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16 July 2014

Testosterone and Prostate Cancer - a paradigm shift

Testosterone and Prostate Cancer - a paradigm shift

"Bye-bye Androgen Hypothesis, Welcome Saturation Model"

A new era of testosterone and prostate cancer: from physiology to clinical implications. Khera M, Crawford D, Morales A, et al., Eur Urol 2014; 65(1): 115-23.

A long-held belief is that testosterone stimulates development of prostate cancer (PCa) and/or accelerates its growth. This summary gives an overview of an in-depth review of current literature regarding the relationship of serum testosterone and PCa and the effect of testosterone replacement therapy (TRT) on PCa progression and recurrence. Key studies which have refuted the old belief that testosterone has harmful effects on the prostate are presented, along the new testosterone-prostate paradigm known as the saturation model.

27 June 2014

Testosterone and Prostate Cancer - a paradigm shift

Testosterone and Prostate Cancer - a paradigm shift

"Bye-bye Androgen Hypothesis, Welcome Saturation Model"

A new era of testosterone and prostate cancer: from physiology to clinical implications. Khera M, Crawford D, Morales A, et al., Eur Urol 2014; 65(1): 115-23.

A long-held belief is that testosterone stimulates development of prostate cancer (PCa) and/or accelerates its growth. This summary gives an overview of an in-depth review of current literature regarding the relationship of serum testosterone and PCa and the effect of testosterone replacement therapy (TRT) on PCa progression and recurrence. Key studies which have refuted the old belief that testosterone has harmful effects on the prostate are presented, along the new testosterone-prostate paradigm known as the saturation model.



Key Points

  • The longstanding concerns regarding putative detrimental effects of testosterone and TRT on PCa, known as the \"androgen hypothesis\", stem from several observations;

    • dependence of the prostate on androgens for normal development and function;
    • beneficial response to androgen-deprivation therapy (ADT) in men with advanced or metastatic PCa;
    • historical reports of rapid PCa progression in men who received testosterone administration;
    • dramatic prostate specific antigen (PSA) declines in men with PCa who undergo ADT;
    • reduction in PSA and prostate volume in men with benign prostatic hyperplasia treated with 5alpha-reductase (5-AR) inhibitors;
    • parallel rise in PSA and serum testosterone upon cessation of luteinizing hormone-releasing hormone (LH-RH) agonists (medications that lower the endogenous production of testosterone).
  • The androgen hypothesis arose from two small studies in the 1940s in which men with metastatic PCa demonstrated clinical and biochemical improvement with androgen deprivation via castration, and rapid PCa progression with testosterone administration. However, these observations were made in a special population (castrated men) and are therefore not relevant to TRT in hypogonadal men.
  • The \"saturation model\" explains the paradoxical observations that prostate tissue is exquisitely sensitive to changes in serum testosterone at low concentrations but becomes indifferent to changes at higher testosterone concentrations.
  • A threshold effect occurs in which increasing androgen concentrations reach a limit (the saturation point) beyond which there is no further ability to induce androgen-driven changes in prostate tissue growth.
  • A mechanism contributing to the saturation model is the finite ability of androgens to bind to the androgen receptor (AR).

    Maximal androgen–AR binding (i.e., saturation) occurs at fairly low androgen levels. It has been established in clinical practice that the saturation point appears to be around 8 nmol/L (230 ng/dL), subject to inter-individual variation.
  • The saturation model explains the following important clinical observations:

    • A comprehensive analysis of pooled worldwide epidemiologic data from 18 prospective studies, comprising a study population of 3886 men with PCa and 6438 age-matched controls, found no relationship between PCa risk and serum concentrations of testosterone, calculated free testosterone or DHT.
    • Two meta-analyses of TRT intervention studies, which specifically focused on analyzing potential adverse effects of testosterone therapy, did not find any significant differences in prostate outcomes between TRT vs. placebo treated men.
    • In the UK Androgen Study, 1365 men 28–87 yr of age (mean 55) received testosterone therapy for up to 20 yr, with PSA and digital rectal examination (DRE) performed every 6month. 14 new cases of PCa, all localized, were detected after 1–12 years (mean 6.3 years). However, this PCa is the same as in a general population which has never been treated with testosterone. Initiating testosterone treatment had no statistically significant effect on total PSA, free PSA or free/total PSA ratio, and any initial PSA change had no predictive relationship to subsequent diagnosis of cancer.
    • In a study on transdermal testosterone patch use for up to 6 years, PSA increased at 3 months from 0.47 to 0.60 ng/ml, followed by negligible change in PSA (0.03 ng/ml per year) over the remaining 5 yr. No PCa was identified in this trial.
  • The current ISA, ISSAM, EAU, EAA, ASA guidelines state:

    • There is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or benign prostatic hyperplasia.
    • There is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer.
  • Provocative new research evidence suggests that it is not high serum T that is problematic for PCa, but to the contrary that it is low serum T that is associated with worrisome cancer features and outcomes, such as high Gleason score, advanced stage of presentation, positive biopsy, and increased risk of biochemical recurrence after surgery. Patients with PCa and lower testosterone levels have undesirable prognosis factors and higher tumor burden before treatment onset. These findings reinforce the idea that low testosterone levels pretreatment are related to a poor prognosis in PCa.
  • New experimental research has uncovered mechanisms that explain why low serum T may be detrimental for prostate health, and support the view that TRT actually may have beneficial effects with regard to PCa. Specifically, androgens promote less aggressive PCa phenotypes and inhibit dedifferentiation (i.e. metastasis) in some PCa cell lines.

27 March 2013

Testosterone for the treatment of obesity in hypogonadal men

Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Saad F, Aversa A, Isidori AM, et al. Curr Diabetes Rev 2012;8(2):131-143.

A recent review of the PubMed literature evaluated studies reporting data on the role of testosterone in counteracting obesity and its associated complications in men with testosterone deficiency (hypogonadism).1 The role of testosterone in this regard was summarized from three perspectives: i) evidence from epidemiological and observational studies; ii) evidence from androgen deprivation therapy (ADT), mainly in men undergoing treatment for prostate cancer (PCa); and iii) evidence from testosterone treatment of men with testosterone deficiency.



Key Points

  • T is an important factor in the etiology of obesity, MetS, T2DM and CVD, with sub-normal T levels increasing the accumulation of fat deposits, particularly abdominal (visceral) fat
  • Lifestyle changes (diet and exercise) are typically recommended by physicians to combat obesity but the often transient effects are only marginally successful and of limited clinical benefit
  • T treatment in hypogonadal men reverses fat accumulation with a significant improvement in lean body mass, insulin sensitivity and markers of cardiovascular risk
  • Medical professionals are largely unaware of the potential benefit and contribution of T in combating obesity and managing MetS in hypogonadal men, with many physicians fearing an increased risk of PCa and CVD (despite the lack of supportive evidence)
  • Combined with lifestyle changes, T may be a useful tool for the treatment of obesity in hypogonadal men; it also improves mood levels and vitality, while reducing fatigue, and may motivate men to adhere to diet and exercise regimens designed to combat obesity

26 October 2012

Efficacy and safety of long-acting testosterone undecanoate in men with hypogonadism in daily clinical practice

IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. Zitzmann M, Mattern A, Hanisch J, et al. J Sex Med 2012 [Epub ahead of print].

This prospective, observational, post-authorization surveillance study investigated the safety and efficacy of intramuscular injections of testosterone undecanoate (TU) in men with testosterone deficiency syndrome (hypogonadism) in a clinical practice setting. The study, conducted in 23 countries throughout Europe, Asia, Latin America and Australia, enrolled 1493 men (mean age 49.2 ± 13.9 years) with a diagnosis of primary or secondary testosterone deficiency syndrome (serum total testosterone 8–12 nmol/L for newly diagnosed treatment-naïve patients). The men received up to five injections of TU during an observation period of 9–12 months. Between the first and second injections of the agent there was an interval of 6–10 weeks, and subsequent injections were given at intervals of 12 ± 2 weeks.

The study aimed to assess treatment outcomes of male patients with testosterone deficiency syndrome who received TU under ‘real-life’ conditions, and to assess the treatment continuation rate in such patients and further confirm the safety profile of TU. Parameters of erectile function, libido, vigor/vitality, mood and ability to concentrate were assessed by physician interview using items and five-point Likert scales. Certain physical and circulatory parameters, as well as other laboratory parameters, were also measured at each injection visit.

Of the 1493 men enrolled, 72.5% were Caucasian, followed by 19.7% and 7.5% of Asian and Latin American descent, respectively. A total of 1438 and 1140 men were evaluable at baseline and at the time of the fifth injection, respectively. At baseline, mean body weight was 86.8 kg, and 54% of those enrolled had previously received androgen therapy. Mean serum testosterone (T) was 9.6 ± 7.5 nmol/L, and comorbidities included erectile dysfunction (ED), hypertension and dyslipidemia.

Key Points

  • Mean trough serum total T increased from 9.6 nmol/L at baseline to 17.3 nmol/L before the fifth injection (p<0.0001)
  • The proportion of patients with a high/very high libido increased from 10% at baseline to 61% at injection 5 (overall p<0.0001)
  • Significant improvements over each injection interval were seen in the overall levels of vigor/vitality, mood and ability to concentrate (p<0.0001 for each)
  • The proportion of patients reporting moderate, severe or extremely severe ED was significantly decreased from baseline at the time of the fifth TU injection, from 65% to 19% (p<0.0001)
  • Statistically significant reduction in waist circumference (Figure 1)
  • Adverse drug reactions related to TU therapy were rare (5.8%).
Last updated: 2018
L.ZA.MKT.GM.10.2016.1381