120, Follingstad AH. Estriol, the forgotten estrogen? JAMA 1978;239(1):29-30).

Regarding the ratio of 2-OH-estrone to 16-alpha-estrone, which is newer to me, I can inform you that a poor 2/16 ratio (lower 2OH : higher 16-alpha) has been shown to be carcinogenic. Extracts of cruciferous vegetables such as I3C (indole-3-carbinole) and its more absorbable metabolite DIM (di-indolyl-methane) apparently improve this ratio thru up-regulation of the CYP1A2 liver enzymes involved in the metabolism of estrogens (Cancer Lett 1997;114(1-2):169-170).

In fact, DIM has been shown to induce a favorable 2/16 ratio and induce apoptosis in breast cancer cells (Biochem Pharmacol 1999; 58(5):825-34, Carcinogenesis 1998; 19(9):1631-9). In addition, I3C also improved 2/16 ratios and induced a complete regression in 50% of patients with cervical dysplasia of CIN II-III (Gynecol Oncol 2000;78(2):123-9).

Therefore, the two strong estrogens, estrone and estradiol, are potentially carcinogenic and are present in these women even if we "do nothing", as they are converted from the adrenal hormones by aromatase enzymes in fat cells. However, estriol and progesterone, which are protective against cancer and dominant during pregnancy, are left deficient in the post-menopausal "un-replaced" state.

With this knowledge in hand, and knowing that this particular patient has a very low Eq, the ethical path before me is to offer her strategies to improve these three important hormonal ratios in an effort to theoretically reduce her risk of breast cancer recurrence. It is my understanding that her current ratios, if left unattended, may have the "deleterious effect" of actually increasing her risks of a recurrence by "stimulating latent breast cancer cells". So, to do nothing results in exactly the adverse effects that you fear.

I hope you can appreciate that I have indeed put a great deal of consideration into my actions, as is necessary when one is willing to stray from the safety net of the "standard of care" in order to optimize patient outcomes. I am fully aware that as recently as 1865 the "standard of care" scoffed at the notion that physicians should wash their hands between performing cadaver dissections and delivering babies as a strategy to reduce mortality from childbed fever. However, for the audacity of proposing the utility of handwashing, Dr. Ignaz Semmelweis died in a Viennese insane asylum just 136 years ago ("Childbed Fever: A Scientific Biography of Ignaz Semmelweis." K. Codell Carter and Barbara R. Carter, Greenwood Press, Westport CT, ISBN# 0-313-29146-2).

My trust is that my colleagues are now more willing to look at the actual data rather than the dogma. Therefore, I hope that you will find this information useful and I look forward to your reply, as well as your eventual acquaintance.

Respectfully,

James Biddle MD

Diplomate, American Board of Internal Medicine