Fw: Testosterone supplementation for post-PCa men

[Guest guest]

http://www.medicalnewstoday.com/articles/222946.php

Testosterone-Prostate Cancer Link Re-Examined Main Category: Prostate / Prostate CancerAlso Included In: Endocrinology; Seniors / AgingArticle Date: 20 Apr 2011 - 3:00 PDT

The long-standing prohibition against testosterone therapy in men with untreated or low-risk prostate cancer merits reevaluation, according to a new study published in The Journal of Urology.

"For many decades it had been believed that a history of prostate cancer, even if treated and cured, was an absolute contraindication to testosterone therapy, due to the belief that testosterone activated prostate cancer growth, and could potentially cause dormant cancer cells to grow rapidly," says Abraham Morgentaler, MD of Men's Health Boston. "Generations of medical students and residents were taught that providing testosterone to a man with prostate cancer was like pouring gasoline on a fire."

This study, involving 13 symptomatic testosterone deficient men who also had untreated prostate cancer, suggests this traditional view is incorrect, and that testosterone treatment in men does not cause rapid growth of prostate cancer. It is the first to directly and rigorously assess changes in the prostate among men with prostate cancer who received testosterone therapy.

The men received testosterone therapy while undergoing active surveillance for prostate cancer for a median of 2.5 years. Median age was 58.8 years. The initial biopsy Gleason score was 6/10 for 12 of the men, 7/10 for the other (Gleason score grades the aggressiveness of prostate cancer by its microscopic appearance on a scale of 2-10. Gleason 6 is generally considered low to moderately aggressive, and Gleason 7 moderately aggressive).

Mean testosterone concentration increased from 238 to 664 ng/dl with treatment, yet neither prostate specific antigen (PSA) concentrations nor prostate volume showed any change. Follow-up biopsies of the prostate were performed in all men at approximately yearly intervals, and none developed cancer progression. In fact, 54 percent of the follow-up biopsies revealed no cancer at all.

Although the number of men in the study was small, and none had aggressive or advanced prostate cancer, Morgentaler observed, "These men were rigorously followed. The cancers in these men were typical of the prostate cancers for which men have undergone invasive treatment with surgery or radiation for 25 years. Clearly, the traditional belief that higher testosterone necessarily leads to rapid prostate cancer growth is incorrect."

In a Journal of Urology editorial comment, M. Miner, MD, of the Miriam Hospital and Warren Alpert School of Medicine of Brown University notes the conclusions represent "a remarkable shift in thinking from only five years ago. ... If testosterone therapy was not associated with disease progression in men with untreated prostate cancer, how concerned must we be about testosterone therapy in men with treated prostate cancer?"

"An increasing number of newly diagnosed men with prostate cancer opting for active surveillance, and with many of them also desiring treatment for their signs and symptoms of testosterone deficiency, the results suggest a reevaluation of the long standing prohibition against offering testosterone therapy to men with prostate cancer," says Morgentaler.

Refraining from testosterone therapy due to unmerited prostate cancer fears may have adverse lifestyle and health consequences, since testosterone therapy in testosterone deficient men has been shown to improve symptoms of fatigue, decreased libido, and erectile dysfunction. Testosterone therapy may also improve mood, blood sugar control, increase muscle, decrease fat, and improve bone density. Four recent studies have shown that men with high testosterone levels appear to live longer than men with low levels, although it has not yet been shown that treating men with testosterone increases longevity.

Morgentaler commented on an Italian study that showed that low levels of testosterone were associated with aggressive prostate cancer. The risk of aggressive cancer was reduced for men with normal testosterone compared with men with low testosterone.

In an editorial in the journal Cancer, "Turning Conventional Wisdom Upside Down: Low Serum Testosterone and High-Risk Prostate Cancer Morgentaler wrote, "After seven decades of circumstantial evidence pointing us in the wrong direction, perhaps it is time to consider the once unthinkable - conducting a testosterone therapy trial of sufficient size and duration to determine whether normalization of serum testosterone in older men many reduce the risk of prostate cancer, particularly high-risk prostate cancer."

Notes: In addition to Morgentaler, a member of the Division of Urology in the BIDMC Department of Surgery and an associate clinic professor of surgery at Harvard Medical School, the study was co-authored by Sweeney, MD of Harvard Medical School and Larry I. Lipshultz, MD, , MD, Desiderio Avila, Jr., MD, and Mohit Khera, MD, of Baylor Medical College.

The authors reported financial interests and/or other relationships with Auxilium Pharmaceuticals, Pharmaceuticals, Slate Pharmaceuticals, Bayer Healthcare, GlaxoKline, Solvay Pharmaceuticals, Pfizer Inc., Eli Lilly & Co., Allergan, Inc., American Medical Systems and Repros Therapeutics.

Source: Jerry BergerBeth Israel Deaconess Medical Center

---------------------------------------

Shifting the Paradigm of Testosterone and Prostate Cancer: The Saturation Model and the Limits of Androgen-Dependent Growth. Eur Urol 2009;55:310–21 Abraham Morgentaler, Abdulmaged M. Traish. The Saturation Model presented by Morgentaler and Traish [1] is a great improvement over the previous model of prostate cancer (PCa) growth being dependent on serum testosterone (T) levels. For any biological model, however, to be an accurate representation of reality, it must be consistent with all known experimental results. Human PCa cell line LNCaP xenografts were transplanted into nude castrated mice to study the effects of T and finasteride (F) [2], a drug that prevents the conversion of T to dihydrotestosterone (DHT). Continuous androgen ablation (CAA) followed by the addition of F resulted in a 91% increase in tumor volume, CAA resulted in a 114% increase in tumor volume, and intermittent androgen ablation

followed by continuous exposure to T resulted in a 128% increase in tumor volume. These findings are all consistent with the Saturation Model, with decreasing agonism of the intracellular androgen receptor (iAR) corresponding to decreased tumor volume. Intermittent ndrogen ablation followed by continuous exposure to T plus F, however, resulted in only a 23% increase in tumor volume. This finding is inconsistent with the Saturation Model, which would predict that T plus F should end up with a tumor volume somewhere between that of T alone and of F alone, since the agonism of iAR by T plus F is between what it is by T alone and by F alone. There is a straightforward explanation for the above results that does not involve the Saturation Model. The membrane androgen receptor (mAR) and the iAR tend to act in opposition to each other, with mAR upregulating proapoptotic proteins such as Fas and iAR downregulating these proteins [3]. By

creating an imbalance in which there ismuchmore agonismofmAR than of iAR, therefore, it is possible to reach a threshold level of proapoptotic proteins that significantly increases the rate of apoptosis. Ordinarily, there is little or no upregulation of proapoptotic proteins by mAR when the agonism of mAR and iAR is roughly in balance. When both T and F are present, however, the agonism to iAR is reduced approximately 5-fold, since DHT binds to iAR five times more strongly than T does [4], while both T and DHT bind equally strongly to mAR [5]. If the above explanation is correct, then increasing the imbalance by using T bound to albumin (T-BSA) in LNCaP cells transplanted into nude mice should be even more effective than T plus F, since T-BSA only binds tomAR. In fact, when T-BSA serumlevels of 107Mwere obtained, there was a 60% reduction in tumor size after 1 mo [5]. Additionally, it would be expected that T alone should be able to kill

PCa cells in the absence of iAR, andthis abilitywasdemonstra tedin the iAR-negative DU145 PCa cell line [5]. To accurately model the effects of T on PCa, it is essential that the properties of iAR and mAR be taken into account with the effect of aromatase on converting T to estradiol. Conflicts of interest: The author has nothing to disclose. References [1] Mogentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgendependent growth. Eur Urol 2009;55:310–21. [2] Eggener SE, Stern JA, Jain PM, et al. Enhancement of intermittent androgen ablation by ‘‘off-cycle’’ maintenance with finasteride in LNCaP prostate cancer xenograft model. Prostate 2006;66:495–502. [3] Friedman AE. Can a single model explain both breast cancer and prostate cancer? Theor Biol Med Model 2007;4:28. [4] Wilbert DM, JE, JD.

Characterization of the cytosol androgen receptor of the human prostate. J Clin Endocr Metab 1983;56:113–20. [5] Hatzoglou A, Kampa M, Kogia C, et al. Membrane androgen receptor activation induces apoptotic regression of human prostatic cancer cells in vitro and in vivo. J Clin Endocr Metab 2005;90:893–903. A. Friedman* Department of Mathematics, University of Chicago, 5734 South University Avenue, Chicago, Illinois, 60076, USA *Tel. +1 ; Fax: +1 E-mail address: ed@.... edu March 24, 2009 Published online on 1 April 2009 Reply to A. Friedman’s Letter to the Editor re: Abraham Morgentaler, Abdulmaged M. Traish. Shifting the Paradigm of Testosterone and Prostate Cancer: The Saturation Model and the Limits of Androgen-Dependent Growth. Eur Urol 2009;55:310–21 We are grateful to Dr. Friedman

[1] for raising discussion of the Saturation Model [2], which we believe offers new and exciting lines of inquiry regarding androgens and prostate cancer. Dr. Friedman writes, ‘‘For any biological model, however, to be an accurate representation of reality, it must be consistent with all known experimental esults.’’ We heartily agree with this comment. Yet it is important to recognize that most cancers are heterogeneous, and different experimental models, especially in vitro systems such as cell culture systems, may produce variable responses to hormones and growth factors. Dr. Friedman appears to be generally in agreement with the Saturation Model. The model posits an exquisite sensitivity of prostate cancer to changes in androgen concentrations at very low levels but indifference to such changes at higher concentrations. Dr. Friedman, however, suggests that a study by Eggener et al [3] provides results that are

inconsistent with the Saturation Model. We disagree. The model used by Eggener et al [3] exposed nude mice implanted with LnCaP tumors to intermittent androgen ablation, a treatment known to cause prostate tumors to escape normal androgenic regulation. Moreover, the study authors themselves recognized a major irregularity in their results, since prostatespecific antigen concentrations failed to decline with androgen deprivation, as is usually seen with LnCaP tumors. This result indicates that this experimental system did not respond normally to androgenic stimuli. For this reason, we do not believe the study by Eggener et al has relevance to the Saturation Model. Dr. Freidman’s comments regarding androgen membrane receptor activity are interesting, but we believe this process is unrelated to the Saturation Model. Conflicts of interest: The authors have nothing to disclose. References [1] Friedman, AE. Re: Abraham Morgentaler,

Abdulmaged M. Traish. Shifting the paradigm of testosterone and prostate cancer: the Saturation Model and the limits of androgen-dependent growth. Eur Urol 2009;55:310–21. Eur Urol. In press. doi:10.1016/ j. eururo.2009. 03.068. [2] Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the Saturation Model and the limits of androgen- dependent growth. Eur Urol 2009;55:310–21. [3] Eggener SE, Stern JA, Jain PM, et al. Enhancement of intermittent androgen ablation by ‘‘off-cycle’’ maintenance with finasteride in LNCaP prostate cancer xenograft model. Prostate 2006;66:495–502. Abraham Morgentaler* Division of Urology, Beth Israel Deaconess Medical Center and Men’s Health Boston, Harvard Medical School, Boston, MA, USA Abdulmaged M. Traish Department of Biochemistry and Division of Urology, Boston University School of Medicine, Boston, MA, USA *Corresponding

author. One Brookline Place, #624, Brookline, MA 02445, USA. Tel. +; Fax: + E-mail address: amorgentyahoo (DOT) com (A. Morgentaler) March 24, 2009 Published online on April 1, 2009

BOB

Subject: Testosterone supplementation for post-PCa menTo: "ProstateCancerSupport " <ProstateCancerSupport >Cc: "domiha@..." Date: Tuesday, April 26, 2011, 2:56 PM

A question was recently raised about testosterone supplementationfor men who have had successful prostate cancer treatment with noevidence of recurrence.The following abstract addresses the issue. The author claimsthat there isn't enough information to know for sure. However healso says, if I understand him correctly, that a relatively lowlevel of testosterone (presumably above castrate level),saturates the prostate. Adding more does not appear to increaseactivity in the prostate.If that's right, it would appear that testosteronesupplementation is safe. But, as he says, the amount ofinformation available on this issue is limited and inadequate fordefinitive conclusions.See: http://tinyurl.com/6kgs4ezYou'll need to register with Urotoday (free) to see

it. Alan