Androgen Regulation of Priapism in Sickle Cell Disease

描述（由申请人提供）：阴茎异常勃起是一种反复发作的非故意性阴茎过度勃起疾病，影响不同人群。它特别影响男性镰状细胞病（SCD），多达40%的这些人经常在年轻的成年人中发展这种疾病。这种疾病导致阴茎组织损伤和正常勃起能力的丧失，沿着毁灭性的心理后果，因此不应该轻视它。今天，治疗仍然缺乏，许多男子和男孩忍受延迟和无效的治疗或与主要副作用相关的阴茎松弛的操纵。最近的努力，以更好地了解科学的障碍提供了希望，以设计基于证据的治疗是合理和有效的。目前认为，与SCD相关的复发性缺血性阴茎异常勃起涉及与首要一氧化氮信号通路相关的正常阴茎勃起分子机制的畸变。雄激素被充分描述为对该途径施加直接调节影响，并且雄激素缺乏经常观察到发生在SCD中。因此，雄激素环境对阴茎异常勃起的病理生理学有一定的作用是理所当然的。该建议的中心假设是雄激素水平和作用的下降有助于与阴茎异常勃起相关的分子紊乱，相反，优化雄激素状态促进防止阴茎异常勃起的调节分子机制。该提案指定了一个转化项目，并结合了临床前研究，以验证假设（具体目标1）和使用SCD小鼠模型研究下丘脑-垂体-性腺轴缺陷（具体目标2），以及临床试验，研究精确的睾酮替代治疗对改善SCD男性性腺功能减退患者的阴茎异常勃起和改善心理健康的潜在益处（具体目标3）。该提案符合资助机构关于生殖生物学和睾丸功能的目标。

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.