The Anticancer Testosterone Metabolite 3β-Adiol

Published in: Townsend Letter

By. Dr. Jonathan v. Wright, MD

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 5a-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?

Stop Suppressing Your Natural Defense
After testosterone is converted to DHT, DHT is in turn normally metabolized into a relatively smaller quantity of 5a-androstane-3a,17b-diol (abbreviated as 3a-Adiol), and a usually larger amount of 5a-androstane-3b,17b-diol (abbreviated as 3b-Adiol). These same researchers also report that while nearly all the 3a-Adiol is converted back to DHT (which presumably makes 3a-Adiol a “pre-procarcinogen”), the 3b-Adiol does not convert back to 5a-DHT. Very importantly, they report that 3b-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 3b-Adiol even more, thus shifting the procarcinogen (DHT) to anticarcinogen (3b-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 [3b-Adiol] thus suppressing [the anticarcinogenic activity of] ERb 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 ERb ligand – [3b-Adiol].”7

Research has found some very specific things that 3b-Adiol does to inhibit prostate cancer growth. According to the title of a 2005 research report: “The androgen derivative 5a-androstane-3b, 17b-diol [3b-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 3b-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 3b-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 3b-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 3b-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 “Snail1″ (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 Snail1 nuclear localization compared to low Gleason grade cancers.”10

Procarcinogenic and Anticarcinogenic Metabolites
The testosterone ® DHT ® 3b-Adiol metabolic pathway is very similar in its pro- and anticancer effects to the estrogen metabolic pathway estrone (E1) ® 16a-hydroxyestrone (16a-OHE1) ® estriol (E3). While 16a-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, 16a-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 3b-Adiol is more abundant than DHT, to “tilt” the balance of a man’s androgens in an anticarcinogenic direction.

Until the recent research about 3b-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 3b-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, 3a-Adiol, and 3b-Adiol (full name: 5a-androstane-3b,17b-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 3a-Adiol (full name: 5a-androstane-3a,17b-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 3b-Adiol and 3a-Adiol are metabolites of DHT, but researchers have found that almost all 3a-Adiol turns back into DHT (thus making it a procarcinogenic precursor), while none of the 3b-Adiol – which stimulates estrogen receptor beta (ERb), and is entirely anticarcinogenic – can “back-metabolize” into DHT again.6

Theoretically, if a man’s 3b-Adiol level is greater than the sum of his DHT plus 3a-Adiol (3b-Adiol > DHT + 3a-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/16a- 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, 3b-Adiol is suppressed even further, so the testosterone metabolite ratio is rebalanced in a procarcinogenic direction. As Professor Imamov 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 ® DHT transformation are “gentler”; their use rarely results in a procarcinogenic testosterone metabolite ratio.

Three Reasons to Test for 3b-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 3b-Adiol than DHT + 3a-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 3b-Adiol
For several months in 2011, compounding pharmacies were able to supply “3b-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 3b-Adiol became entirely unavailable. Surprised, anyone?

Fortunately, researchers are reporting possibilities for stimulating the natural endogenous biosynthesis of 3b-Adiol with natural substances which stimulate 3b-HSD and/or 17b-HSD, the enzymes that convert 5a-DHT into 3b-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 3b-Adiol itself, but rather activity and/or quantity of the enzymes that “lead to” 3b-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 3b-Adiol levels. (In my own practice, I’ve observed that several of the items below have been associated with improved 3b-Adiol levels in individuals, but it’s too early to report that any one is reliably associated with improvement in low 3b-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 3b-HSD and 17b-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 3b-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 3b-HSD type 2.18 Although this might suggest that T3 may stimulate 3b-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 3b-Adiol.

3b-HSD also requires NAD (niacinamide adenine dinucleotide), but once again there are no studies yet linking NADH supplementation with improved levels of 3b-Adiol.19
In a study of adrenal cell activity, lithium was reported to increase synthesis of 3b-HSD type 2. (Obviously the adrenals and testes are entirely different, but the 3b-HSD enzyme is the same enzyme in both areas).

Lastly (for now) all-trans retinoic acid (ATRA) has been shown to increase 3b-HSD type 2.20 As too much ATRA can become toxic, this one is available only by prescription.


References

1. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215–224.
2. Wilt TJ, et al. Five-alpha-reductase Inhibitors for prostate cancer prevention. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD007091.
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.
4. Zhu X, Leav I, Leung YK, et al. Dynamic regulation of estrogen receptor beta expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol. 2004;164:2003–2012.
5. Oliveira AG et al. 5a-Androstane-3b,17b–diol, an estrogenic metabolite of 5a-dihydrotestoserone, is a potent modulator of estrogen receptor b (ERb) in the ventral prostate of adult rats. Steroids. 2007;72:914–922.
6. Imamov O, Lopatkin NA, Gustafsson JA. Estrogen receptor beta in prostate cancer. N Engl J Med. 2004 Dec 23;351(26):2773–2774.
7. Imamov O, Shim G-J, Warner M, Gustafsson J-A. Estrogen receptor beta in health and disease. Biol Reprod. 2005; 73(5):866–871.
8. Guerini V, Sau D, et al. The androgen derivative 5a-androstane-3b,17b-diol inhibits prostate cancer cell migration through activation of the estrogen receptor beta subtype. Cancer Res. 2005;65:5445–5453.
9. Dondi D, Piccolella M, et al. Estrogen receptor b and the progression of prostate cancer: role of 5a-androstane-3b, 17b-diol. Endocr Relat Cancer. 2010;17:731–742.
10.Mak P, Leav I, et al. Erb impedes prostate cancer EMT by destabilizing HIF-1a and inhibiting VEGF-mediated Snail nuclear localization: implications for Gleason grading. Cancer Cell. 2010 April 13;17(4):319–332.
11.Armamento-Villareal RC, Napoli N, et al. The oxidative metabolism of estrogen modulates response to ERT/HRT in postmenopausal women. Bone. 2004;35(3):682–688.
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(9):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 MJ, 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, E L, Kolodziejczyk J, et al. Triiodothyronine stimulates 3beta-hydroxysteroid dehydrogenase activity in the porcine corpus luteum. Endocr Regul. 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 glial GI-1 Cells via the induction of steroidogenic genes. J Biochem. 2009;146(6):917–923.

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