For Jeannette when your doctor says: You have breast cancer, so you have to stop taking hormones……….

Jeannette: What’s a hormone?

Dr. Odom’s Answer: A chemical substance, formed in one organ or part of the body and carried in the blood to another organ or part; depending on the specificity of their effects, hormones can alter the functional activity, and sometimes the structure, of just one organ or of various numbers of them [1].

Jeannette: I am taking estradiol, estriol, progesterone, testosterone, levothyroxine, triiodothyronine, calcitonin, (the 3 previous found in Thyroid USP), cholecalciferol (=D3), and melatonin. Are they hormones?

Dr. Odom’s Answer: Yes. They are all made in the human body and affect tissues distant from the point of production [2].

Jeannette: What is “HRT” ? Doesn’t that mean “hormone replacement therapy”?

Dr. Odom’s Answer: Well, it does to you and me, but not to gynecologists and WHI (“Women’s Health Initiative”) researchers! To them, HRT is a buzz-word meaning “PremPro®”, a combination of Premarin® and Provera®.

Jeannette: What is the Women’s Health Initiative (WHI)?

Dr. Odom’s Answer: The WHI was a 15+ year multi-million dollar study established by the United States National Institutes of Health begun in 1991. Concerning HRT, this was a randomized, controlled, double-blinded set of clinical trials. It is the largest, most respected study to date of the use of horse estrogen and the drug Provera®. The study was administered by the NHI (National Health Institute) from their headquarters in Bethesda, MD, the data was produced in 40 academic medical centers throughout the US, and data collection was coordinated by the Fred Hutchinson Cancer Research Center in Seattle. In this study, women, mostly in their late 50’s and early 60’s were divided into three groups. 5,370 women were given Premarin® alone. 8,304 women were given PremPro®. 13,673 women took no hormone product whatsoever, thus giving a background incidence of heart attack, stroke, cancer, and Alzheimers disease. Although the clinical trials have ended, follow-up studies and further investigation of the data continue.

Other, very large respected clinical studies preceding the WHI are the “Postmenopausal
Estrogen/Progestin Interventions Trial” (PEPI) and the “Heart and the Estrogen-Progestin Replacement Study” (HERS) [6]. These latter two studies investigated the relationship of HRT with heart disease. As well, there are dozens of small studies delving into issues of the relationship of hormones to cancer.

Jeannette: What are Premarin® and Provera®? And are Premarin® and Provera® hormones?

Dr. Odom’s Answer: Well, yes & no. Premarin is a mixture of horse estrogens. Provera is a drug. Although Provera attaches to Progesterone receptor sites in the human body, it is not produced in the human body, nor is it found anywhere in the natural world. Premarin® is a brand name for CEE or “conjugated equine estrogens”. The word “Premarin®” is a contraction of the phrase, “pregnant mare’s urine” and is a combination of over 10 estrogens found in horses, only two of which, estradiol & estrone, are also produced in humans. Estradiol is the major human estrogen. Estrone in humans is a metabolic breakdown product of estradiol [3].

Jeannette: Didn’t the WHI or the other two studies look at using hormones naturally produced in humans?

Dr. Odom’s Answer: All 3 studies looked at Premarin® and Provera®. Only the PEPI trials had one arm that studied the effects of the combination of Premarin® plus natural progesterone on selected cardiac risk factors. However, the only form of Progesterone used was a particular product that is swallowed and notorious for producing low blood levels.

Jeannette: Does Premarin® cause cancer?

Dr. Odom’s Answer: Not that we can tell. In fact, the rate for breast cancer among subjects receiving Premarin® alone as part of the WHI was lower than that of participants receiving no hormone product [4,5].

On the other hand, we know that Premarin® contains at least 10 alien horse estrogens that metabolize into different metabolic footprints. These abnormal metabolites may be cancer causing [7]. The major metabolites of Premarin® are equilin and equilenin, which can cause breaks in DNA, thus, perhaps cancer causing [8,9]. So, regardless of the WHI results, I do not advise horse estrogens. Isn’t it obvious? Humans are constitutionally equipped to metabolize human hormones. Horses are capable of safely metabolizing horse hormones!

Jeannette: Does Provera® cause cancer?

Dr. Odom’s Answer: Yes. The WHI study confirmed what was already known from previous studies [10,11,12]. “About 6 million American women take estrogen-plus-progestin therapy. That would translate into nearly 6,000 more breast cancer cases every year, and, if all of the women took the therapy for 5 years, that could result in 30,000 more breast cancer cases.” [6]

Jeannette: It seems reasonable that human hormones are better for us than synthetic hormones. But, are they?

Dr. Odom’s Answer: A landmark article confirming that understanding was published in 1989, demonstrating that estradiol and natural progesterone reproduced all of the benefits of synthetic HRT, but produced better outcomes with fewer side effects. In addition, better patient compliance was shown [42]. Since then, numerous articles and a vast amount of clinical experience has demonstrated enthusiastic acceptance by patients.

Jeannette: Do human hormones cause cancer?

Dr. Odom’s Answer: Let’s start with estrogen. Estradiol is the major human estrogen. There is no clear and convincing evidence that Estradiol causes breast cancer. Certainly, Estradiol doesn’t have the cancer causing effects of the magnitude of Provera®! However, Estradiol stimulates growth of cells including breast tissue [13]. Women who are estrogen dominant (not balanced by progesterone) frequently complain of breast swelling and soreness. We also know that breast cancer cells frequently produce receptors for estrogen on their cell membranes, so that Estradiol will definitely stimulate growth in pre-existing breast cancer cells.

However, in health and in youth, women produce Progesterone along with estrogen in monthly cycles. Progesterone “down regulates” estrogen receptor sites, preventing undue estrogen stimulation [13,14]. This provides protection from cancer [15]. So, the anti-proliferative effect of progesterone is not limited to the endometrium of the uterus, as is commonly stated by gynecologists [16,17,18]. The fact is that there are progesterone receptor sites all over the body including brain, heart, and bone!

Although this discussion is specifically about the relationship of hormone replacement therapy and cancer, I should say as an aside that the partnership of Estradiol and Progesterone also extends into other protective realms: prevention of bone loss with enhancement of bone production; and prevention of heart disease. By itself, Estradiol has another benefit: prevention of Alzheimer’s Disease [3].

Lastly, it is important to point out that Estradiol without the partnership of progesterone does not prevent cancer. But an interesting aspect of breast cancer seen in women who have been supplementing estrogen prior to the diagnosis of breast cancer: The cancers are much less aggressive and the prognosis more favorable as compared to women not using estrogen at the time of diagnosis [19,20]. As well, data shows a lower risk of recurrence and mortality in women who used hormone replacement therapy after diagnosis as compared to women who did not use it [21].

Jeannette: How about the other hormones I am taking? Do they cause cancer?

Dr. Odom’s Answer: Estriol is also a human estrogen that increases greatly during pregnancy. Estriol is commonly prescribed in combination with Estradiol during Natural Hormone Replacement Therapy (N-HRT). As well, the other hormones produced in the ovary, Progesterone and Testosterone, are prescribed simultaneously. These prescribed hormones are commonly referred to as “bio-identical” because they are exact copies of human hormones that are manufactured from botanical precursors. Various estrogens are produced from soy, and progesterone from Mexican yam. The hormones are manufactured in Europe and China and imported into the US for inclusion into products produced by specially trained compounding pharmacists.

Estriol does not cause proliferative stimulation of tissues as Estradiol does [33]. Estriol has not been implicated in causing cancer [34].

Testosterone stimulates pre-existing prostate cancer, but has not been shown to cause prostate cancer [42, 43,44]. Cholecalciferol (D3) [22,23], Progesterone [46-57], DHEA [38-41], and Melatonin [45] have all been shown to have cancer protective effects.

We know that hormones generally decline in production with age. (Exceptions to that rule are cortisol and insulin, which can, unfortunately, increase in the body during middle age and beyond.)

As well, thyroid hormones always decline in production sometime during the aging process. So, at menopause, not only is there a sudden decline in the manufacture of hormones made in the ovary, thyroid hormones are usually measured at distinctly lower levels during the same time frame. So, in youth, the ovarian, brain, DHEA (an adrenal hormone), and thyroid hormones are all produced in optimal levels, but decline together with age.

These hormones naturally work together as an orchestra, not as solo performers. An unnatural situation is replenishing only one of those hormones in the aging person, but not the remainder of the complementary hormones.

An interesting situation is the solo use of thyroid in postmenopausal women. Thyroid has not been shown to cause cancer. The use of the inactive form of the thyroid hormone, levothyroxine, has not been shown to cause osteoporosis. However, the role of thyroid is to raise the metabolic rate. Thyroid does have a stimulatory effect upon cell proliferation, although less than that of estradiol [24]. So in the unnatural situation of thyroid administration without the simultaneous use of the complementary and protective hormones, like Cholecalciferol (D3), Progesterone and DHEA, we can imagine that thyroid can rev up whatever processes are occurring in the body at the time. Thus, like testosterone in prostate cancer and estrogen in breast cancer that is positive for estrogen receptor sites, we can imagine that thyroid could be implicated in fostering the growth of a pre-existing cancer [24]. So, the bottom line is not to seek the benefits of testosterone, estradiol, and thyroid without also taking the protective hormones Cholecalciferol, Progesterone, DHEA, and Melatonin.

The take home message is that substances made in your body by your body are much less likely to cause any mischief at any dose than substances not native to humans! Drugs, not native to the human body, can cause impotence, depression, heart disease, cancer, and sudden death.

And so, to repeat your question: “Do human hormones cause cancer?” The answer is “No”, no one has shown that any hormone produced in the human body causes cancer. But some can rev up cancers already in existence, and others can protect against the occurrence of cancer.

Jeannette: Why is it that I am getting contradictory advice from doctors?

Dr. Odom’s Answer: The use of bio-identical hormones to produce benefit with much lower incidence of side effects is a relatively new point of view espoused by a growing number of medical doctors over the past 15 to 20 years.

But, of course, doctors, like everyone else, vary in their opinions. Opinions are necessarily affected by study and experience.

Doctors generally follow lines of thought and practice fostered by academic physicians well-known in their own fields. These “opinion makers” have tremendous influence. As well, pharmaceutical companies are well-adept at influencing medical doctors to use their patented alien molecules through these “opinion makers” and via other means.

Much good scientific research is ignored by doctors who persist in following convention without proactively seeking benefit for patients. And example of this is the continuing use of the breast cancer drug Tamoxifen® when the aromatase inhibitor, Arimidex® has been proven to provide superior benefit for patients. Another example of the perseveration of conventional thinking is the adamant refusal by many doctors to advise the use of bio-identical ovarian hormones to enhance the quality of life of the survivors of breast cancer.

Pharmaceutical companies view the use of bio-identical substances that cannot be controlled by patents as streams of revenue flowing in the wrong direction. They have bankrolled “research” papers decrying use of Saw Palmetto, Vitamin E, DHEA, and others. “Research” on their own products is used by the FDA to make decisions about the efficacy and safety of new drugs! “Research” paid for by drug companies have made there way into numerous medical journals. A notorious recent example was a paper accepted to be published in the highly rated Annals of Internal Medicine touting the use of the discredited drug, Vioxx. This so-called research paper was written by a public relations firm for the drug giant, Pfizer. They then paid a professor of rheumatology at the University of Arizona School of Medicine to “author” it [25,26]. This practice is likely not unusual [27,28,29].

There is a current effort by the FDA in favor of their client drug company, Wyeth, to stop the compounding of natural hormones by pharmacists [31]. Because of the negative results of the Women’s Health Initiative (WHI) and the availability of compounded natural ovarian hormones, Wyeth has lost tremendous market share for its horse estrogen product, Premarin® [32]. And they want that money coming back to them! Although Wyeth filed its petition with the FDA on October 6, 2005 [30], the FDA did not make its first move until January 2008, when it warned compounding pharmacists to avoid the use of the human hormone, Estriol and of the term “bio-identical” [35,36].

Doctors, of course, should have the well-being of their patients primary in their minds. But, in a crescendoing effect over the recent years, doctors are influenced by the “big three”: hospital administrations; insurance companies (including the government); and pharmaceutical companies.

Jeannette: Wait a minute! The AMA is the big power broker, isn’t it?!?!

Dr. Odom’s Answer: Actually, only 15% of practicing US physicians belong to the AMA! [37] The only power retained by the AMA is its government mandated monopoly over creation of the diagnostic codes used for insurance billing. They are also in the magazine business (medical journals).

Jeannette: Where can I get good advice about Natural Hormone Replacement Therapy?

Dr. Odom’s Answer: Here are several good books….. A good basic book is How to Achieve Healthy Aging, by Neal Rouzier, MD, Worldlink Medical Publishing (2007). You can find this one at Amazon or Barns & Noble. Another is, Ageless: The Naked Truth About Bioidentical Hormones, by Suzanne Somers, which is widely available at any bookstore. For the more technically minded is The Hormone Handbook, by Thierry Hertoghe, MD, International Medical Books (2006). Hertoghe is from Belgium and is a well-known endocrinologist in Europe.

The best organization for the general public is the Life Extension Foundation headquartered in Florida. They have an extensive website and are the premier patient advocate in this country for Natural Hormone Replacement Therapy.

I hope that this is helpful. I wish you the best in your drive to maintain and enhance your health.

Yours truly,

David M. Odom, MD

1 Stedman’s Medical Dictionary, Williams & Wilkins, publisher, (any edition).
2 Dorland’s Medical Dictionary for Health Consumers. Saunders, div of Elsevier, Inc (2007).
3 Zhao, Liqin & Brinton, Roberta Diaz, Select estrogens within the complex formulation of conjugated equine estrogens (Premarin®) are protective against neurodegenerative insults: implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer’s disease, BMC Neurosci. 2006;7:24. Pgs 1471-2202.
4 The Women’s Health Initiative Steering Committee, Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy, JAMA. 2004;291:1701-1712.
5 Stefanick, Marcia L., et al, Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy, JAMA.2006;295:1647-1657.
7 Bhavnani BR: Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism. Proc Soc Exp Bio Med 1998 Jan;217(1):6-16.
8 Chen, Y., et al; The Equine Estrogen Metabolite 4-Hydroxyequilenin Causes DNA Single-Strand Breaks and Oxidation of DNA Bases in Vitro, Chem. Res. Toxicol.;1998; 11(9); 1105-1111.
9 Zhang, F., et al; The Major Metabolite of Equilin, 4-Hydroxyequilin, Autoxidizes to an o-Quinone Which Isomerizes to the Potent Cytotoxin 4-Hydroxyequilenin-o-quinone, Chem. Res. Toxicol.; 1999; 12(2); 204-213.
10 Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy, Magnusson, C., et al, International Journal of Cancer, Volume 81, Issue 3, Date: 5 May 1999, Pages: 339-344.
11 Catherine Schairer; Jay Lubin; Rebecca Troisi; Susan Sturgeon; Louise Brinton; Robert Hoover. Menopausal Estrogen and Estrogen-Progestin Replacement Therapy and Breast Cancer Risk, JAMA, Jan 2000; 283: 485 – 491.
12 Bush, Trudy L., et al, Hormone Replacement Therapy and Breast Cancer: A Qualitative Review, Obstetrics & Gynecology 2001;98:498-508.
13 Chang K-J, Lee TTY, Linares-Cruz G, Fournier S, de Lignieres B. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertility and Sterility 1995;63:785-791.
14 Cowan LD, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiology 1981;114:209-217.
15 Formby, B. and Wiley, TS, Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53, Annals of Clinical and Laboratory Science, Vol 28, Issue 6, 360-369.
16 Gompel A, et al, Bcl-2 Expression in Normal Endometrium during the Menstrual Cycle, Am.J.Pathol, Vol.144 No.6, June 1994,1195-1202.
17 Bu, Shi-Zhong, et al, Progesterone induces apoptosis and Up-Regulation of p53 Expression in Human Ovarian Carcinoma Cell-Lines, Cancer , May 15,1997, Vol.79, No.10, 1944-50.
18 Haldar, Subrata, et al, Down-regulation of Bcl-2 by p53 in breast cancer cells, Cancer Research 54, April 15, 1994, 2095-7.
19 Gapstur, SM, et al, Hormone replacement therapy and risk of breast cancer with favorable histology, JAMA 1999; 281, 2091-2097.
20 Sellers, TA, et al, The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer, Ann Intern Med. 1997, 127: 973-980.
21 Meara, ES, et al, Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality, J Natl Cancer Inst. 2001:93:754-762.
22 Garland, C. Nutrition Reviews, August 2007; vol 65: pp S91-S95. National Institutes of Health Office of Dietary Supplements: “Dietary Supplement Fact Sheet: Vitamin D.” Reuters.
23 Garland, C, et al, Vitamin D and prevention of breast cancer: Pooled analysis, The Journal of Steroid Biochemistry and Molecular Biology, Vol 103, pages 708-711.
24 Hall, Linda C, et al, Effects of thyroid hormones on human breast cancer cell proliferation, J. Steroid Biochemistry & Molecular Biology, Vol 109, Mar 2008, Pages 57-66.
25 Lisse JR, Perlman M, Johansson G, Shoemaker JR, Schechtman J, Skalky CS, Dixon ME, Polis AB, Mollen AJ, Geba GP for the ADVANTAGE Study Group. Gastrointestinal Tolerability and Effectiveness of Rofecoxib versus Naproxen in the Treatment of Osteoarthritis: A Randomized, Controlled Trial. Ann Intern Med, Oct 2003; 139: 539 – 546.
26 The Whistleblower: Confessions of a Heathcare Hitman, by Peter Rost, MD, Soft Skull Press(2006).
27 Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib. A case study of industry documents from rofecoxib litigation.JAMA 2008; 299:1800-1812.
28 Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment. A case study based on documents from rofecoxib litigation. JAMA 2008; 299:1813-1817.
29 DeAngelis CD, Fontanarosa PB. Impugning the integrity of medical science the adverse effects of industry influence. JAMA 2008; 299:1833-1835.
33 Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol. Melamed M, Castano E, Notides AC, Sasson S. Mol Endocrinol. 1997 Nov;11(12):1868-78.
34 Prospective study of estrogens during pregnancy and risk of breast cancer, Pentii K. Siiteri, Robert I. Sholtz, Piera M. Cirillo, Richard D. Cohen, Roberta E. Christianson, Barbara J. van den Berg, William R. Hopper, and Barbara A. Cohn, Public Health Institute, U.S. Army Medical Research and Materiel Command under DAMD17-99-1-9358.
38 Yang NC, Jeng KC, Ho WM, Hu ML. ATP depletion is an important factor in DHEA-induced growth inhibition and apoptosis in BV-2 cells. Life Sci. 2002 Mar 15,70(17):1979-88.
39 Schulz S, Klann RC, Schonfeld S, Nyce JW. Mechanisms of cell growth inhibition and cell cycle arrest in human colonic ade- nocarcinoma cells by dehydroepiandros- terone: role of isoprenoid biosynthesis. Cancer Res. 1992 Mar 1;52(5):1372-6.
40 Loria RM. Immune up-regulation and tumor apoptosis by androstene steroids. Steroids. 2002 Nov;67(12):953-66.
41 Aoki K, Nakajima A, Mukasa K, Osawa E, Mori Y, Sekihara H. Prevention of diabetes, hepatic injury, and colon cancer with dehydroepiandrosterone. J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):469- 72.
42 Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma – A longitudinal study, Ritva Heikkilä, Ph.D., Cancer 1999;86:312-5.
43 Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies, Eaton, NE, et al, British Journal of Cancer(1999)80(7), 930-934.
44 Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring, Ernani Luis Rhoden, M.D., and Abraham Morgentaler, M.D., NEJM, Volume 350:482-492, Jan29, 2004.
45 Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis, Edward Mills, et al., Journal of Pineal Research, Volume 39 Issue 4 Page 360-366, November 2005.
46 Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet. 1997 Feb 15;349(9050):458-61.
47 Cowan LD, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol. 1981 Aug;114(2):209-17.
48 Creasman WT. Hormone replacement therapy after cancers. Curr Opin Oncol. 2005 Sep;17(5):493-9.
49 De Vivo I, Huggins GS, Hankinson SE, et al. A functional polymorphism in the promoter of the progesterone receptor gene assiciated with endometrial cancer risk. Proc Natl Acad Sci USA. 2002 Sep 17;99(19):12263-8.
50 Formby B, Wiley TS. Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. Ann Clin Lab Sci. 1998 Nov-Dec;28(6):360-9.
51 La Vecchia C, Brinton LA, McTiernan A. Cancer risk in menopausal women. Best Pract Res Clin Obstet Gynaecol. 2002 Jun;16(3):293-307.
52 Mahavni V, Sood AK. Hormone replacement therapy and cancer risk. Curr Opin Oncol. 2001 Sep;13(5):384-9.
53 Medina RA, Meneses AM, Vera JC, et al. Differential regulation of glucose transporter expression by estrogen and progesterone in Ishikawa endometrial cancer cells. J Endocrinol. 2004 Sep;182(3):467-78.
54 Mohr PE, Wang DY, Gregory WM, Richards MA, Fentiman IS. Serum progesterone and prognosis in operable breast cancer. Br J Cancer. 1996 Jun;73(12):1552-5.
55 Ravn SH, Rosenberg J, Bostofte E. Postmenopausal hormone replacement therapy—clinical implications. Eur J Obstet Gynecol Reprod Biol. 1994 Feb;53(2):81-93.
56 Samsioe G. The endometrium: effects of estrogen and estrogen-progestogen replacement therapy. Int J Fertil Menopausal Stud. 1994;39 Suppl 2:84-92.
57 Southcott BM. Carcinoma of the endometrium. Drugs. 2001;61(10):1395-405.