雄性循环SHBG增龄性升高的原因及初步机制的研究

Late-onset hypogonadism (LOH) might be harmful to multiple organ systems, even decrease the quality of life and the life expectancy of male. Testosterone replacement therapy is the currently main treatment for LOH, but its side effects and drug dependence severely restrict its use. As a result, new idea for LOH treatment is urgent needed. In the previous study, we found the serum levels of total testosterone remained stable or even slightly increased, the incidence rate of total testosterone deficiency remained stable, but serum levels of sex hormone-binding globulin (SHBG) showed significantly increase with aging,in Chinese adult males. To infer, LOH among Chinese might caused by the significant decrese of serum level of bioactivity testosterone, and the latter might caused by increased level of SHBG with aging. In order to explore the causes of the increase of SHBG with aging, the project intends to do: 1. From the way of generation of SHBG, the level of potential influence factors (such as HNF-4α, COUP TF, PPARγ, etc.) and SHBG in serum and tissues of male and male rats from youth to old will be detction, and the relationship between these level and age will be analysed; Also, the role of potential influence factors for SHBG gene transcription activity will be explored using vitro experiments; 2, From the way of metabolize and clearance of SHBG, the distribution, accumulation and clearance of SHBG in male rats from youth to old will be observed, and the relationship between SHBG modification and its clearance will be analysed. Aim to verify the causes and mechanisms of age-related increase of SHBG in male, to provide new ideas for treatment of LOH.

迟发性性腺功能减退症（LOH）严重降低男性生命质量和预期寿命。睾酮替代治疗是目前治疗LOH的主要措施，但可能存在严重副作用和药物依赖。LOH治疗急需新思路。针对前期发现的我国成年男性血清总睾酮水平及缺乏率随年龄增加维持不变，但血清中性激素结合球蛋白（SHBG）水平随年龄增加而显著升高的问题，提出LOH可能是因SHBG增龄性升高、导致生物活性睾酮下降所致。本项目拟通过：1，观测不同年龄段男性和雄鼠血清、组织中相关转录因子（如HNF-4α、COUP TF、PPARγ等）及SHBG的变化，体外实验调控转录因子后SHBG基因转录活性及蛋白水平的变化，评价年龄对SHBG转录合成的影响；2、观测SHBG在不同年龄雄鼠体内的分布、蓄积与清除，及与SHBG修饰、变异的关系，分析年龄对SHBG代谢清除的影响及可能原因；以进一步查证雄性循环SHBG水平增龄性升高的原因和机制，为LOH治疗提供新思路。

前期研究中我们发现男性血清中性激素结合球蛋白（SHBG）呈现增龄性升高，可能是导致生物活性睾酮下降、进而诱发或加重LOH（迟发性性腺功能减退症）的主要原因。然而，SHBG在组织中的水平是否随年龄增加而显著升高，SHBG呈增龄性增加的原因及机制是什么尚不明确。为了回答以上问题，我们通过人群调查，动物实验和细胞实验进行了研究。.人群调查发现，成年男性血清SHBG水平随年龄增加而显著增加（P<0.05）；动物实验表明，随年龄增加，大鼠血清SHBG的水平呈现增龄性升高趋势（P>0.05），肝脏中显著升高（P<0.05），但在睾丸、前列腺中变化不明显（P>0.05）。表明雄性体内SHBG总体水平是增龄性升高的，并与SHBG分布、蓄积的增龄性变化无关。.人群调查发现，SHBG合成促进因子HNF-4α和抑制因子PPAR-γ均下降（均P<0.05），但促进因子降幅较低，抑制因子下降幅度较大，推测SHBG的增龄性升高可能是因为合成增加所致。动物实验表明，随着年龄增加，大鼠血清中HNF-4α、PPAR-γ的水平均随年龄升高而下降，但肝脏中HNF-4α表达水平随大鼠月龄增加而增加，PPAR-γ及COUP-TF随着大鼠的年龄增加明显的的递减（均P<0.05），表明SHBG的增龄性升高的原因可能是因为肝脏的合成增加所致。.体外细胞实验初步验证，PPAR-γ、COUP-TF对SHBG转录合成发挥负调控作用。.本项目证实了SHBG随年龄增加而升高的现象，并发现SHBG的增龄性升高与分布、蓄积无关，可能是因为肝脏的增龄性合成增加所致。研究为如何维持SHBG水平的相对稳定，保持中老年雄性的生物活性睾酮水平、减缓男性LOH的症状、提高LOH患者的生活质量与生命质量提供了重要的前期基础研究数据。