The anticancer testosterone metabolite 3[beta] - Adiol.
Testosterone (Health aspects)
Testosterone (Physiological aspects)
Metabolites (Health aspects)
Finasteride (Dosage and administration)
Finasteride (Complications and side effects)
|Author:||Wright, Jonathan V.|
|Publication:||Name: Townsend Letter Publisher: The Townsend Letter Group Audience: General; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 The Townsend Letter Group ISSN: 1940-5464|
|Issue:||Date: July, 2012 Source Volume: 348|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
Age-related decline of testosterone in men is often seen as part of
the "normal" aging process. Why, then, does the risk of
prostate cancer increase with age? We could blame it on declining
hormones, but not all men with declining (or elevated, for that matter)
hormones get prostate cancer. For a long time, male hormone testing has
been centered on testing only testosterone and sometimes (more
frequently lately) free testosterone. One heavily researched area is the
effect of dihydrotestosterone (DHT) on the prostate. But is testing DHT
enough? The short answer: No.
Much of the DHT research has been associated with the patent medicine finasteride (Proscar, Propecia) and other related patent medicines. Finasteride greatly slows the metabolism of testosterone into the more potent (and more carcinogenic) metabolite DHT. (For the technically inclined, finasteride is a 5-alpha reductase inhibitor.)
Since DHT is generally agreed to be carcinogenic, the thought was that reducing the transformation of testosterone into DHT would reduce cancer risk. In the Prostate Cancer Prevention Trial (PCPT), 18,882 men over age 55 years with normal prostate examinations and a PSA below 3.0 were randomly assigned finasteride or placebo for seven years. (1)
Slightly Lower Cancer Risk, Much Higher Killer Cancer Risk
The results were a surprise to the researchers, who found--as they expected--a lower rate of cancer in the finasteride group than in the placebo group (18.4% versus 24.4%). What surprised them was the considerably higher number of significantly aggressive cancers--for the technically inclined, higher Gleason scores--among those in the finasteride group with cancer versus those with cancer in the placebo group (37% versus 22.3%).
That's why you never saw a television commercial about finasteride preventing prostate cancer. To be accurate it would have to say, "Take finasteride! It lowers your risk of prostate cancer, but if you do get prostate cancer, you're more likely to die of it!"
The PCPT researchers concluded, "finasteride prevents or delays the appearance of prostate cancer, but this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer."
A separate meta-analysis published as a Cochrane Review found that 5 [alpha] -reductase inhibitors, including finasteride, have inadequate evidence to say that these patent medicines reduce mortality, in terms of prostate cancer. (2)
It's true that if DHT alone is considered, elevated levels of DHT might be thought to increase your prostate cancer risk, as DHT is a procarcinogenic (for the technically inclined, dedifferentiating) metabolite. (3), (4)
But Nature hasn't provided DHT alone! If we take the metabolites of DHT into consideration, too, elevated DHT may or may not have this effect. One of these metabolites may actually offset or even reduce any DHT-increased risk. How does that happen?
After testosterone is converted to DHT, DHT is in turn normally metabolized into a relatively smaller quantity of 5 [alpha] -androstane-3 [alpha], 17 [beta] -diol (abbreviated as 3 [alpha] -Adiol), and a usually larger amount of 5 [alpha] -androstane-3 [beta], 17 [beta] -diol (abbreviated as 3 [beta] -Adiol). These same researchers also report that while nearly all the 3 [alpha] -Adiol is converted back to DHT (which presumably makes 3 [alpha] -Adiol a "pre-procarcinogen"), the 3 [beta] -Adiol does not convert back to 5 [alpha] -DHT. Very importantly, they report that 3 [beta] -Adiol is an anticarcinogen (for the technically inclined, a redifferentiating agent) that activates estrogen receptor beta, an anticarcinogenic estrogen receptor present in large numbers in the prostate gland. (5) (Estrogen receptor beta is present in many other tissues in both sexes, but that's a topic to be explored at another time.)
What's that? A testosterone metabolite that activates an estrogen receptor? A testosterone metabolite that doesn't activate any androgen receptors at all? That's right, and (very unfortunately for the men involved) my observation has been that many men who take finasteride to suppress procarcinogenic DHT end up suppressing their own anticarcinogenic 3 [beta] -Adiol even more, thus shifting the procarcinogen (DHT) to anticarcinogen (3 [beta] -Adiol) ratio toward a greater risk of cancer. I've also seen this occasionally with high doses of saw palmetto.
In a letter to the editor of the New England Journal of Medicine, Otabek Imamov, MD, et al. state, "[DHT] is the fulcrum in this balance. It suggests that finasteride, by blocking the conversion of testosterone to [DHT], inhibits the production of [3 [beta] -Adiol] thus suppressing [the anticarcinogenic activity of] ER [beta] and preventing the [re]-differentiation of epithelium. This mechanism could account for the higher incidence of poorly differentiated tumors in the finasteride group in the Prostate Cancer Prevention Trial." (6)
A review in the Biology of Reproduction Journal states, "We believe that a higher incidence of low-differentiated [more aggressive] tumors in the finasteride-treated arm observed in the PCPT is caused by altering the normal differentiation of prostatic epithelium in the environment lacking the natural ER [beta] ligand--[3 [beta] -Adiol]." (7)
Research has found some very specific things that 3 [beta] -Adiol does to inhibit prostate cancer growth. According to the title of a 2005 research report: "The androgen derivative 5a-androstane-3b, 17b-diol [3 [beta] -Adiol] inhibits prostate cancer cell migration through activation of the estrogen receptor beta subtype." (8) Other researchers reported that "3b-Adiol not only inhibits PC3-Luc cell [a specific type of prostate cancer cell] migratory properties, but also induces a broader antitumor phenotype [type of cell] by decreasing the proliferation [growth] rate, increasing cell adhesion [cancer cells don't "stick" as normal cells do] and reducing invasive capabilities in vitro." (9) But these researchers went beyond test-tubes to living mice, writing "In vivo, continuous administration of 3 [beta] -Adiol reduces growth of established tumors and counteracts metastasis formation when PC3-Luc cells are engrafted subcutaneously in nude mice or are injected into the prostate."
The conclusion to this research article was very encouraging: "Since 3 [beta] -Adiol has no androgenic activity, and cannot be converted to androgenic compounds, the effects here described entail a novel potential application of this agent against human PC." (9) A novel potential application of 3 [beta] -Adiol, a totally natural human testosterone, against human prostate cancer! Where are the headlines? This article was published in 2010!
For the really technically inclined, here are several "mechanisms of action" of 3 [beta] -Adiol, all of which come from stimulation of estrogen receptor beta:
* repression of VEGF-A (vascular endothelial growth factor A) expression
* destabilization of HIF-1a (hypoxia-inducible factor 1a)
* reduction of "Snaill" (can't identify this acronym) relocation from the cytoplasm to the nucleus of cancer cells
According to the researchers who published the above mechanisms of action, "... high Gleason grade cancers ... exhibit significantly more HIF-1a and VEGF-A and Snaill nuclear localization compared to low Gleason grade cancers." (10)
Procarcinogenic and Anticarcinogenic Metabolites
The testosterone [right arrow] DHT [right arrow] 3 [beta] -Adiol metabolic pathway is very similar in its pro-and anticancer effects to the estrogen metabolic pathway estrone (E1) [right arrow] 16 [alpha] -hydroxyestrone (16 [alpha] -OHE1) [right arrow] estriol (E3). While 16 [alpha] -OHE1 has a "good side" and helps protect against osteoporosis, its bad side is that too much 16-OHE1 increases breast and prostate cancer risk. (11-14) But like DHT, which also increases cancer risk, 16 [alpha] -OHE1 is transformed into the anticarcinogenic "good-guy" (more precisely, "good-girl") estriol. Just as we want to promote the formation of more estriol to "tilt" the balance of a woman's estrogens in an anticarcinogenic direction, we want to make sure that 3 [beta] -Adiol is more abundant than DHT, to "tilt" the balance of a man's androgens in an anticarcinogenic direction.
Until the recent research about 3 [beta] -Adiol became available, when physicians saw an elevated DHT test, they frequently recommended reducing the man's testosterone dose--even if he didn't feel as well with that lower dose--because of understandable concern about higher cancer risk. There has been no test for 3 [beta] -Adiol, no way for men using testosterone replacement or the physicians prescribing it to assess the pro-and anticarcinogenic balance of major testosterone metabolites.
The Test That Could Save Your Life
Now that test is available. Thanks to the work of Dawn Huo, PhD, at Meridian Valley Laboratory, you or your physician can request a blood test for testosterone, DHT, 3 [alpha] -Adiol, and 3 [beta] -Adiol (full name: 5 [alpha] -androstane-3 [beta], 17 [beta] -diol), check the relative proportions of each, and have a more clear idea about your cancer risk. Termed "testosterone metabolites," this blood serum test also measures androstenedione (spelled almost but not quite exactly the same way as "androstanediol"), another androgen metabolite, and 3 [alpha] -Adiol (full name: 5 [alpha] -androstane-3 [alpha], 17 [beta] -diol. (Extensive quality control testing by Dr. Huo has shown that presently available tests for urine DHT are far less accurate than serum DHT.)
Remember, both 3 [beta] -Adiol and 3 [alpha] -Adiol are metabolites of DHT, but researchers have found that almost all 3 [alpha] -Adiol turns back into DHT (thus making it a procarcinogenic precursor), while none of the 3 [beta] -Adiol--which stimulates estrogen receptor beta (ER [beta]), and is entirely anticarcinogenic--can "back-metabolize" into DHT again. (6)
Theoretically, if a man's 3 [beta] -Adiol level is greater than the sum of his DHT plus 3 [alpha] -Adiol (3 [beta] -Adiol > DHT + 3 [alpha] -Adiol), his "testosterone metabolite ratio" should be anticarcinogenic. Please keep in mind that at this time, the testosterone metabolite ratio is theoretical, supported by inference from considerable scientific research, but not absolutely proven. Unlike the 2-hydroxyestrogen/16 [alpha]- hydroxyestrogen ratio ("2/16" ratio), which has been proved to predict lower and higher cancer risk in premenopausal women, or the estrogen quotient (EQ), the testosterone metabolite ratio has not yet been studied in groups of men over time, which is necessary to absolutely prove a theory.
Over the years, I've had occasion to observe the multiple adverse effects of patent medications on normal metabolism. My observation has been that when men are given a patent medication that slows down the metabolization of testosterone into DHT, much more often than not, 3 [beta] -Adiol is suppressed even further, so the testosterone metabolite ratio is rebalanced in a procarcinogenic direction. As Professor I rnamov explained, this is very likely why the Prostate Cancer Prevention Trial found a significantly higher proportion of highly aggressive cancers in the men who despite taking the patent medicine finasteride still developed prostate cancer. (7) Note that, in addition to finasteride (Proscar, Propecia), dutasteride (Avodart) can have this effect, as can very large quantities of saw palmetto. And as "bonus points," many men who take these patent medicines also have diminished libido, and varying degrees of erectile dysfunction (ED).
By contrast, I usually recommended quantities of zinc, GLA (gamma-linolenic acid), and other natural inhibitors of the testosterone [right arrow] DHT transformation are "gentler"; their use rarely results in a procarcinogenic testosterone metabolite ratio.
Three Reasons to Test for 3 [beta] -Adiol and the Procarcinogenic Estrogen Metabolites.
I realize that despite my best attempts to explain testosterone metabolite testing in plain English, the preceding is highly technical. Please consider testosterone metabolite testing if you're:
1. using testosterone replacement therapy. For unknown reasons, "replacement" testosterone metabolizes into DHT more than internally secreted testosterone. It's best to make sure that if this happens, you have a greater quantity of 3 [beta] -Adiol than DHT + 3 [alpha] -Adiol;
2. taking Proscar, Propecia, Avodart, or very large amounts--usually over 500 milligrams--of saw palmetto daily. Particularly with the use of these patent medications, the "testosterone metabolite ratio" is most often decidedly procarcinogenic;
3. a man whose family has a history of prostate cancer. In this case, you want to check for estrogen metabolites too, as a low "2/16" estrogen ratio has been associated with higher prostate cancer risk. (12)
The testosterone metabolite test can be drawn at any lab and sent from there by the usual means to the Meridian Valley Laboratory (www.meridianvalleylab.com or 425-271-8689) for performance and reporting
Potential Endogenous Stimulation of 3 [beta] -Adiol
For several months in 2011, compounding pharmacies were able to supply "3 [beta] -Adiol" at a relatively reasonable prices. But--according to compounding pharmacists--a certain agency of los federales began to interfere with freedom of trade. The price quickly escalated, and then 3 [beta] -Adiol became entirely unavailable. Surprised, anyone?
Fortunately, researchers are reporting possibilities for stimulating the natural endogenous biosynthesis of 3 [beta] -Adiol with natural substances which stimulate 3 [beta] -HSD and/or 17 [beta] -HSD, the enzymes that convert 5 [alpha] -DHT into 3 [beta] -Adiol. But there's a caution: Although these studies are theoretically promising, none of them have as yet actually measured "before and after" quantities of 3 [beta] -Adiol itself, but rather activity and/or quantity of the enzymes that "lead to" 3 [beta] -Adiol. Until this research has been done, the best alternative is measuring the "before and after" levels in individuals, especially individuals found to personally have low 3 [beta] -Adiol levels. (In my own practice, I've observed that several of the items below have been associated with improved 3 [beta] -Adiol levels in individuals, but it's too early to report that any one is reliably associated with improvement in low 3 [beta] -Adiol levels.)
Let's start with (no kidding) coconut oil and olive oil. In 2008 and 2009, researchers reported that these two oils, used separately, significantly stimulated the activity of 3 [beta] -HSD and 17 [beta] -HSD, as well as significantly raising testosterone levels in experimental animals, while grapeseed oil and soy oil did not have any significant effect. (15), (16)
Then there's our old "male health" standby, zinc. Studies in male rats demonstrated that zinc deficiency decreased 3 [beta] -HSD activity. Zinc deficiency also was associated with a very significant reduction in testosterone itself. (17)
Hypothyroidism and "subclinical" hypothyroidism are relatively common. Here's another reason to be ever-vigilant for these problems: T3 stimulates 3 [beta] -HSD type 2. (18) Although this might suggest that T3 may stimulate 3 [beta] -Adiol, there are as yet no publications exploring this possibility. However, it's easy enough to check in any one individual with lower than desirable 3 [beta] -Adiol.
3 [beta] -HSD also requires NAD (niacinamide adenine dinucleotide), but once again there are no studies yet linking NADH supplementation with improved levels of 3 [beta] -Adiol. (19)
In a study of adrenal cell activity, lithium was reported to increase synthesis of 3p-HSD type 2. (Obviously the adrenals and testes are entirely different, but the 3 [beta] -HSD enzyme is the same enzyme in both areas).
Lastly (for now) all-trans retinoic acid (ATRA) has been shown to increase 3 [beta] -HSD type 2. (20) As too much ATRA can become toxic, this one is available only by prescription.
Thanks to Dawn Huo, PhD, developer of the testosterone metabolite test, and Ronald Steriti, ND, for compiling most of the underlying research on this topic.
This article is updated from its original publication in Dr. Wright's Nutrition & Healing newsletter for February 2011.
To learn more about Dr. Wright's seven-volume Library of Nutritional Cures and his newsletter Nutrition & Healing and/or to subscribe to the newsletter, please visit www.wrightnewsletter.com, or call 888-213-0685.
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(3.) Warner JA et al. An endocrine pathway in the prostate, ER-beta, AR, 5alpha-androstane-3-beta,17-beta-diol, and CYP7B1, regulates growth. Proc Natl Acad Research Sci USA. 2002; 99:13589-13594.
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(12.) Castagnetta LA, Granata OM, et al. Tissue content of hydroxyestrogens in relation to survival of breast cancer patients. Clin Cancer Res. 2002;8(10):3146-3155.
(13.) Wellejus A, Olsen A, et al. Urinary hydroxyestrogens and breast cancer risk among postmenopausal women: a prospective study. Cancer Epidemiol Biomarkers Prev. 2005;14(91:2137-2142.
(14.) Muti P, Bradlow l., et al Urinary estrogen metabolites and prostate cancer: a case-control study in the United States. Cancer Causes Control. 2002 Dec;13(10):947-955.
(15.) Hurtado de Catalfo GE, de Alaniz MJ, et al. Dietary lipids modify redox homeostasis and steroidogenic status in rat testis. Nutrition. 2008;24(7-8):717-726.
(16.) Hurtado de Catalfo GE, de Alaniz M), et al. Influence of commercial dietary oils on lipid composition and testosterone production in interstitial cells isolated from rat testis. Lipids. 2009;44(4):345-357.
(17.) Mansour MM, Hafiez AA, et al. Role of zinc in regulating the testicular function. Part 2 Effect of dietary zinc deficiency on gonadotropins, prolactin and testosterone levels as well as 3 beta-hydroxysteroid dehydrogenase activity in testes of male albino rats. Nahrung. 1989;33(10):941-947.
(18.) Gregorasczuk, EL, Kolodziejczyk J, et al. Triiodothyronine stimulates 3beta-hydroxysteroid dehydrogenase activity in the porcine corpus luteum. Endocr Regui. 1999;33(4):155-160.
(19.) Chaudhuri-Sengupta S, Sarkar R, et al. Lithium action on adrenomedullary and adrenocortical functions and serum ionic balance in different age-groups of albino rats Arch Physiol Biochem. 2003;111(3):246-253.
(20.) Kushida A, Tamura H. Retinoic acids induce neurosteroid biosynthesis in human filial GI-1 Cells via the induction of steroidogenic genes. J Blochem. 2009;146(6):917-923.
by Jonathan V. Wright, MD
Jonathan V. Wright, MD, has degrees from both Harvard University (cum laude) and the University of Michigan. More than any other doctor, he practically invented the modern science of applied nutritional biochemistry, and he has advanced nutritional medicine for nearly three decades. Dr. Wright is credited with introducing the nutritional remedy for benign prostate disease (BPH), the first successful treatment to reverse macular degeneration, the safe medical use of DHEA therapy, natural hormone replacement therapy for women, and many other revolutionary natural cures.
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