Metabolic and cardiovascular effects of androgen deprivation therapy

Prostate cancer is the most common gender-specific malignancy in men in the USA. Androgen-deprivation therapy (ADT) is commonly used in the treatment of metastatic or recurrent prostate cancer. The use of ADT is increasing with the advocacy of adjuvant and neoadjuvant ADT for treating asymptomatic patients with locally advanced prostate cancer. Although the use of ADT has resulted in improved survival in men with advanced prostate cancer, ADT, with its resulting severe hypogonadism, causes profound metabolic side-effects. We comprehensively reviewed previous reports using Medline searches of English-language literature (1950 to the present), with the keywords 'hypogonadism', 'testosterone', 'androgen deprivation therapy', 'hormonal treatment', 'prostate cancer', 'diabetes', 'metabolic syndrome', and 'cardiovascular disease'. Men with prostate cancer who undergo long-term ADT are at greater risk of developing dyslipidaemia, insulin resistance, hyperglycaemia and metabolic syndrome. These metabolic and physiological changes are a direct result of the induced severe hypogonadism and might predispose patients to a greater risk of cardiovascular morbidity and mortality. There is a need for prospective studies aimed and designed to investigate the metabolic and cardiovascular adverse effects of ADT, and assess the benefit/risk ratio, especially in special populations such as diabetics.     

Management of bone and metabolic effects of androgen deprivation therapy

Androgen deprivation therapy (ADT) is commonly given to men with prostate cancer. Both its benefits as well as its adverse effects are a direct consequence of sex steroid withdrawal. While ADT improves oncologic outcomes in appropriately selected men, it is associated with adverse effects, including accelerated bone loss leading to increased fracture risk, and with metabolically unfavorable body composition changes that predispose to diabetes and may increase cardiovascular risk. In this review, we will describe the pathophysiology behind these ADT-associated adverse effects, and discuss the clinical evidence guiding clinical assessment and management. A proactive approach is important to minimize ADT-associated adverse sequelae, so that the benefit-risk ratio of this treatment is optimized.     

Patients and partners lack knowledge of androgen deprivation therapy side effects

ObjectiveAndrogen deprivation therapy (ADT) is the primary treatment for advanced prostate cancer (CaP). There is growing evidence that ADT negatively affects men's psychosocial well-being (e.g., causing sexual dysfunction, bodily feminization) and physical health (e.g., increasing the risk of osteoporosis and metabolic syndrome). Although strategies for managing the majority of side effects exist, it is not clear that patients are benefiting from this knowledge.MethodsSeventy-nine newly prescribed ADT patients and 54 of their partners were given a checklist of various common and uncommon ADT side effects. They were asked to indicate the drug side effects that they had heard of or anticipated.ResultsBoth patients and their partners were poorly informed about the side effects of luteinizing hormone-releasing hormone (LHRH) agonists used for ADT. More than 70% did not know that anemia, memory problems, loss of body hair, and depression can occur following treatment. Over 50% were unaware of significant potential side effects such as reduced muscle mass, osteoporosis, increased fracture risk, weight gain, genital shrinkage, and gynecomastia. Concurrently, more than 20% mistakenly anticipated dizziness and itching.ConclusionThe lack of awareness of ADT side effects may partially explain why ADT currently results in significant decreases in the quality of life of patients and their partners. Patients uninformed about side effects do not engage in behaviors to prevent or reduce the risk of adverse effects. Improved efforts to educate patients about treatment side effects and coping strategies may result in improved psychosocial and physical health for CaP patients undergoing ADT.     

Adverse effects of androgen deprivation therapy in men with prostate cancer: a focus on metabolic and cardiovascular complications

Prostate cancer (PCa) is the most common malignancy in men. Prostate being an androgen responsive tissue, androgen deprivation therapy (ADT) is used in the management of locally advanced (improves survival) and metastatic (improves pain and quality of life) PCa. Over the past two decades, the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences, though without any evidence of survival advantage. Hypogonadism resulting from ADT is associated with decreased muscle mass and strength, increased fat mass, sexual dysfunction, vasomotor symptoms, decreased quality of life, anemia and bone loss. Insulin resistance, diabetes and cardiovascular disease have recently been added to the list of these complications. As the majority of men with PCa die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount. Here we review data evaluating metabolic and cardiovascular complications of ADT.     

Prostate-specific antigen and androgen deprivation therapy

Summary Prostate-specific antigen (PSA) is a kallikrein-like serine protease that, for all practical purposes, is specific for prostatic tissue. PSA is usually detected at low concentrations (0.0–4.0 ng/ml) in the serum and is the most important tumor marker for detecting otherwise unsuspected prostate cancer; it also useful for monitoring the response of prostate cancer to various types of therapy. Androgen deprivation therapy (ADT) includes bilateral orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonists, antiandrogens, and 5-alpha-reductase inhibitors. Treatment of benign prostatic hypertrophy (BPH) or prostate cancer with ADT usually decreases the serum PSA concentration. Recent basic science research has demonstrated that the expression of the PSA gene is controlled by androgens acting via the androgen receptor. Therefore, in some patients a low serum PSA concentration will be the result of hormonal down-regulation of the genetic expression of PSA and not the result of the antitumorigenic activity of the therapy. Nevertheless, in spite of the direct effect of ADT on PSA expression, PSA remains a valuable prostate cancer tumor marker for prognosticating the response to ADT and portending clinical progression after this type of treatment for most patients.     

Hematological changes during androgen deprivation therapy

Androgen deprivation therapy (ADT) has been associated with a plethora of adverse effects, consistent with the androgen dependency of multiple reproductive and somatic tissues. One such tissue is the hemopoietic system, and one of the most predictable consequences of ADT is the development of anemia. Although anemia caused by ADT is rarely severe, ADT is often given to frail, elderly men with increased susceptibility to anemia due to multiple other causes. ADT-associated anemia may contribute to fatigue and reduced quality of life (QoL) in such men, although this requires further study. While anemia is an independent risk factor of mortality in men with prostate cancer, it is not known whether treatment of ADT-associated anemia alters clinically important outcomes, or whether treatment affects mortality. Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia. However, assessment and treatment of more severe anemia may be required. This should be determined on an individual basis. In contrast to the well-described actions of ADT on erythropoiesis, its effect on other hemopoietic lineages has been less well elucidated. While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils, lymphocytes and platelets, the implications of these findings for men with prostate cancer receiving ADT require further studies.     

Gleason score predicts androgen independent progression after androgen deprivation therapy

OBJECTIVE: The Gleason system is the most widely utilized histologic grading system for prostate cancer and a powerful predictor of cancer behavior. In this study, we evaluated the prognostic value of the Gleason grading system in predicting progression to androgen independent prostate cancer (AIPC). METHODS: Records from 150 patients with advanced or metastatic prostate cancer treated with androgen deprivation therapy (ADT) were retrospectively reviewed. Androgen independent progression was defined as two consecutive elevations of serum prostate specific antigen (PSA) above the nadir value. Kaplan-Meier and the Cox proportional hazards methods were used to assess potential predictors of progression to AIPC. RESULTS: Patients with low and moderate Gleason scores experienced significantly longer remissions compared to those with Gleason score of 8-10 (p=0.0006, Log-Rank test). The cumulative hazard of progressing to AIPC increased by almost 70% for each unit increase in total Gleason score. CONCLUSION: In this patient cohort the Gleason score was the only independent predictor of progression to AIPC.     

前列腺癌去雄激素治疗不良反应的预防和处理

目的观察去雄激素治疗前列腺癌的不良反应,并探讨其预防和治疗。方法回顾性分析1998年7月-2006年1月112例去雄激素治疗晚期前列腺癌的临床资料。结果112例患者中,97例完成了不良反应的调查。随访3-36月,去雄激素治疗后潮热、性功能障碍、病理性骨折发生率分别为46％、75％、4％;患者潮热、精神疲乏、四肢乏力、纳差症状明显加重(P<0．05);性功能明显减退(P<0．05)。12例潮热症状严重者使用抗抑郁药博乐欣(25mg,tid)1-2周症状减轻。7例有骨转移性疼痛或严重骨质疏松患者,应用唑来膦酸4mg静脉滴注,每45d一次,骨痛症状缓解。结论去雄激素对前列腺癌患者生活质量有一定影响。博乐欣可减轻患者潮热症状,唑来膦酸可预防和治疗去雄激素相关的骨质疏松并发症。     

Impact of androgen deprivation therapy on sexual function

Many patients with prostate cancer for whom androgen deprivation therapy (ADT) is indicated are young and desire to remain sexually active. In such patients, the side effects of androgen therapy on sexual function can be a source of serious reduction in overall quality of life. Providing the appropriate treatment options in this patient population is therefore essential. Nevertheless, treating such patients is challenging and an understanding of the underlying mechanisms of sexual physiology and pathophysiology is crucial to optimal patient care. In this paper, we reviewed what was known regarding the effects of ADT on sexual function in animal models and we also provided a detailed review on the effects of ADT on sexual health in humans and its treatment.     

Information needs of men on androgen deprivation therapy

Study Type – Needs assessment survey Level of Evidence 2b What's known on the subject? and What does the study add? Although androgen deprivation therapy (ADT) is widely used to treat men with prostate cancer, little is known about the information needs of patients on ADT. We found that patients are generally very satisfied with using ADT and expressed minimal decisional regret with its use up to four years later. For men receiving ADT in the adjuvant setting, their survival estimates with the addition of ADT were quite reasonable when compared to findings in randomized trails. A key area to enhance patient education appears to be side effects, especially around hot flashes and fatigue, which were also the most bothersome treatment sequelae for patients.

OBJECTIVE

• ? To evaluate information needs of men receiving androgen deprivation therapy (ADT).

PATIENTS AND METHODS

• ? A cross‐sectional survey was distributed to English‐speaking prostate cancer patients receiving ADT adjuvant to radical therapy or for biochemical relapse.
• ? Three cohorts were recruited based on duration of ADT use: <6 months (cohort 1), 6–18 months (cohort 2) and 18 months to 4 years (cohort 3).
• ? Several validated questionnaires were used, including the Control Preferences Scale (CPS), Satisfaction with Treatment Decision Scale (SWD) and Decisional Regret Scale (DRS).
• ? Patients on adjuvant ADT were asked to estimate their overall survival with and without ADT.

RESULTS

• ? Eighty‐five men were recruited, of whom 91.8% were receiving a gonadotrophin‐releasing hormone agonist, 4.7% were receiving anti‐androgen monotherapy and 3.5% were receiving combined androgen blockade.
• ? Patients preferred the following decision‐making roles: 23.5% active, 50.6% collaborative, 27.0% passive.
• ? Mean patient satisfaction for ADT use was high at 24.0/30 and decisional regret was low at 7.9/25.
• ? There was a perceived overall survival benefit of 3.9–6.9% at 5 years, 3.6–17.8% at 10 years and 5.7–18.1% at 15 years with the addition of adjuvant ADT.
• ? Hot flushes and fatigue were reported as the most common theoretical adverse effects as well as those experienced most commonly by patients.

CONCLUSIONS

• ? Patients on ADT were generally satisfied with their decisions to start ADT and expressed minimal decisional regret up to 4 years later.
• ? A key area to enhance patient education appears to be adverse effects, especially around hot flushes and fatigue.

     

Androgen deprivation therapy and cardiovascular disease

Prostate cancer (PCa) is the most common cancer among men. Advances in early detection and successful treatments have improved cancer-specific survival. With prolonged survival, PCa patients now suffer from the effects of aging and are at increasing risk for the development of cardiovascular (CV) risk factors and CV disease. Androgen deprivation therapy (ADT) is the mainstay treatment of advanced PCa. There is conflicting evidence about whether or not ADT is associated with increased CV morbidity and mortality. Metabolic abnormalities such as increasing body weight, reduced insulin sensitivity, dyslipidemia, and activation of T cells to the Th1 phenotype, resulting in atherosclerotic plaque destabilization, have been proposed as possible mechanisms by which ADT may increase the risk of CV events. Type of ADT and preexisting CV history also seem to play a major role in the risk of subsequent CV events. Ongoing prospective clinical trials will help define whether there is any difference between gonadotropin-releasing hormone agonists and antagonists in terms of CV morbidity and mortality.     

The nonsteroidal effects of diethylstilbestrol: the rationale for androgen deprivation therapy without estrogen deprivation in the treatment of prostate cancer

PURPOSE: During the last 2 decades there has been an increase in the number of men with prostate cancer placed on luteinizing hormone releasing hormone (LH-RH) agonist therapy. In addition, the duration of individual therapy has extended from what was once only a few months to, in many cases, several years. As a result there has been an increase in the incidence of side effects, including osteoporosis, decreased cognitive abilities, vascular stiffness and fatigue. We explored the use of estrogen in the form of diethylstilbestrol (DES) as an alternative treatment for men with prostate cancer, and introduce the concept of androgen deprivation without estrogen deprivation. In doing so we hope to elucidate some of the nonhormonal nonsteroidal effects of DES. Furthermore, we hope to define the mechanisms by which DES can be useful when LH-RH agonist therapy or orchiectomy has failed. MATERIALS AND METHODS: We comprehensively reviewed the literature from 1935 to the present regarding estrogen and antiandrogen therapy. Our search focused on issues pertaining to side effects, efficacy and nonsteroidal effects of antiandrogens and estrogens. RESULTS: It is readily apparent from the literature that androgen deprivation with DES can achieve effective prostate cancer control with demonstrable benefits compared to conventional LH-RH agonist therapy. In particular, rates of bone resorption and osteoporosis are less with the use of estrogen therapies. Estrogen has a clear beneficial effect on cognitive function. The estrogen metabolite 2-methoxyestradiol has significant antiangiogenic and pro-apoptotic effects. These effects give estrogens an added anticancer effect not otherwise seen in conventional LH-RH agonist therapy. CONCLUSIONS: The efficacy of 1 mg DES extends well beyond its androgen suppressive effects. Androgen deprivation without estrogen deprivation is a concept that deserves further attention in the urological community.     

Contemporary role of androgen deprivation therapy for prostate cancer

Context

Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk-benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease.

Objective

Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds.

Evidence acquisition

A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated.

Evidence synthesis

Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone-releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality.

Conclusions

Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk-benefit ratio.