Angela Black

Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations

To assess the effects of testosterone supplementation in men with testosterone deficiency syndrome (TDS) after external beam radiotherapy (EBRT) for localized prostate cancer.

The reliability of clinical and biochemical assessment in symptomatic late-onset hypogonadism: can a case be made for a 3-month therapeutic trial?

To assess whether testosterone (T) supplementation in men considered to have symptomatic late‐onset hypogonadism (SLOH) can be evaluated clinically and biochemically.

Adding to the controversy: Pitfalls in the diagnosis of testosterone deficiency syndromes with questionnaires and biochemistry

Purpose. To determine the value of available questionnaires used for the diagnosis of testosterone deficiency syndromes (TDS) by correlating their ratings with a panel of hormonal determinations in a male population. Materials and methods. Participants completed the ADAM questionnaire and underwent biochemical evaluation at the local site. Assessments determined entry into Group A (symptomatic) or Group B (non-symptomatic). After stratification, subjects provided a morning sample of blood, completed the Aging Male Survey (AMS) and the newly developed Canadian Society for the Study of the Aging Male (CSAM-Q) questionnaires. Serum aliquots were analysed at a central lab for 8 putative markers commonly associated with symptomatic testosterone deficiency associated with aging: total testosterone (T); bioavailable T (BT); dehydroepiandrosterone sulphate (DHEA-S); sex-hormone binding globulin (SHBG); luteinizing hormone (LH), prolactin (PRL); thyroid-stimulating hormone (TSH) and insulin-like growth factor-1 (IGF-1). Results. 92 men were screened; of these 59 (mean age of 58 ± 11 years) completed the study, 30 (51%) scored positively (mean 61.5 years) to the ADAM while 29 (49%) did not (mean 54.1 years). For the AMS the weight of the three domains (psychological, somato-vegetative and sexual) was significantly greater in Group A (p < 0.001) than in Group B. Equally, for the CAS questionnaire, the scores for the variables energy, global performance, frequency of intercourse, mood and quality of sleep were lower in Group A than in their asymptomatic counterparts (p < 0.001). The domain of memory assessment within the CSSAM-Q was not discriminatory. ADAM and AMS are self-administered and completed within 10 minutes. CSSAM-Q is more time consuming, requires an investigator to administer, and memory domain is biased in favour of specific professional training. No difference was found between the two groups in 6 of 8 biochemical tests. However, significant lower values (p < 0.001) were found for DHEA-S and IGF-1 in the symptomatic group as compared with the non-symptomatic cohort. Conclusions. This study confirms that newer, more complex tools perform similarly to the simpler ADAM questionnaire. The lack of correlation between the clinical picture and the most commonly used biochemical confirmatory tests, again, clearly points to the paramount importance of the clinical evaluation. An emphasis and reliance on serum T alone hinders the clinicians ability to manage testosterone deficiency syndromes (TDS).

Androgens and sexual function: a placebo-controlled, randomized, double-blind study of testosterone vs. dehydroepiandrosterone in men with sexual dysfunction and androgen deficiency

Purpose. Supplemental administration of androgens has been advocated for men with sexual dysfunction (SD) and hypoandrogenism. The preponderance of evidence indicates that most delivery forms of testosterone (T) are effective but the role of dehydroepiandrosterone (DHEA) is controversial. A placebo-controlled, randomized trial of oral androgen (T versus DHEA) supplementation was carried out to determine their efficacy. Materials and methods. Eighty-six men with SD and decreased levels of serum T and/or DHEA, participated in a study receiving oral T undecanoate (OTU) (n = 29) 80 mg twice daily, DHEA (n = 28) 50 mg twice daily, or placebo (n = 29). Outcomes included evaluation of sexual performance by the International Index of Erectile Function (IIEF), the Androgen Deficiency in the Aging Male (ADAM), Aging Male Symtom Scale (AMS), and Global Assessment Questionnaire (GAQ) questionnaires. Biochemical evaluations included measurement of T and DHEA, prolactin, gonadotropins, and PSA. Results. Seventy-nine men completed the study. There were no significant differences in outcomes as assessed by four different instruments: the ADAM, IIEF, AMS, and GAQ in regard to sexual interest or erectile function. Biochemically, a significant increase in serum DHEA between baseline and final visit was documented in the group receiving DHEA. The levels of T, on the other hand, increased insignificantly between entry and final visit in the T cohort. No biochemical changes were observed in the placebo group. Levels of PSA remained stable in all three groups. Conclusions. This study did not suggest a clinical benefit of OTU or DHEA supplementation in men with hypoandrogenism and SD. The recommended dose of OTU may have been inadequate or poorly absorbed. Increased doses or an alternative T delivery form may result in a different response.

The Significance of Biological Variation in the Diagnosis of Testosterone Deficiency, and Consideration of the Relevance of Total, Free and Bioavailable Testosterone Determinations

PURPOSE The diagnosis of testosterone deficiency syndrome is based on clinical manifestations and documentation of low testosterone. Which biochemical tests to use and the importance of morning sampling are still controversial. Biological variation (including interindividual and intraindividual biological variation) must be considered when interpreting individual results as it determines the usefulness of reference intervals and the change (reference change value) necessary for a significant difference between results. MATERIALS AND METHODS A total of 87 healthy men (50 to 70+ years old) provided blood in the morning of the first day, and 4 weeks later in the morning and afternoon. Samples were frozen (-70C) and analyzed in the same run for serum testosterone, sex hormone-binding globulin and albumin, and bioavailable testosterone and free testosterone were calculated. RESULTS Serum testosterone was lower in the afternoon by 1.5 nmol/l (43 ng/dl, p <0.05), with larger changes observed with higher morning values. However, this diurnal effect was dwarfed by the normal biological variation observed for repeat morning samples (serum testosterone +/- 4 nmol/l [115 ng/dl]). Between day intra-individual biological variation for morning serum testosterone was 18.7% while within day intra-individual biological variation was 12.9%. A change of 52% (reference change value) is necessary between serial morning results to confirm a significant difference. The biological variation parameters of calculated bioavailable testosterone and calculated free testosterone confer no advantage over total testosterone. CONCLUSIONS Marked individuality of serum testosterone is evident even in healthy men. Because intraindividual biological variation is less than interindividual biological variation, reference intervals are marginally useful. The homeostatic set point of a patient could decrease by half and still be within the reference interval. Prospective establishment of an individuals baseline over repeated measurements or symptoms regardless of serum testosterone concentration should be used to guide clinical decisions.

Serum follicle-stimulating hormone levels predict time to development of castration resistant prostate cancer

INTRODUCTION Treatment of advancing prostate cancer focuses on blocking the activation of the androgen receptor with resultant prolonged perturbation of the hypothalamic-pituitary-gonadal axis. Androgen deprivation therapy (ADT) is marked, however, by eventual progression to castration- resistant prostate cancer (CRPC). Emerging evidence has postulated that follicle-stimulating hormone (FSH) may lead to proliferative and mutagenic responses of prostate cancer. We investigated the association of serum FSH and time to castration resistance. METHODS This was a single-centre retrospective study assessing serum FSH levels of patients undergoing ADT for advancing prostate cancer. The primary outcome was time of ADT initiation to the development of CRPC. For each patient on treatment and with castrate levels of testosterone, the maximum FSH value between ADT commencement and CRPC was identified and recorded. FSH was analyzed as a continuous and categorical variable. Cox multivariate regression in a step-wise fashion was used to explore the association between FSH levels and time to CRPC. RESULTS From a database of 323 prostate cancer patients actively managed with ADT, 103 men had a documented FSH value while castrate, with 45 men progressing to CRPC. The mean ± standard deviation maximum FSH value of these patients was 6.66 ± 4.22 mIU/mL (range: 1.5-28.1). The mean duration from ADT commencement to CRPC was 3.03 ± 0.34 years (range: 0.36-9.71). Univariate analysis suggested a trend of a negative correlation between FSH values and time to castrate resistance. A FSH value of less than or equal to the lowest tertile (4.8 mIU/mL) was associated with a longer time to CRPC (hazard ratio 0.46; p = 0.006). In the Cox regression analysis, elevated FSH was associated with a shorter duration time to CRPC (p = 0.03). CONCLUSIONS This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated palliatively with ADT for advancing prostate cancer. Further clinical investigation in a larger cohort of men is required to determine any clinical utility of FSH as a biomarker of progression or target for therapy.

Clinical practice experience with testosterone treatment in men with testosterone deficiency syndrome

To report on a clinical practice series of testosterone‐replacement therapy (TRT) in men with testosterone deficiency syndrome (TDS), examining clinical efficacy, biochemical parameters and effects on prostate health over a 2‐year period.

Effects of androgen-deprivation therapy on hypercoagulability in prostate cancer patients: A prospective, longitudinal study

INTRODUCTION Androgen-deprivation therapy (ADT) is the mainstay of systemic therapy for advanced prostate cancer (PCa), but has significant adverse effects, including increasing concern for cardiovascular (CV) and thromboembolic (TE) complications. This study carefully investigates any relationship between ADT use and hypercoagulability as a possible mechanism of these adverse effects. METHODS We performed a prospective, longitudinal study in a cohort of patients with advanced PCa initiating ADT (n=18). Controls included men with biochemical failure after local therapy on watchful waiting (n=10), as well as healthy controls (n=8). Global hemostasis was evaluated using the sensitive global hemostasis assay, thromboelastography (TEG). Patients were evaluated at baseline and every three months for a minimum of 12 months. RESULTS The results of the TEG studies demonstrated 14/18 (78%) of advanced PCa patients had evidence of a hypercoagulable state before initiating therapy. Significant baseline hypercoagulability was documented in this cohort compared to the two control groups. ADT did not appear to exacerbate hypercoagulability over time as a whole: only 10/18 (56%) patients had TEG findings consistent with hypercoagulability at the end of study. However, 3/18 (17%) PCa patients initiating ADT had significantly new hypercoagulable TEG changes on treatment compared to baseline. CONCLUSIONS This prospective pilot study demonstrates a complex interaction between ADT and hypercoagulable state in men with advanced PCa. TEG abnormalities were mostly associated with volume of cancer as compared to ADT use; however, it is possible that ADT may lead to hypercoagulability in a subset of men, suggesting that sensitive monitoring of coagulation of men on ADT could help identify those at risk of developing CV/TE complications. Study limitations include the relatively small cohort of men followed after initiating ADT and these results require confirmation in a larger trial to rule out subtle effects on hypercoagulability.

Abstract 2690: Evaluation of the hemostatic status in patients with prostate cancer using thromboelastography and tissue factor- microparticles

Coagulopathy is reported as the second most common cause of death from cancers, particularly prostate cancer. DVT and pulmonary embolism are two major thrombotic complications in prostate cancer and the risk is even higher with chemotherapy and hormonal therapy. Thromboelastography (TEG) is a global hemeostatic test that detects and specifies the type of coagulopathy encountered through a vesicoelastic trace that reflects the kinetics of the clot from the initial fibrin thread till and fibrinolysis. We performed a hemostatic study in 27 patients (age range 59-88 years) diagnosed with prostate cancer at various stages (metastatic and non-metastatic) as compared to a control group (n=9) matching the same age range and with -ve pathology for prostate cancer. The study included whole blood TEG and flow cytometry analysis of microprticles (MPs) in plasma using Annexin V- FITC and anti-tissue factor - PE. Analysis of the data revealed hypercoagulable state in all patients except two who were maintained on coumadin as prophylaxis for previous DVT. Hypercoagulability was indicated by shorter R time, increased alpha angle, MA and clot index. The mean values for TEG parameters in the patients were: R: 6.01 vs 9.8 minutes in the control group, alpha angle: 68.3 vs 53.1 degrees in controls, MA: 69.3 vs 57.9 mm in controls, and CI: 3.32 vs 0.7 in controls. Paired student t test showed significant differences as regards R time (P=0.009), MA (p=0.053) and CI (P=0.051). Microparticle assay revealed significant elevation in the number of microparticles carrying tissue factor in the patient group compared to the control group (p=0.05). The mean plasma TF-MPs in patient group was 5,142 MPs/uL compared to 2,914 MPs/ uL in the control group suggesting a link between elevated tissue factor and hypercoagulability observed in these patients. To our knowledge, this is the first report for the use of TEG in patients with prostate cancer. TEG is a relatively simple test that uses a small volume of blood and can be a useful tool for evaluation of patients’ thrombotic potential and may help identification of those who may require anticoagulant prophylaxis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2690. doi:1538-7445.AM2012-2690

Biopsychosocial impact of prostate cancer and androgen-deprivation therapy

INTRODUCTION Prostate cancer is the most non-cutaneous malignancy in men, and androgen-deprivation therapy (ADT) is a cornerstone of management in advanced disease. The aim of this study was to evaluate the association of ADT with changes in depression and mental and physical quality of life (QoL) within a prospective patient cohort design. METHODS Patients were prospectively recruited and consented at a single academic health sciences centre in Ontario, Canada. Inclusion criteria included those men with adenocarcinoma of the prostate and either on watchful waiting or initiating ADT as palliation or as an adjuvant therapy for high-risk localized disease. All three cohorts were followed in routine care and completed psychosocial evaluations, including depression, social support, anxiety, and QoL measures. RESULTS In comparison to the control cohort of patients with prostate cancer on watchful waiting, initiation of ADT over a two-year period of time was not associated with any changes in depression or mental QoL. Instead, all patients, regardless of treatment cohort, showed increased depression scores and reduced mental QoL scores over time; however, for patients receiving ADT, a significant reduction in physical QoL compared to patients who did not receive ADT was demonstrated. CONCLUSIONS ADT does not appear to significantly impact depressive symptoms and mental QoL over a two-year period; however, the depressive symptoms in this limited sample of men with prostate cancer was higher than expected and monitoring for these may be advisable for those who care for such patients.