August 24, 2005
Testosterone Replacement Therapy May Up Prostate Cancer Risk
While the evidence is by no means conclusive a small study of prostate cancer patients suggests that testosterone therapy increases the risk of prostate cancer.
Researchers in the United States say that prostate cancer developed in 20 men within months to a few years after they began testosterone supplementation, to correct a deficiency of the hormone.
Dr. Franklin D. Gaylis from the University of California at San Diego Medical Center, says that there are several anecdotal case reports, small studies, and observational studies such as theirs, that raise concern but do not as yet, provide conclusive evidence.
A major method of treatment for prostate cancer is the use of drugs that knock out the body's production of testosterone. This typically adds a few years to the lives of prostate cancer sufferers until the prostate cancer mutates into a form that is called "hormone refractory" or "androgen independent". At that point the cancer cells no longer need testosterone in order to grow.
That such a large fraction of the men developed prostate cancer in the first year of testosterone use suggests testosterone contributed to the development of prostate cancer.
To describe the characteristics of prostate cancer in men taking testosterone, researchers reviewed 20 cases of prostate cancer that developed among men taking testosterone. A majority of these cancers developed during the first two years on testosterone, and roughly one-third developed in the first year. Prostate cancer was detected by abnormalities in both prostate-specific antigen (PSA) levels and findings on digital-rectal exam (DRE) in 40% of men, by abnormal DRE alone in 35% of men, and by elevated PSA alone in 25% of men.
A lot of old guys have very low testosterone levels.
Testosterone therapy products have been approved by the U.S. Food and Drug Administration for treating a limited number of conditions, particularly hypogonadism associated with low testosterone levels. Hypogonadism occurs in men of various ages, and most clinical studies of the therapy so far have been in younger men. Recent studies have shown that a significant percentage of otherwise healthy older men have testosterone levels consistent with hypogonadism. Data also suggests that low testosterone in elderly men is associated with a loss of lean body mass and muscle strength and increased central body fat. There may also be decreased bone density and mental dysfunction associated with low testosterone levels. For these reasons an increasing number of elderly men are being treated with exogenous testosterone. However, the risks of administering testosterone to elderly men have yet to be defined.
I am skeptical of the notion that hormone replacement therapies can provide net benefit for most aged people. Testosterone is not that hard to synthesize. Therefore its decline may not be due to damage to pathways that make it. The aging body does not lose the ability to synthesize the complex cholesterol molecule from which testosterone gets made Cholesterol is a 4 ringed polycyclic aromatic hydrocarbon with some chains hanging off it. Relatively minor modifications and pruning of those chains (which my aging brain can no longer remember) produce testosterone, estrogen, and the other sex hormones and corticosteroids. Therefore the decline in testosterone in aged men might be a product of evolutionary selective pressures to lower the risk of prostate cancer and possibly to lower the risks of other types of cancers as well.
If we had effective and safe cures for prostate cancer and other cancers that feed off of sex hormones then some of the hormone replacement therapies might provide a net benefit. Also, as genetic screening for cancer risks becomes more advanced then it might turn out that some aging people with the right genetic variations can derive a net benefit from replacement hormone therapies.
This reminds me of the research on thyroid hormone levels and breast cancer. Women with underactive thyroids have less risk of getting breast cancer.
Researchers at The University of Texas M. D. Anderson Cancer Center have found that women with a common thyroid gland disorder appear to have a reduced chance of developing invasive breast cancer, according to a study published in the March 15 issue of Cancer, out online Feb. 14.
In a retrospective case-control study of 2,226 females, researchers found that women with primary hypothyroidism (under-active thyroid) had a 61 percent lower risk of developing invasive breast cancer. Additionally, women newly diagnosed with breast cancer were 57 percent less likely to have the under-active thyroid gland condition compared to a control group of healthy women.
Also, women with underactive thyroids who did get breast cancer got less aggressive forms of breast cancer on average.
"Women with a history of hypothyroidism had many more stage I and II breast cancers and very few stage III diseases," lead researcher Massimo Cristofanilli, MD, tells WebMD. "Overall, their disease was less aggressive." He is with The University of Texas M.D. Anderson Cancer Center.
When our aged cells get run at youthful speed the cells are more likely to spin out of control and go cancerous. We need to repair or replace our old cells so that we can turn up the accelerators on our bodies and function once again at youthful levels. We also need great, fast, safe, and effective cures for cancer and treatments that tell pre-cancerous cells to commit cellular suicide. Cancer is a major obstacle in the way of rejuvenation.
“Therefore the decline in testosterone in aged men might be a product of evolutionary selective pressures to lower the risk of prostate cancer and possibly to lower the risks of other types of cancers as well.”
Since prostate cancer usually affects old men (*) and old men were pre-historically rare, I doubt that low testosterone levels in old age evolved to lower the risk of prostate cancer. Since low testosterone levels should lower mating success, any slight selection pressure in old men should favor higher testosterone levels even if the chance of prostate cancer were elevated.
In my view it is more likely that testosterone patterns in the old aren’t being directly selected. Instead they might result from youthful regulatory genetic scripts that have continued their effects past the main breeding years. Or it might represent a general system failure as the self-regulation of many biological systems begins to fail. Or it might reflect depletion of germ stem cells whose presence triggers sex hormone production. (The comparison with egg cell production in mice is suggestive. http://www.medicalnewstoday.com/medicalnews.php?newsid=28210)
I agree that our body has evolved mechanisms to reduce cancer risk. I suspect that the decline in the immune function is a major factor increasing cancer risk with age.
* “Age is the most common risk factor, with nearly 70 percent of prostate cancer cases occurring in men age 65 and older” http://cis.nci.nih.gov/fact/5_29.htm
The testosterone production decline certainly could have been selected for. Testosterone gradually declines starting from a much younger age. Prostate cancer would probably occur at a much higher rate in middle age without that decline.
The decline is greater in populations which experience higher peaks in their youths.
Check out how constantly testosterone declines:
Unlike the predictable 90% fall in serum oestradiol across the menopause (Burger et al., 2002), testosterone levels in men begin to decline in the late third or early fourth decade and diminish at a constant rate thereafter (Baker et al., 1976b; Leifke et al., 2000; Harman et al., 2001).
Concomitant with the fall in total testosterone is a rise in SHBG levels with ageing (Field et al., 1994; Harman et al., 2001), estimated to be 1·3% per year in a cohort aged 40 years and over (Feldman et al., 2002). As a result of the combined effects of a rise in SHBG and a fall in total testosterone, calculated free testosterone levels decrease by approximately 2-3% per year (Feldman et al., 2002). The relationship between the changes in total testosterone and SHBG is unclear. Excluding obese men, in whom SHBG levels are reduced as a function of adiposity (Field et al., 1994), one group has described a fall in total testosterone from the age of 30 years with SHBG levels rising only from the age of 50 years (Leifke et al., 2000), whereas others have identified an earlier rise in SHBG with total testosterone levels falling only from the age of 55 years (Vermeulen et al., 1996).
The mechanism to cause the decline might be designed to play out over decades to gradually compensate for higher cancer risk due to cell damage accumulation.
“Prostate cancer would probably occur at a much higher rate in middle age without that decline.”
High testosterone seems to aggravate a pre-cancerous condition that is associated with aging. Is there clinical evidence that young men with high testosterone levels have significantly higher cancer rates?
“The decline is greater in populations which experience higher peaks in their youths.”
This result is also consistent with early testosterone peaks leading to earlier depletion of germ stem cells.
“The mechanism to cause the decline might be designed to play out over decades to gradually compensate for higher cancer risk due to cell damage accumulation.”
DHEA levels also closely tracks biological age. As does immune system function. Both could track diminishing stem cell regenerative capabilities or could track failing system regulation as important cell systems accumulate damage at a regular rate.
I do believe that cancer prevention has been an important selective force in human evolution. I just doubt that lowered testosterone levels in older men increase fitness.
“I just doubt that lowered testosterone levels in older men increase fitness.”
I should have said: “evolutionary fitness”.
Men who are alpha male testoterone jugheads do in their late years develop BPH (which is really ultra-low grade cancer and should be called such but isn't) and prostate cancer at higher rates.
DHEA, 7-keto DHEA etc supplementation is a near-endless stream of good news. I don't know why there is continued pushes towards testosterone replacement in the face of both the DHEA angle as well as the healthiest way to do all this: L-arginine coupled to squats coupled to mild aerobic activity. The growth hormone pulses released go a long way towards maintaining on a non-hypo-gonadotropic environs. And then there are the sexual benefits. ;)
And yep, there are few "evolutionary selective pressures" on old age males, which is a phenomenon only of the last couple millenia. Remember the Darwinian adage -- reproduce and die. We are living long after our geological-time reproductive windows puberty-30 yrs of age. It's a fortuitous accident that the system behaves as well as it does in old age males.
As regards selective pressure in old age: Most humans who didn't make it to old age died when they were quite young: i.e. before reproducing. The argument that we've raised average age just lately misses this point. Plenty of those who made it into their 20s lived into their 50s and 60s. They'd managed to fight off the pathogens that killed the young. Their immune systems had enough resistance to fight off more pathogens. Therefore they tended to die of the same deteriorations that we die from now.
Also, the ability to continue to live after one's offspring themselves reproduced had selective advantage. I saw a study a couple of years ago (sorry, no URL) done with records from Finland or Sweden back in the 1500s and/or 1600s that found women who had surviving mothers had more of their progeny survive than women who did not have mothers still alive when their children were growing up. So grandmas increase reproductive fitness. It is easy to see why. They can care for the kids while mom works in fields or does other work.
Randall, I agree, but neither here nor there. My point:
Geologically/evolutionarily speaking civilization is a recent thing. About 8K years. In a civilization, if infectious disease doesn't kill you may live to old age. Granted. Prior to that, for uncountable millenia, (a) humans were on the verge of extinction and (b) died young barely managing to reproduce. So there were no significant numbers of old folks. Hence no such thing as selective pressures in old age let alone mechanisms at work regarding prostate cancer. As for the rest, I don't think anything significant happened to the species over the last 8K years.
Which is why I also agree with you on grandmothers. The rise of grandmothers is simultaneous with the rise of civilizations. In fact, the more important role of grandmothers is that they allowed for the accumulation of knowledge in the tribe that eventually gave us enough of a bundle of knowledge and survival time to make the kernels of what became civilizations.
This now begs the question -- what changed so that grandma's showed up in numbers enough to seriously deflect the survival pattern of the species?
A few points:
1) First off, 1000 years is a long time in human evolutionary history. For example, Henry Harpending and Greg Cochran argue that Ashkenazi Jewish higher IQ was selected for between 800 AD and 1600 AD. I happen to think that Henry and Greg are right on this.
2) Dog breeds take about the same number of genetic markers to tell them apart as human races do. Well, dog breeds are, in many cases, just a few hundred years old or less.
3) Russian fox breeders accidentally bred domesticated foxes in about 50 years time. They were just selecting for foxes less likely to bite when their cages were opened for feeding. The result is foxes that act like dogs.
4) In some parts of Africa people live little changed from thousands of years ago. Yet they have plenty of grandmothers. So I don't buy the argument that the survival of grandmothers was a relatively recent thing.
How about Human Growth Hormone taken as food supplement. It is written that this is a very helpful drug, but what are the dangers of taking HGH?
I read your post on Hormone replacement cancer risks with some personal interest as I do supplement my own testosterone and Thyroid. I have followed both sides of the debate for 5 or 6 years. The data on testosterone is quite mixed. It is hard to get to the truth of the matter as for many people there is a philisophical component to the debate. There is great resistance to the whole idea of "rejuvenation" therapy, or even the idea of using supplements. In the article on testosterone you linked, they did not give any information on the number of men who received T therapy and did not get cancer (no control group). It seems to be the case that testosterone, Estrogen ect. are accelerators of existing cancer, but are not mutagenic. At any rate, every time I read these negative articles there seems to be an underlying theme of let nature take it's course (If you do anything to improve your life now you will certainly pay later). It looks like people almost want to find a negative result.
My great-great-grandfather, Alexander, had 28 (acknowledged) children siring the youngest when he was in his 70's. I respectfully suggest that declining testosterone levels with aging might increase the reproductive fitness of established alpha males. Had prostate cancer struck Alexander down at 50, he would have impregnated significantly fewer women and would have had significantly fewer children.
I fail to see how you arrive at your conclusion that humans died young throughout our evolution. The stone aged tribes of north america had plenty of old people when the europeans arrived just a few hundred years ago with many tribes having a cultural reverence for the aged.
What is the success rate of replacemetent therapy?