Gaining acc ess to the study setting

The penis is a part of the male urogenital organ. It is naturally erectile and expansile with sexual stimulation.⁷⁶ Anatomically, it contains three erectile bodies, two of which are called corpora cavernosa and one ventrally located corpus spongiosum. The urethra which is the channel for urine and ejaculate runs in the spongiosum.^76-78 The corpora carvenosa contains a spongy tissue made up of smooth muscles, fibrous tissues, veins and arteries. A membrane , called the tunica albuginea, surround each of the corpora.^76-78 Veins located in the tunica albuginea drain blood out of the penis. The venous drainage consist of the dorsal, superficial and deep veins in the corpora carvenosa. The arterial supply is derived from the pudendal artery bilaterally giving off branches as bulbar, urethral, dorsal and deep penile arteries to the penis.^77,78

The primary penile nerve supply is from dorsal nerve, a branch of pudendal nerve.^77,78 The carvenosal nerves are part of autonomic nervous system giving off sympathetic and parasympathetic fibres.⁷⁸ They act by regulating blood flow during erection and detumescence while the somatic dorsal nerves are responsible for penile sensation.^77,78 Sexual behaviour involves the participation of both the autonomic and somatic nerves in conjunction with the numerous spinal and supraspinal sites in the central nervous system(CNS).^77,78

Figure 2.1. Anatomy of Penis

2.3.1 PHYSIOLOGY OF PENILE ERECTION

Penile erection occurs from physiologic processes involving the neurovascular and hormonal system. An abnormality in any of these systems either from drugs or disease will affect the ability to have or sustain erection, leading to erectile dysfunction.^2,4 The pathway of erection and detumescence involves the nitric oxide (NO) pathway. It begins with sexual stimulation in the brain, causing the release of nitric oxide (the major neurotransmitter involved in the process of erection) from the cavernosal nerve ending in the penis.^79-81 The process is that of a complex neuropsychological process i.e. sexual stimulation can be tactile or mental (having sexual fantasies).^79-81 There is then the higher cortical input and a sacrally mediated parasympathetic reflex combining to stimulate erection.^64,65 Outputs are sent through the pudendal nerves to the penile nerves, activating

the nitric oxide sythetase producing nitric oxide(NO).^79,80 It is important to note, that NO is produced and released by the autonomic nerves and endothelium, serving the penile arteries and nerve terminals of the corpus cavernosum^80,81

Nitric oxide activates guanylate cyclase in the smooth muscle membrane which in turn catalyses the production of cyclic guanosine monophosphate (cGMP) from Guanosine triphosphate (GTP).^4,79 Cyclic GMP is a potent vasodilator⁸² which causes membrane hyperpolarisation across potassium channels and blocking of calcium channels, resulting in the decrease of calcium ion available leading to muscle relaxation.⁸² All these allows for dilatation of arteries and arterioles causing increased blood flow, trapping of blood and expansion in the cavernosal sinuses.⁷⁹ The venous plexus is compressed leading to an almost total occlusion of venous blood flow with increase in intracavernosal pressure and partial pressure of oxygen all resulting in erection.^2,79

The inhibition of neurotransmitter release and breakdown of cGMP to GTP by phosphodiestearase allows for muscle contraction and opening of venous channels causing blood to be expelled and thereby leading to flaccidity of the penis and detumnescence². Inhibition of phosphodiesterease leads to the inhibition of cGMP breakdown, which makes more cGMP available to promote the erectile response.^2,79 This forms the basis and mode of action of most of the readily available drugs in the treatment of erectile dysfunction.^2,79

2.3.2. PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION

Nitric oxide has been found to be involved in many of the known aetiologies and co morbidities of ED and elucidating its pathway has helped in the understanding of erection and in the treatment of erectile dysfunction.^79,80 Another important pathological pathway in ED involves damage to the epithelium of blood vessels thereby hindering blood flow.^79,80

The vascular endothelium of the penis plays an important function in adjusting the tone in the vessels and blood flow into the penis in response to humoral, neural, and mechanical stimuli.⁸¹

In endothelial dysfunction, the regulatory role of the endothelium is hindered, resulting in decreased responsiveness to vasodilatory mediators and/or increased sensitivity to various vasoconstricting agents.⁸¹ This endothelial dysfunction is often the case in many medical conditions associated with ED.^79,81 The affectation can be in the form of problems with the corporal veno-occlusive mechanism, which does not allow blood to be trapped in the penis⁴ or by causing trapped blood to leak out leading to poorly sustained erection or an erection that is lost easily.^4,81 This mode of ED causation is seen in medical conditions such hypertension, hyperlipidemia, diabetes mellitus, and cases of blunt perineal or pelvic injury, pelvic irradiation, and the social habit of cigarette smoking.^4,62,80 The endothelial dysfunction subsequently results in decrease in endothelial-dependent corpora cavernosal smooth muscle relaxation through reduced production and action of neuronal and endothelial NO synthase, leading to impairment of NO release, and/or increased destruction or total loss of NO activity in the penis.⁸¹

Impairment in androgen production which affects the development of sexual interest and desires, also affects the ability to have erections.⁴ Disruption of the central nervous system, causing inhibition of the autonomic pathway that supplies the nerves to the penis by any disease or dysfunction affecting the brain, spinal cord, cavernous and pudendal nerves, can induce different degrees of dysfunction, through the affectation of the neurogenic aspect of the process of erection.^4,80 Some psychological conditions such as stress, anxiety, depression, schizophrenia, have been associated with erectile dysfunction by causing a lack of sexual arousability and lack of awareness of sensory experience leading to difficulty in achieving an erection.^4,79 Other conditions found to be associated

with erectile dysfunction include some social habits such as alcohol ingestion, illicit drug use and smoking.⁴⁸ Some medications have been linked with ED through different mechanism.^48,83 They include β-blockers which act by blocking the receptors which have adrenergic properties which are located in smooth muscles and arteries thereby inhibiting smooth muscle contraction in penile vessels leading to ED.⁸³ Methyldopa, a centrally acting sympatholytic potentiates its effect by blocking the impulses from adrenergic postganglionic fibres to organs and tissues, also inhibiting sympathetic functions of smooth muscle contraction and glandular secretion.⁸³ Diuretics such as thiazides are known to cause same type of effect at the vascular smooth wall while spironolactone causes endocrine dysfunction because of its structural similarity to sex hormone leading to increased clearance of testosterone. ^84-86 SSRI’s mode of causing ED is not clear, several pathways have been suggested.^48,61 It is hypothesized that some SSRI’s cause low nitric oxide levels thereby causing poor erection in the men using the drugs.⁶¹ Some school of thoughts believe that SSRI’s cause the suppression of rapid eye movement sleep leading to reduced nocturnal and early morning erections.⁶¹ Others believe that its effect is seen at both central and peripheral nervous system in which the supraspinal areas and preganglionic sacral neurons involved in sexual excitement produce some serotonin. Some authors even argue that SSRI’s do not cause ED, while some others believe it’s the psychosocial stress in these individuals causing the ED.⁶¹ Tricyclic antidepressants cause anticholinergic side effect, giving lower urinary tract symptoms such as urgency and frequency leading to anxiety, poor sleep, and fatigue which all affect sexuality in the men.⁸³