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An Assessment of Testosterone and its Essential Metabolites for Prostate Cancer Risk.

5a-Androstane-3[beta], 17 [beta]-diol, 3[beta]-Adiol, is a testosterone metabolite that has been shown to provide protection against prostate cancer. In vitro and in vivo studies have shown that 3[beta]-Adiol inhibits the proliferation, migration, invasiveness, and metastasis of prostate cancer cell lines via estrogen receptor [beta] (ER[beta]) activation in the prostate gland. (1-6) Further, 3[beta]-Adiol has no androgenic activity. It does not bind to the androgen receptor, nor is it converted to androgenic compounds. Theoretically, these properties make 3[beta]-Adiol an attractive biomarker for prostate cancer risk and a potential novel agent in the treatment of this disease. Meridian Valley Lab offers the only androgen steroid hormone profile that provides an assessment of 3[beta]-Adiol.

The Prostate Cancer Prevention Trial

The clinical relevance and utility of 3[beta]-Adiol came out of the surprising findings of the Prostate Cancer Prevention Trial (PCPT). The PCPT was a Phase III, randomized, double-blind, placebo-controlled clinical trial of finasteride, a 5a-reductase inhibitor, for the prevention of prostate cancer. A total of 18,882 essentially healthy men, aged 55 and older, were randomized to receive finasteride (5 mg daily) or placebo for seven years. The study began in October 1993 and ended June 2003. The results showed that finasteride reduced the risk of developing prostate cancer by 25 percent. However, the incidence of high-grade prostate cancer (Gleason score 7-10) was 67 percent higher in the finasteride-treated group compared to placebo.

An explanation of this finding comes from the research of Imamov et al, (7) who suggest that the increased incidence of high-grade prostate cancer in the finasteride-treated group was a deleterious consequence of blocking testosterone to dihydrotestosterone conversion. Specifically, the downstream production of 3[beta]-Adiol from dihydrotestosterone is also blocked. 3[beta]-Adiol is the natural ligand for ER[beta], which is highly expressed in adult prostatic epithelium. Activation of ER[beta] suppresses proliferation and promotes differentiation of the prostatic epithelium. Without its ligand, ER[beta] activation is diminished and the proliferative action of androgen receptor activation within the prostate goes un-opposed. Akin to the Chinese Yin and Yang relationship, Imamov et al suggest a dynamic balance between ER[beta] activation vs androgen receptor activation within the prostate, controlling cell growth. This balance is disrupted through inhibition of testosterone-dihydrotestosterone conversion.

The Testosterone Metabolites Profile

As a research and investigational tool. Meridian Valley Laboratory has been offering the measurement of 3[beta]-Adiol through serum for the last six years as part of a full Testosterone Metabolites Profile. This test further evaluates the balance of 3[beta]-Adiol with "proliferative" testosterone metabolites. Practitioners have found this test particularly helpful for their male patients whom they regard at higher risk for prostate cancer. Male patients on testosterone replacement therapy, those with a past medical or family history of prostate cancer, those currently or with a history of using 5a-reductase inhibitors (i.e., finasteride, dutasteride, and high-dose saw palmetto), or those with low 5a-reductase activity as previously measured on a urine hormone profile are all candidates for further evaluation.

Specifically, this test measures and reports the following analytes: Androstenedione; Total Testosterone; 5[alpha]-Dihydrotestosterone (5[alpha]-DHT); ratio of Total Testosterone/5[alpha]-DHT; 3[beta]-Adiol; 5[alpha]-Androstane-3[alpha],17[beta]-diol (3[alpha]-Adiol); and the ratio 3[beta]-Adiol/(5[alpha]-DHT+3[alpha]-Adiol). A brief explanation of each follows.

Androstenedione

Androstenedione is considered a weak androgen in men and is secreted primarily by the testes. In the prostate gland androstenedlone Is synthesized from the adrenal precursor steroids dehydroepiandrosterone sulfate (DHEA-S) and DHEA. Androstenedlone is the primary precursor to testosterone, which is readily reconverted to androstenedlone via the enzyme I7[beta]-hydroxysteroid dehydrogenase (I7[beta]-HSD). It is also an Intermediate in the biotransformation of DHEA to estrone via the aromatase enzyme. Aromatase can also synthesize estradiol using testosterone as the precursor For this test, elevated levels of androstenedione typically suggest increased aromatization and should be followed-up with a screen for levels of carcinogenic estrogen metabolites. Aberrant high expression of aromatase enzyme activity and estrogen synthesis have been identified In prostate cancer and are implicated In prostate cancer genesis. Conversely, low levels of androstenedione in serum may suggest low upstream substrate or DHEA, the precursor for androstenedione.

Testosterone

Testosterone is the principle circulating androgen in men, secreted primarily by the testes. Testosterone and its metabolites are synthesized In the prostate as well. Adrenal-derived DHEA-S and DHEA is converted by 3[beta]-hydroxysteroid dehydrogenase (3[beta]-HSD) into androstenedione and testosterone --the latter being the downstream metabolite of androstenediol produced from DHEA via I7[beta]-HSD Type V, which is in close proximity to 3[beta]-HSD In the prostate epithelium. Interestingly, following medical or surgical castration, the intraprostatic concentration of DHT is about 40% of that measured in the prostates of intact 65-yr-old men. (8) This signifies a significant level of local androgen production and a reservoir capable of stimulating growth.

Most testosterone circulates in the blood bound to sex hormone binding globulin (SHBG) and to a lesser extent, albumin. Under physiologic conditions, only 1-2% of total circulating testosterone is free or biologically available. The Testosterone Metabolites Profile measures total testosterone in serum. Typically, elevated levels of total testosterone on this test are commonly seen in patients on testosterone replacement therapy simply because of the demographics commonly tested: the andropausal male. In cases like this, the indication is to decrease exogenous testosterone dosage. Although its long-term effects on the prostate are unknown, the mainstream view is that testosterone is contraindicated in men with prostate cancer or those at risk.

Currently, there is no clear evidence that an elevated testosterone level promotes the development of prostate cancer. (9) However, it seems reasonable that elevated levels may fuel excess aromatization to estradiol in addition to increasing 5a-DHT, both of which are proliferative to the prostate. 5a-DHT for example, derived from testosterone within prostate cells, mediates prostatic growth and is the initiating factor to androgen-dependent prostate disease. Low endogenous serum testosterone levels, on the other hand, may be associated with androgen deficiency-type symptoms, such as decreased energy and libido, erectile dysfunction, and a host of symptoms central to the pathology of metabolic syndrome--insulin resistance, dyslipidemia, hypertension and obesity. For these reasons, further evaluation of a high or low out-of-range serum total testosterone should be assessed against a serum measurement of free testosterone and SHBG. Measurements of luteinizing hormone and follicle-stimulating hormone to assess any suspected abnormalities of testosterone homeostasis in depth may also be clinically warranted.

Testosterone/DHT Ratio

Testosterone is primarily measured on this test as a participant in the testosterone/DHT ratio. Measurement of this ratio assesses for 5a-reductase enzyme activity. A high ratio can bring to the doctor's attention the deleterious inhibiting actions of a patient's prescribed 5a-reductase inhibitor (i.e., finasteride, dutasteride). As noted above from the PCPT, 5a-reductase inhibition is associated with a reduced risk of developing low-grade prostate cancer but increased risk of developing high-grade, more aggressive forms of prostate cancer. A low T/DHT ratio on the other hand may suggest enhanced 5a-reduction, which has been implicated in the pathogenesis of pancreatic cancer, benign prostate growth (BPH) and lower urinary tract symptoms, obesity, insulin resistance and type 2 diabetes.

DHT and Its Metabolites

Testosterone is converted to the more potent androgen, 5a-DHT, by the 5a-reductase enzyme within the prostate. 5a-DHT is the principle androgenic stimulus with trophic action on the prostate via the androgen receptor. Unlike testosterone, 5a-DHT is not aromatized to estrogens; rather it is converted to two principle metabolites, 3a-Adiol and 3[beta]-Adiol. Both of these 5a-DHT metabolites possess little activity at the androgen receptor; however, 3[beta]-Adiol binds to and activates ER[beta] within the prostate epithelium. ER[beta] activation with its ligand mediates against excess cell proliferation and stimulates apoptosis and re-differentiation. Notably ER[beta] expression is significantly decreased in malignant prostate tissue.

The conversion of 5a-DHT to 3a-Adiol is reversible. 3a-Adiol is synthesized from 5a-DHT through the action of 3a-HSD and back to 5a-DHT via the "3a-HSD-like" enzyme, RL-HSD, which is highly expressed in the prostate. As a "reservoir" for 5a-DHT, 3a-Adiol may indirectly potentiate the proliferative or trophic actions of 5a-DHT. 3[beta]-Adiol is synthesized from 5a-DHT via 3a-and 3[beta]-HSD. Unlike the conversion of 3a-Adiol from 5a-DHT, the synthesis of 3[beta]-Adiol from 5a-DHT is not reversible. (10)

The combined total of 3a-Adiol and 5a-DHT serve as a basis for comparison to 3[beta]-Adiol in assessing 3[beta]-Adiol sufficiency. The optimum ratio of 3[beta]-Adiol/(5a-DHT+3a-Adiol) is yet to be determined but is expected to be greater than 1.0, which would theoretically suggest a greater proportion of the anti-proliferative 5a-DHT metabolite. In other words, higher ratios are favorable.

3[beta]-HSD

Noteworthy to this discussion is the pivotal role played by the enzyme 3[beta]-HSD. The 3[beta]-HSD isoenzymes catalyze an essential first step in the formation of all steroid hormones: sex steroids, mineralocorticoids, and glucocorticoids. In addition to its role in the biosynthesis of 3[beta]-Adiol from 5a-DHT, this nicotinamide adenine dinucleotide (NAD (+))-dependent enzyme catalyzes the conversion of pregnenolone, 17[alpha]-hydroxypregnenolone, DHEA, and androstenediol into their respective ketosteroids: progesterone, 17a-hydroxyprogesterone, androstenedione, and testosterone (Figure 1). The 3[beta]-HSD isoenzymes control crucial steroid-forming reactions and are found not only in "classical" steroidogenic tissues, namely the adrenal cortex, ovary and testis, but also in a variety of peripheral target tissues, such as the breast, skin, brain, and prostate. The isoenzyme Type I 3[beta]-HSD is predominantly expressed in peripheral tissues. Type II 3[beta]-HSD is predominantly expressed in the adrenal gland, ovary, and testis. (8)

Interestingly 3[beta]-HSD genes are associated with prostate cancer risk. There is a significant association between genetic variants of either Type I and Type II 3[beta]-HSD enzyme and prostate cancer susceptibility. More importantly, a joint effect of a genetic variant of both Type I and II combined has been shown to provide a stronger association for prostate cancer risk than a single variant genotype of either Type I or II. (11) According to Dr. Bruce Ames, (*) as many as one-third of mutations in a gene result in the corresponding enzyme having a poorer binding affinity (an increased [K.sub.m] for its coenzyme. This in turn lowers the rate of its reaction. Dr. Ames further suggests that many of the carriers of over fifty human genetic diseases caused by defective enzymes can be remedied by administering high doses of B-vitamin cofactors of the corresponding coenzyme. This may increase levels of the coenzyme and partially restore enzymatic activity. (12) For those with a genetic predisposition for prostate cancer, NAD supplementation and other factors to support this enzyme may prove beneficial.

It is important to note that steroid hormone biosynthesis begins in the mitochondria where the conversion of cholesterol to pregnenolone (the precursor for all steroid hormones) takes place. (13) From Dr. Ames' research, age-associated mitochondrial decay (i.e., oxidative damage) can also decrease the functional capacity of key enzymes, lowering their rate of reaction. And, high doses of the corresponding cofactors, which will raise the coenzyme level, may at least partially restore enzymatic activity Thus, supporting mitochondrial function becomes a crucial component in supporting steroidogenesis.

Factors Affecting 3[beta]-HSD Activity

A number of natural agents have been shown to influence 3[beta]-HSD and/or 17[beta]-HSD enzyme activity in various tissues. These include NAD, lithium, T3, zinc, vitamin A, olive oil and coconut oil. These agents could have a beneficial effect in supporting the synthesis of 3[beta]-Adiol in the prostate gland.

The 3[beta]-HSD enzyme belongs to the NADPH/NAD (+)-dependent oxidoreductases which as its name implies catalyzes the oxidation-reduction of its steroidal substrate at the corresponding 3[beta]-position. As mentioned, both 5a-DHT metabolites, 3a-Adiol and 3[beta]-Adiol, are products of hydroxysteroid dehydrogenases.

Both enzymes have the same cofactor requirement: Vitamin B3, the component of niacinamide adenine dinucleotide (NAD). While there are no studies linking improved levels of 3[beta]-Adiol with NAD intake, NAD supplementation may hold promise in light of the fact that 3[beta]-HSD enzyme genetic variants are associated with prostate cancer susceptibility. As suggested by Dr. Ames, increasing cofactors may improve enzyme activity.

In a study on 3[beta]-HSD enzyme activity of the adrenal gland in rats, lithium treatment was reported to stimulate the synthesis of 3[beta]-HSD Type II, the isozyme predominantly expressed in the adrenals, ovary, and testis. (14) A simultaneous increase in corticosterone levels, a steroid product of 3[beta]-HSD enzyme activity, was also noted following lithium treatment in vivo. In both measures, corticosterone levels and 3[beta]-HSD enzyme activity, lithium action was largely dependent on the duration of treatment with long-term treatment (25 days) showing a greater response than short-term treatment (10 days).

From a clinical perspective, although adverse effects such as adrenocortical hyperactivity, hypothyroidism, and diabetes mellitus have been noted with long-term pharmacologic doses, lithium at 20 mg or less carries no ill side effects. This represents a physiologic dose that may fulfil the needs of individuals with a lithium deficiency and/or those that have a genetically-driven higher requirement for lithium. (15)

Triiodothyronine (T3) has also been shown to stimulate 3[beta]-HSD Type II. In a study on 3[beta]-HSD enzyme activity of the porcine corpus luteum, in vitro treatment of cultured luteal cells with T3 showed a marked increase in progesterone concentrations, measured via radioimmunoassay, against trilostane, a competitive inhibitor 3[beta]-HSD. (16) In the corpus luteum, 3[beta]-HSD catalyzes the conversion from pregnenolone to progesterone.

Zinc plays a key role in the activity of 3[beta]-HSD and hence testicular steroidogenesis. In a study of male rats, a great reduction in the activity of 3[beta]-HSD and testosterone levels was demonstrated histochemically in the testes of zinc-deficient rats compared to both control and zinc-supplemented ones. The authors of this study conclude that a hypogonadal state or Leydig cell failure can be induced with zinc deficiency altering testicular steroidogenesis. (17) It can be presumed from these results that a decrease in 3[beta]-HSD activity and testosterone levels would also result in decreased downstream production of 3[beta]-Adiol in the testes.

The vitamin A derivatives, retinoic acids and retinol, have been reported to regulate steroid biosynthesis in steroidogenic tissues such as human glial cells, adrenal gland, ovary and testis. In adult rat Leydig cell cultures, both retinol and retinoic acid-enriched media showed a direct stimulatory effect on testosterone biosynthesis via 3[beta]-HSD compared to control media, as measured by radioimmunoassay. (18) All-trans-retinoic acid (ATRA), an active metabolite of vitamin A, has been shown to induce the expression of the 3[beta]-HSD gene and its activity in cultured human glial cells. (19) The synthetic form of this retinoid is available by prescription only as it is toxic in high doses. Both studies described above establish an integral role for vitamin A in enhancing 3[beta]-HSD activity and steroidogenesis.

Dietary fats show a direct impact not only on the lipid composition of the Leydig cells of the testes but, in turn, influence local steroidogenesis. Specifically male rats supplemented with coconut oil or olive oil for sixty days showed a marked increase in testosterone levels compared to their counterparts supplemented with soybean or grape seed oil. In agreement with this finding, the activity of 3[beta]-HSD and I7[beta]-HSD was higher in the olive and coconut oil-supplemented groups compared to those supplemented with soybean or grape seed oil, where no significant effect was seen. (20,21)

The studies described above suggest that certain natural agents may support the production of 3[beta]-Adiol via stimulation of 3[beta]-HSD and/or 17[beta]-HSD. However, there are a few points to consider 3[alpha]-Adiol is also a product of this enzyme family, via 3[alpha]-HSD. 3a-Adiol is readily transformed back to 5a-DHT and functions as a secondary pool for 5a-DHT Both enzymes, 3[beta]-HSD and 3a-HSD have the same cofactor requirements. With regards to Type I vs Type II 3[beta]-HSD, Type I is predominantly expressed in peripheral tissues such as the prostate and adipose tissue. Type II is predominantly expressed in the adrenal gland, ovary and testis. Although, Type II shares 93.5% identity with Type I, it's quite possible that Type I vs Type II may be under differential regulatory influences. They may also differ in their binding affinities for their coenzymes and cofactors. For example, in the presence of its coenzyme, NADH, Type I is reported to show a higher activity in the conversion of 5a-DHT to 3[beta]-Adiol than Type II. (22) Further, there are no publications definitively linking the use of these natural agents in the production of 3[beta]-Adiol and a resulting clinical effect. In other words, no "before-and-after" clinical studies. Still, the research on these agents in influencing 3[beta]-HSD activity is interesting and offers therapeutic promise.

Test Logistics

For the purpose of the Testosterone Metabolites Profile, it is advised that the patient have his blood drawn early morning when endogenous testosterone levels are at their highest. For the male patient on testosterone replacement therapy, it is recommended to collect the blood sample mid-point from the time of his last dose to the time of his next dose. This is to avoid a bolus effect on the measured value. To make this easy for the patient, the patient should decide when he plans to have his blood drawn in the morning and then apply his testosterone twelve hours prior, the previous evening. In other words, if he is planning on having his blood drawn at 7 am, he would apply his testosterone at 7 pm. As this test requires a fasting morning blood sample, preparing for an early draw will allow him to eat breakfast sooner rather than later.

In Conclusion

The prostate is one of the major targets for DHT DHT acts as the principle androgenic stimulus within this gland. Binding to the androgen receptors promotes proliferation and dedifferentiation of the prostatic epithelium. DHT can be metabolized to 3[alpha]-Adiol and 3[beta]-Adiol, the latter of which binds to and activates ER[beta]. Activation of ER[beta] can suppress proliferation and promote differentiation of the prostatic epithelium, counteracting the physiological action of androgen receptor activation. 3[beta]-Adiol is a potent inducer of ER[beta] expression but is then rapidly and irreversibly converted to downstream inactive metabolites for excretion. 3[alpha]-Adiol, on the other hand, may be converted back to DHT, thus serving as a reservoir for this potent androgen. With this in mind, supporting the production of 3[beta]-Adiol as a strategy to inhibit prostate cancer cell growth seems intuitive for the forward-thinking clinician, and the select nutrients described are innovative measures in this respect. Though not yet proven by prospective or controlled studies, the use of 3[beta]-Adiol as a laboratory marker and treatment strategy are revolutionary approaches to promote prostate health.

Thank you to Dr. Pushpa Larsen for her generous help in editing this article.

References

(1.) Dondi D, et al. Estrogen receptor [beta] and the progression of prostate cancer: role of 5a-androstane-3[beta],17[beta]-diol. Endocrine-Related Cancer. 2010; 17:731-742.

(2.) Weihua Z, et al. An endocrine pathway in the prostate, ER[beta], AR, 5a-androstane-3[beta], 17[beta]-diol, and CYP7B1, regulates prostate growth. Proceedings of the National Academy of Sciences. 2002; 99:13589-13594.

(3.) Weihua Z, et al. Estrogen receptor [beta] in the prostate. Molecular and Cellular Endocrinology. 2002; 193:1-5.

(4.) Imamov O, et al. Estrogen receptor [beta] in prostate cancer. New England Journal of Medicine. 2004; 351:2773-2774.

(5.) Guerini V, et al. The androgen derivative 5a-androstane-3[beta], 17[beta]-diol inhibits prostate cancer cell migration through activation of the estrogen receptor [beta] subtype. Cancer Research. 2005; 65: 5445-5453.

(6.) Koehler KF, et al. Reflections on the discovery and significance of estrogen receptor [beta]. Endocrine Reviews. 2005; 26: 465-478.

(7.) Imamov O, et al. Estrogen receptor beta in health and disease. Biology of Reproduction. 2005; 73:866-871.

(8.) Simard J, et al. Molecular biology of the 3[beta]-hyd roxysteroid dehydrogenase/[[DELTA].sup.5]-[[DELTA].sup.4] isomerase gene family. Endocrine Reviews. (2005); 26(4):525-582.

(9.) Michaud JE, et al. Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk. Therapeutic Advances in Urology. 2015; 7(6):378-387.

(10.) Handa RJ, et al. A role for the androgen metabolite, 5alpha androstane 3beta, 17beta Diol (3[beta]-Diol) in the regulation of the hypothalamo-pituitary-adrenal axis. Frontiers in Endocrinology. 2011; 2(65):1-10.

(11.) Chang BL, et al. Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility. Cancer Research. 2002; 62:1784-1789.

(12.) Ames BN, et al. High-dose vitamins stimulate variant enzymes with decreased coenzyme-binding affinity (increased Km): relevance to genetic disease and polymorphisms. The American Journal of Clinical Nutrition. 2002; 75:616-658.

(13.) Ramalho-Santos J, Amaral S. Mitochondria and mammalian reproduction. Molecular and Cellular Endocrinology 2013; 379(1-2):74-84.

(14.) Chaudhuri-Sengupta S, et al. Lithium action on adrenomedullary and adrenocortical functions and serum ionic balance in different age-groups of albino rats. Archives of Physiology and Biochemistry. 2003; lll(3):246-253.

(15.) Greenblatt J. (2017, 6) Lithium: the billion-year journey from mineral to medicine to nutritional genomics. Presented at the 2017 Annual International Conference, Institute for Functional Medicine, Los Angeles, OA.

(16.) Gregoraszczuk EL, et al. Triiodothyronine stimulates 3[beta]-hydroxysteroid dehydrogenase activity in the porcine corpus luteum. Endocrine Regulations. 1999; 33:155-160.

(17.) Mansour MMS, 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. Die Nahrung. 1989; 10:941-947.

(18.) Chaudhary LR, et al. Effect of retinol and retinoic acid on testosterone production by rat Leydig cells in primary culture. Biochemical and Biophysical Research Communications. 1989; 158(2):400-406.

(19.) Kushida A, Tamura H. Retinoic acids induce neurosteroid biosynthesis in human glial GI-1 cells via the induction of steroidogenic genes. Journal of Biochemistry 2009; 146(6): 917-923.

(20.) Hurtado de Catalfo GE, et al. Dietary lipids modify redox homeostasis and steroidogenic status in rat testis. Nutrition. 2008; 717-726.

(21.) Hurtado de Catalfo GE, et al. Influence of commercial dietary oils on lipid composition and testosterone production in interstitial cells isolated from rat testis. Lipids. 2009; 44: 345-357.

(22.) Rheaume E, et al. Structure and expression of a new complementary DNA encoding the almost exclusive 3[beta]-hydroxysteroid dehydrogenase/[[DELTA].sup.5]-[[DELTA].sup.4]-isomerase in human adrenals and gonads. Molecular Endocrinology 1991; 1147-1157.

by Shalima Gordon, ND

With gratitude, Dr. Shalima Gordon earned a Bachelor of Science degree in cell biology from the University of British Columbia, Canada, and a degree in naturopathic medicine from Bastyr University, Washington. Her background is in functional medical testing. She currently serves as a consulting physician at Meridian Valley Laboratory in Tukwila, Washington.

sgordon@meridianvalleylab.com

(*) The renowned Dr Ames is a Senior Scientist at Children's Hospital Oakland Research Institute (CHORI), director of their Nutrition & Metabolism Center, and a professor emeritus of biochemistry and molecular biology, University of California, Berkeley. His research has focused on illuminating the mechanisms by which poor nutrition accelerates the degenerative diseases of aging. With over 550 scientific publications, he is among the few hundred most-cited scientists, in all fields.
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