Testosterone,testosterone therapy and prostate cancer

Abstract

With prostate cancer not observed in eunuchs and total androgen suppression by castration an effective first-line treatment for advanced prostate cancer, the dramatic regression seen in tumour symptoms after castration, lead to the theory that high levels of circulating androgens were a risk factor for prostate cancer. This theory however, ignored the effects testosterone variations within a physiologic range could have on early tumour events and since the early 2000s, clinical evidence discounting testosterone as a linear mechanistic cause of prostate cancer growth mounted, with alternative mechanistic hypotheses such as the saturation model being proposed. Together with a growing understanding of the negative health effects and decreased quality of life in men with testosterone deficiency or hypogonadism, a paradigm shift away from testosterone as a prostate cancer inducer occurred allowing clinicians to use testosterone therapy as potential treatment for men with difficult and symptomatic hypogonadism that had been previously treated for prostate cancer. In this review we contextualise the idea of testosterone as a risk factor for prostate cancer inducement and compile the most current literature with regards to the influence of testosterone and testosterone therapy in prostate cancer.     

Testosterone deficiency and the metabolic syndrome

Evidence is presented to link components of the metabolic syndrome to testosterone deficiency and obesity. Testosterone deficiency in hypogonadism or testosterone deprivation in normo-gonadotropic men increases fat mass as well as fasting insulin levels. Testosterone supplementation (TS) in a dose dependent manner, increase lean body mass (LBM), reduces fat mass, body mass index (BMI) and waist hip ratio in both young and elderly hypogonadal men. A negative association between T and insulin resistance as well as impaired glucose intolerance has been demonstrated and in type 2 diabetic men TS improves metabolic parameters. TS improves most components of the metabolic syndrome and also reduces inflammatory cytokines.     

Time for international action on treating testosterone deficiency syndrome

Aim. Testosterone deficiency is having an increasing impact on men's health because of global aging, higher levels of obesity, diabetes and metabolic syndrome and adverse environmental factors such as stress xenoestrogens and anti-androgens. The question addressed is to what extent the large body of evidence on the benefits and safety of testosterone therapy is applied in clinical practice.

Methods. Demographic data for men over the age of 50 from different regions of the world have been compared with the number of men in that age group estimated from sales figures to be receiving testosterone treatment.

Results. On the basis of estimate that 20% of men over 50 in the general population of each region could be expected to have testosterone deficiency symptoms, on average only these men (0.69%) in most European countries were receiving treatment. Proportion was higher in the UK (1.00%) and Germany (1.89%), but lower in France (0.49%), Italy (0.51%) and Russia (0.54%). Interestingly, Australia had higher figures (1.64%), in spite of tight state control measures on androgen use. The USA has the highest treatment rate (7.96%) and this is increasing rapidly.

If the basis for the diagnosis was the more conventional combination of symptoms plus biochemical evidence of low total and free testosterone levels, androgen deficiency would be expected in at least 5% of men over 50, and percentage treatment rates therefore four times higher. However, even on that basis, only in the USA do these exceed 10%.

Conclusions. International action is urgently needed to raise awareness in the medical profession in the various countries of these remarkably low levels of testosterone treatment. Improvement in this requires education and motivation of doctors and those regulating the healthcare systems. A public awareness campaign is needed to educate men about the symptoms of testosterone deficiency and its impact on their health.     

Effects of oral testosterone undecanoate therapy on bone mineral density and body composition in 322 aging men with symptomatic testosterone deficiency: a 1-year,randomized, placebo-controlled,dose-ranging study

Abstract

Objective: We investigated the effects of oral testosterone undecanoate (TU) on bone mineral density (BMD), lean body mass (LBM) and body fat mass (BFM) in aging men with symptomatic testosterone deficiency (TD).

Methods: Three hundred twenty-two men ≥50 years with TD symptoms and calculated free testosterone <0.26?nmol/L participated in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to placebo, oral TU 80?mg/d, oral TU 160?mg/d, or oral TU 240?mg/d, administered as divided doses with normal meals. BMD of the hip and lumbar spine were evaluated by dual energy X-ray absorptiometry (DEXA), and body composition (LBM and BFM) by whole body DEXA.

Results: Oral TU significantly increased BMD at Month 12 at the lumbar spine (240?mg/d), total hip (240?mg/d), and trochanter and intertrochanter (160 and 240?mg/d) compared with placebo. Oral TU significantly increased LBM at Months 6 and 12 for all oral TU groups compared with placebo. BFM significantly decreased at Month 6 (all oral TU groups) and Month 12 (160?mg/d) compared with placebo. The effects on BMD and body composition showed a clear dose response.

Conclusions: Treatment with oral TU led to improvement in BMD, LBM and BFM in aging men with symptomatic TD.     

Prevalence,incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania

Objective.?Low total testosterone levels (TT) have been associated with increased morbidity and mortality. However, the prevalence and incidence of testosterone deficiency (TD) in association with its risk has not been assessed systematically to date.

Methods.?Data from the prospective population-based Study of Health in Pomerania were used. From the 2117 men aged 20–79 years at baseline, 1490 men with complete TT data were analysed. Crude and age-specific prevalence and incidence rates of TD were estimated by TT levels below the age-specific 10th percentile. Analysis of covariance and Poisson regression models were used to assess the association of socio-demographic characteristics, health-related lifestyle, as well as somatometric, medical and laboratory measures with risk of incident TD.

Results.?TD baseline prevalence was 10.4% (N?=?155) and incidence 11.7 per 1000 person-years. TT levels showed a significant age-related decline with an unadjusted rate of 0.05 nmol/l per year. Obesity, metabolic syndrome, diabetes and dyslipidaemia were identified as risk factors of incident TD. Subpopulations of men without the revealed risk factors at both examinations maintained constant TT levels over time.

Conclusions.?Besides aging alone, lifestyle and different comorbidities were associated with TT level decline, suggesting that the age-related TT decline may be at least partly prevented through the management of potentially modifiable risk factors and health related behaviour.     

Aging male symptomatology and eating behavior

Objective: The literature on eating disorders in older males is still very limited. We assessed the relationship between aging male symptomatology and eating behavior in middle-aged and older men.

Method: We distributed anonymous questionnaires to men aged 40–75?years living in or near Innsbruck, Austria, covering demographic items, current eating disorder symptoms (as defined by DSM-5), and associated measures of eating pathology, body image, and sports activity (including exercise addiction). We also administered the Aging Males’ Symptoms scale (AMS), and classified respondents as “high-AMS” (AMS score ≥37; N?=?82) or “low-AMS” (AMS score <37; N?=?386).

Results: High-AMS men reported a significantly higher mean current BMI, a greater prevalence of eating disorder symptoms, higher scores on the Eating Disorder Examination Questionnaire, greater risk of exercise addiction, and more negative body image than low-AMS men.

Discussion: We found a marked association between aging-male symptomatology and eating-disorder symptomatology in aging men. Our findings suggest that clinicians should carefully inquire about eating disorder symptoms in men aged 40 and above reporting aging-male symptomatology. Importantly, several men in the study reported “purging” via excessive exercise (as opposed to the more common methods of vomiting or use of laxatives or diuretics), and therefore this should be a subject of inquiry in clinical evaluations. To pursue these findings, subsequent studies of eating disorders in older men should consider assessing endocrinological measures, particularly testosterone levels, and should use longitudinal designs.     

Effects of testosterone treatment on body composition in males with testosterone deficiency syndrome

Abstract

Objective: We evaluated the safety of testosterone treatment and its efficacy on body composition in males with testosterone deficiency syndrome (TDS) over 24 months.

Methods: 50 males aged 50–65 years with TDS (Aging Males Symptoms Scale [AMS]?>?26 and calculated free testosterone [cFT] 250?pmol/l) were administered 50?mg testosterone gel daily for one year. During the second year, patients received 1000?mg of testosterone undecanoate every 2–3 months. Outcome measures were clinical chemistry values and total testosterone; sex hormone-binding globulin and cFT, changes in AMS and International Prostate Symptom Score; and changes in body composition measured by dual-energy-x-ray absorptiometry.

Results: There were no clinically significant changes in clinical chemistry safety parameters. There were significant improvements in both total and cFT and in AMS scores after three months (p?<?0.001). Lean mass increased 2.35% at 12 months and 4.5% at 24 months, but proportionally more muscle mass was gained in arms and legs than in the trunk. Fat mass decreased 4.2% at 12 months and 9.1% at 24 months.

Conclusions: Testosterone treatment in males with TDS leads to body changes affecting lean and fat mass with significant improvement in AMS scores, and has an excellent safety profile.     

Free testosterone by direct and calculated measurement versus equilibrium dialysis in a clinical population

Abstract

Introduction: The value of clinically available free testosterone (FT) assays remains controversial. Here, we evaluate the agreement between the radioimmunoassay (RIA) and calculated FT (cFT) versus equilibrium dialysis (EqD), considered the gold standard.

Methods: Fifty-six consecutive men (aged 26–77) had blood samples assessed for FT, including men with treated and untreated testosterone deficiency (TD) and men without TD. Samples were split and tested by the two methodologies at a Quest Diagnostics national reference laboratory. cFT was calculated by the Vermeulen method.

Results: A robust correlation was noted for RIA and EqD (r?=?0.966) and for cFT and EqD (r?=?0.986). Strong correlations were observed for men receiving testosterone therapy and for men in the lowest and highest quartiles for total and FT. The correlation of total testosterone with FT was similar for cFT (r?=?0.843), RIA (r?=?0.806), and EqD (r?=?0.809). Sex-hormone binding globulin (SHBG) was not correlated with any measure of FT. Bland–Altman analysis demonstrated similar bias for both cFT and RIA, although cFT consistently overestimated FT. Numerical values for RIA were approximately one seventh of EqD values.

Conclusions: These results support the clinical use of both RIA and cFT as measures of FT. Due to numerical differences, each test requires its own set of reference values.     

Interleukin-18 and testosterone levels in men with metabolic syndrome

Objective: Interleukin 18 (IL-18) is an adipokine associated with obesity. Data about the relationship of IL-18 to the metabolic syndrome (MS) are still scarce. Low testosterone (T) levels are common in men with MS, but we did not find data about the levels of IL-18 in men with low T. The aim of this study was to determine the levels of IL-18 in men with MS with or without low T.

Patients and methods: A total of 251 men were included in the study. Of them 218 had MS (IDF 2005) and they were divided according to their morning total testosterone (TT) level (cutoff 10.4?nmol/l) into two groups: MS-low T (N?=?84) and MS-normal T (N?=?134). The control group consisted of 33 men without MS and low T. IL-18 was determined in serum using enzyme-linked immunosorbent assay. A small group of eight men with MS and low T levels received testosterone therapy for three months and physical and laboratory parameters were monitored at the end of that period.

Results: MS men were at mean age (±SD)?=?53.77?±?9.59 years; body mass index (BMI)?=?34.0?±?6.3?kg/m²; and TT?=?12.59?±?5.66?nmol/l. The control group was at age?=?52.12?±?5.2 years (NS); BMI?=?25.6?±?2.4?kg/m² (p?p?p?p?p?p?Conclusions: In this study, higher IL-18 levels were found in the presence of MS compared to healthy men, but they did not differ between men having MS with or without LOH.     

The impact of testosterone replacement therapy on glycemic control,vascular function,and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes

Objective: This study set out to assess effects of testosterone replacement therapy (TRT) on parameters of metabolic syndrome and vascular function in obese hypogonadal males with type 2 diabetes mellitus (DM2).

Study design: Fifty-five obese hypogonadal diabetic males on oral hypoglycemic treatment were enrolled into this one-year, double-blind, randomized, placebo-controlled clinical study. Group T (n?=?28) was treated with testosterone undecanoate (1000?mg i.m. every 10?weeks) while group P (n?=?27) received placebo.

Methods: Anthropometrical and vascular measurements – flow-mediated dilatation (FMD) and intima media thickness (IMT) – biochemical and hormonal blood sample analyses were performed at the start of the study and after one year. Derived parameters (BMI, HOMA-IR, calculated free testosterone (cFT) and bioavailable testosterone (BT)) were calculated.

Results: TRT resulted in reduction of HOMA-IR by 4.64?±?4.25 (p?p?p?=?.005).

Conclusion: TRT normalized serum testosterone levels, improved glycemic control and endothelial function while exerting no ill effects on the study population.     

Transversal European survey on testosterone deficiency diagnosis

Background: Despite being one of the relevant public health threats among ageing men, testosterone deficiency syndrome (TDS) is under-recognized and under-diagnosed. Objective: To assess current clinical practices of European physicians regarding diagnosis and management of TDS compared with current guidelines. Methods: Postal survey conducted June–November 2008 in France, Germany, Italy and Spain among urologists, endocrinologists and general practitioners to collect information regarding knowledge of TDS. Results: Among 801 respondents, the majority of endocrinologists and urologists had received training on TDS, either initially or as part of continuous medical education. TDS was recognized by 86.5% of physicians as a true clinical entity, and estimated the prevalence at 10–15% of the male population; 73.5% considered that symptoms and a low level of testosterone were required for diagnosis. Treatment preferences were quarterly intramuscular injections (26.3% of physicians), percutaneous gels (23.9%), matrix patch (21.2%), semi-monthly injections (15.4%) and oral therapy (13.4%). Adverse effects of testosterone replacement therapy, such as benign prostatic hyperplasia and prostate cancer, were a concern for physicians. Conclusions: TDS management appeared to be close to that recommended in international guidelines. Signs and symptoms of testosterone deficiency were fairly well known, but some diagnostic and treatment variations were observed.     

The prevalence and severity of varicocele in adult population over the age of forty years old: a cross-sectional study

Objectives: To investigate the prevalence and severity of varicocele in adult population over the age of 40. We also measured testicular size, consistency, and total testosterone levels with an aim to observe the effect of varicocele on testis as men age.

Methods: Two hundred twenty-four patients with varicocele, 241 patients without varicocele who admitted to our clinic were enrolled in the study. We stratified participants by four age groups (40–49, 50–59, 60–69, >70?yr). Patients were grouped according to varicocele grade and laterality. The morning testosterone level was drawn. The subgroups were compared with each other.

Results: Overall, varicocele prevalence was 48%. Of the patients, 104 had unilateral, 120 had bilateral varicocele. Of the patients with varicocele, 62 (13.30%) were found as grade 3, 99 (21.10%) were grade 2, and 63 (13.60%) were grade 1. The percentages of smaller testes in grade 1, grade 2, and grade 3 varicocele group were 20.60, 79.80, and 88.70 and a significant association was detected. Age stratification of the data revealed the smaller and soft testis prevalence as well as higher grade varicocele prevalance increased in older age groups.

Conclusions: Varicocele presence is associated with lower testicular size, softer testicular consistency, and lower testosterone levels, especially in older patients with bilateral and high-grade varicocele.     

Diagnostic significance of free salivary testosterone measurement using a direct luminescence immunoassay in healthy men and in patients with disorders of androgenic status

The accurate measurement of testosterone remains a challenge. The determination of the blood testosterone concentrations in serum by conventional immunoassays is inaccurate in men and even more so in females and children. A new luminescence enzyme immunoassay (LIA) has been developed and validated. The high analytical (8.7 pmol/L) and functional (17.3 pmol/L) sensitivity allows the quantification of the very low concentration in saliva, as well as in serum, after 1/40 dilution. This study measured salivary testosterone levels and compared the results with the free levels calculated from total testosterone and sex hormone-binding globulin in eugonadal and hypogonadal men. Salivary testosterone concentrations in healthy men in morning hours were 369 pmol/L (mean), range 263–544 pmol/L, which was statistically significantly higher than that in men with androgen deficiency, 215 pmol/L (mean), range 51–249 pmol/L.

Repetitive determination of free testosterone concentrations in saliva (once a week for 5 weeks) showed high stability of results over time, with coefficient of variation 9% (range 5–23%).

In this study we showed that free salivary testosterone levels in morning samples correlated well with calculated free testosterone in blood, both in healthy men (R = 0.754, P = 0.001), and in patients with androgen deficiency (R = 0.889, P = 0.0001), though in cases with very low testosterone, salivary concentrations were systematically higher than calculated free testosterone levels in blood.     

Oral Abstracts

Hypogonadism is associated with a range of disease states that have significant effects on morbidity and mortality, and also affect quality of life. The ESPRIT study (Energy, Sexual desire and body PropoRtions wIth AndroGel®, Testosterone 1% gel therapy) is a 6-month, multinational, open label, observational study in hypogonadal men being treated with transdermal AndroGel® in usual daily clinical practice; 1,700–2,400 patients will be enrolled in Canada, Germany, Central and Eastern Europe, Russia and the Middle East. The main objective will be to evaluate the effect of AndroGel® on symptoms of hypogonadism and quality of life as assessed by the Aging Males' Symptoms scale. Further objectives include evaluating the effect and time to onset of improvement in erectile dysfunction and libido/sexual desire (International Index of Erectile Function), fatigue (Multi-dimensional Fatigue Index) and body composition (waist circumference, body mass index). Subgroup analyses will be performed: <50 years versus ≥ 50 years; absence versus presence of metabolic syndrome. The safety of AndroGel® will also be assessed. The study population will consist of newly diagnosed hypogonadal men (age ≥ 18 years), in whom testosterone deficiency has been confirmed by clinical features and biochemical tests according to international guidelines, who are currently being prescribed AndroGel® (testosterone 1% gel, starting dose 50 mg testosterone per day).     

The efficacy and safety of short-acting testosterone ointment (Glowmin) for late-onset hypogonadism in accordance with testosterone circadian rhythm

Introduction: It is well known that there is a reduction of circadian rhythm in blood testosterone levels with aging. Our previous report revealed that 3?mg of short-acting testosterone ointment (Glowmin: GL) elevated serum testosterone levels to within the physiological range for 4–6?h. The aim of this study was to clarify the clinical efficacy and safety of GL used topically once every morning, to enhance the circadian rhythm of testosterone, for late-onset hypogonadism (LOH).

Methods: A total of 61 LOH patients received 3?mg of GL topically once a day in the morning on scrotal skin for 24 weeks. The clinical efficacy of GL was evaluated by the aging males symptoms (AMS) scale, and blood sampling tests were measured before and after GL treatment.

Results: Mean patients age was 55.3?±?9.2 years old. Total AMS scores at 4, 12, and 24 weeks after GL treatments significantly decreased. The results of sub-analysis of AMS, including psychological, physical, and sexual factors also significantly improved after GL treatments. No severe adverse reactions or abnormal laboratory data were reported.

Conclusions: This study shows that TRT for LOH with once daily GL treatment supports testosterone circadian rhythm and should be considered to be an effective and safe therapy for LOH.     

Impact of metabolic status on the association of serum vitamin D with hypogonadism and lower urinary tract symptoms/benign prostatic hyperplasia

Objective: The objective of this study is to investigate the impact of metabolic status on associations of serum vitamin D with hypogonadism and lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH).

Patients and methods: A total of 612 men underwent physical examination, biochemical/hormonal blood testing, and transrectal prostate ultrasound. Moreover, the subjects filled out standard questionnaires for identification and grading of LUTS and hypogonadism symptoms. Parameters were statistically compared with independent t-tests and correlation analyses.

Results: Vitamin D levels positively correlated with total testosterone (TT) but not with prostate volume or International Prostate Symptom Score (IPSS). Patients with metabolic syndrome had significantly lower vitamin D levels, which were not correlated with TT, prostate volume, or IPSS. However, vitamin D was positively correlated with TT, and negatively correlated with prostate volume and quality-of-life IPSS in subjects without metabolic syndrome.

Conclusion: The clinical usefulness of vitamin D for treatment of hypogonadism or LUTS/BPH varies according to metabolic status.     

Validation of an Arabic ADAM questionnaire for androgen deficiency screening in the Arab community

Background.?It is well documented that testosterone levels decline with age, this decline is associated with symptoms which could be assessed denoting androgen deficiency. We investigated the validity of an Arabic version of the Saint Louis University androgen deficiency in ageing men (ADAM) questionnaire to screen for androgen deficiency in Saudi and non Saudi Arabic speaking men.

Methods.?It was a cross sectional study of ambulatory community-based Arabic Saudi men recruited from Volunteers in Riyadh city, Capital of Saudi Arabia, aged 18–80 years. Seven hundred thirty men agreed to fill the Arabic ADAM questionnaire, they were invited to a morning blood sample for total testosterone and sex hormone binding globulin and those who agreed to complete the whole study were only 407 men. Low serum bioavailable testosterone (BT) levels (androgen deficiency) were defined as <10th percentile of serum BT levels in young healthy Saudi men (18–30 years).

Results.?Cronbach's Alpha of 0.71 (n?=?730) showed a good internal consistency of the Arabic ADAM questionnaire. Among participants, 18.2% and 77.6% had low serum BT levels and a positive ADAM questionnaire, respectively. The prevalence of positive ADAM and low serum BT is increasing with age. The Arabic ADAM questionnaire had a high sensitivity of 86.5%, a low specificity of 24.3%, and positive predictive values (+PVs) and negative (?PVs) of 20.3% and 89%, respectively.

Conclusion.?The Arabic ADAM questionnaire has a very good sensitivity but very low specificity for screening of androgen deficiency in Saudi men, therefore biological confirmation is needed especially when clinical symptoms of androgen deficiency are present.     

Analysis of cardiovascular risk factors associated with serum testosterone levels according to the US 2011–2012 National Health and Nutrition Examination Survey

Objective: To investigate associations between cardiovascular disease risk factors, including fasting glucose, cholesterol, high density lipoprotein cholesterol (HDL-c), LDL-c, blood pressure, body mass index (BMI), C-peptide, creatinine kinase, smoking, alcohol use, physical activity, C-reactive protein as well as homocysteine levels and cardiovascular events.

Methods: Data from 1545 men aged ≥40?years, with testosterone deficiency (TD) (<300?ng/dL) and non-TD (≥300?ng/dL) which were extracted from the National Health and Nutrition Examination Survey database 2011–2012 and analyzed.

Results: Multivariate logistic regression analysis showed positive associations between TD and BMI (≥35 vs.?p?=?.016), HDL-c (<0.91 vs. ≥0.91: OR?=?1.60, 95% CI: 1.14–2.24, p?=?.006) and diabetes (diabetes vs. non-diabetes: OR?=?1.48, 95% CI: 1.14–1.92, p?=?.004) as well as negative associations between TD and metabolic equivalent scores (≥12 vs. <12: OR?=?0.69, 95% CI: 0.52–0.91, p?=?.009) and smoking (Ever vs. never: OR?=?0.69, 95% CI: 0.51–0.94, p?=?.018). Furthermore, total serum testosterone levels were lower in patients with heart failure (p?=?.04) and angina/angina pectoris (p?=?.001) compared with subjects without these cardiac problems.

Conclusion: Low serum testosterone was associated with multiple risk factors for CHD.     

Association between serum levels of testosterone and biomarkers of subclinical atherosclerosis

Objective: To investigate the association between serum levels of testosterone and biomarkers of subclinical atherosclerosis based on data from 119 middle-aged men of the general population.

Methods: Testosterone, Apolipoprotein A-1 (ApoA-1), Apolipoprotein B (ApoB), Apolipoprotein B-to-Apolipoprotein A-1 ratio (ApoB-to-ApoA-1), high-sensitive C-reactive protein (hsCRP), and fibrinogen levels were measured. Data were also gathered based on age, BMI, waist circumference, smoking, alcohol consumption, and family history of cardiovascular diseases. Men were classified into two groups based on testosterone levels: hypogonadal (testosterone ≤12?nmol/L) and eugonadal men (testosterone >12?nmol/L).

Results: When compared to eugonadal, the hypogonadal men were significantly older (56?years vs. 55?years, p?=?.03), had greater BMI (28?kg/cm² vs. 26?kg/cm², p?=?.01), and higher waist circumference (104?cm vs. 100?cm, p?=?.01). Moreover, ApoB, ApoB-to-ApoA-1 ratio, and hsCRP were significantly higher in hypogonadal men compared to eugonadal men (1.1?g/L vs. 1.0?g/L, p?=?.03), (0.8 vs. 0.7, p?=?.03), (3.3?mg/L vs. 2.0?mg/L, p?=?.01), respectively. On the other hand, ApoA-1 and fibrinogen levels did not differ significantly between groups (p?>?.05). In an adjusted multivariate regression analysis model, only ApoB showed a significant negative association with testosterone levels (β?=??0.01; 95% CI?=??0.02, ?1.50; p?=?.04).

Conclusion: Testosterone levels showed an inverse relation to ApoB, a biomarker implicated in subclinical atherosclerosis. These findings support the hypothesis that low testosterone levels play a role in atherosclerosis.