Re: TRT ok for my Dad after prostate removal?
Testosterone treatment in elderly hypogonadal patients does not increase prostate cancer risk: results of a prospective comparative study. 7 years follow up analysis to age-matched controls
http://www.aua2012.org/abstracts/printpdf.cfm?ID=372
Conclusions - Hypogonadal subjects have smaller prostates and lower PSA than eugonadal ones. TRT doesn't increase CaP incidence. TRT group had smaller tumors and less malignancy. Hypogonadism offers no protection against the development of biopsy-detectable prostate cancer. Lower levels of testosterone were associated with an increased risk of cancer.
LONG-TERM FOLLOW-UP OF THE SAFETY AND EFFICACY OF TESTOSTERONE REPLACEMENT THERAPY FOLLOWING RADICAL PROSTATECTOMY
http://www.aua2012.org/abstracts/printpdf.cfm?ID=1487
Conclusions - In our experience, TRT has demonstrated long-term safety and efficacy in the treatment of the hypogonadal patient post-RP, with only a single high-risk patient experiencing BCR. This recurrence rate is likely lower than that expected for this cohort of RP patients.
Testosterone Replacement Therapy in Patients with High Risk Prostate Cancer After Radical Prostatectomy: Long-Term Follow-Up
http://www.aua2012.org/abstracts/printpdf.cfm?ID=1488
Conclusions- TRT remains a viable treatment alternative in men with a history of CaP who have undergone prostatectomy, even those with CaP bearing high risk characteristics, with recurrence rates in our series below those published in other series of comparably matched men not treated with TRT.
Testosterone Replacement Therapy After Radiation Therapy for Prostate Cancer
http://www.aua2012.org/abstracts/printpdf.cfm?ID=1489
Conclusions - Our data demonstrate that TRT in the setting of CaP after treatment with XRT results in a rise in serum total testosterone levels and improvement in hypogonadal symptoms without evidence of CaP recurrence or progression.
Isbarn H, Pinthus JH, Marks LS, et al. Testosterone and prostate cancer: revisiting old paradigms. Eur Urol 2009;56(1):48-56. ScienceDirect.com - European Urology - Testosterone and Prostate Cancer: Revisiting Old Paradigms
CONTEXT: Androgens are vital for growth and maintenance of the prostate; however, the notion that pathologic prostate growth, benign or malignant, can be stimulated by androgens is a commonly held belief without scientific basis. Therefore, the current prostatic guidelines for testosterone therapy (TT) appear to be overly restrictive and should be reexamined.
OBJECTIVE: To review the literature addressing the possible relationship between testosterone and prostate cancer (PCa) and to summarize the main aspects of this issue.
EVIDENCE ACQUISITION: A Medline search was conducted to identify original articles, review articles, and editorials addressing the relationship between testosterone and the risk of PCa development, as well as the impact of TT on PCa development and its natural history in men believed to be cured by surgery or radiation.
EVIDENCE SYNTHESIS: Serum androgen levels, within a broad range, are not associated with PCa risk. Conversely, at time of PCa diagnosis, low rather than high serum testosterone levels have been found to be associated with advanced or high-grade disease. The available evidence indicates that TT neither increases the risk of PCa diagnosis nor affects the natural history of PCa in men who have undergone definitive treatment without residual disease. These findings can be explained with the saturation model (which states that prostatic homeostasis is maintained by a relatively low level of androgenic stimulation) and with the observation that exogenous testosterone administration does not significantly increase intraprostatic androgen levels in hypogonadal men. It must, however, be recognized that the literature remains limited regarding the effect of TT on PCa risk. Nonetheless, the current European Association of Urology guidelines state that in hypogonadal men who were successfully treated for PCa, TT can be considered after a prudent interval.
CONCLUSIONS: Although no controlled studies have yet been performed and there is a paucity of long-term data, the available literature strongly suggests that TT neither increases the risk of PCa diagnosis in normal men nor causes cancer recurrence in men who were successfully treated for PCa. Large prospective studies addressing the long-term effect of TT are needed to either refute or corroborate these hypotheses.
Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol 2006;7(5):363-9.
Since the early 1940s when Huggins showed that severe reductions in serum testosterone by castration or estrogen therapy caused regression of prostate cancer (PCa), it has been assumed that higher testosterone levels cause enhanced growth of PCa. For this reason, it has been considered taboo to offer testosterone replacement therapy (TRT) to any man with a prior history of PCa, even if all objective evidence suggests he has been cured. The fear has been that higher testosterone levels would "awaken" dormant cells and cause a recurrence. Thus, US Food and Drug Administration-mandated language in all testosterone package inserts states that testosterone is contraindicated in men with a history of, or suspected of having, PCa. Although there is little modern experience with administration of testosterone in men with known history of PCa, there is a varied and extensive literature indicating that TRT does not pose any increased risk of PCa growth in men with or without prior treatment. For instance, the cancer rate in TRT trials is only approximately 1%, similar to detection rates in screening programs, yet biopsy-detectable PCa is found in one of seven hypogonadal men. Moreover, PCa is almost never seen in the peak testosterone years of the early 20s, despite autopsy evidence that men in this age group already harbor microfoci of PCa in substantial numbers. The growing number of PCa survivors who happen to be hypogonadal and request treatment has spurred a change in attitude toward this topic, with increasing numbers of physicians now offering TRT to men who appear cured of their disease. Publications have now reported no prostate-specific antigen (PSA) recurrence with TRT in small numbers of men who had undetectable PSA values after radical prostatectomy. Although still controversial, there appears to be little reason to withhold TRT from men with favorable outcomes after definitive treatment for PCa. Monitoring with PSA and digital rectal examination at regular intervals is recommended.
Raynaud JP. Prostate cancer risk in testosterone-treated men. J Steroid Biochem Mol Biol 2006;102(1-5):261-6.
Men with classical androgen deficiency have reduced prostate volume and blood prostate-specific antigen (PSA) levels compared with their age peers. As it is plausible that androgen deficiency partially protects against prostate disease, and that restoring androgen exposure increases risk to that of eugonadal men of the same age, men using ART should have age-appropriate surveillance for prostate disease. This should comprise rectal examination and blood PSA measurement at regular intervals (determined by age and family history) according to the recommendations, permanently revisited, published by ISSAM, EAU, Endocrine Society.... Testosterone replacement therapy is now being prescribed more often for aging men, the same population in which prostate cancer incidence increases; it has been suggested that administration in men with unrecognised prostate cancer might promote the development of clinically significant disease. In hypogonadal men who were candidates for testosterone therapy, a 14% incidence of occult cancer was found. A percentage (15.2%) of prostate cancer has been found in the placebo group (with normal DRE and PSA) in the prostate cancer prevention study investigating the chemoprevention potential of finasteride. The hypothesis that high levels of circulating androgens is a risk factor for prostate cancer is supported by the dramatic regression, after castration, of tumour symptoms in men with advanced prostate cancer. However these effects, seen at a very late stage of cancer development, may not be relevant to reflect the effects of variations within a physiological range at an earlier stage. Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer. A study on a large prospective cohort of 10,049 men, contributes to the gathering evidence that the long standing "androgen hypothesis" of increasing risk with increasing androgen levels can be rejected, suggesting instead that high levels within the reference range of androgens, estrogens and adrenal androgens decrease aggressive prostate cancer risk. Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone. Furthermore, pre-treatment total testosterone was an independent predictor of extraprostatic disease in patients with localized prostate cancer; as testosterone decreases, patients have an increased likelihood of non-organ confined disease and low serum testosterone levels are associated with positive surgical margins in radical retropubic prostatectomy. A clinical implication of these results concerns androgen supplementation which has become easier to administer with the advent of transdermal preparations (patch or gel) that achieve physiological testosterone serum levels without supra physiological escape levels. During the clinical development of a new testosterone patch in more than 200 primary or secondary hypogonadal patients, no prostate cancer was diagnosed.
Raynaud JP. Testosterone deficiency syndrome: treatment and cancer risk. J Steroid Biochem Mol Biol 2009;114(1-2):96-105.
Testosterone deficiency syndrome (TDS) can be linked to premature mortality and to a number of co-morbidities (such as sexual disorders, diabetes, metabolic syndrome, ...). Testosterone deficiency occurs mainly in ageing men, at a time when prostate disease (benign or malign) start to emerge. New testosterone preparations via different route of administration appeared during the last decade allowing optimized treatment to these patients. One potential complication of this treatment is the increased risk of prostate and breast cancer. Consequently, the guidelines from the agencies and the institutions, the recommendations of the scientific expert committees and the attitude of the clinicians to who, when and how to treat hypogonadal patients, is very conservative, not to say, highly restrictive. To date, as documented in many reviews on the subject, nothing has been found to support the evidence that restoring testosterone levels within normal range increases the incidence of prostate cancer. In our experience, during a long-term clinical study including 200 hypogonadal patients receiving a patch of testosterone, 50 patients ended 5 years of treatment and no prostate cancer have been reported. In fact, the incidence of prostate cancer in primary or secondary testosterone treated hypogonadal men is lower than the incidence observed in the untreated eugonadal population. However, even if the number of patients treated in well-conducted clinical trials for whom cancer of the prostate has been reported is insignificant (a very few), the observed population is still too small to raise definite conclusions. Low testosterone levels have been reported in patients undergoing radical prostatectomy and the outcomes are of worse diagnostic in this population; at a later stage, testosterone deficiency can be induced by anti hormonal manipulation of patient with a prostate cancer, leading to the symptoms of hypogonadism. The question is to know whether it is justified, in case of profound symptoms, to supplement those patients with testosterone. Some attempts have been made and the results are encouraging: so it is time to re-examine our position and to question about the definite recommendation that patients with prostate cancer should never receive testosterone supplementation therapy; this is already the situation when intermittent androgen blockade is initiated if the biological response is satisfactory. Furthermore, it has been advocated that, under a rigorous surveillance, patients cured of prostate cancer can be treated with testosterone supplementation with beneficial results.
Morgentaler A. Guilt by association: a historical perspective on Huggins, testosterone therapy, and prostate cancer. J Sex Med 2008;5(8):1834-40. Guilt by Association: A Historical Perspective on Huggins, Testosterone Therapy, and Prostate Cancer - Morgentaler - 2008 - The Journal of Sexual Medicine - Wiley Online Library
INTRODUCTION: A long-standing belief is that higher testosterone (T) will increase the risk of prostate cancer (PCa), yet recent studies do not support this view. AIM: To identify the key historical and scientific events leading to the establishment and persistence of the belief in a T-dependent model of PCa growth, despite evidence to the contrary.
METHODS: Review of key historical scientific articles regarding T and PCa.
RESULTS: The T-dependent model of PCa growth arose from the work of Huggins and coworkers, who in 1941 demonstrated dramatic responses to castration among men with advanced PCa. These authors and others also reported a rapid clinical progression with T administration. This led to the concept that T was like "food for a hungry tumor" for men with PCa. Fowler and Whitmore recognized in 1981 that the negative effect of T administration did not occur unless men had been previously castrated. However, this critical observation was either forgotten or dismissed amid major changes in PCa diagnosis and management during the 1980s. More recent studies have failed to provide clinical evidence supporting the belief that higher T represents a risk for PCa. Factors contributing to the persistence of the T-dependent model included dramatic effects of castration, continued use of androgen deprivation for treatment of PCa, an influential spokesperson (Huggins), groupthink (failure to acknowledge evidence inconsistent with the prevalent ideology), and an imprecise formulation of the model ("more T, more cancer growth"), making refutation difficult.
CONCLUSIONS: The fear that higher T will increase PCa growth stems from a theory of T-dependent PCa growth that originated with observations in a special population (castrated men) that is not particularly relevant to T therapy in hypogonadal men. The negative view of T with regard to PCa should be recognized for what it is--guilt by association.
Morgentaler A. Testosterone therapy in men with prostate cancer: scientific and ethical considerations. J Urol 2009;181(3):972-9. http://www.cenegenicsfoundation.org..._Scientific_and_Ethical_Considerations_1_.pdf
PURPOSE: Pertinent literature regarding the potential use of testosterone therapy in men with prostate cancer is reviewed and synthesized.
MATERIALS AND METHODS: A literature search was performed of English language publications on testosterone administration in men with a known history of prostate cancer and investigation of the effects of androgen concentrations on prostate parameters, especially prostate specific antigen.
RESULTS: The prohibition against the use of testosterone therapy in men with a history of prostate cancer is based on a model that assumes the androgen sensitivity of prostate cancer extends throughout the range of testosterone concentrations. Although it is clear that prostate cancer is exquisitely sensitive to changes in serum testosterone at low concentrations, there is considerable evidence that prostate cancer growth becomes androgen indifferent at higher concentrations. The most likely mechanism for this loss of androgen sensitivity at higher testosterone concentrations is the finite capacity of the androgen receptor to bind androgen. This saturation model explains why serum testosterone appears unrelated to prostate cancer risk in the general population and why testosterone administration in men with metastatic prostate cancer causes rapid progression in castrated but not hormonally intact men. Worrisome features of prostate cancer such as high Gleason score, extracapsular disease and biochemical recurrence after surgery have been reported in association with low but not high testosterone. In 6 uncontrolled studies results of testosterone therapy have been reported after radical prostatectomy, external beam radiation therapy or brachytherapy. In a total of 111 men 2 (1.8%) biochemical recurrences were observed. Anecdotal evidence suggests that testosterone therapy does not necessarily cause increased prostate specific antigen even in men with untreated prostate cancer.
CONCLUSIONS: Although no controlled studies have been performed to date to document the safety of testosterone therapy in men with prostate cancer, the limited available evidence suggests that such treatment may not pose an undue risk of prostate cancer recurrence or progression.
Morgentaler A, Lipshultz LI, Bennett R, Sweeney M, Avila D, Jr., Khera M. Testosterone Therapy in Men With Untreated Prostate Cancer. J Urol.
PURPOSE: A history of prostate cancer has been a longstanding contraindication to the use of testosterone therapy due to the belief that higher serum testosterone causes more rapid prostate cancer growth. Recent evidence has called this paradigm into question. In this study we investigate the effect of testosterone therapy in men with untreated prostate cancer. MATERIALS AND METHODS: We report the results of prostate biopsies, serum prostate specific antigen and prostate volume in symptomatic testosterone deficient cases receiving testosterone therapy while undergoing active surveillance for prostate cancer.
RESULTS: A total of 13 symptomatic testosterone deficient men with untreated prostate cancer received testosterone therapy for a median of 2.5 years (range 1.0 to 8.1). Mean age was 58.8 years. Gleason score at initial biopsy was 6 in 12 men and 7 in 1. Mean serum concentration of total testosterone increased from 238 to 664 ng/dl (p <0.001). Mean prostate specific antigen did not change with testosterone therapy (5.5 +/- 6.4 vs 3.6 +/- 2.6 ng/ml, p = 0.29). Prostate volume was unchanged. Mean number of followup biopsies was 2. No cancer was found in 54% of followup biopsies. Biopsies in 2 men suggested upgrading, and subsequent biopsies in 1 and radical prostatectomy in another indicated no progression. No local prostate cancer progression or distant disease was observed.
CONCLUSIONS: Testosterone therapy in men with untreated prostate cancer was not associated with prostate cancer progression in the short to medium term. These results are consistent with the saturation model, ie maximal prostate cancer growth is achieved at low androgen concentrations. The longstanding prohibition against testosterone therapy in men with untreated or low risk prostate cancer or treated prostate cancer without evidence of metastatic or recurrent disease merits reevaluation.
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(2):310-20.
CONTEXT: The traditional belief that prostate cancer (PCa) growth is dependent on serum testosterone (T) level has been challenged by recent negative studies in noncastrated men.
OBJECTIVE: To provide an improved framework for understanding the relationship of PCa to serum T level that is consistent with current evidence and is based on established biochemical principles of androgen action within the prostate.
EVIDENCE ACQUISITION: A literature search was performed of publications dating from 1941 to 2008 that addressed experimental and clinical effects of androgens on prostate growth. Review of studies investigating the prostatic effects of manipulation of androgen concentrations in human and animal studies, and in PCa cell lines.
EVIDENCE SYNTHESIS: Prostate growth is exquisitely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels. This pattern is consistent with the observation that androgens exert their prostatic effects primarily via binding to the androgen receptor (AR), and that maximal androgen-AR binding is achieved at serum T concentrations well below the physiologic range. A Saturation Model is proposed that accounts for the seemingly contradictory results in human PCa studies. Changes in serum T concentrations below the point of maximal androgen-AR binding will elicit substantial changes in PCa growth, as seen with castration, or with T administration to previously castrated men. In contrast, once maximal androgen-AR binding is reached the presence of additional androgen produces little further effect.
CONCLUSIONS: The evidence clearly indicates that there is a limit to the ability of androgens to stimulate PCa growth. A Saturation Model based on androgen-AR binding provides a satisfactory conceptual framework to account for the dramatic effects seen with castration as well as the minor impact of T administration in noncastrated men.
Chuu CP, Kokontis JM, Hiipakka RA, et al. Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer. J Biomed Sci 2011;18:63. Journal of Biomedical Science | Full text | Androgens as Therapy for Androgen Receptor-Positive Castration-Resistant Prostate Cancer
Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.
Morgentaler A. Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer. (1743-6109 (Electronic)).
http://www.watchwait.com/docs/two-yrs-trt-pca.pdf
INTRODUCTION: Testosterone (T) therapy has long been considered contraindicated in men with prostate cancer (PCa). However, the traditional view regarding the relationship of T to PCa has come under new scrutiny, with recent reports suggesting that PCa growth may not be greatly affected by variations in serum T within the near-physiologic range. AIM: This report details the clinical and prostate-specific antigen (PSA) response of a man with untreated PCa treated with T therapy for 2 years. METHODS: Measurements of serum PSA, total and free T concentrations were obtained at regular intervals at baseline and following initiation of T therapy.
MAIN OUTCOME MEASURE: Serum PSA during T therapy.
RESULTS: An 84-year-old man was seen for symptoms of hypogonadism, with serum total T within the normal range at 400 ng/dL, but with a reduced free T of 7.4 pg/mL (radioimmunoassay [RIA], reference range 10.0-55.0). PSA was 8.5 ng/mL, and 8.1 ng/mL when repeated. Prostate biopsy revealed Gleason 6 cancer in both lobes. He refused treatment for PCa, but requested T therapy, which was initiated with T gel after informed consent regarding possible cancer progression. Serum T increased to a mean value of 699 ng/dL and free T to 17.1 pg/mL. PSA declined to a nadir of 5.2 ng/mL at 10 months, increased slightly to 6.2 ng/mL at 21 months, and then declined to 3.8 ng/mL at 24 months after addition of dutasteride for voiding symptoms. No clinical PCa progression was noted.
CONCLUSION: A decline in PSA was noted in a man with untreated PCa who received T therapy for 2 years. This case provides support for the notion that PCa growth may not be adversely affected by changes in serum T beyond the castrate or near-castrate range.
