HRT and Breast Cancer

How "Hormone Replacement Therapy" may Cause Breast Cancer

(NEW SUPPORT added below)

SUMMARY: Sent to many recipients beginning August 14, 2003:

"Support for a Hypothetical Mechanism of Cancer that may Explain Increase in Breast Cancer Caused by HRT (Hormone Replacement Therapy)

April 11, 1994, I published my hypothetical explanation of how breast cancer is activated by a combination of low dehydroepiandrosterone (DHEA) and high testosterone (The Morning News of Northwest Arkansas, March 14, 1994, page 4A; three major journals rejected my idea in 1994). The two requirements of the mechanism have since been supported. One of these directly connects my mechanism to the increase in breast cancer recently attributed to HRT.

As of April, 1994, low DHEA and high testosterone were already known to occur frequently in breast cancer, but no one else had suggested these characteristics are part of a mechanism of breast cancer. My mechanism has since been supported. "…testosterone might be more strongly associated with [breast cancer] risk than estradiol." (Journal of the National Cancer Institute 2002; 94: 606-616), and it was found that DHEA is lower in women born in the West (British Journal of Cancer 2002; 87: 54-60). Breast cancer is higher in women in the West.

HRT further decreases DHEA. "DHEA levels showed a progressive decline starting from the 3-month follow-up, without significant differences between the transdermal and oral groups, as well as among the ten groups, independently of the presence and type of progestin molecule used." (Gynecological Endocrinology 2003; 17: 65-77). I suggest HRT increases the incidence of breast cancer in women of low DHEA by further reducing DHEA.

My mechanism of breast cancer remains intact, is supported by current research, and continues to provide a basis of current findings in breast cancer epidemiology."

How "Hormone Replacement Therapy" may Cause Breast Cancer

An Update and Further Confirmation of a Potential Explanation of Breast Cancer: The Connection of Testosterone in Female Breast Cancer and the Connection of Low DHEA in Breast Cancer Associated with HRT

In 1994 I developed an explanation of breast cancer which may also explain other cancers. This explanation has since been supported and may explain why hormone replacement therapy in women may cause breast cancer. It is easiest to demonstrate in breast cancer.

Basically my explanation suggests that levels of dehydroepiandrosterone (DHEA) are directly connected with growth and differentiation of all tissues. My principal hypothesis is DHEA was selected by evolution because it opitimizes replication and transcription of DNA by participating in strand separation. Very briefly here is the mechanism. When DHEA is high it participates in intensive cellular divisions, that is, the intensive replication of DNA. As cell mass increases (within the zygote and later), the ratio of DHEA to DNA is reduced. As growth continues, the ratio of DHEA to cell mass continues to decrease.

As the DHEA to cell mass ratio declines, growth declines and differential gene activation (transcription) begins. This occurs because DNA is not homogeneous. Different genes compete for available DHEA. Since some genes are able to "open" more easily than others, the levels of available DHEA will help activate some genes before others. (As DHEA availability declines, genes that require less DHEA are opened while those requiring more DHEA are not.) I suggest this is how differential transcription evolved and eventually resulted in multicellular organisms. This mechanism resulted in tissue formation. A continuum exists in which growth is gradually slowed as tissue formation continues. As tissues form, DHEA availability is reduced by use of an entire organism and cellular surface area declines in cells united in tissues. This maintains the differentiated, or "adult" form until the decline of DHEA of old age cannot maintain this state.

Oncogenes are genes that function inappropriately. I suggest they function appropriately during a time of high DHEA as they are involved in DNA replication. As DHEA begins to normally decline during old age, there is less DHEA to maintain the differentiated state. Specifically, I suggest a major aspect of the differentiated state is the maintenance of tight cell to cell contact. These are the adhesion molecules that hold tissues together. (This may have been an evolutionary mechanism which produced multicellularity and, eventually, resulted in differential gene activation within cells in different locations within simple multicellular organisms.) Anyway, cell adhesion molecules may have been part of the beginnings of multicellularity and tissues so they may have evolved early, during a time in evolution when the DHEA to cell mass ratio was high. I suggest cell adhesion "genes" require high levels of DHEA. Cells stick together before they make tissue specific proteins. (Multicellular organisms evolved before organisms with tissues.) My point is that our tissues stick together but must still have a certain amount of DHEA to keep our bodies together. (This may explain the degeneration of our bodies as DHEA naturally begins to decline during old age; as we loose DHEA we simply "fall apart.")

As DHEA begins to decline at the beginning of old age, some cells may not absorb sufficient DHEA to maintain their adhesions. Some cells may simply slough away because of this; the wasting of old age. However, this exposes other cells and expands their surface areas which may increase absorption of DHEA. I suggest some of these cells contain genes of cell duplication which are triggered by this increase in DHEA. This may be "normal, dormant" genes which simply were restrained by lack of surface area sufficient to absorb enough DHEA, damaged genes, etc. which are oncogenes. This activation of these genes during old age would explain why cancers are more common in the elderly but grow less rapidly. The reduction in DHEA exposes these oncogenes but there is less DHEA to activate cell replication.

In 1994, I had developed hypotheses regarding the interaction of testosterone and DHEA. I think DHEA evolved before testosterone. I suggest testosterone evolved as a "director" of DHEA use. That is, testosterone increases gene activation of tissues by causing cells to utilize more DHEA. Hence, testosterone increases growth of tissues which absorb more testosterone. (Males are bigger because they produce more testosterone.) This use of DHEA by "testosterone target tissues" causes a competition. Testosterone target tissues will absorb more DHEA and, therefore, will reduce the availability of DHEA. Testosterone, I suggested, causes a reduction in DHEA availability which may trigger oncogenes when DHEA declines. I suggested, therefore, that low DHEA and high testosterone may trigger oncogenes because of the mechanism stated above, even in breast cancer. I came to this decision because I think increased testosterone is driving the secular trend and I think the secular trend is generating the increase in breast cancer. In 2002 and 2003, my connection of testosterone with breast cancer was supported: "testosterone might be more strongly associated with [breast cancer] risk than estradiol" (Journal of the National Cancer Institute 2002; 94: 606-616). "The estimated relative [breast cancer] risks between upper and lower tertiles were 2.07 (95% confidence interval [CI] 0.97-4.41) for estrone in postmenopausal women, 2.01 (95% CI 0.96-4.21) for testosterone in premenopausal women, and 2.40 (95% CI 1.11-5.21) for testosterone in postmenopausal women, after adjusting for age at first live birth, waist-to-hip ratio, total calorie intake, a history of fibroadenoma, a family history of breast cancer and SHBG." (International Journal of Cancer 2003; 105: 92-7).

After I found this was supported, I took another look at hormone replacement therapy (HRT). Until just recently, I assumed that HRT produced beneficial effects because of a similar mechanism between testosterone and estradiol and progestin. I think in women who can produce sufficient DHEA, the HRT revives the DNA of the target tissues by increasing use of DHEA. That is, I assumed these hormones also evolved to direct the use of DHEA in tissues. When HRT is given to women of low enough DHEA, these hormones should produce the same reduction in DHEA availability and trigger oncogenes, if they exist within the woman. The key to the activation of oncogenes in these women is a reduction in DHEA following HRT. This was supported in 2003: "DHEA levels showed a progressive decline starting from the 3-month follow-up, without significant differences between the transdermal and oral groups, as well as among the ten groups, independently of the presence and type of progestin molecule used." (Gynecological Endocrinology 2003; 17: 65-77) I suggest women who exhibit this phenomenon may be low DHEA throughout their lives, or have experienced some event which lowered their DHEA, and increased the probability of low DHEA exposing an oncogene. When HRT is used late in life, I suggest this produces a further decline in DHEA which may expose oncogenes earlier than would have have occurred in the life span.

NEW SUPPORT

Added August 18, 2003: More potential support that HRT reduces DHEA and produces consequences of lower DHEA:

J Neurol Sci. 1999; 169(1-2):126-7.

Estrogen replacement therapy in women with amyotrophic lateral sclerosis.

"Amyotrophic Lateral Sclerosis (ALS) occurs more commonly in men than in women, and women get the disease later in life compared to men. This epidemiologic aspect of the disease raises the question as to whether estrogen may be neuroprotective in delaying or preventing ALS. Postmenopausal women with ALS were separated into two groups dependent upon whether or not they took estrogen replacement therapy. Women who used estrogen had onset of their disease at an earlier age compared to those not taking hormonal replacement. There was no difference in survival in those patients taking estrogen compared to those not on the medication. Women with ALS were more likely to take estrogen compared to a control group of patients with neurological diseases other than motor neuron disease. Therefore, no evidence for a neuroprotective role of estrogen in postmenopausal women with ALS was found."

"DHEA deficiency is found in many people, including those with ALS. Several physicians have reported "dramatic improvements" in neurological symptoms in patients treated with DHEA." (http://www.cancer-treatment-centers.com/als-2.htm)

In this case, Dr. Rudnicki found that estrogen replacement therapy in postmenopausal women "had onset of their disease [ALS] at an earlier age compared to those not taking hormonal replacement." With the statement just above in mind that DHEA is deflicent in ALS, I suggest this is the same phenomenon I explained for HRT and breast cancer. This is further support and I suspect I will find other diseases, involving low DHEA, affected the same way by HRT

Added September 10, 2003: More potential support that HRT reduces DHEA and produces consequences of lower DHEA:

Metabolism 2001; 50(4): 488-93

Effect of estrogen on serum DHEA in younger and older women and the relationship of DHEA to adiposity and gender.

"This case-controlled study consisted of 2 parts. The objective of part 1 was to determine the relationship between DHEA, body mass index (BMI), and age in young males, young females, and postmenopausal (PM) females. Part 2 examined the effects of estrogen on DHEA by analyzing the relationship between DHEA and age in young females on and off oral contraceptives (OCs) and PM females on and off estrogen or hormone replacement therapy (ERT/HRT). The study was performed at the Obstetrics and Gynecology Clinic, Texas Tech Health Sciences Center-Amarillo, Exercise Physiology Laboratory at Southeastern Louisiana University, and Woman's Health Research Institute, Woman's Hospital, Baton Rouge, LA. Part 1 groups consisted of: (1) young males between the ages of 18 to 40 years; (2) normally cycling females off OCs, ages 18 to 40 years; and (3) PM females older than 40 years not receiving ERT/HRT. Part 2 groups consisted of: (1) normally cycling females on OCs, ages 18 to 40 years;, (2) normally cycling females off OCs, ages 18 to 40 years; (3) PM females 50 years or older not receiving ERT/HRT; and (4) PM females 50 years or older receiving ERT/HRT. The main outcome measure was serum DHEA concentrations. For part 1, there were significant (P <.05) inverse relationships between DHEA and age for young males; young females, off OCs; PM females, no ERT/HRT r = -.44, -.26, and -.25, respectively. There were no significant relationships between DHEA and BMI for any of the groups. DHEA concentrations were significantly higher in young males than young females even after accounting for age. For part 2, DHEA concentrations were significantly higher in young females off OCs compared with young females on OCs, and significantly higher in PM women off ERT/HRT than those on ERT\HRT. There were significant inverse relationships between DHEA and age for young females and PM females on and off ERT/HRT. From these findings, we conclude that there is an inverse relationship between DHEA and age for young males, young females off OCs, and PM females, no ERT/HRT. No relationship between BMI and DHEA was observed in these same 3 groups. These results agree with previous findings in young men, but differ from previous findings in obese young females. The data also suggest that estrogen treatment (OCs and ERT/HRT) suppresses DHEA concentrations in premenopausal and PM females, and that DHEA declines with age in PM females regardless of estrogen treatment. Copyright 2001 by W.B. Saunders Company"

(How the sex hormones produce different anatomical structures from the same tissues: I suggest estradiol and testosterone direct the use of DHEA in different levels so these two hormones cause differences in cell differentiation and tissue formation. Back to my basic explanation, different levels of DHEA will cause different genes to express themselves, hence, some tissues become "female" and others "male.")