Androgen Regulation of Priapism in Sickle Cell Disease

描述(申请人提供)：阴茎异常勃起是一种影响不同人群的非故意、过度勃起的疾病。它特别影响患有镰状细胞病(SCD)的男性，其中多达40%的人往往在年轻时患上这种疾病。这一障碍会导致阴茎组织损伤和正常勃起能力的及时丧失，以及毁灭性的心理后果，因此不应小题大做。今天，仍然缺乏治疗，许多男人和男孩忍受着延迟和无效的治疗或与主要副作用相关的阴茎松弛的操作。最近更好地了解这种疾病的科学的努力为设计合理而有效的循证治疗提供了希望。现已认识到，与SCD相关的复发性缺血性阴茎异常勃起涉及与主要的一氧化氮信号通路相关的正常阴茎勃起的分子机制的异常。雄激素被很好地描述为对这一途径施加直接调节影响，并且雄激素缺乏在SCD中经常被观察到。因此，理所当然地，雄激素环境对异常勃起的病理生理学有贡献。这一建议的中心假设是，雄激素水平和作用的下降导致了与异常勃起相关的分子错乱，反过来，优化雄激素状态促进了防止异常勃起的调节分子机制。该提案指定了一个翻译项目，并结合了验证假设的临床前研究(特定目标1)和使用SCD小鼠模型调查下丘脑-垂体-性腺轴缺陷(特定目标2)，以及临床试验，调查精确的睾酮替代对改善性腺功能低下的SCD男性异常勃起和改善心理健康的潜在益处(特定目标3)。该提案符合该资助机构在生殖生物学和睾丸功能方面的目标。 与公共卫生相关：阴茎异常勃起是一种非故意、过度勃起的疾病，影响不同人群，包括患有镰状细胞病的男性。这一领域的持续研究对于设计出合理有效的循证疗法是必要的。这项建议探讨了以阴茎勃起机制中涉及的男性激素途径为靶点作为治疗阴茎异常勃起的临床疗法的可能性。

DESCRIPTION (provided by applicant): Priapism is a disorder of non-willful, excessive penile erection recurrences affecting diverse populations. It particularly affects males with sickle cell disease (SCD), and as many as 40% of these individuals develop the disorder often in their young adult years. The disorder accounts for penile tissue damage and loss of normal erectile ability in time, along with devastating psychological consequences, and thus it should not be trivialized. Today, treatments remain lacking, and many men and boys endure delayed and ineffective therapies or manipulations of penile flaccidity associated with major side-effects. Recent efforts to better understand the science of the disorder offer hope to devise evidence-based therapies that are rational and effective. It is now understood that recurrent, ischemic priapism associated with SCD involves aberrations of the molecular mechanisms of normal penile erection associated with the premier nitric oxide signaling pathway. Androgens are well described to exert a direct regulatory influence on this pathway, and androgen deficiency is frequently observed to occur in SCD. Accordingly, it stands to reason that the androgen milieu contributes to the pathophysiology of priapism. The central hypothesis of this proposal is that a decline in androgen levels and actions contributes to the molecular derangements associated with priapism and, conversely, optimizing androgen status promotes regulatory molecular mechanisms that protect against priapism. The proposal specifies a translational project and combines preclinical studies testing the hypothesis (Specific Aim 1) and investigating the hypothalamic-pituitary-gonadal axis defect (Specific Aim 2) using a mouse model of SCD and clinical trial investigating the potential benefit of precise testosterone replacement for ameliorating priapism and improving psychological well- being (Specific Aim 3) in hypogonadal men with SCD. The proposal fits with goals of the funding agency pertaining to reproductive biology and testis function. PUBLIC HEALTH RELEVANCE: Priapism is a disorder of non-willful, excessive penile erection recurrences affecting diverse populations, including men with sickle cell disease. Continued research in this field is necessary to devise evidence-based therapies that are rationale and effective. This proposal explores the possibility of targeting the male hormone pathway involved in the mechanisms of penile erection as a clinical therapy for treatment of priapism.