CHAPTER ONE

INTRODUCTION

Erectile dysfunction, ED, is a sexual dysfunction that affects the reproductive systems of both men and women. By definition according to National Institute of Health consensus Development Panel on impotence (1993), in Males, it is a sexual dysfunction characterized with the inability to develop or maintain an erection of the penis sufficient for satisfactory sexual performance. It is also known as Male impotence or Baby D syndrome, while in women, according to American Psychiatric Association (1994), it is characterized with the persistent or recurrent inability to attain, or maintain until completion of the sexual activity, an adequate Lubrication- Swelling response that otherwise is present during female sexual arousal and sexual activity is thus prevented. Hence, it is called Women impotence or female erectile dysfunction.

The word impotence may also be used to describe other problems that may interfere with sexual intercourse and reproduction, such as lack of Sexual Desire and problems with ejaculation or orgasm. Using the term

Òerectile dysfunction,Ó however makes it clear that those other problems are not involved (NIH, 2005).

An erection occurs as a hydraulic effect due to blood entering and being retained in sponge-like bodies within the penis and clitoris. The process is most often than not initiated as a result of sexual arousal, when signals are transmitted from the brain to nerves in the pelvis.

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Erectile dysfunction is, therefore indicated when an erection is consistently difficult or impossible to produce, despite arousal (Laumann et al., 1999).

1.1 PREVALENCE OF ERECTILE DYSFUNCTION IN WOMEN

Erectile dysfunction which is known as Female erection dysfunction in women occurs in about 43% of American Women (NIH Consensus Conference, 1993). And this medical Condition is a persistent or recurrent inability to attain or maintain clitoral erection until completion of the sexual activity, an adequate Lubrication ÐSwelling response that is normally present during Female sexual arousal and sexual activity is therefore, absent. The individual having the condition is said to experience frigidity (American Psychiatric Association, 1994). Again,

According to Otubu et al. (1998) about 8.7% of Women suffer from this very condition in the United States while between 35.3 – 40%, according to Adequnloye (2002) and Eze (1994) of Women in Nigeria suffer from this condition. Spector and Carey (1994) reported 5-10% in the United States.

In addition, Female erectile dysfunction occurs at any age but majorly in old age. Hence, the most significant age related change is menopause (Karen, 2000) and (Rod et al., 2005). However, erectile dysfunction may be caused by diabetes, atherosclerosis, hormonal imbalances, neurological problems etc. (Organic causes) or stress, depression etc.

Because treating the underlying causes (Organic or Psychological), the first line treatment of ED consists of a trial of PDES inhibitor (the first of which was Sildenafil or Viagra). In some cases, treatment can involve prostag-Landin tablets in the Urethra, intravenous injection with a fine needle into the penis or clitoris that causes swelling of Penis or Clitoris Pump or Vascular surgery, estrogen replacement therapy for the women etc.

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Although there are various methods and techniques that are used to treat this very condition, however, for the purpose of this project, the treatment is restricted to Yohimbe, an extract from Pausinystalia yohimbe.

1.2 PREVALENCE OF ERECTILE DYSFUNCTION IN MEN

Erectile dysfunction, ED, varies in severity; some men have a total inability to achieve an erection, others have inconsistent ability to achieve an erection, and still others can sustain only brief erection. The variation in severity of erectile dysfunction makes estimating its frequency difficult.

Many men also are reluctant to discuss erectile dysfunction with their doctors, and thus, the condition is under-diagnosed. Nevertheless, experts have estimated that ED affects 30 million men in the United States. Again, according to the statistical research carried out by Adegunloye (2002) and Eze (1994) respectively in Nigeria, results shows that about 23-26.4% of men suffer from this condition while according to Spector and Carey (1999) discovered that about 4-9% of men suffer from the condition in the United States.

While erectile dysfunction can occur at any age, it is uncommon among young men and more common in the elderly. By the age of 45, most men have experienced erectile dysfunction at least some of the time. According to the Massachusetts Male Aging Study, complete impotence increases from 5% among Men 40 years of age to 15% among Men 70 years and older. Population studies conducted in the Netherlands found out that some degree of ED occurred in 20% of Men between 50 – 54 and in 50% of men between ages 70 – 78. In 1998, the National Ambulatory Medical care Survey counted 1,520,000 Doctor Offices visited for ED.

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1.3 OBJECTIVE STUDY AND AIMS

This project focuses to give a clear picture of the effect on erectile tissues of the Penis, Clitoris of both Men and Women.

1.4 NITRIC OXIDE-CYCLIC GMP PATHWAY WITH SOME

EMPHASIS ON CAVERNOSAL CONTRACTILITY

Nitric Oxide (NO) is formed from the conversion of L- arginine by nitric oxide synthase (NOS), endothelial (eNOS), and inducible (iNOS). nNOS is expressed in penile neurons innervating the corpus Cavernosum, and eNOS protein expression has been identified primarily in both Cavernosal Smooth Muscle and endothelium. NO is released from nerve endings and endothelial cells and stimulates the activity of soluble guanylate cyclase (sGC), leading to an increase in cyclic guanosine- 3?,5?,-Monophosphate (cGMP) and, finally, to Calcuim depletion from the cytosolic space and Cavernous Smooth muscle relaxation. The effect of cGMP are mediated by cGMP dependent Protein Kinase, cGMP-gated ion channels, and cGMP-regulated Phosphodiesterases (PDE). Thus, cGMP effect depends on the expression of a Cell-Specific cGMP-receptor protein in a given cell type. Numerous systemic vasculature diseases that cause erectile dysfunction (ED) are highly associated with endothelial dysfunction, which has been shown to contribute to decrease erectile function in men and a number of animal models of penile erection. Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, selective PDE inhibitors have recently been introduced in the treatment of ED. Phosphodiesterase-5 (PDE5) inactivates cGMP, which terminates NO-cGMP-mediated SMooth Muscle relaxation. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP

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degradation. Development of pharmacologic agents with this effect has closely paralleled the emerging science.

?International Journal of impotence Research (2004)?. Nitric oxide (NO) was first described by Stuehr and Marletta (1985) as a product of activated murine machrophages. Also, the substance known as endothelium- derived relaxing factor (EDRF), described by Furchgott and Zawadzki (1980), has been identified as NO.

Soluble guanylate cyclase (sGC), responsible for the enzymatic conversion of guanosine -5- triphosphate (GTP) to cyclic guanosine -3?5?-monophosphate (cGMP), was first identified as a constituent of mammalian cells almost three decades ago. No and cGMP together comprise an especially wide-ranging signals transduction system when one considers the many roles of cGMP in physiological regulation, including smooth muscle relaxation, visual transduction, intestinal ion transport, and platelet function.

Erectile dysfunction (ED) is defined as the constituent inability to achieve or maintain an erection sufficient for satisfactory sexual performance and is considered to be a natural process of ageing. Studies have shown that ED is caused by inadequate relaxing of the corpus cavernosum with defeat in NO production.

It is clear that NO is the predominant neurotransmitter responsible for cavernasal Smooth muscle relaxation and hence penile erection. Its action is medicated through the generation of the second messenger cGMP. Neutrally, derived NO has been established as a mediator of smooth muscle relaxation in the penis and it is thought that constitutive forms of nitric oxide synthase (NOS) work to mediate the convesion of GTP to the intracellular second messenger cGMP in smooth muscle cells. An increase in cGMP modulates cellular events, such as relaxation of smooth muscle cells.

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This review will describe current knowledge of cellular events involved in cavernosal relaxation and the range of putative factors involved in NO-mediated relaxation.

1.5 SYNTHESIS OF Nitric Oxide (NO).

Recent observation suggest that the main site of NO biosythesis in

human corpus cavernosum is within the terminal branches of cavernosal nerves supplying the erectile tissue. It is strongly suggested that NO released from nonadrenergic Ð noncholinergic (NANC) neurons increases the production of cGMP, which in turn relaxes the cavernous smooth muscle. Endothelial Ðderived NO plays a major role in the penis. Some suggest that NO is highly labile, therefore it cannot be stored as a preformed neurotransmitter. Other proerectile mediators, such as acetylcholine, calci-tonin gene related peptide (CGRP) or substance P, act via endothelialcells by prompting the synthesis and release of NO by these cells, ?Bivalacqua et al., 2001). Found in their study that in vivo adenoviral gene transfer of CGRP in combination with adrenomedullin (ADM) or prostaglandin E1(PGEI) induce penile erection by activating different receptors.

The combination of molecular oxygen and the amino acid arginine in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and NO synthase, (NOS) yields citruline nitrogen of L- arginine. L- citrulline can be converted by arginine synthase (AS) to form L-arginine, the precursor for NO. Each of these enzymes, co-factors, or transport systems could be an eventual target of pharmacologic intervention in the NO cascade.