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Androgens and prostate cancer; pathogenesis and deprivation therapy

https://doi.org/10.1016/j.beem.2013.05.001Get rights and content

Although androgen receptor signaling is critical for prostate cancer growth and survival, evidence supporting a favorable risk–benefit ratio of androgen deprivation therapy (ADT) is currently limited to men with high-risk or metastatic disease. This is in part because ADT has been associated with a number of constitutional and somatic side effects, consistent with the widespread tissue expression of sex steroid receptors. ADT is the most common contemporary cause of severe hypogonadism, and men receiving this therapy represent a unique model of severe sex steroid deficiency with a defined time of onset. This review will present an update on the role of ADT in the treatment of prostate cancer, will summarize recent evidence regarding ADT-associated adverse effects with particular emphasis on cardiometabolic and musculoskeletal health, and will provide recommendations for further research.

Introduction

Prostate cancer is the most common solid tumor in men in the developed world, and accounts for 15% of male cancers compared with 4% in developing countries.1 Lifetime risk of diagnosis in the US American men is one in six, with a median age at diagnosis of 67 years. In 2012, an estimated 241,740 new cases of prostate cancer will be diagnosed in the United States alone.2 In Europe, the incidence rate of prostate cancer is 214 cases per 1000 men, outnumbering lung and colorectal cancer.1 In a global survey, prostate cancer was among the 3 most common cancers diagnosed in men across 184 countries, with a lower prevalence in underdeveloped countries likely because of delayed diagnosis.3 Incidence and mortality is lower in Asian men, but rising, in part due to increasing westernization of lifestyle.4 Especially in developed countries, prostate cancer prevalence has increased primarily because of the increased use of prostate-specific antigen (PSA) testing: PSA detection is responsible for earlier diagnosis by up to 12.3 years5 and has led to an increase in early-stage diagnosis. In the US, prostate cancer mortality has fallen substantially in spite of the marked increase in diagnosis. There are three possible explanations for this effect: (1) early detection and (2) advances in therapy are producing a mortality benefit, and (3) especially in elderly men with a short life expectancy, diagnosis may occur in patients with disease which may have remained subclinical until death from another cause. Indeed, estimates suggest that 23%–42% of all US screen-detected cancers are overdiagnosed and overtreated.5 Presently, 90% of men are diagnosed with loco-regional disease, where the 5-year cancer specific survival approaches 100%. However, 5-year relative survival for the 10% of men with metastatic disease is only 30%.1, 2 In addition, 30% of newly diagnosed cases have high-risk disease, which ultimately may have a lethal course if left untreated.1, 2 The majority of men whose disease recurs after initial therapy are incurable.

Due to the high prevalence, prostate cancer represents, despite a relatively low case-fatality rate, the second most common lethal cancer in men in affluent countries, with an expected 28,170 US American deaths in 2012, and a median age at death of 80 years.2 By contrast, prostate cancer is the leading cause of cancer-related mortality in men from Africa and the Caribbean, due to delayed diagnosis and treatment.6 Death from this disease is invariably due to the emergence of castrate resistance, and overall about 33% of men with prostate cancer progress to have incurable metastatic disease. The median survival duration in men with castrate-resistant prostate cancer (CRPC) is 2–3 years,1, 2 although this may improve with newer therapies.∗7, ∗8

Section snippets

Role of androgens in prostate carcinogenesis

Since Huggins and Hodges first demonstrated the responsiveness of prostate cancer to androgen deprivation, it has been clear that prostate cancer is dependent on androgen receptor activation (AR) for growth and survival.9 This is consistent with genome-wide association studies showing that DNA sequences associated with prostate cancer risk are enriched in AR- or AR-coactivator binding sites,10 and with the recent identification of a germline gene mutation in the AR-interacting homeobox

Anti-androgen therapy: therapeutic use

Androgen deprivation therapy (ADT) encompasses any treatment that results in suppression of androgen activity. This can be achieved by either decreasing testicular and/or extra-gonadal androgen production with medical or surgical castration (i.e. AR ligand reduction), or by using anti-androgens to block AR signaling (AR deactivation). The combination of both approaches is referred to as complete androgen blockade. The therapeutic efficacy of ADT is due to upregulation in the expression of

Anti-androgen therapy: epidemiology and patterns of use

ADT remains the most common form of systemic therapy for prostate cancer, and is currently prescribed to 3% of the Male Medicare population, corresponding to over 400,000 men. The overall use of ADT has doubled during the 1990s. By 1999, nearly half of patients with prostate cancer were receiving ADT within a year after diagnosis, with US Medicare expenditure exceeding 1 billion US dollars in 2003 alone.34 More recent registry data suggests that the use of ADT in the US has leveled in the early

Androgen deprivation therapy: adverse effects

While comparatively less toxic than chemotherapy, ADT has a number of important side effects. These side effects are a consequence of the induced severe sex steroid deficiency, and, consistent with the widespread expression of sex steroid receptors, affect multiple somatic and psychosocial domains (Table 2). Adverse effects generally increase with the duration of ADT and individual susceptibility varies among patients depending on age, baseline comorbidities, and other, poorly understood

Androgen deprivation therapy: metabolic complications

Since even moderate reduction in circulating testosterone have been associated with increased risk of the metabolic syndrome and diabetes,45 men receiving ADT may be at even higher risk of metabolic complications, considering the severity of their testosterone deficiency. Given that ADT induces severe testosterone deficiency with a temporally defined onset, the study of men commencing ADT serves as a valuable model to study direction of causality of the association of low testosterone with

Androgen deprivation therapy: cardiovascular effects

Whether metabolic effects of ADT discussed above translate to increased cardiovascular morbidity and mortality remains unproven and controversial. While low testosterone levels have been associated with increased cardiovascular mortality in the general population, the direction of causality remains uncertain and testosterone may simply be a biomarker of poor health.∗59, ∗60, ∗61 Some observations52 but not all48 suggest that the ADT-induced metabolic syndrome may differ from classical metabolic

Monitoring and management of ADT-associated cardiometabolic side effects

It remains unclear whether strategies for screening, prevention and treatment of diabetes and cardiovascular disease in men receiving ADT should differ from the general population, as definitive clinical trial evidence for interventions specific to such men is currently lacking. Suggested monitoring and management guidelines have previously been developed on behalf of the Australian Endocrine, Bone and Mineral and Urological Societies,73 and are summarized in Table 3.

Androgen deprivation therapy: skeletal effects

Acquired hypogonadism leads to accelerated bone resorption, and testosterone therapy reduces bone turnover, possibly through aromatization to estradiol. Most observational studies suggest that circulating estradiol is more closely associated with reduced bone mineral density (BMD) and increased fracture risk in men than testosterone.74 Increased SHBG levels, which reduce sex steroid bioavailability, have been associated with reduced bone mass in men. In a prospective study from the osteoporotic

Androgen deprivation therapy: effects on muscle

Consistent with the anabolic actions of testosterone on muscle mass, men lose about 3% of lean body mass during the first 12 months, and most of this loss is evident as early as 6 months after therapy is commenced.47, 48 A more recent prospective study reported a continuous 1% per year decline of lean body mass with up to 3 years of continuous ADT, which was more pronounced in older men, and this ongoing loss occurred despite the fact that men had already received a mean of 20 months of ADT

Androgen deprivation therapy: possible effects on prostate cancer progression and immune function

Since epidemiological and mechanistic studies have associated enhanced insulin signaling with prostate cancer development,14 a potential concern is that ADT-associated hyperinsulinaemia may accelerate prostate cancer progression. Consistent with this possibility, insulin has been shown to enhance androgen synthesis in CRPC cells through upregulation of the insulin receptor substrate 2 (IRS2).96 Preliminary evidence has linked a single nucleotide polymorphism at the IRS2 gene to survival in

Summary

The identification of men who derive sufficient benefit from ADT to justify its toxicity remains challenging in a substantial proportion of men with prostate cancer. This is because clinical endpoint trials and reliable biomarkers predictive of ADT-mediated response or harm are largely lacking. ADT should certainly be avoided in men without proven evidence of benefit. Initiation of ADT should not only involve an assessment of cardiometabolic and musculoskeletal comorbidity, but also patient

Acknowledgments

We are most grateful to Professor Ian Davis, Monash University, for his helpful comments. M Grossmann was supported by a NHMRC Career Development Fellowship (# 1024139), and A Cheung was supported by a NHMRC Postgraduate Research Scholarship (# 1017233).

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