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1、ERECTILE DYSFUNCTION,Abstract,The molecular and clinical understanding of erectile function continues to gain ground at a particularly fast rate. The understanding of the nitric oxide (一氧化氮) pathway has aided not only in the molecular understanding of the tumescence (肿胀,肿大) but also aided greatly in
2、 the therapy of erectile dysfunction. anatomical, molecular, and dynamic knowledge base of erectile function and dysfunction,ERECTILE DYSFUNCTION,TOPIC,Hemodynamics(血流动力学) and Mechanism of Erection and Detumescence(退肿,消肿) Neuroanatomy and Neurophysiology of Penile Erection Molecular Mechanism of Smo
3、oth Muscle Contraction and Relaxation Pathophysiology of Erectile Dysfunction /Classification of Male Erectile Dysfunction,ERECTILE DYSFUNCTION,CHAPTER 1 Hemodynamics and Mechanism of Erection and Detumescence,penile erectile tissue :cavernous (多孔的,海绵状的) smooth musculature (肌组织,肌肉系统) and the smooth
4、muscles of the arteriolar (小动脉的) and arterial (动脉的) walls In the flaccid (软弱的,软垂的,柔弱的) state, these smooth muscles are tonically (紧张的,强直的) contracted, allowing only a small amount of arterial flow for nutritional purposes Sexual stimulation triggers release of neurotransmitters (神经递质) from the caver
5、nous (多孔的,海绵状的) nerve terminals,ERECTILE DYSFUNCTION,Hemodynamics and Mechanism of Erection and Detumescence,This results in relaxation of these smooth muscles and the following events: 1、 Dilatation (膨胀度) of the arterioles (小动脉) and arteries by increased blood flow 2、 Trapping (诱捕,吸收,抑制) of the inc
6、oming blood by the expanding sinusoids (窦状的) ; 3、 Compression of the subtunical（螺旋的） venular (小静脉) plexuses (丛) , reducing the venous outflow (静脉回流) ; 4、 Stretching伸直; 伸长 of the tunica (被膜) to its capacity , occludes (堵塞, 封闭) the emissary veins (导静脉) ; 5、 An increase in PO2 and intracavernous (海绵窦内的
7、) pressure ; 6、 A further pressure increase with contraction of the ischiocavernosus (坐骨海绵体肌) muscles (rigid-erection phase),ERECTILE DYSFUNCTION,three phases of detumescence(退肿,消肿),first : a transient (暂时的) intracorporeal (体内的) pressure increase Second: a slow pressure decrease -reopening of the ve
8、nous channels with resumption (恢复) of the basal level of arterial flow Third: a fast pressure decrease with fully restored (恢复) venous outflow (流出；外流 ) capacity.,ERECTILE DYSFUNCTION,Erection involves sinusoidal (窦状隙) relaxation, arterial dilatation (膨胀度) , and venous compression (压缩,缩小),The hemodyn
9、amics of the corpus spongiosum尿道海绵体and glans penis阴茎头 are somewhat different from those of the corpora cavernosa (阴茎海绵体) During erection, the arterial flow increases is similar ; but the pressure in the corpus spongiosum (尿道海绵体) and glans is only one third to one half of that in the corpora cavernos
10、a (阴茎海绵体) because the tunical covering (thin over the corpus spongiosum and virtually absent over the glans) ensures minimal venous occlusion. full-erection phase, partial compression of the deep dorsal and circumflex veins between Bucks fascia and the engorged corpora cavernosa contribute to glanul
11、ar tumescence, although the spongiosum and glans essentially function as a large arteriovenous shunt during this phase. rigid-erection phase, the ischiocavernosus (坐骨绵体肌) and bulbocavernosus (球海绵体肌) muscles forcefully compress the spongiosum (皮肤棘细胞层) and penile veins, which results in further engorg
12、ement (充血,肿胀) and increased pressure in the glans and spongiosum.,ERECTILE DYSFUNCTION,CHAPTER 2 Neuroanatomy and Neurophysiology of Penile Erection,Peripheral (外周的,末梢的) Pathways Autonomic (自律的,自主的) Pathways Somatic（躯体的, 体细胞的）Pathways Supraspinal（棘上的,脊椎上的）Pathways and Centers Central Neural Activati
13、on during Sexual Arousal （激醒, 唤醒）,ERECTILE DYSFUNCTION,Peripheral(外周的,末梢的)Pathways,Innervation 神经分布/支配 of the penis : autonomic (sympathetic and parasympathetic副交感神经) and somatic 躯体神经 systemsensory and motor the sympathetic and parasympathetic nerves merge to form the cavernous nerves -enter the cor
14、pora cavernosa 阴茎海绵体and corpus spongiosum 尿道海绵体 -affect the neurovascular 神经血管的 events during erection and detumescence The somatic nerves are primarily responsible for sensation 感觉 and the contraction of the bulbocavernosus 球海绵体肌and ischiocavernosus 坐骨海绵体肌 muscles.,ERECTILE DYSFUNCTION,Autonomic(自律
15、的,自主的)Pathways,sympathetic pathway : T11 L2 the lumbar splanchnic内脏的 nerves inferior mesenteric肠系膜下的and superior hypogastric plexuses下腹上丛 pelvic plexus下腹下丛,盆丛 ; In humans , the sacral and caudal ganglia cells 骶尾神经节细胞 projecting to the penis parasympathetic pathway :intermediolateral中间外侧的cell columns
16、(S2-S4) -preganglionic (神经)节前的fibers pass in the pelvic nerves盆神经 to the pelvic plexus盆丛,ERECTILE DYSFUNCTION,Autonomic(自律的,自主的)Pathways,Stimulation pelvic plexus and the cavernous nerves erection； stimulation sympathetic trunk detumescence the sacral parasympathetic input tumescence ； the thoracolu
17、mbar胸腰的sympathetic pathway detumescence,ERECTILE DYSFUNCTION,Somatic躯体的, 体细胞的Pathways,pain/temperature/touch sensory receptors ( penile skin, glans阴茎头, urethra尿道 and within the corpus cavernosum海绵体)dorsal nerve of penis pudendal阴部的nerve S2-4spinal cord central gray region of lumbosacral腰骶的segment sp
18、inothalamic脊髓丘脑的and spinoreticular脊髓网状束的pathways thalamus丘脑 and sensory cortex感觉皮层 for sensory perception感知觉 dorsal nerve :mixed nerve-somatic and autonomic components regulate erectile and ejaculatory射精的function,ERECTILE DYSFUNCTION,Somatic躯体的, 体细胞的Pathways,Onufs nucleus in the second to fourth sac
19、ral spinal segments is the center of somatomotor躯体运动神经的 penile innervation the sacral nerves pudendal阴部的 nerve ischiocavernosus坐骨海绵体肌and bulbocavernosus球海绵体肌muscles Contraction of the ischiocavernosus rigid-erection ; Rhythmic有节律的contraction of the bulbocavernosus ejaculation neurotransmitters :A5-c
20、atecholaminergic儿茶酚胺能的 adrenergic肾上腺素能的 serotonergic 5-羟色胺能 oxytocinergic催产素能的,ERECTILE DYSFUNCTION,Supraspinal棘上的,脊椎上的Pathways and Centers,integration整合 centers for sexual function and penile erection :medial preoptic视交叉前的area (MPOA) and the paraventricular室旁的nucleus (PVN) of the hypothalamus下丘脑and
21、 hippocampus海马 Neurotransmitters involved in penile erection :oxytocin催产素,(垂体)后叶催产(激)素and vasopressin后叶加压素,抗利尿激素 Several brain stem and medullary骨髓的, 髓质的, 延髓的centers are also involved :hypothalamus下丘脑, thalamus丘脑, neocortex新(大脑)皮质and spinal cord limbic边的; 缘的system,ERECTILE DYSFUNCTION,Central Neural
22、 Activation during Sexual Arousal激醒,唤醒,powerful tool -Positron emission tomography (PET) 正电子发射x线体层照相术and functional MRI (fMRI) scanning measure increases in regional cerebral blood flow or changes in regional cerebral activity during a particular moment in time Brain activation centers and correspon
23、ding function: table1,ERECTILE DYSFUNCTION,Table 1,ERECTILE DYSFUNCTION,Central Neural Activation during Sexual Arousal激醒,唤醒,three types of erection: psychogenic心理性的; 精神性的: audiovisual stimuli or fantasy spinal erection centers (T11-L2 and S2-S4) reflexogenic发生反射的: tactile stimuli spinal erection ce
24、nters nocturnal夜晚的; 夜出的 : during rapid-eye-movement (REM) sleep,ERECTILE DYSFUNCTION,CHAPTER 3 Molecular Mechanism of Smooth Muscle Contraction and Relaxation,Smooth muscle contraction and relaxation : regulated by cytosolic细胞质的(sarcoplasmic肌浆的) free Ca2+ nerve endings norepinephrine去甲肾上腺素 endotheli
25、um内皮activate receptors on smooth muscle cells -endothelins内皮素and prostaglandin前列腺素 F2inositol triphosphate肌醇三磷酸and diacylglycerol二脂酰甘油 sarcoplasmic reticulum肌浆网- release of calcium or opening of calcium channels influx流入,注入of calcium cytosolic free Ca2+ Ca2+ binds to calmodulin钙调蛋白conformation chang
26、edexpose sites of interaction with myosin肌球蛋白light-chain kinase phosphorylation磷酸化of myosin light chains ： cycling循环of myosin crossbridges横桥 myosin ATPase(+) hydrolyzes水解ATP provide energy for muscle contraction,ERECTILE DYSFUNCTION,RhoA/Rho kinase pathway: the calcium sensitization致敏作用pathway.,RhoA
27、, a small, monomeric单体的G protein that activates Rho-kinase RhoA: activated Rho-kinase phosphorylates inhibits the regulatory subunit of smooth muscle myosin肌球蛋白phosphatase磷酸酶preventing dephosphorylation of myofilaments肌丝 myofilaments maintain contractile有收缩性的tone (Figure 2). characteristic : via act
28、ivation of excitatory receptors coupled to偶联 G-proteins which can also cause contraction by increasing calcium sensitivity without any change in cytosolic Ca2+,ERECTILE DYSFUNCTION,RhoA/Rho kinase pathway: the calcium sensitization致敏作用pathway,RhoA and Rho-kinase: expressed in penile smooth muscle (i
29、n the cavernosal is 17 fold higher than in the vascular smooth muscle) A selective inhibitor of Rhokinaseelicit relaxation of human corpus cavernosum in vitro在体外 and to induce penile erection in animal models other mechanisms : caldesmon钙调素结合蛋白may be involved in the latch门闩/阀state,ERECTILE DYSFUNCTI
30、ON,Relaxation of the muscle follows a decrease of free Ca2+ in the sarcoplasma肌浆,Calmodulin dissociates分离,离解from myosin light-chain kinase and inactivates it myosin detaches from the actin filament muscle relaxes Others : NO-cGMP inhibitory pathway in corpus cavernosum smooth muscle decreasing the r
31、ate of crossbridge横桥recruitment复原through phosphorylation cAMP and cGMP : involved in smooth muscle relaxationactivate PKA/PKG phosphorylate certain proteins and ion channels result : (1) open the potassium钾 channels and hyperpolarization超极化; (2) sequestration隔绝of intracellular胞内的 calcium by the endo
32、plasmic reticulum内质网; (3) inhibition of voltage-dependent calcium channels, blocking calcium influx. The consequence is a drop in cytosolic free calcium and smooth muscle relaxation (Figure 3),ERECTILE DYSFUNCTION,CHAPTER 4 Pathophysiology of Erectile Dysfunction,classifications : based on the cause
33、 (diabetic糖尿病的, iatrogenic医源性的, traumatic外伤的) based on the neurovascular mechanism of the erectile process (failure to initiate neurogenic, failure to fill arterial, and failure to store venous recommended by the International Society of Impotence Research is shown in Table 2,ERECTILE DYSFUNCTION,TA
34、BLE 2 Classification of Male Erectile Dysfunction,ERECTILE DYSFUNCTION,Classification of Male Erectile Dysfunction,Psychogenic ED : the most common type Two possible mechanisms in psychogenic dysfunction: 1 direct inhibition of the spinal erection center ; 2 excessive sympathetic outflow or elevated
35、 peripheral 外周的catecholamine儿茶酚胺levels OR higher levels of serum浆液, 血清norepinephrine去甲肾上腺素 Animal studies : stimulation of sympathetic nerves or systemic infusion of epinephrine肾上腺素 detumescence of the erect penis,ERECTILE DYSFUNCTION,Neurogenic Erectile Dysfunction 10 - 19%,integration centers for
36、sexual drive and penile erection : MPOA内侧视前区, paraventricular室旁的nucleus, and hippocampus海马 Pathologic病理学的processes in these regions, such as Parkinsons disease, stroke, encephalitis脑炎, or temporal lobe epilepsy癫痫症, are often associated with ED Other lesions损伤 : tumors, dementias痴呆, Alzheimers diseas
37、e阿耳茨海默(氏)病, Shy-Drager syndrome夏-德综合征, and trauma创伤.,ERECTILE DYSFUNCTION,Neurogenic Erectile Dysfunction,spinal cord injury, their erectile function depends largely on the nature, location, and extent of the spinal lesion addition to ED they may also have impaired ejaculation and orgasm性高潮 Other di
38、sorders at the spinal level (e.g., spina bifida脊柱裂, disc herniation形成疝, syringomyelia脊髓空洞症, tumor, transverse myelitis横贯性脊髓炎, and multiple sclerosis多发性硬化症) may affect the afferent传入的 or the efferent传出的 neural pathway in a similar manner,ERECTILE DYSFUNCTION,Neurogenic Erectile Dysfunction,pelvic fra
39、cture: ED can be a result of cavernous nerve injury or vascular insufficiency or both In diabetics糖尿病患者, impairment of neurogenic and endothelium内皮 -dependent relaxation results in inadequate NO release NADPH diaphorase硫辛酸脱氢酶staining of the NANC非肾上腺素能,非胆碱能nerve fibers in penile biopsy活检 specimens样品,
40、标本has been proposed as an indicator of neurogenic status,ERECTILE DYSFUNCTION,Endocrinologic(内分泌性) ED,Androgens雄激素 : effects on libido性冲动 and sexual behavior ; testosterone睾酮: (1) enhances sexual interest; (2) increases frequency of sexual acts; (3) increases the frequency of nocturnal夜间的；夜出的erectio
41、ns but has little or no effect on fantasy-induced or visually induced erections In rats, castration去势,阉割 arterial flow, venous leakage, and reduce about half of the erectile response to stimulation of the cavernous nerve long-term androgen ablation除去,切除therapy for prostate cancer poor libido and ED,
42、ERECTILE DYSFUNCTION,Endocrinologic(内分泌性) ED,hypothalamic-pituitary axis下丘脑-垂体轴 : hypogonadotropic促性腺激素分泌不足的hypogonadism hypogonadism性腺机能减退 Hyperprolactinemia高催乳素血症( pituitary脑垂体的adenoma腺瘤or drugs) reproductive and sexual dysfunction. Symptoms ： loss of libido, ED, galactorrhea乳溢, gynecomastia男子乳腺发育
43、, and infertility不育症 Hyperthyroidism甲亢 circulating estrogen雌激素levels diminished libido hypothyroidism甲状腺机能减退 : testosterone secretion, prolactin催乳素levels ED,ERECTILE DYSFUNCTION,Arteriogenic 动脉性 ED,Atherosclerotic动脉粥样硬化的or traumatic arterial occlusive闭塞的disease of the hypogastric下腹的,髂内动脉的-cavernous-
44、helicine螺旋状的arterial tree decrease the perfusion灌注pressure and arterial flow to the sinusoidal窦状隙spaces, increasing the time to maximal erection and decreasing the rigidity of the erect penis. In the majority of patients with arteriogenic ED, the impaired penile perfusion灌流,环流is a component of the g
45、eneralized泛发的,全身的atherosclerotic动脉粥样硬化的process erectile dysfunction can be a manifestation显示,证明 of generalized or focal arterial disease,ERECTILE DYSFUNCTION,Mechanism of Arteriogenic ED,1. Structural Changes : a narrowed lumen内腔 or increased wall to lumen内腔 ratio in the arteries ; increase in extra
46、cellular matrix expansion 2. Vasoconstriction血管收缩 : enhanced basal and myogenic肌(原)性的tone ; enhanced sympathetic nerve activity 3. Impaired Endothelium内皮 -dependent Vasodilatation血管舒张 : be ascribed把归于to angiotensin血管紧张素II thromboxane血栓素 and superoxide超氧化物in arteries from high blood pressure per se本身
47、; 本质上,ERECTILE DYSFUNCTION,Cavernosal (Venogenic) ED,Veno-occlusive静脉闭塞的dysfunction has been proposed as one of the most common causes of vasculogenic impotence血管(原)性阳萎. Veno-occlusive静脉闭塞的dysfunction may result from : The presence or development of large venous channels draining the corpora caverno
48、sa(阴茎海绵体?) Degenerative变性的,退化的changes (Peyronies disease纤维性海绵体炎, ageing, diabetes) or traumatic injury to the tunica albuginea白膜 Structural alterations in the fibroelastic components venous leak Insufficient trabecular小梁的,柱的smooth muscle relaxation Acquired后天性,获得的 venous shunts旁路,分流,吻合,ERECTILE DYSFUNCTION,Classification of Male Erectile Dysfunction,Others: Fibroelastic纤维弹性组织的Component: intracavernous海绵窦内的 fibrosis纤维化/纤维变性 ，diabetes, hypercholesterolemia高胆固醇血症, vascular disease, penile injury, or old age increased deposition of collagen and decreased elastic fibers弹性纤维