雄激素、雌激素与男性骨质疏松症

近年研究发现男性骨质疏松症与体内雄激素和雌激素水平呈正相关.雄激素通过刺激成骨细胞增殖和发育来促进骨骼生长,对维持骨量和提高骨密度起重要作用.雌激素对骨的作用可能是降低骨吸收而非促进骨形成,通过与成骨细胞上的受体结合而间接调控成骨细胞功能.但有研究认为睾酮对雄激素受体的亲和力和活性相对较低.睾酮在5α还原酶作用下代谢为双氢睾酮,进而代谢为雌二醇,或在芳香化酶作用下直接转变为雌激素,与雌激素受体结合而发挥生理学作用.该文就雄激素和雌激在男性骨质疏松症中的作用机制及激素替代疗法临床应用进展作一综述.     

雄激素与骨质疏松

雄激素是由 19个碳原子组成的同化激素 ,主要由睾丸 (95 % )、肾上腺皮质(4 %～ 5 % )和卵巢产生 ,在胎盘中也可产生。雄激素的主要生理功能是 :(1)通过垂体 下丘脑系统调节促性腺激素的分泌 ;(2 )促进并维持曲精管的精子产生 ;(3)在胚胎性分化期形成男性生殖器官 ;(4 )在青春期刺激男性副性征和附属器官的发育、成熟 ,并维持其成熟状态与功能。现将近年来关于雄激素与骨质疏松关系的研究综述如下。一、雄激素对骨细胞的调节在人与鼠的成骨细胞上有雄激素、雌激素受体。在鼠成骨细胞上 ,雄激素受体主要位于核内及核周围[1] 。雄激素受体ｍ…     

胆固醇对骨代谢影响的研究进展

正常骨代谢是动态调节的周期过程,破骨细胞负责的骨吸收与成骨细胞负责的骨形成相互偶联维持动态平衡。当骨形成和骨吸收的动态平衡被破坏时,就会引起骨量丢失及相关骨病。流行病学证据表明,胆固醇会抑制或促进骨代谢,这取决于胆固醇的种类。胆固醇及其代谢产物通过调节成骨细胞和破骨细胞的分化及活化来影响骨代谢的动态平衡。本文就胆固醇对骨代谢影响的研究进展作一综述。     

细胞因子对骨代谢的调节

骨组织是循环、免疫、心血管系统重要的组成部分，对于维持机体正常的功能具有重要的作用。骨代谢的平衡的维持需要破骨细胞（osteoclast，OC）引发的骨吸收和成骨细胞（osteoblast，OB）引发的骨形成作用间的动态平衡和偶联。多种细胞因子参与了该过程中的调控。在多种代谢性骨病发病机制研究中，细胞因子对骨代谢的调控作用日益受到人们的广泛关注。     

雄激素与骨质疏松

雄激素除了诱导男性性分化、促进性器官的生长发育和性成熟、维持第二性征及男性生殖系统的功能（如精子发生）外，还影响其他靶器官，如肌肉组织、心血管、中枢神经、免疫系统和骨骼，但对于雄激素的这种性外作用了解甚少。早在1940年，Albright及Reifenstein就首先提出了雄激素具有同化代谢和抗骨质疏松特性。近年来，男性骨质疏松的发病率呈上升趋势，     

miRNA在骨重建中的作用

微小RNA(micro RNA,miRNA)是一类具有组织特异性或发育阶段特异性表达特征的非编码调控小RNA,近年来,miRNA与骨形成和代谢的关系已成为研究热点之一,许多研究发现miRNA在骨代谢中的调控作用巨大。部分miRNA能够调节骨重建过程中的血管生成以及成骨细胞、破骨细胞的分化,通过改变相关miRNA表达水平进而深入研究miRNA在骨重建中的调控作用,同时miRNA可作为早期检测骨代谢疾病的生物标志物。本文通过对已知的miRNA在骨重建中血管生成及成骨细胞、破骨细胞中生物学和骨病理学作用机制的总结,说明其在骨重建过程中的重要作用。基于miRNA在骨重建中的调控作用,并在骨代谢相关疾病的临床实践中开辟新的领域,进而对骨代谢疾病有治疗作用。     

破骨细胞骨吸收机制研究进展

以绝经后骨量迅速下降为主要特征的绝经后骨质疏松症是生殖健康领域中的重要问题。破骨细胞 (osteoclast)作为骨吸收的主要细胞 ,对于骨量的变化具重要作用。因此 ,研究破骨细胞的生物学特性及骨吸收的机理对于预防和治疗骨质疏松症等代谢性骨病具有十分重要的意义。本综述着重论述破骨细胞的生物学特性及骨吸收的分子生物学机制和机理 ,抑制破骨细胞骨吸收的相关因素 ,以期进一步推动破骨细胞骨吸收功能的研究 ,加强骨质疏松等骨代谢疾病的治疗。一、破骨细胞的生物学特性破骨细胞来源于希腊文“Osteon”(骨 )和“klio”(破坏 )两词的组合…     

肠道菌群对骨代谢影响的研究进展

肠道菌群在人体中发挥着重要的作用,与人体的骨量减低及骨质疏松的发病相关。其可能通过自身代谢产物,影响宿主代谢及免疫系统等几方面来影响破骨细胞和成骨细胞的相对活性,从而影响骨代谢,甚至导致骨质疏松。本文将从上述几个方面对肠道菌群对骨代谢的影响进行综述。     

【特刊综述】骨骼两性异形中的雄激素和雌激素

骨骼是表达雄激素、雌激素受体以及类固醇代谢酶的一种内分泌组织。循环性激素的生物活性通过六种性激素结合球蛋白以及在骨组织中的局部转变来进行调节,例如,睾酮通过芳香酶转变成雌二醇,或通过5α还原酶转变成双氢睾酮。由于高分辨外周CT应用的增多,我们对造成骨骼强度性别差异的结构基础的认识在近几年有很大进步。这些对微小结构的观察是理解性激素对男性峰值骨量及对骨皮质和骨小梁之间转变的影响的基础。最近的研究利用Cre／LoxP技术使我们在整体基因敲除小鼠上机械的认识精确到性激素及其在成骨细胞、破骨细胞、骨细胞以及其它造成男性骨质疏松的细胞上的核受体的直接作用。同时,这些研究加强了这样的观点：雄激素和雌激素的缺乏通过与例如胰岛素样生长因子1、炎症、氧化应激、骨骼代谢的中枢神经系统控制、机械负荷的适应等的交互作用发挥直接和多种效应。这篇综述将总结性激素在男性骨骼自身平衡作用这个领域有关方面最近的进展。     

生物钟基因与骨免疫研究进展

昼夜节律是生命体为适应自然环境而产生的一种生物特性,生物钟基因调节着生命体的节律,Bmal1、Clock、PERs、CRYs、Rev-erbα等生物钟基因及下游的钟控基因发挥了重要作用。免疫细胞与骨细胞之间通过共同的细胞因子和信号通路相互作用,调节骨代谢平衡,免疫紊乱会导致骨代谢异常。骨免疫学的诞生有利于深入研究骨骼系统与免疫系统的相互作用,骨免疫参与了许多骨科疾病和免疫性疾病的发生和进展。生理状态下,生物钟基因通过调控骨骼系统与免疫系统的生物节律,在维持骨免疫的平衡状态中发挥着重要作用。病理状态下,生物钟基因功能异常不但导致骨骼系统和免疫系统的节律紊乱,进一步导致骨量丢失和免疫炎症反应,而且通过IL-1、IL-6、TNF-α、RANKL等骨免疫因子对骨代谢产生作用。反过来,免疫炎症反应也会对生物钟基因正常功能产生影响,进而影响骨代谢。根据生物钟基因和骨代谢自身的特点,认识生理病理状态下生物钟基因与骨免疫的相互作用,对骨骼系统疾病和免疫系统疾病的防治有一定的指导意义。     

Regulation of global gene expression in the bone marrow microenvironment by androgen: androgen ablation increases insulin-like growth factor binding protein-5 expression

BACKGROUND: Prostate cancer frequently metastasizes to bone. Androgen suppression treatment is initially highly effective, but eventually results in resistant cancer cells. This study evaluates the effects of androgen suppression on the bone and bone marrow (BM). In particular we questioned whether the androgen therapy could adversely facilitate prostate cancer progression through an increase growth factor secretion by the bone microenvironment. METHODS: Global gene expression is analyzed on mPEDB DNA microarrays. Insulin-like growth factor binding protein-5 (IGFBP5) is detected by immunohistochemistry in mouse tissues and its regulation measured by qPCR and Western blotting in human BM stromal cells. Effects of extracellular matrix-associated IGFBP5 on human prostate epithelial cells are tested in an MTS cell-growth assay. RESULTS: Castration increases expression of 159 genes (including 4 secreted cytokines) and suppresses expression of 84 genes. IGFBP5 is most consistently increased and the increase in expression is reversed by testosterone administration. IGFBP5 protein is detected in vivo in osteoblasts, BM stromal cells, and endothelial cells. Primary human stromal cell cultures secrete IGFBP5. In vitro, treatment of immortalized human marrow stromal cells with charcoal-stripped serum increases IGFBP5 mRNA expression, which is reversed by androgen supplementation. IGFBP5 is incorporated into the extracellular matrix. Further, IGFBP5 immobilized on extracellular matrices of stromal cells enhances the growth of immortalized prostate epithelial cells. CONCLUSIONS: Androgen suppressive therapy increases IGFBP5 in the BM microenvironment and thereby may facilitate the progression of prostate cancer.     

Androgens and osteoporosis

Androgen receptors are present in relevant numbers in osteoblasts. Stimulation of androgen receptors in osteoblastic bone marrow stromal cells inhibits the differentiation of osteoclasts in the bone marrow cavity. Androgens not only inhibit osteoclastogenesis but also increase cortical bone formation mainly by stimulating periosteal bone formation. Clinically, androgen action is crucial for the gain of bone mass during puberty and the maintenance of bone mass after puberty. Therefore, androgen replacement is necessary in hypogonadal men. However, the role of androgen replacement in partial androgen deficiency still remains unclear. Thus far, only testosterone has established its role in androgen replacement. However, further clinical and basic research should better define the selective role of androgen versus oestrogen receptor stimulation in male skeletal homeostasis.     

Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer

PURPOSE: Androgen deprivation therapy in patients with prostate cancer is associated with bone loss and an increased risk of fractures. Zoledronic acid protects against bone mineral density loss when initiated concurrently with androgen deprivation therapy. We evaluated the effect of zoledronic acid initiated subsequent to androgen deprivation therapy on bone mineral density and biochemical markers of bone turnover. MATERIALS AND METHODS: Patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less were randomized to 4 mg zoledronic acid or placebo intravenously every 3 months for 1 year. Patients were stratified according to androgen deprivation therapy duration (less than 6 vs 6 to 12 months). The primary end point was the change in femoral neck and lumbar spine bone mineral density in the 2 groups. The secondary end point was the change in serum bone specific alkaline phosphatase and urine N-telopeptide levels. Total hip bone mineral density was also measured. RESULTS: The 120 patients with prostate cancer received zoledronic acid (61) or placebo (59). Compared with placebo, zoledronic acid increased femoral neck, total hip and lumbar spine bone mineral density yearly by 3.6% (p = 0.0004), 3.8% (p <0.0001) and 6.7% (p <0.0001), respectively. The effects of zoledronic acid on bone mineral density at these 3 sites were not differentiated according to androgen deprivation therapy duration. Additionally, mean bone specific alkaline phosphatase and N-telopeptide levels were decreased in the zoledronic acid group (each p <0.0001) and were increased in the placebo group (p <0.0001 and p = 0.004, respectively). CONCLUSIONS: Zoledronic acid increased bone mineral density and suppressed bone turnover markers in patients with prostate cancer without bone metastases when initiated during year 1 of androgen deprivation therapy.     

睾酮与男性骨质疏松

男性骨质疏松的病因是多方面的 ,雄激素水平下降是很重要的一个因素。雄激素不仅在获得骨峰值及维持骨量中起重要作用 ,雄激素水平下降与随增龄而发生的骨丢失关系也很密切。雄激素通过雄激素受体影响成骨细胞功能 ,各种局部因子起调节作用。老年人部分睾酮替代治疗可提高骨密度 ,但其利弊需进一步观察。同时雌激素在男性骨质疏松中所起作用开始受到关注     

雄激素对脂质代谢及心血管系统的影响

雄激素在男科中的应用越来越广泛,其对血脂、心血管系统的影响不可忽视。雄激素与血脂之间的关系较为复杂,受到多种因素的影响。内源性雄激素对血脂的影响因年龄、环境、营养状态、性别而不同;外源性雄激素对血脂的影响也因其使用制剂、应用方式及治疗疾病种类的不同而有所差异。雄激素可以通过影响脂质代谢、血管内皮功能、单核-巨噬细胞、血管平滑肌、血管张力、凝血纤溶系统、血小板功能等来调节心血管系统功能,并影响动脉粥样硬化的发生与发展。雄激素受体基因CAG多态性对心血管系统的影响也不可忽视,但目前关于此方面的研究尚存争议,有待进一步探讨。     

The androgen receptor pathway is by-passed in prostate cancer cells generated after prolonged treatment with bicalutamide

BACKGROUND: Experimental work in various prostate cancer models revealed that the androgen receptor is frequently upregulated and implicated in tumor progression. However, little attention has been paid to the androgen receptor-signaling pathway in the development of therapy resistance in patients who receive chronic treatment with a non-steroidal anti-androgen. METHODS: We have generated a novel subline, LNCaP-Bic, after prolonged treatment with androgen and bicalutamide in vitro. Proliferation of LNCaP-Bic cells in the absence or presence of androgen, tocopherol succinate, and/or bicalutamide was assessed by cell counting. Androgen receptor expression was determined by Western blot. Luciferase activity was measured in cells transfected with an androgen-responsive reporter. RESULTS: In basal conditions, proliferation of LNCaP-Bic cells increased more than threefold over that of control LNCaP cells. Neither synthetic androgen R1881 nor bicalutamide showed any effect on LNCaP-Bic growth in vitro. Androgen receptor expression did not differ between the cell subline generated in the presence of bicalutamide and parental LNCaP cells. The ability of R1881 to induce reporter gene activity in LNCaP-Bic cells was reduced by 56%. Tocopherol succinate caused inhibition of proliferation only in the parental cell line although the androgen receptor and prostate-specific antigen were down regulated by the vitamin E derivative in both parental LNCaP and LNCaP-Bic cells. CONCLUSIONS: Androgen receptor-mediated signal transaction is not enhanced in cells selected in the presence of bicalutamide. Our data may suggest that a more differentiated approach in targeting the androgen receptor is needed in prostate cancers that become resistant to classic endocrine treatment.     

雄激素剥夺治疗前列腺癌引起的骨代谢变化

雄激素剥夺治疗(androgen deprivation therapy,ADT)是治疗转移性前列腺癌(PCa)的基石,显著延长了PCa患者生存期。然而在ADT治疗的PCa患者中,每年平均骨密度下降2%~10%,导致骨折发病率、相关发病率和死亡率增加,应该引起临床医师的注意。这种骨代谢状态,目前认为主要是雄激素、雌激素水平明显减低导致。临床工作者可通过监测骨转换指标、骨密度及FRAX算法筛选出需要提前干预的患者,并对该类患者提供生活方式的指导及干预,以达到减少骨质不良事件的发生。这些干预措施包括适当锻炼、减少吸烟喝酒、补充钙和维生素D、双膦酸盐、部分选择性雌激素受体调节剂(如托瑞米芬)和靶向RANK配体抑制剂等。     

Metabolic changes in patients with prostate cancer during androgen deprivation therapy

Androgen deprivation therapy continues to be widely used for the treatment of prostate cancer despite the appearance of new‐generation androgen‐receptor targeting drugs after 2000. Androgen deprivation therapy can alleviate symptoms in patients with metastatic prostate cancer and might have a survival benefit in some patients, but it causes undesirable changes in lipid, glucose, muscle or bone metabolism. These metabolic changes could lead to new onset or worsening of diseases, such as obesity, metabolic syndrome, diabetes mellitus, cardiovascular disease, sarcopenia or fracture. Several studies examining the influence of androgen deprivation therapy in Japanese patients with prostate cancer also showed that metabolic changes, such as weight gain, dyslipidemia or fat accumulation, can occur as in patients in Western countries. Efforts to decrease these unfavorable changes and events are important. First, overuse of androgen deprivation therapy for localized or elderly prostate cancer patients should be reconsidered. Second, intermittent androgen deprivation therapy might be beneficial for selected patients who suffer from impaired quality of life as a result of continuous androgen deprivation therapy. Third, education and instruction, such as diet or exercise, to decrease metabolic changes before initiating androgen deprivation therapy is important, because metabolic changes are likely to occur in the early androgen deprivation therapy period. Fourth, routine monitoring of weight, laboratory data or bone mineral density during androgen deprivation therapy are required to avoid unfavorable events.     

The physiological and pharmacological basis for the ergogenic effects of androgens in elite sports

Androgen doping in power sports is undeniably rampant worldwide. There is strong evidence that androgen administration in men increases skeletal muscle mass, maximal voluntary strength and muscle power. However, we do not have good experimental evidence to support the presumption that androgen administration improves physical function or athletic performance. Androgens do not increase specific force or whole body endurance measures. The anabolic effects of testosterone on the skeletal muscle are mediated through androgen receptor signaling. Testosterone promotes myogenic differentiation of multipotent mesenchymal stem cells and inhibits their differentiation into the adipogenic lineage. Testosterone binding to androgen receptor induces a conformational change in androgen receptor protein, causing it to associate with beta-catenin and TCF-4 and activate downstream Wnt target genes thus promoting myogenic differentiation. The adverse effects of androgens among athletes and recreational bodybuilders are under reported and include acne, deleterious changes in the cardiovascular risk factors, including a marked decrease in plasma high-density lipoproteins （HDL） cholesterol level, suppression of spermatogenesis resulting in infertility, increase in liver enzymes, hepatic neoplasms, mood and behavioral disturbances, and long term suppression of the endogenous hypothalamic-pituitary-gonadal axis. Androgens are often used in combination with other drugs which may have serious adverse events of their own. In spite of effective methods for detecting androgen doping, the policies for screening of athletes are highly variable in different countries and organizations and even existing policies are not uniformly enforced.     

Androgens and bone

Androgen receptors are present at low densities in osteoblasts. Androgens are also metabolized in bone. (Non)aromatizable androgens probably induce proliferation of osteoblasts and differentiation. A direct effect of androgens on osteoclasts has not been demonstrated. Androgens may however inhibit bone resorption indirectly, by an inhibition of the recruitment of osteoclast precursors from bone marrow, by decreased secretion of interleukin-6 and/or prostaglandin E₂, and/or by an increased sensitivity of marrow cells or osteoblasts for bone resorption stimulating factors such as PTH. The recent demonstration of androgen receptors in bone marrow stromal and osteoclast-like cells opens new perspectives in this respect. During puberty, androgens stimulate bone growth both directly and indirectly. Observations in androgen-resistant animals clearly demonstrated that the sexual dimorphism of bone depends on the presence of a functional androgen receptor. Optimal peak bone mass seems related to an appropriately timed androgen secretion. In adults, androgens are also involved in maintenance of the male skeleton. Androgen replacement may prevent further bone loss in hypogonadal men, however, it seems difficult to fully correct bone mass in these men.