Hypogonadism and Pain Perception in Androgen-Deprived Men with Prostate Cancer

描述（由申请方提供）：本提案的总体目标是评价接受雄激素剥夺治疗（ADT）的前列腺癌（PCa）男性患者的临床和实验性疼痛变化，并将其与未接受ADT（非ADT）的PCa男性患者进行比较。ADT的使用与生活质量（QOL）的显著下降相关，SF-36 QOL问卷的身体和精神组成部分均明显下降。物理复合物的一个方面是对疼痛的感知。初步的横断面研究表明，与非ADT组和年龄匹配的健康对照组相比，接受ADT的男性报告更多的临床疼痛。由于这种增加的疼痛感觉甚至在那些雄激素缺乏的男性中也可以看到，这些发现暗示了深刻的性腺功能减退症是这些症状的主要病因。男性性腺功能减退症是一种炎症状态，与促炎细胞因子如IL-6和TNF-α的增加有关，这两者都与临床和实验性疼痛有关。雄激素剥夺治疗也与代谢异常如胰岛素抵抗和高血糖症有关。因此，尚不清楚接受ADT的男性中疼痛的患病率/严重程度增加是由于性腺功能减退的直接影响还是继发于这些代谢异常。我们提出了一项前瞻性研究，其中：1）我们将比较6个月内接受ADT与非ADT男性之间临床疼痛报告和心理物理疼痛反应的变化，2）我们将评估各种代谢和炎症标志物与接受ADT男性疼痛感知和疼痛阈值的相关性。这项拟议的研究，除了推进我们对ADT男性疼痛发展机制的理解外，还可能对ADT患者的整体健康管理产生重大临床影响。本研究的结果将指导医生将ADT用于适当的适应症，并在ADT期间筛选这些患者的偶发疼痛。由于雄激素替代治疗在PCa男性中是禁忌的，因此本研究将为评估新型抗炎药、胰岛素增敏剂或SARMS（选择性雄激素受体调节剂）在ADT期间预防和治疗疼痛中的作用的前瞻性试验奠定基础。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to evaluate the change in clinical and experimental pain in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT) and compare them with men with PCa not receiving ADT (non-ADT). The use of ADT is associated with a significant decrease in quality of life (QOL).This decrease is evident in both physical and mental composites of SF-36 QOL questionnaire. One of the aspects of the physical composite is the perception of pain. Preliminary cross-sectional studies have shown that men undergoing ADT report more clinical pain when compared with men in the non-ADT group and with age-matched healthy controls. As this increased pain perception is seen even in those androgen-deprived men without any metastatic disease, these findings implicate profound hypogonadism as the main etiology for these symptoms. Male hypogonadism is an inflammatory state associated with an increase in pro-inflammatory cytokines like IL-6 and TNF-¿, both of which have been associated with clinical and experimental pain. Androgen deprivation therapy is also associated with metabolic abnormalities such as insulin resistance and hyperglycemia. Hence, it is unclear whether the increased prevalence/severity of pain in men on ADT is due to direct effects of hypogonadism or secondary to these metabolic abnormalities. We propose a prospective study in which: 1) we will compare changes in clinical pain reports and psychophysical pain responses between men undergoing ADT vs. non-ADT over a 6-month time period, and 2) We will assess the associations of various metabolic and inflammatory markers with pain perception and pain threshold in men undergoing ADT. The proposed study, in addition to advancing our understanding of the mechanism of pain development in men on ADT, is likely to have a significant clinical impact on the overall health-management of patients on ADT. The results of this study will guide physicians to use ADT for appropriate indications and to screen these patients for incident pain during ADT. Since androgen replacement is contraindicated in men with PCa, this study will lay the groundwork for prospective trials assessing the role of novel anti-inflammatory agents, insulin- sensitizing agents or SARMS (selective androgen receptor modulators) in the prevention and treatment of pain during ADT.