Prostate ...

[Michael Scally MD]

Castration-resistant prostate cancer does not necessarily require the presence of testosterone and growth in the absence of hormonal stimulation is frequently observed.

Thus, standard androgen deprivation therapy is ineffective at this stage of the disease.

Now, Schweizer et al. have pursued a different approach, based on evidence that cancer cells adapted to low-androgen conditions may not be able to tolerate high amounts of testosterone.

A clinical trial of “bipolar androgen therapy,” leading to alternation between very high and low concentrations of testosterone in the patients’ blood, showed that the regimen was well tolerated and has therapeutic potential.

In addition to its direct anticancer effects, intermittent testosterone dosing may restore the tumors’ sensitivity to antiandrogen agents, further expanding patients’ treatment options.

Schweizer MT, Antonarakis ES, Wang H, et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study. Science Translational Medicine 2015;7(269):269ra2. http://stm.sciencemag.org/content/7/269/269ra2.abstract

Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer.

Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs).

Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment.

However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death.

Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28).

After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy.

Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar androgen therapy (BAT).

BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients).

Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year.

All patients (10 of 10) demonstrated PSA reductions upon receiving androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs.

BAT shows promise as treatment for CRPC and should be further evaluated in larger trials.

 

[Michael Scally MD]

Goetz T, Burnett AL. Prostate cancer risk after anti-androgen treatment for priapism. Int Urol Nephrol 2014;46(4):757-60. http://link.springer.com/article/10.1007/s11255-013-0583-z

BACKGROUND: Patients with recurrent ischemic priapism have historically been treated with anti-androgen therapy due to the limited available evidence for more targeted therapies to treat the underlying pathophysiologic mechanisms of this condition. We report a case in which anti-androgen therapy caused significant adverse side effects and likely masked this patient's elevated prostate-specific antigen (PSA) levels, which adversely impacted the timely diagnosis and treatment of his prostate cancer.

CASE REPORT: A 69-year-old man treated with anti-androgens for priapism initially developed unwanted anti-androgenic side effects such as gynecomastia, erectile dysfunction, and decreased libido. After decreasing his anti-androgen dosage and starting a specified regimen of phosphodiesterase type 5 inhibitor therapy, his serum PSA levels were found to be elevated. He was subsequently diagnosed with adenocarcinoma of the prostate and underwent a radical prostatectomy with the pathologic finding of high-grade, locally progressive disease.

CONCLUSION: Anti-androgen therapy carries significant complication risks, including the potential to alter the diagnosis and treatment of prostate cancer. Clinicians administering this therapy for priapism management should be aware of these possible risks.

 

[Michael Scally MD]

Leon P, Seisen T, Cussenot O, et al. Low circulating free and bioavailable testosterone levels as predictors of high-grade tumors in patients undergoing radical prostatectomy for localized prostate cancer. Urol Oncol. http://www.urologiconcology.org/article/S1078-1439(14)00399-8/abstract

OBJECTIVE: Controversy exists regarding the propensity of hypogonadism and metabolic disorders to promote the development of high-risk prostate cancer (PCa). Our aim was to prospectively test whether preoperative circulating testosterone levels, obesity, and metabolic syndrome (MetS) were correlated with aggressive pathological features after radical prostatectomy (RP).

MATERIAL AND METHODS: Overall, 354 patients undergoing robot-assisted RP at our academic institution, between 2010 and 2013, to treat clinically localized PCa were included in this prospective study. Pelvic lymphadenectomy was performed in 116 (32.8%) patients and confirmed the absence of nodal metastases in all of them. Cardiovascular risk factors and body-mass index (BMI) were used to define MetS and obesity, respectively. Total testosterone (TT) levels were assessed using an immunoassay method, whereas bioavailable testosterone (BT) and free testosterone (FT) levels were estimated using Vermeulens formula. Multivariate logistic regression analyses assessed independent predictors for postoperative aggressive pathological features (i.e., a pathological Gleason score [GS]>/=7, extracapsular extension [ECE], seminal vesicle invasion [SVI], and positive surgical margins [PSM]) and GS upgrading.

RESULTS: Low TT, BT, and FT levels were found in 54 (15.2%), 70 (19.8%), and 62 (17.5%) patients, respectively. Median BMI was 26.3kg/m2 (range: 17.4-43.9), and prevalence of MetS was 18.9%. Significantly higher rates of pathological GS>/=7 were observed in groups with a low TT level (46.3% vs. 33.3%; P = 0.01), low BT level (44.3% vs. 33.1%; P<0.001), and low FT level (46.8% vs. 32.9%; P = 0.001). Multivariate analyses demonstrated that only low BT and FT levels were independent predictors of pathological GS>/=7 (odds ratio [OR] = 1.76; P<0.001 and OR = 1.39; P<0.001, respectively) and GS upgrading (OR = 2.82; P<0.001 and OR = 1.71; P<0.001, respectively), but there was no significant correlation between low circulating testosterone levels and ECE, SVI, or PSM. Furthermore, BMI (OR = 1.28; P = 0.04) and MetS (OR = 1.19; P = 0.01) were only correlated with PSM.

CONCLUSION: Hypogonadism, obesity, and MetS were not independent predictors of pathological GS >/=7, ECE, or SVI after RP. Our data suggest that only low BT and FT levels, which might logically result in an active androgen-depleted environment, were linked with high-grade PCa.

 

[Michael Scally MD]

[Hypothesis] Vitamin K: The Missing Link To Prostate Health

Donaldson MS. Vitamin K: The missing link to prostate health. Med Hypotheses. http://www.medical-hypotheses.com/article/S0306-9877(15)00011-0/abstract

Though age-related prostate enlargement is very common in Western societies, and the causes of benign prostate hyperplasia, BPH, have been diligently sought after, there is no biological, mechanistic explanation dealing with the root causes and progression of this very common disorder among men.

All treatments to date are based on symptomatic relief, not a fundamental understanding of the cause of the disease. However, recent advances have shown that even subclinical varicoceles, which are more common than generally realized, cause retrograde blood flow from the testes past the prostate gland causing over a 130-fold increase in free testosterone in the veins near the prostate.

By treating the varicoceles via embolization of the internal spermatic vein and its communicating and connected vessels the prostate enlargement can be reversed with corresponding symptomatic relief.

So, varicose veins in the pampiniform venous plexus, varicoceles, are the direct cause of BPH. But what causes varicoceles?

Recent research has uncovered the role of vitamin K in the calcification of varicose veins as well as a role in the proliferation of smooth muscle cells in the media layer of the vein wall. Vitamin K is intimately involved in the formation of varicose veins.

The hypothesis is that poor prostate health is essentially a vitamin K insufficiency disorder.

By providing vitamin K in the right form and quantity, along with other supporting nutrients and phytochemicals, it is likely that excellent prostate health can be extended much longer, and perhaps poor prostate health can be reversed. A protective role for vitamin K with respect to advanced prostate cancer was already found in the Heidelberg cohort of the EPIC study.

This hypothesis can be further evaluated in studies examining the connection between vitamin K and varicoceles, and also by examining the connection between varicoceles and benign prostate hyperplasia.

If this hypothesis is found to be true, management of prostate health will be radically altered. Rather than focusing on prostate health as a hormonal imbalance, prostate enlargement will be seen as a result of poor health of the veins in general and the internal spermatic veins in particular.

Factors which promote the health of the veins will become a greater focus of research, including the role of vitamin K. Finally, the emerging understanding of the cause of BPH will empower men to take care of their bodies so they can enjoy much better health through their entire lifespan.

 

[Michael Scally MD]

Zambon JP, Almeida FG, Conceicao RD, et al. Prostate-Specific Antigen testing in men between 40 and 70 years in Brazil: database from a check-up program. Int Braz J Urol 2014;40(6):745-52. http://www.brazjurol.com.br/november_december_2014/Zambon_745_752.htm

Objectives: To evaluate the PSA in a large population of Brazilian men undergone to check up, and correlate the PSA cutoffs with prostate size and urinary symptoms.

Materials and Methods: This is a cross sectional study performed with men between 40 and 70 years undergone to check-up. All men were undergone to urological evaluation, digital rectal examination, prostate-specific antigen, and ultrasonography The exclusion criteria were men who used testosterone in the last six months, or who were using 5 alpha-reductase inhibitors.

Results: A total of 5015 men with an average age of 49.0 years completed the study. Most men were white and asymptomatic. The PSA in the three different aging groups were 0.9 +/- 0.7ng/dL for men between 40 and 50; 1.2 +/- 0.5ng/dL for men between 50 and 60; and 1.7 +/- 1.5ng/dL for men greater than 60 years (p=0.001).

A total of 192 men had PSA between 2.5 and 4ng/ml. From these men 130 were undergone to prostate biopsy. The predictive positive value of biopsy was 25% (32/130). In the same way, 100 patients had PSA >4ng/mL. From these men, 80 were undergone to prostate biopsy. In this group, the predictive positive value of biopsy was 40% (32/100). The Gleason score was 6 in 19 men (60%), 7 in 10 men (31%) and 8 in 3 men (9%).

Conclusions: The PSA level of Brazilian men undergone to check up was low. There was a positive correlation with aging, IPSS and prostate size.

 

[Michael Scally MD]

Morgentaler A, Conners WP. Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations. Asian J Androl. http://www.ajandrology.com/preprintarticle.asp?id=148067

For several decades any diagnosis of prostate cancer (PCa) has been considered an absolute contraindication to the use of testosterone (T) therapy in men.

Yet this prohibition against T therapy has undergone recent re-examination with refinement of our understanding of the biology of androgens and PCa, and increased appreciation of the benefits of T therapy.

A reassuringly low rate of negative outcomes has been reported with T therapy after radical prostatectomy (RP), radiation treatments, and in men on active surveillance.

Although the number of these published reports are few and the total number of treated men is low, these experiences do provide a basis for consideration of T therapy in selected men with PCa.

For clinicians considering offering this treatment, we recommend first selecting patients with low grade cancers and undetectable prostate-specific antigen following RP. Further research is required to define the safety of T therapy in men with PCa.

However, many patients symptomatic from T deficiency are willing to accept the potential risk of PCa progression or recurrence in return for the opportunity to live a fuller and happier life with T therapy.

 

[Michael Scally MD]

Zhang Q, Gray PJ. From bench to bedside: bipolar androgen therapy in a pilot clinical study. Asian J Androl. http://www.asiaandro.com/news/upload/20150205-201520.pdf

Prostate cancer remains a leading cause of cancer death in Europe and the United States and is an emerging problem in Asia despite significant improvements in available treatments over the last few decades.

Androgen deprivation therapy (ADT) has been the core treatment of advance-staged disease since the discovery of prostate cancer’s androgen dependence in 1941 by Huggins and colleagues.

Options for initial medical treatment include GnRH analgoues such as leuprolide (LHRH agonist) and degarelix (LHRH antagonist) and androgen receptor (AR) binding agents such as bicalutamide.

Although most patients will initially respond to either surgical or medical castration there is almost always progression to castration-resistant prostate cancer (CRPC) necessitating treatment with more novel agents.

However, even drugs such as abiraterone and enzalutamide, two next-generation agents used commonly in metastatic CRPC, have failed to demonstrate persistent efficacy in most patients

Emerging research has proposed several mechanisms of resistance to ADT including constitutively active AR splice variants, overexpression of AR, and mutations of the ligand-binding-domain (LBD) of AR.

Pre-clinical studies published by Isaacs et al. and Haffner et al. on adaptive auto-regulation of AR and induction of DNA damage with testosterone therapy in CRPC cells provide a rationale for a novel approach to overcoming castration resistance: bipolar androgen therapy (BAT). http://stm.sciencemag.org/content/7/269/269ra2.abstract

By actively exposing cells with adaptive changes in AR function to supraphysiologic levels of androgen, nuclear AR loses the flexibility to be removed from origin of DNA replication sites (ORS) thereby interrupting mitosis and causing tumor cell death.

This is then followed by a return to a castrate level of testosterone leaving surviving cells with baseline low AR or adaptive down-regulated AR again vulnerable to cell death.

This initial clinical study shows encouraging results for BAT as a novel treatment for patients with metastatic CRPC.

 

[Michael Scally MD]

For the management of prostate cancer it has remained a significant clinical challenge to identify biomarkers that can be used as prognostic indicators to facilitate early treatment decisions and indicate patients at risk for castrate-resistant bone-metastatic prostate cancer in need of more aggressive treatment.

In this report, serum antibodies to alpha-2–Heremans–Schmidt glycoprotein (fetuin-A) were demonstrated to display increased reactivity with concomitant development of metastatic castrate-resistant disease in a large cohort of prostate cancer patients.

Furthermore, metastatic prostate cancer cell lines and bone metastasis samples displayed robust fetuin-A expression.

To our knowledge, this is the first report to indicate that serum autoantibodies reactive to fetuin-A show utility as a prognostic indicator for prostate cancer patients at risk for progressing to metastatic disease.

Mintz PJ, Rietz AC, Cardo-Vila M, Ozawa MG, Dondossola E, et al. Discovery and horizontal follow-up of an autoantibody signature in human prostate cancer. Proceedings of the National Academy of Sciences. http://www.pnas.org/content/early/2015/02/03/1500097112.abstract

In response to an urgent need for improved diagnostic and predictive serum biomarkers for management of metastatic prostate cancer, we used phage display fingerprinting to analyze sequentially acquired serum samples from a patient with advancing prostate cancer.

We identified a peptide ligand, CTFAGSSC, demonstrating an increased recovery frequency over time.

Serum antibody reactivity to this peptide epitope increased in the index patient, in parallel with development of deteriorating symptoms.

The antigen mimicking the peptide epitope was identified as alpha-2–Heremans–Schmid glycoprotein, also known as fetuin-A.

Metastatic prostate cancer cell lines and bone metastasis samples displayed robust fetuin-A expression, and we demonstrated serum immune reactivity to fetuin-A with concomitant development of metastatic castrate-resistant disease in a large cohort of prostate cancer patients.

Whereas fetuin-A is an established tumor antigen in several types of cancer, including breast cancer, glioblastoma, and pancreas cancer, this report is to our knowledge the first study implicating fetuin-A in prostate cancer and indicating that autoantibodies specific for fetuin-A show utility as a prognostic indicator for prostate cancer patients prone to progress to metastatic disease.

 

[MR10X]

Just that much more reason to to get your DRE and PSA Done,the sooner its diagnosed the better it can be treated. Mine was still confined to the prostrate and treatment so far has been sucessful.....after 2 years my PSA went from 11.2 to 0.40..........

 

[Michael Scally MD]

Kenfield SA, Van Blarigan EL, DuPre N, Stampfer MJ, Giovannucci EL, et al. Selenium Supplementation and Prostate Cancer Mortality. Journal of the National Cancer Institute. 2015;107(1). http://jnci.oxfordjournals.org/content/107/1/dju360.abstract

Background: Few studies have evaluated the relation between selenium supplementation after diagnosis and prostate cancer outcomes.

Methods: We prospectively followed 4459 men initially diagnosed with nonmetastatic prostate cancer in the Health Professionals Follow-Up Study from 1988 through 2010 and examined whether selenium supplement use (from selenium-specific supplements and multivitamins) after diagnosis was associated with risk of biochemical recurrence, prostate cancer mortality, and, secondarily, cardiovascular disease mortality and overall mortality, using Cox proportional hazards models. All P values were from two-sided tests.

Results: We documented 965 deaths, 226 (23.4%) because of prostate cancer and 267 (27.7%) because of cardiovascular disease, during a median follow-up of 8.9 years. In the biochemical recurrence analysis, we documented 762 recurrences during a median follow-up of 7.8 years. Crude rates per 1000 person-years for prostate cancer death were 5.6 among selenium nonusers and 10.5 among men who consumed 140 or more μg/day. Crude rates per 1000 person-years were 28.2 vs 23.5 for all-cause mortality and 28.4 vs 29.3 for biochemical recurrence, for nonuse vs highest-dose categories, respectively. In multivariable analyses, men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 or more μg/day of supplemental selenium had a 1.18 (95% confidence interval [CI] = 0.73 to 1.91), 1.33 (95% CI = 0.77 to 2.30), and 2.60-fold (95% CI = 1.44 to 4.70) greater risk of prostate cancer mortality compared with nonusers, respectively, P trend = .001. There was no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.

Conclusion: Selenium supplementation of 140 or more μg/day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. Caution is warranted regarding usage of such supplements among men with prostate cancer.

 

[Michael Scally MD]

[Not] Learning From History in Micronutrient Research

Brasky TM, Kristal AR. Learning From History in Micronutrient Research. Journal of the National Cancer Institute. 2015;107(1). http://jnci.oxfordjournals.org/content/107/1/dju375.full

George Santayana, the Spanish philosopher, is credited with the often paraphrased quote that “those who cannot remember the past are condemned to repeat it.” In our most cynical moments, these words ring true as a commentary on micronutrient supplements for cancer prevention.

Four years ago, Tim Byers eloquently summarized in an editorial titled “Anticancer Vitamins du Jour: The ABCED’s So Far” that chemoprevention trials of vitamin supplements have been largely fruitless (pardon the pun). http://aje.oxfordjournals.org/content/172/1/1.full

This year, John Potter wrote a review, “The Failure of Cancer Chemoprevention,” which was sharply critical of chemoprevention research. Each of these essays noted that, based on results of trials thus far, a single-agent, supraphysiologic dose of a nutrient does not typically have its intended effect. http://carcin.oxfordjournals.org/content/35/5/974.full

Missing from the design of these supplementation trials is a nuanced understanding of human nutrition.

There is reasonable agreement on the intakes of micronutrients that are required to prevent clinical manifestations of deficiency and on intakes high enough to cause acute toxicity; but optimal micronutrient intakes are likely within more narrow ranges than between these two extremes, and studies have demonstrated repeatedly that micronutrient intakes well below those associated with acute toxicity can increase the risks of several cancers.

 

[Michael Scally MD]

Lu J, der Steen TV, Tindall DJ. Are androgen receptor variants a substitute for the full-length receptor? Nat Rev Urol.advance online publication. http://www.nature.com/nrurol/journal/vaop/ncurrent/full/nrurol.2015.13.html

Androgen receptor splice variants (AR-Vs)—which are expressed in castration-resistant prostate cancer (CRPC) cell lines and clinical samples—lack the C-terminal ligand-binding domain and are constitutively active.

AR-Vs are, therefore, resistant to traditional androgen deprivation therapy (ADT).

AR-Vs are induced by several mechanisms, including ADT, and might contribute to the progression of CRPC and resistance to ADT.

AR-Vs could represent a novel therapeutic target for prostate cancer, especially in CRPC.



Hypothetical model of the regulation of gene expression by AR‑FL and AR‑Vs in prostate cancer cells.

The canonical AR signalling pathway remains intact with androgen-bound AR‑FL forming a homodimer, translocating into the nucleus and binding to AREs.

AR‑Vs can translocate into the nucleus in the absence of androgen and might form homodimers or heterodimers with androgen-bound AR‑FL.

These homodimers or heterodimers could potentially bind to specific cis-acting elements (ARV-REs) and recruit different coregulators to form transcription complexes, resulting in a distinct transcriptional programme for AR‑Vs in prostate cancer cells.

Abbreviations: AR, androgen receptor; ARE, androgen response element; AR‑FL, full-length androgen receptor; AR‑V, androgen receptor variant; ARV-RE, AR‑V response elements; DHT, dihydrotestosterone; HSP, heat shock protein; T, testosterone.

 

[Michael Scally MD]

Kuhn CM, Strasser H, Romming A, Wullich B, Goebell PJ. Testosterone Replacement Therapy in Hypogonadal Men Following Prostate Cancer Treatment: A Questionnaire-Based Retrospective Study among Urologists in Bavaria, Germany. Urol Int. http://www.karger.com/Article/Abstract/371725

Background: Several reports suggest testosterone replacement therapy (TRT) may be an option in selected hypogonadal patients with a history of prostate cancer (PCa) and no evidence of disease after curative treatment. Our aim was to assess TRT experience and patient management among urologists in Bavaria.

Materials and Methods: Questionnaires were developed and mailed to all registered urologists in Bavaria (n = 420) regarding their experience with TRT in patients with treated PCa.

Results: One hundred and ninety-three (46%) urologists returned the questionnaire and reported their experience with TRT in hypogonadal patients after curative treatment for PCa. Complete data was available for 32 men.

Twenty-six patients (81%) received TRT after prostatectomy, 1 patient after external beam radiation, 3 patients after high-dose brachytherapy and 2 patients after high-intensity focused ultrasound. Of the PCa cases, 88.5% (23/26) were organ confined (pT2a-c), and 3 were pT3 tumors. All patients were pN0/cN0, and only 1 patient (pT3a) had a positive surgical margin status postoperatively.

After a mean follow-up of 39.8 months, no biochemical relapse was observed.

Conclusion: To date, there is no clear evidence to withhold TRT from hypogonadal men after curative PCa treatment. Our findings, although with limitations, fit in with the available data showing that TRT does not put patients at an increased risk after curative treatment of PCa.

 

[Michael Scally MD]

Shumway DA, Hamstra DA. Ageism in the Undertreatment of High-Risk Prostate Cancer: How Long Will Clinical Practice Patterns Resist the Weight of Evidence? Journal of Clinical Oncology. http://jco.ascopubs.org/content/early/2015/01/05/JCO.2014.59.4093.full

Age discrimination is defined as “the denial of privilege or other unfair treatment based on the age of the person who is discriminated against,”1 and is a topic that has been studied at length in the field of oncology. For instance, despite obtaining similar survival benefit as younger patients, elderly patients are less likely to receive either surgery or radiation therapy (RT) for oropharyngeal squamous cell carcinoma.2 With rectal cancer, patients older than age 65 are less likely to receive preoperative radiotherapy, which has been demonstrated to reduce local recurrence rates and is widely considered as the standard of care for intermediate and locally advanced disease.3

Alarmingly, age-based discrimination is especially prevalent in men with high-risk prostate cancer; some have noted that for men older than 75 years of age with high-risk prostate cancer, 67% received primary androgen-deprivation therapy (ADT) or no therapy at all, and only 33% received any local therapy.4 With recent guidelines recommending against prostate-specific antigen screening5 and increased attention given to the role of active surveillance for low-risk prostate cancer, it is easy to lose sight of the fact that prostate cancer is a leading cause of cancer mortality in men, second only to lung cancer.6

Ultimately, the majority of men diagnosed with locally advanced or high-risk prostate cancer will succumb to their disease within 15 years with conservative treatment, regardless of their age at diagnosis.7 Yet numerous studies have demonstrated widespread undertreatment of high-risk prostate cancer in older men,4,8,9 despite the observation that older men are more likely to have high-risk disease4 and account for approximately half of deaths as a result of prostate cancer.10 Furthermore, undertreatment of high-risk prostate cancer is a growing problem, with an increasing use of primary ADT monotherapy over time.8

Given that an average 75-year-old man in the United States has a remaining life expectancy of 11 years,11 and that the 10-year cause-specific mortality from conservatively treated high-risk prostate cancer is approximately 26%,12 this represents a serious potential for age-dependent bias against therapy.

 

[blazinshotguns]

is .8 psa high for a 20 year old?

 

[Michael Scally MD]

is .8 psa high for a 20 year old?

No

 

[Michael Scally MD]

Hoque A, Yao S, Till C, Kristal AR, Goodman PJ, et al. Effect of Finasteride on Serum Androstenedione and Risk of Prostate Cancer Within the Prostate Cancer Prevention Trial: Differential Effect on High- and Low-grade Disease. Urology. 2015;85(3):616-20. http://www.goldjournal.net/article/S0090-4295(14)01320-X/abstract

OBJECTIVE: To evaluate the effect of finasteride on serum androst-4-ene-3,17-dione (androstenedione) and its association with prostate cancer risk among subjects who participated in the Prostate Cancer Prevention Trial.

METHODS: We analyzed serum androstenedione levels in 317 prostate cancer cases and 353 controls, nested in the Prostate Cancer Prevention Trial, a randomized placebo-controlled trial that found finasteride decreased prostate cancer risk. Androstenedione is the second most important circulating androgen in men besides testosterone and also a substrate for 5alpha-reductase enzyme.

RESULTS: We observed a 22% increase in androstenedione levels compared with the baseline values in subjects who were treated with finasteride for 3 years. This significant increase did not vary by case-control status. Adjusted odds ratio and 95% confidence interval for the third tertile of absolute change in androstenedione levels compared with the first tertile were 0.42 (95% confidence interval, 0.19-0.94) for low-grade (Gleason score <7) cases. Similar results were observed when analyzed using percent change. There were no significant associations between serum androstenedione levels and the risk of high-grade disease.

CONCLUSION: The results of this nested case-control study confirm that finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT) and of androstenedione to 5alpha-androstanedione-3,17-dione, which also leads to the reduction of DHT formation. This decrease in DHT may help reduce the risk of low-grade prostate cancer in men. Our data on a differential effect of androstenedione also suggest that some high-grade prostate cancers may not require androgen for progression.

 

[Michael Scally MD]

Scovell JM, Butler P, Ramasamy R, Lamb DJ. Re: Testosterone Treatment Is a Potent Tumor Promoter for the Rat Prostate. Eur Urol. 2015;67(4):814-5. http://www.europeanurology.com/arti...-a-potent-tumor-promoter-for-the-rat-prostate

[Bosland MC. Testosterone Treatment is a Potent Tumor Promoter for the Rat Prostate. Endocrinology:en.2014-1688. http://press.endocrine.org/doi/abs/10.1210/en.2014-1688 ]

Experts’ summary:

This animal study compared the effect of testosterone supplementation on prostatic and all-site carcinogenesis in the male rat after androgen deprivation treatment (n = 28–30 per treatment group). Using various treatment approach models, rats aged 10–12 wk were pretreated with antiandrogen therapy for 3 wk, subsequently had testosterone replaced with injectable testosterone propionate for 3 d, and finally were treated with the toxic compoundN-nitroso-N-methylurea (NMU) to induce carcinogenesis. After this pretreatment regimen, various numbers of slowly eluting testosterone implants were placed in the rats, including a placebo. Previous studies have shown prostatic carcinogenesis using a combination of NMU and implantable testosterone; this study aimed to provide dose-response data.

An increase in serum testosterone was only seen for two or more implants (p < 0.001), and this response was durable up to 20 wk (p < 0.05). The untreated control group had 0% incidence of prostatic/accessory (p/ag) gland malignancy, and rats that underwent the pretreatment regimen all had some incidence of p/ag tumors. Pretreated rats without testosterone had the lowest incidence of p/ag malignancy (4%) followed by rats with one tube (57%), two tubes (71–76%), and four tubes (76%). Rats that had two or four implantable tubes had greater rates of p/ag adenocarcinoma compared to rats that did not receive implantable testosterone (p < 0.0001). In rats without pretreatment therapy, there was a greater incidence of p/ag carcinoma in animals with two implantable tubes but not four implantable tubes when compared to controls (four tubes, 13%,p = 0.06; two tubes, 25%,p < 0.05; 0 tubes, 0%).

Experts’ comments:

Prostatic hyperplasia and eventual adenocarcinogenesis are dependent on testosterone. This animal model demonstrates the differentiating effect of testosterone on prostatic epithelial tissue. These concerns are not new; indeed, they were the paradigm until relatively recently. Huggins et al [1] raised the initial concerns that exogenous testosterone use could result in the generation of new lesions and stimulate existing adenocarcinoma. However, the concern that testosterone supplementation therapy will result in increased levels or severity of prostatic carcinoma has been tempered in recent years [2]. The literature suggests that physiological levels of serum testosterone have already saturated prostatic androgen receptors, and that at supraphysiological levels the stimulatory effect of testosterone on the prostate is negligible [3].

Bosland sought to explore this relationship between testosterone and prostatic adenocarcinoma. This research supports the understanding that testosterone is necessary for the development of prostatic adenocarcinoma, which has been demonstrated by negligible rates of prostate cancer in the eunuch male population [4]. Specifically, this study sought to demonstrate increasing prevalence of prostate cancer in a dose-dependent response to testosterone implants. To stimulate the growth of prostate cancer by testosterone, the strong alkylating agent NMU was used. NMU led to the genesis of other benign and malignant tumors in tissues not associated with androgen action (pituitary adenomas, lymphomas, Zymbal gland carcinomas, skin tumors). Furthermore, carcinogenesis originated in some cases in seminal vesicles, which is distinct in origin from prostate cancer. The clinically relevant information from this study is that the prevalence of prostatic adenocarcinoma did not increase after serum testosterone reached physiological or supraphysiological levels. This is corroborated by the aforementioned research suggesting that testosterone at or above physiological levels has a negligible effect on the prostate.

Bosland also found that exogenous testosterone treatment alone increased the risk of malignant tumors, but this finding has not been confirmed by other studies. Bosland's work builds on a study by McCormick et al [5], who found that testosterone and NMU together increase tumor incidence. However, this study differs from the previous one in that McCormick et al found that testosterone alone (at eugonadal levels) was responsible for a tumor incidence of <10% versus Bosland's finding of 25%. It is tempting to speculate that exogenous testosterone administration (even at low doses) was involved in the development of prostate cancer.

Researchers and practitioners in the field should interpret these findings with caution. It is clear that testosterone is critical for the development and progression of prostate adenocarcinoma. However, these results provide further evidence that at or above physiological levels, there is no increase in the risk of carcinogenesis. Further research is also required to determine whether exogenous testosterone alone leads to significantly higher incidence of prostate tumors. Until prospective randomized trials that may be able to answer these questions are completed [6], prostate cancer should remain a risk factor for testosterone supplementation. Our understanding of the literature and experience suggests that there is no clinically appreciable risk with regard to prostatic adenocarcinoma in men treated with testosterone supplementation therapy.

References

[1] C. Huggins, R.E. Stevens Jr., C.V. Hodges. Studies on prostatic cancer II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209-223. http://archsurg.jamanetwork.com/article.aspx?articleid=545269

[2] E.L. Rhoden, A. Morgentaler. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350:482-492. http://www.nejm.org/doi/full/10.1056/NEJMra022251

[3] A. Morgentaler. Goodbye androgen hypothesis, hello saturation model. Eur Urol. 2012;62:765-767. http://www.europeanurology.com/arti...ye-androgen-hypothesis-hello-saturation-model

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[Michael Scally MD]

Gray H, Seltzer J, Talbert RL. Recurrence of prostate cancer in patients receiving testosterone supplementation for hypogonadism. Am J Health Syst Pharm. 2015;72(7):536-41. http://www.ajhp.org/content/72/7/536

PURPOSE: The relationship between recurrent prostate cancer risk and testosterone replacement therapy (TRT) for hypogonadal men is explored.

SUMMARY: The medical literature was searched to identify articles evaluating the use of TRT in symptomatic hypogonadal men with a history of prostate cancer. Eight English-language articles investigating TRT use in hypogonadal men with a history of prostate cancer were analyzed. For evaluative purposes, the normal ranges used for prostate-specific antigen (PSA) and total testosterone levels were less than 4.0 ng/mL and 300-1000 ng/dL, respectively. Most trials were small and involved patients with localized prostate cancer treated with radical prostatectomy or radiotherapy, though patients with metastatic disease or a Gleason score of >/=8 were included in a few studies. TRT was administered in a variety of dosages and dosage forms for up to nine years to manage hypogonadal symptoms. Testosterone concentrations increased, as expected, after TRT, but serum PSA levels remained below 0.1 ng/mL in the majority of patients. PSA levels were found to increase in select patients with high-risk and metastatic disease, but these elevations were not accompanied by disease progression. These studies have suggested a potential benefit for TRT use in select symptomatic hypogonadal men with a history of prostate cancer. Data were limited, however, by the retrospective nature of most studies, the lack of control groups, small sample sizes, and short follow-up periods.

CONCLUSION: There is insufficient evidence to withhold TRT in certain populations of men with a history of prostate cancer.

 

[Michael Scally MD]

Sakamoto S. Editorial Comment to Prostate-specific antigen-based prostate cancer screening: Past and future. International Journal of Urology. http://onlinelibrary.wiley.com/doi/10.1111/iju.12783/full


Alberts AR, Schoots IG, Roobol MJ. Prostate-specific antigen-based prostate cancer screening: Past and future. International Journal of Urology. http://onlinelibrary.wiley.com/doi/10.1111/iju.12750/full

Prostate-specific antigen-based prostate cancer screening remains a controversial topic. Up to now, there is worldwide consensus on the statement that the harms of population-based screening, mainly as a result of overdiagnosis (the detection of clinically insignificant tumors that would have never caused any symptoms), outweigh the benefits. However, worldwide opportunistic screening takes place on a wide scale. The European Randomized Study of Screening for Prostate Cancer showed a reduction in prostate cancer mortality through prostate-specific antigen based-screening. These population-based data need to be individualized in order to avoid screening in those who cannot benefit and start screening in those who will. For now, lacking a more optimal screening approach, screening should only be started after the process of shared decision-making. The focus of future research is the reduction of unnecessary testing and overdiagnosis by further research to better biomarkers and the value of the multiparametric magnetic resonance imaging, potentially combined in already existing prostate-specific antigen-based multivariate risk prediction models.