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Medical Forum / General / General / June 2005Testosterone and Cancer and Cancer Increase
Testosterone and Breast Cancer and Breast Cancer Increase Copyright 2005, James Michael Howard, Fayetteville, Arkansas, U.S.A. I suggest the pattern of cancer incidence reported by Hall, et al., (Urbanization and Breast Cancer Incidence in North Carolina, 1995-1999; Ann Epidemiol. 2005 May 25), that breast cancer may be higher in urban counties and that "These results suggest that there are urban effects that influence the incidence of lung cancer that are not explained entirely by smoking behaviour." (Soc Sci Med. 2005 Jun;60(12):2833-43. Epub 2005 Jan 21) may be explained by testosterone levels. It is my hypothesis (1994) that high testosterone is involved in initiation of female breast cancer, as well as other cancers, male and female, (Annals of Internal Medicine 2005; 142: 471-2). A report comparing rural areas and a large city found that testosterone is higher in the large city (Folia Histochem Cytobiol. 2001;39 Suppl 2:38-9). I suggest the pattern of cancer incidence reported in the article may be due to the effects of higher levels of testosterone in urban populations. Also, it is my hypothesis that the "secular trend," the increase in size and earlier puberty in children is caused by an increase in the percentage of individuals of higher testosterone within populations with time. Therefore, as this percentage increases with time, cancer also increases. > Testosterone and Breast Cancer and Breast Cancer Increase > [quoted text clipped - 11 lines] > rural areas and a large city found that testosterone is higher in the large city > (Folia Histochem Cytobiol. 2001;39 Suppl 2:38-9). > > I suggest the pattern of cancer incidence reported in the article may be due to [quoted text clipped - 3 lines] > testosterone within populations with time. Therefore, as this percentage > increases with time, cancer also increases. Sorry, but testosterone has been shown to prevent breat cancer in a recent article in the Journal of the North American Menopause Society. See the link at: http://www.healthtalk.ca/breast_cancer_risk_09192004_8932.php Also, my recent paper (http://www.tbiomed.com/content/2/1/10) showed conclusively that testosterone kills prostate cancer, and as the recent study on obesity shows, high estrogen and low testosterone levels greatly increase the risk of prostate cancer. Ed Friedman >> Testosterone and Breast Cancer and Breast Cancer Increase >> [quoted text clipped - 31 lines] > >Ed Friedman ' Thank you for the response, Dr. Friedman. Here are some citations of support and my response to your remarks below these: "testosterone might be more strongly associated with [breast cancer] risk than estradiol." (Journal of the National Cancer Institute (U.S.A.) 2002; 94: 606-616). "RESULTS: Increased risks of breast cancer were associated with elevated serum concentrations of testosterone (odds ratio [OR] for highest versus lowest quartile = 1.73, 95% confidence interval [CI] = 1.16 to 2.57; P(trend) = .01), androstenedione (OR for highest versus lowest quartile = 1.56, 95% CI = 1.05 to 2.32; P(trend) = .01), and DHEAS (OR for highest versus lowest quartile = 1.48, 95% CI = 1.02 to 2.14; P(trend) = .10) but not SHBG." (J Natl Cancer Inst. 2005 May 18;97(10):755-65) "CONCLUSIONS: High serum testosterone and advanced education predicted ER+ breast cancer. If confirmed, high testosterone level may be more accurate than family history of breast cancer and other conventional risk factors for identifying older women who are most likely to benefit from antiestrogen chemoprevention." (Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1047-51) "High testosterone predicts breast cancer recurrence. Further studies are required to determine whether dietary or other medical intervention to reduce testosterone can reduce the recurrence of breast cancer." (Int J Cancer. 2005 Jan 20;113(3):499-502) "FT [free testosterone] was significantly associated with BC risk: relative risk (RR; adjusted for age, body mass index and ovarian cycle variables) of highest vs. lowest tertile was 2.85 [95% confidence interval (CI) = 1.11-7.33, p for trend = 0.030]. Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 (95% CI = 0.15-1.08, p for trend = 0.077), significantly so in women with regular menses, where adjusted RR was 0.12 (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of BC in premenopausal women." (Int J Cancer. 2004 Nov 1;112(2):312-8) "The risk of breast cancer was associated with the highest versus lowest quartiles of estrone, OR: 2.58 (1.50-4.44), estradiol (dichotomised: high versus low) (1.73: 1.04-2.88), and testosterone (1.87: 1.08-3.25)." (Cancer Causes Control. 2003 Sep;14(7):599-607) "The estimated relative 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. These results, in general, are consistent with the findings in Caucasian women and indicate that high sex steroid hormones in the circulation, both androgen and estrogen, are associated with increased risk of breast cancer even in populations with relatively low sex hormones." (Int J Cancer. 2003 May 20;105(1):92-7) About your paper: "One model[1] proposes that high levels of androgens are responsible for PCa. This model is unable to explain the fact that androgen levels drop with age while the incidence of PCa increases." It is my hypothesis that low DHEA may trigger cancer. DHEA begins to decline around age 20-25, reaching low levels in old age. Therefore, according to my explanation, cancer should increase with old age. It is also my hypothesis that testosterone and estradiol both reduce levels of DHEA. Hence, HRT and oral contraceptives and testosterone should increase cancer by reducing DHEA. (I am too lazy today to write it all again, please see http://www.anthropogeny.com/HRT%20and%20Breast%20Cancer.htm if you want more detail.) Now, at some point individuals who have a high ratio of testosterone to DHEA may exhibit increase cancer formation. So, when they are in the period of high testosterone, this may trigger cancer and when they are old, their low DHEA may still trigger cancer, even as testosterone declines. It is the low DHEA that may trigger oncogene formation, whether caused by these hormones or old age. Hence, even when testosterone and estradiol are in decline, prostate and breast cancer may sill form because of low DHEA. Now, regarding the link you provided that accessory testosterone may reduce breast cancer, I suggest that DHEA is, again, involved. It is known that cancer occurs more often in old age but grows less rapidly. I suggest this is due to my suggestion that all tissues, including cancer, live on DHEA. As DHEA declines, then cancer cannot grow as well for the same reason that all tissues decline in old age: low DHEA. Given the change in the study you mentioned, that from 380 cancers per 100,000 women to 293 per 100,000 in those who also took testosterone, I may, may now, have an explanation. I have just pointed out that HRT and testoserone both reduce DHEA. If cancer has to "grow" to be detected, I suggest that the numbers of detectable cancers in this group of women "declines" somewhat because the HRT and testosterone both reduce DHEA. The result will be a combined reduction in available DHEA for cancer growth. In the second citation, above, you will note that high DHEAS is connected with increased breast cancer. Well, DHEAS is the source from which DHEA is converted. High DHEAS indicates to me that DHEA is not being made. Therefore, high DHEAS may really mean that DHEA is low. This fits my explanation of the connection of testosterone, and estradiol, with DHEA levels in cancer formation: high testosterone and low DHEA (or high DHEAS) are involved in cancer formation. James Michael Howard Fayetteville, Arkansas, U.S.A. > "FT [free testosterone] was significantly associated with BC risk: relative risk > (RR; adjusted for age, body mass index and ovarian cycle variables) of highest [quoted text clipped - 5 lines] > ovarian hyperandrogenism associated with luteal insufficiency increases the risk > of BC in premenopausal women." (Int J Cancer. 2004 Nov 1;112(2):312-8) James, I'm afraid that it takes a bit of time to digest all that is in my paper, but doing so will help you understand the causes and potential treatment of both prostate cancer(PC) and breast cancer(BC). First, if you concentrate on hormones, you are never going to get any conclusive answers. In PC, there are cell lines that grow more rapidly in the presence of T, and some that are killed by T; there are some that grow more rapidly in the presence of DHT, and some that are killed by DHT; there are some that grow more rapidly in the presence of estradioil(E2), and some that are inhibited by E2. I suspect that the same holds true for progestorone, but I haven't located any such articles. Basically, you have to look at the hormone receptors and not the hormones. In PC, you have membrane androgen receptor (mAR) which produce proteins that induce apoptosis. You also have intracellular androgen receptors (iAR) which protect against these apoptotic proteins (probably through downregulating them, but experiments haven't been done to test this yet). So in strains that are lacking iAR, both T and DHT will kill the PC. For iAR, DHT binds 5 times more strongly than T. In normal cells, apoptosis does not occur because there is enough DHT binding to iAR to offset the apoptotic proteins created by T binding to mAR. For PC, using high doses of T accompanied by 5AR2 inhibitors (to prevent DHT formation) result in apoptosis both in vitro and in vivo. In both PC and BC, the first step is telomere formation, which in both is caused by high levels of E2. Normal prostate cells do not have aromatase(aro) activity, but all PC has aro activity and at the same rate as BC. For PC, in order to evade apoptosis, you need either low levels of T, sufficiently high levels of DHT, or both. Basically, at teenage levels of T and DHT, any PC that arises has a rate of apoptosis that is greater than the rate of growth. At young adult levels of T and DHT, late stage PIN arises in which the rate of apoptosis is exactly the same as the rate of growth. As men continue to age and T levels continue to drop, the rate of growth remains exactly the same as for PIN, but the rate of apoptosis decreases and PC occurs. The reason that higher levels of free T is correlated with a higher occurrence of PC (and presumably for BC as well) is that for the same total levels of T, the higher the amount of free T the more T that will bind to iAR, either as T or as DHT. Before you condemn T for either PC or BC, try to find any indication that anyone with optimal teenage levels of T and DHT have ever come down with either PC or BC. Now all of what I've said above is a proven fact for PC. The case for BC is more circumstantial. It would be trivial to prove that the effect of hormone binding to hormone receptor is identical for both PC and BC, but the key experiments haven't been done yet. However, all known experiments are consistent with the hypothesis that the hormone receptors behave the same for both cancers. Finally, you should check out: http://www.medscape.com/viewarticle/473445_6 in order to see for yourself that T plus 5AR2 inhibitors is by far the most powerful treatment yet discovered for systemic treatment of PC - over 3.83 times more powerful that continuous blockade. Ed Friedman P.S. I do agree with you that low DHEA levels is bad news. It probably leads to increased cancer rates in general due to impairment of the immune system. >> "FT [free testosterone] was significantly associated with BC risk: relative risk >> (RR; adjusted for age, body mass index and ovarian cycle variables) of highest [quoted text clipped - 72 lines] >leads to increased cancer rates in general due to impairment of the >immune system. Well, I will take a look at what you posted. I will get back to this when I can, if I think it is worth a debate. However, for anyone who may be interested in this thread, I am posting my full message, which you deleted above. Thank you for the response, Dr. Friedman. Here are some citations of support and my response to your remarks below these: "testosterone might be more strongly associated with [breast cancer] risk than estradiol." (Journal of the National Cancer Institute (U.S.A.) 2002; 94: 606-616). "RESULTS: Increased risks of breast cancer were associated with elevated serum concentrations of testosterone (odds ratio [OR] for highest versus lowest quartile = 1.73, 95% confidence interval [CI] = 1.16 to 2.57; P(trend) = .01), androstenedione (OR for highest versus lowest quartile = 1.56, 95% CI = 1.05 to 2.32; P(trend) = .01), and DHEAS (OR for highest versus lowest quartile = 1.48, 95% CI = 1.02 to 2.14; P(trend) = .10) but not SHBG." (J Natl Cancer Inst. 2005 May 18;97(10):755-65) "CONCLUSIONS: High serum testosterone and advanced education predicted ER+ breast cancer. If confirmed, high testosterone level may be more accurate than family history of breast cancer and other conventional risk factors for identifying older women who are most likely to benefit from antiestrogen chemoprevention." (Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1047-51) "High testosterone predicts breast cancer recurrence. Further studies are required to determine whether dietary or other medical intervention to reduce testosterone can reduce the recurrence of breast cancer." (Int J Cancer. 2005 Jan 20;113(3):499-502) "FT [free testosterone] was significantly associated with BC risk: relative risk (RR; adjusted for age, body mass index and ovarian cycle variables) of highest vs. lowest tertile was 2.85 [95% confidence interval (CI) = 1.11-7.33, p for trend = 0.030]. Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 (95% CI = 0.15-1.08, p for trend = 0.077), significantly so in women with regular menses, where adjusted RR was 0.12 (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of BC in premenopausal women." (Int J Cancer. 2004 Nov 1;112(2):312-8) "The risk of breast cancer was associated with the highest versus lowest quartiles of estrone, OR: 2.58 (1.50-4.44), estradiol (dichotomised: high versus low) (1.73: 1.04-2.88), and testosterone (1.87: 1.08-3.25)." (Cancer Causes Control. 2003 Sep;14(7):599-607) "The estimated relative 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. These results, in general, are consistent with the findings in Caucasian women and indicate that high sex steroid hormones in the circulation, both androgen and estrogen, are associated with increased risk of breast cancer even in populations with relatively low sex hormones." (Int J Cancer. 2003 May 20;105(1):92-7) About your paper: "One model[1] proposes that high levels of androgens are responsible for PCa. This model is unable to explain the fact that androgen levels drop with age while the incidence of PCa increases." It is my hypothesis that low DHEA may trigger cancer. DHEA begins to decline around age 20-25, reaching low levels in old age. Therefore, according to my explanation, cancer should increase with old age. It is also my hypothesis that testosterone and estradiol both reduce levels of DHEA. Hence, HRT and oral contraceptives and testosterone should increase cancer by reducing DHEA. (I am too lazy today to write it all again, please see http://www.anthropogeny.com/HRT%20and%20Breast%20Cancer.htm if you want more detail.) Now, at some point individuals who have a high ratio of testosterone to DHEA may exhibit increase cancer formation. So, when they are in the period of high testosterone, this may trigger cancer and when they are old, their low DHEA may still trigger cancer, even as testosterone declines. It is the low DHEA that may trigger oncogene formation, whether caused by these hormones or old age. Hence, even when testosterone and estradiol are in decline, prostate and breast cancer may sill form because of low DHEA. Now, regarding the link you provided that accessory testosterone may reduce breast cancer, I suggest that DHEA is, again, involved. It is known that cancer occurs more often in old age but grows less rapidly. I suggest this is due to my suggestion that all tissues, including cancer, live on DHEA. As DHEA declines, then cancer cannot grow as well for the same reason that all tissues decline in old age: low DHEA. Given the change in the study you mentioned, that from 380 cancers per 100,000 women to 293 per 100,000 in those who also took testosterone, I may, may now, have an explanation. I have just pointed out that HRT and testoserone both reduce DHEA. If cancer has to "grow" to be detected, I suggest that the numbers of detectable cancers in this group of women "declines" somewhat because the HRT and testosterone both reduce DHEA. The result will be a combined reduction in available DHEA for cancer growth. In the second citation, above, you will note that high DHEAS is connected with increased breast cancer. Well, DHEAS is the source from which DHEA is converted. High DHEAS indicates to me that DHEA is not being made. Therefore, high DHEAS may really mean that DHEA is low. This fits my explanation of the connection of testosterone, and estradiol, with DHEA levels in cancer formation: high testosterone and low DHEA (or high DHEAS) are involved in cancer formation. James Michael Howard Fayetteville, Arkansas, U.S.A. > Well, I will take a look at what you posted. I will get back to this when I > can, if I think it is worth a debate. However, for anyone who may be interested > in this thread, I am posting my full message, which you deleted above. James, Please let me know if you do find any articles involving hormones and PC which are not explained straightforwardly by my model. It is impossible to read every single article ever published (I certainly haven't), and I would be extremely interested in any findings which seem at odds with my model. Ed Friedman |
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