Role of Estrogen
Estrogen is a cell growth promoter that has been implicated in the development of prostate cancer.25,26
Life Extension members have long been urged to keep estradiol (an estrogen) levels in the range of 18-30 pg/mL, yet many aging men present with estradiol levels around 40 pg/mL or higher, which markedly increase all-cause mortality.27
In a published analysis of the Proscar® study, scientists looked at levels of various sex hormones beyond just DHT. They found that men with the highest pre-treatment concentrations of testosterone were associated with a 36% reduced rate of prostate cancer when taking Proscar®.28 These same scientists also noted men with the highest level of estrone (an estrogen) had a 38% higher risk when taking Proscar®.28
This study supports the theory that when prostate cancer cells are deprived of a primary growth factor like DHT, they may readily adapt to utilizing estrogen to fuel propagation.28 The doctors who conducted this study concluded:
Further research is needed to evaluate whether “low post-treatment serum estrogens may identify men more likely to benefit from the use of finasteride to prevent prostate cancer.” 28
Life Extension’s long-standing position has been for aging men to have their estrogen blood level tested and if it is elevated, initiate aromatase-inhibiting therapy to suppress estrogen to safe ranges. This may be of particular importance for men seeking to impede or reverse the course of prostate cancer. It also helps explain why some men taking Proscar® developed prostate cancer despite suppressing their DHT level.
The Proscar® (Finasteride) Studies
The Prostate Cancer Prevention Trial (PCPT) was a large-scale, long-term randomized, placebo-controlled study designed to evaluate if Proscar® (finasteride) could reduce risk of prostate cancer.14
Participants in this PCPT study were all aged 55 years or older and had baseline PSA levels less than or equal to 3 ng/mL. One group received 5 mg/ day of finasteride and the other a placebo.3
This study was initiated based on multiple lines of evidence available in the early 1990s that suggested that treatment with finasteride (Proscar®) would reduce a man’s risk of developing prostate cancer. Finasteride functions to inhibit the 5-alpha-reductase enzyme, which then lowers dihydrotestosterone (DHT) levels.21
The plan was to evaluate the prevalence of prostate cancer in each group (finasteride and placebo) during the 7-year trial. About 15 months before the trial was scheduled to end, however, it was terminated because it had already met its primary objective.14
The PCPT study demonstrated a 24.8% reduction in the prevalence of prostate cancer with finasteride treatment. An unanticipated finding, however, was that cancers with a high-grade Gleason score of 7-10 were more common in men treated with finasteride (6.4%) than in men treated with placebo (5.1%).21
To put these percentages of high-grade Gleason scores into perspective, they suggest that if all 18,882 men who entered the trial were given the placebo, 963 of them would have been diagnosed with high-grade disease. If all 18,882 men had taken finasteride, 1,208 men would have been diagnosed with high-grade disease. The difference is 245 more men being diagnosed with high-grade disease based on this assumption.
Of these 18,882 men, however, 4,323 would have contracted any grade of prostate cancer if all were given placebo based upon the results of the study, whereas only 3,134 would have contracted any grade of prostate cancer if all were given finasteride.21 That’s a difference of 1,189 men who would have avoided prostate cancer altogether during the study trial period if they all took finasteride.
We at Life Extension are well aware that high-grade prostate cancer grows faster and is more likely to spread beyond the prostate gland.6 Depending on your long-term longevity objectives, however, the data showing 1,189 fewer men developing any form of prostate cancer compared to 245 more men being diagnosed with high-grade disease might favor the finasteride group. And as you’ve read already, it was much easier to detect prostate cancer in men taking finasteride, meaning that the drug itself should not be blamed for the higher rate of diagnosis.21
As we’ve shown, there appears to be no increase in high-grade disease in men taking finasteride, just higher rates of biopsy detection based on smaller size prostate volume, along with misinterpreted pathologies of biopsies that later showed 27% fewer high-grade cases in men taking finasteride based on examination of surgically-removed prostate glands.14
The Avodart® (Dutasteride) Study
A study involving over 8,000 men was initiated to ascertain if Avodart® (dutasteride) could reduce prostate cancer risk over a 4-year period.4 The criteria to participate in this trial were:
- Age between 50 and 75 years
- PSA level of 2.5 to 10 ng/mL
- A single pre-study negative needle biopsy of the prostate
- A prostate volume ≤ 80 mL
Patients were randomized to receive 0.5 mg of Avodart® daily or placebo. All patients received 10-core prostate biopsies at baseline and 10-core prostate biopsies at 2 years and at 4 years after study enrollment.4
Here are summary results of the trial:4
- The mean age of the men enrolled was 63 years in each arm.
- The mean PSA level of the patients in each arm at baseline was 5.9 ng/mL.
- Avodart® reduced the risk of prostate cancer by 22.8% compared to placebo over the 4 years of the study.
- Avodart® reduced the rate of acute urinary retention by 77.3% compared with placebo.
- The Avodart® group showed a 33% increase in high-grade (8-10) Gleason scores 0.9% for Avodart® compared to 0.6% for placebo.
The higher number of high-grade Gleason scores in the Avodart® group can be attributed to the same factors identified in the finasteride (PCPT) study, such as higher rates of biopsy detection based on smaller prostate gland size in men taking Avodart®, along with biopsy bias based on collapsing prostate glands that may have made some tumors appear higher-grade than they really were.4
The FDA’s response, however, was to issue a label change for Avodart® and Proscar® to warn of the increased risk of being diagnosed with a higher-grade prostate cancer while taking these drugs.29 This warning provides little benefit to aging men who are routinely prescribed these drugs to treat benign prostate hyperplasia. It creates confusion as patients query their doctor as to why a drug that FDA says is potentially dangerous is being prescribed to them.
In 2012, the results of another study (Lancet) were released showing that Avodart® was effective in slowing the progression of low-grade prostate tumors in 38% of men undergoing active surveillance (watchful waiting).30 This study of 302 men diagnosed with low-grade prostate cancer used 12-core biopsies obtained at 1.5 and 3 years. This Lancet study showed there to be slightly fewer (14%) higher-grade tumors in the Avodart group compared to placebo (16%).30
A study published in May 2013 evaluated 82 men with very low-risk prostate cancer who underwent active surveillance (watchful waiting) and were treated with a 5-alpha reductase inhibitor drug over a 3-year period. The results demonstrated the safety of the drugs and noted that at the first re-staging biopsy, 54% of the subjects no longer had prostate cancer.31 This small study helps substantiate the value of Avodart® or Proscar® for low-risk prostate cancer patients, but is not relevant to those with high-grade tumors that often require aggressive treatment.
We Must Avoid A “Tomato Effect”
“The Tomato Effect” was first described in the Journal of the American Medical Association in 1984.33 It analogized how doctors historically have ignored or rejected efficacious treatments that did not fit with accepted theories of disease prevention/treatment at the time.
“The Tomato Effect” is named for a period from the 1600s to early 1800s in America where tomatoes were considered poisonous and therefore unsafe to eat. This fear persisted despite the fact that Americans knew Europeans were regularly eating tomatoes with no ill effects.
The perception of the tomato changed in 1820 when a man ate a tomato on the steps of a New Jersey courthouse to prove they are safe.33 Within a decade, Americans were regularly eating tomatoes that for over 200 years were considered poisonous.
In today’s world, we have an opposite problem that nonetheless can create a lethal “tomato effect” when it comes to rejecting lifesaving therapies. Physicians and patients are overloaded with information and lack the time to analyze data to accurately determine safety and efficacy.
Humans have a strong propensity to remember negative details. This human failing has caused many physicians and patients to reject 5-alpha reductase inhibitors because they recall something about more high-grade prostate tumors in men taking Proscar® or Avodart®. Never mind hard facts showing the opposite. People today want a succinct summary, a curbside explanation, and not too many distracting details.
As we have repeatedly shown in this article, what appeared to be more high-grade tumors in two studies of Proscar® and Avodart® were apparently based on a mistaken interpretation of the data.
In the haste of today’s busy medical practices, we are concerned that huge numbers of men who could benefit enormously from 5-alpha reductase inhibitors will not be prescribed them. We hope Life Extension members appreciate the effort we have made to analyze the data so that they can make rational choices when confronted with real or potential low-grade prostate cancer.