i

PREVALENCE OF MALE AND ITS CORRELATION AT CLINICS IN EGYPT

A DISSERTATION BY DR. KHALED ABDEL MONEIM GADALLA

A DISSERTATION SUBMITTED TO THE FACULTY

OF THE AMERICAN ACADEMY OF CLINICAL

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

CAIRO, EGYPT 2017

ii

Copyright © 2017 by Khaled A. Gadalla All Rights Reserved 3

Dissertation Approval

This dissertation submitted by Khaled A. Gadalla has been read and approved by three committee members of the American Academy of Clinical Sexologists.

The final copies have been examined by the Dissertation Committee and the signatures which appear here verify the fact that any necessary changes have been incorporated and the dissertation is now given the final approval with reference to content, form and mechanical accuracy.

The dissertation is therefore accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Signatures

______

Krista Bloom, Ph.D. LCSW Date

Committee Chair

______

William A. Granzig, Ph.D., FAACS. Date

Committee Member

______

James Walker, Ph.D., FAACS Date

Committee Member

4

Acknowledgments

First, I would like to praise and thank Allah (GOD), the most merciful and beneficial for his help to complete this work.

I am greatly indebted to Professor Dr William Granzig, Professor Dr James Walker and Professor Dr Krista Bloom, my supervisors, for the guidance and mentorship they rendered to me during the preparation and accomplishment of this dissertation.

I would like to acknowledge all members of the American Academy of Clinical Sexologists for their assistance and encouragement during all stages of preparation and accomplishment of this dissertation.

I would like to thank all Consultants, Specialists, Residents, Registrars and Nurses at our Man Clinic Andrology Centers and Clinics for all the invaluable assistance and support they offered me during all the stages in the accomplishment of this work. I worked with them very peacefully.

Finally, I would like to express my deep gratitude to my parents, my wife and my children-Sara, Omar, Heidi, Shadi & Sandy- for their never ending support throughout all steps of my life.

5

Vita

Khaled A. Gadalla received his MD degree from the biggest Islamic university all over the world, Al-Azhar University and working as lecturer of since 2010 and is

Fellow of the European Joint Committee of , American board of sexology, American

Diploma of American board and academy of regenerative medicine, board certified in integrative medicine, and He is one of the most famous Andrologists and Sexologists over Arabic TV shows.

6

Abstract This dissertation in Clinical Sexology examines the prevalence of and associated risk factors among men attending Andrology clinics at Man Clinic center for Andrology and Male at Egypt. The results have shown that ED iscommon in our environment. Therefore, there is aneed to upgrade and improve the existing healthcarefacilities, in order to deal with factors responsiblefor its development. Health education on lifestyle modification is also important and can help primarilyin reducing the cardiovascular components of therisk factors. There is also a need for public enlightenment campaigns to reduce stigma andincrease awareness on the causes of ED. This will help in discouraging cultural and traditional approaches to management of erectile dysfunctionin our environment.

7

Table of Contents ACKNOWLEDGENTS……………………………………………………………………………………….. iv VITA……………………………………………………………………………………………………………….. v ABSTRACT………………………………………………………………………………………………………. vi CHAPTER 1: lITERATURE REVIEW 8 A BRIEFON SEXUAL DYSFUNCTION 8 INTRODUCTION………………………………………………………………………………….. 8 CATEGORIES (CLASSIFICATION)…………………………………………………………… 8 CAUSES………………………………………………………………………………………………. 12 …………………………………………………………………………….. 15 TREATMENT FOR MALES…………………………………………………………………….. 18 TREATMENT FOR FEMALES…………………………………………………………………. 19 CHAPTER 2: ERECTILE DYSFUNCTION 20 INTRODUCTION…………………………………………………………………………………….. 20 EPIDEIOLOGY………………………………………………………………………………………… 20 ERECTILE DYSFUNCTION IN ARAB COUNTRIES………………………………………. 21 PHYSIOLOGY OF PENILE ……………………………………………………….. 30 PATHOPHYSIOLOGY AND CAUSES…………………………………………………………. 32 DIAGNOSIS……………………………………………………………………………………………. 37 TREATMENT………………………………………………………………………………………….. 60 CHAPTER 3: 70 METHODOLOGY……………………………………………………………………………………………. 70 CHAPTER 4: 73 RESULTS AND ANALYSIS……………………………………………………………………………….. 73 CHAPTER 5: 91 DISCUSSION AND CONCLUSIONS………………………………………………………………….. 91 GLOSSARY……………………………………………………………………………………………………. 96 LIST OF TABLES……………………………………………………………………………………………. 97 LIST OF FIGURES………………………………………………………………………………………….. 98 REFERENCES……………………………………………………………………………………………….. 99

8

Chapter 1

Literature Review

A brief on sexual dysfunction Introduction Sexual dysfunction or sexual malfunction is difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including physical pleasure, desire, preference, arousal or . According to the DSM-5, sexual dysfunction requires a person to feel extreme distress and interpersonal strain for a minimum of 6 months (excluding substance or medication-induced sexual dysfunction). Sexual dysfunctions can have a profound impact on an individual's perceived quality of sexual life (Nolen-Hoeksema 2014, 366-367). A thorough sexual history and assessment of general health and other sexual problems (if any) are very important. Assessing (performance) , , and are integral to the optimal management of sexual dysfunction. Many of the sexual dysfunctions that are defined are based on the human sexual response cycle, proposed by William H. Masters and Virginia E. Johnson, and then modified by Helen Singer Kaplan (Kaplan 1974, 255).

Categories (Classification) Sexual dysfunction disorders may be classified into four categories, (1) disorders, (2) arousal disorders, (3) orgasm disorders and (4) pain disorders. Sexual desire disorders Sexual desire disorders or decreased are characterized by a lack or absence for some period of time of sexual desire or libido for sexual activity or of sexual fantasies. The condition ranges from a general lack of sexual desire to a lack of sexual desire for the current partner. The condition may have started after a period of normal sexual functioning or the person may always have had no/low sexual desire (Coretti & Baldi 2007, 58-59). The causes vary considerably, but include a possible decrease in the production of normal in women or in both men and women. Other causes may be aging, fatigue, , medications (e.g., SSRIs) or psychiatric conditions, such as and anxiety. Loss of libido from SSRIs usually reverses after SSRIs are discontinued, but in some cases it does not. This has been called "Post-Ssri Sexual Dysfunction, PSSD"; however, this is not a classification that would be found in any current 9 medical text. While a number of causes for low sexual desire are often cited, only some of these have ever been the object of empirical research. Many rely entirely on the impressions of therapists (Maurice 2007, 26).

Sexual arousal disorders disorders were previously known as "frigidity in women" and "impotence in men", though these have now been replaced with less judgmental terms. Impotence is now known as erectile dysfunction, and frigidity has been replaced with a number of terms describing specific problems with, for example, desire or arousal (Laan et al. 2008, 1424-35). For both men and women, these conditions can manifest themselves as an aversion to, and avoidance of, sexual contact with a partner. In men, there may be partial or complete failure to attain or maintain an erection, or a lack of sexual excitement and pleasure in sexual activity. There may be medical causes to these disorders, such as decreased blood flow or lack of . Chronic disease can also contribute, as well as the nature of the relationship between the partners (Laan et al. 2008, 1424-35).

Erectile dysfunction Erectile dysfunction or impotence is a sexual dysfunction characterized by the inability to develop or maintain an erection of the . There are various underlying causes, such as damage to the Nervi erigentes which prevents or delays erection, or as well as , which simply decreases blood flow to the tissue in the penis, many of which are medically reversible. The causes of erectile dysfunction may be psychological or physical. Psychological erectile dysfunction can often be helped by almost anything that the patient believes in; there is a very strong effect. Physical damage is much more severe. One leading physical cause of ED is continual or severe damage taken to the Nervi erigentes. These nerves course besides the arising from the sacral plexus and can be damaged in prostatic and colo-rectal surgeries (Montague et al. 2005, 230-9). Due to its embarrassing nature and the shame felt by sufferers, the subject was for a long time, and is the subject of many urban legends. Folk remedies have long been advocated, with some being advertised widely since the 1930s. The introduction of perhaps the first pharmacologically effective remedy for impotence, (trade name: Viagra), in the 1990s caused a wave of public attention, propelled in part by the news-worthiness of stories about it and heavy advertising (NIH Consensus Conference 1993, 83-90). 10

It is estimated that around 30 million men in the United States and 152 million men worldwide suffer from Erectile Dysfunction. However, social stigma, low and social lead to under-reporting which makes an accurate prevalence rate hard to determine. The Latin term impotentia coeundi describes simple inability to insert the penis into the . It is now mostly replaced by more precise terms (Ayta et al. 1999, 50-6).

Premature is when ejaculation occurs before the partner achieves orgasm, or a mutually satisfactory length of time has passed during intercourse. There is no correct length of time for intercourse to last, but generally, premature ejaculation is thought to occur when ejaculation occurs in less than 2 minutes from the time of the insertion of the penis. For a diagnosis, the patient must have a chronic history of premature ejaculation, poor ejaculatory control, and the problem must cause feelings of dissatisfaction as well as distress the patient, the partner or both (Diaz Jr & Close 2010, 473-89). Historically attributed to psychological causes, new theories suggest that premature ejaculation may have an underlying neurobiological cause, which may lead to rapid ejaculation (Laumann et al. 2005, 39-57).

Orgasm disorders Orgasm disorders are persistent delays or absence of orgasm following a normal sexual excitement phase. The disorder can have physical, psychological, or pharmacological origins. SSRI are a common pharmaceutical culprit, as they can delay orgasm or eliminate it entirely (Landén et al. 2005, 100-6).

Sexual pain disorders Sexual pain disorders affect women almost exclusively and are also known as (painful intercourse) or (an involuntary spasm of the muscles of the vaginal wall that interferes with intercourse). Dyspareunia may be caused by insufficient lubrication (vaginal dryness) in women. Poor lubrication may result from insufficient excitement and stimulation, or from hormonal changes caused by , pregnancy, or -feeding. Irritation from contraceptive creams and foams can also cause dryness, as can fear and anxiety about sex. It is unclear exactly what causes vaginismus, but it is thought that past sexual trauma (such as or abuse) may play a role. Another female sexual pain disorder is called or vulvar vestibulitis. In this condition, women experience 11 burning pain during sex which seems to be related to problems with the skin in the vulvar and vaginal areas. The cause is unknown (Landén et al. 2005, 100-6).

Uncommon sexual disorders in men Erectile dysfunction from is usually seen only amongst elderly individuals who have . Vascular disease is common in individuals who have diabetes, peripheral vascular disease, and those who smoke. Any time blood flow to the penis is impaired, erectile dysfunction is the end-result. deficiency is a relatively rare cause of erectile dysfunction. In individuals with testicular failure like in , or those who have had , or childhood exposure to , the testes may fail and not produce testosterone. Other hormonal causes of erectile failure include brain tumors, , or disorders of the (Dougherty 2014).

Structural abnormalities of the penis like Peyronie's disease can make difficult. The disease is characterized by thick fibrous bands in the penis, which leads to a deformed-looking penis. Drugs are also a cause of erectile dysfunction. Individuals who take drugs to lower , uses , antidepressants, sedatives, , antacids or alcohol can have problems with sexual function and loss of libido (Gupta et al. 2003, 395-400). is a painful erection that occurs for several hours and occurs in the absence of . This condition develops when blood gets trapped in the penis and is unable to drain out. If the condition is not promptly treated, it can lead to severe scarring and permanent loss of erectile function. The disorder occurs in young men and children. Individuals with sickle-cell disease and those who abuse certain medications can often develop this disorder (Dougherty 2014).

Causes General There are many factors, which may result in a person experiencing a sexual dysfunction. These may result from emotional or physical causes. Emotional factors include interpersonal or psychological problems, which can be the result of depression, sexual fears or guilt, past sexual trauma, sexual disorders, among others (Michetti et al. 2006, 170-74). 12

Sexual dysfunction is especially common among people who have anxiety disorders. Ordinary anxiousness can obviously cause erectile dysfunction in men without psychiatric problems, but clinically diagnosable disorders such as commonly cause avoidance of intercourse and premature ejaculation. Pain during intercourse is often a comorbidity of anxiety disorders among women (Coretti & Baldi 2007, 58-59). Physical factors that can lead to sexual dysfunctions include the use of drugs, such as alcohol, , narcotics, stimulants, anti-hypertensives, , and some psychotherapeutic drugs. For women, almost any physiological change that affects the reproductive system, , pregnancy, postpartum, menopause, can have an adverse effect on libido. Injuries to the back may also impact sexual activity, as would problems with an enlarged prostate gland, problems with blood supply, nerve damage (as in injuries). Disease, such as , , tumors, and, rarely, tertiary may also impact on the activity, as would failure of various organ systems (such as the heart and lungs), endocrine disorders (, pituitary, or adrenal gland problems), hormonal deficiencies (low testosterone, other , or estrogen) and some birth defects (Kingsberg 2002, 431-7). In the context of heterosexual relationships, one of the main reasons for the decline in sexual activity among these couples is the male partner experiencing ED. This can be very distressing for the male partner, causing poor body image and it can also be a major source of low desire for these men. In aging women, it is natural for the vagina to narrow and become atrophied. If a woman has not been participating in sexual activity regularly (in particular, those activities involving vaginal penetration) with her partner, if she does decide to engage in penetrative intercourse, she will not be able to immediately accommodate a penis without risking pain or injury. This can turn into a vicious cycle, often leading to female sexual dysfunction (Kingsberg 2002, 431-7). Female sexual dysfunction Several theories have looked at female sexual dysfunction, from medical to psychological perspectives. Three social psychological theories include; the self-perception theory, the over-justification hypothesis, and the insufficient justification hypothesis: - Self-perception theory; people make attributions about their own attitudes, feelings, and behaviors by relying on their observations of external behaviors and the circumstances in which those behaviors occur. 13

- Over-justification hypothesis; when an external reward is given to a person for performing an intrinsically rewarding activity, the person‟s intrinsic interest will decrease. - Insufficient justification; based on the classic theory (inconsistency between two cognitions or between a cognition and a behavior will create discomfort), this theory states that people will alter one of the cognitions or behaviors to restore consistency and reduce distress. (Kingsberg 2002, 431-7).

The importance of how a woman perceives her behavior should not be underestimated. Many women perceived sex as a chore as opposed to a pleasurable experience, and they tend to consider themselves sexually inadequate, which in turn does not motivate them to engage in sexual activity. Several factors influence a women‟s perception of her sexual life. These can include race, her gender, ethnicity, educational background, socioeconomic status, , financial resources, culture, and religion. Cultural differences are also present in how women view menopause and its impact on health, self- image, and sexuality. A study has found that African American women are the most optimistic about menopausal life; Caucasian women are the most anxious, Asian women are the most inhibited about their symptoms, and Hispanic women are the most stoic (Kingsberg 2002, 431-7).

Menopause Research on sexual dysfunction is more difficult in menopausal women because of the changes that are taking place during their specific physiological state. The female sexual response system is complex and even today, not fully understood. The most prevalent of female sexual dysfunctions that have been linked to menopause include lack of desire and libido; these are predominantly associated with hormonal physiology. Specifically, it is the decline in serum that causes these changes in sexual functioning. depletion may also play a role, but currently this is less clear. The hormonal changes that take place during the menopausal transition have been suggested to affect women‟s sexual response through several mechanisms, some more conclusive than others (Eden & Wylie 2009, 385-96.). Many studies have demonstrated the dramatic changes in sexual functioning that can take place during this transition phase. Studies have found that as many as 25% of 14 menopausal women are unable to experience orgasm, 20% reported no pleasure with sex, and another 20% had lubrication difficulties. While there has been controversy over whether these are due to the natural causes of aging or whether they‟re specific to the menopause transition, it seems like most studies have come to the conclusion that decreases in sexual interest and sexual satisfaction are due to menopause. Furthermore, one study found that all aspects of sexual life were significantly compromised in postmenopausal women without hormone replacement therapy (HRT) compared to both menstruating women and postmenopausal women with HRT (Eden & Wylie 2009, 385-96.). Aging in women Whether or not aging directly affects women‟s sexual functioning during menopause is another area of controversy. However, many studies including Hayes and Dennerstein‟s critical review, have demonstrated that aging has a powerful impact on sexual function and dysfunction in women, specifically in the areas of desire, sexual interest, and frequency of orgasm. In addition, Dennerstien and colleagues found that the primary predictor of sexual response throughout menopause is prior sexual functioning. This means that it is important to understand how the physiological changes in men and women can affect their sexual desire. Despite the seemingly negative impact that menopause can have on sexuality and sexual functioning, sexual confidence and wellbeing can improve with age and menopausal status. Furthermore, the impact that a relationship status can have on quality of life is often underestimated (Eden & Wylie 2009, 385-96.). Testosterones, along with its metabolite, dihydrotesosterone, are extremely important to normal sexual functioning in men and women. is the most prevalent androgen in both men and women. Testosterone levels in women at age 60 are, on average, about half of what they were before women were 40. Although this decline is gradual for most women, those who have undergone bilateral oophorectomy experience a sudden drop in testosterone levels; this is because the ovaries produce 40% of the body is circulating testosterone. Sexual desire has been related to three separate components- drive, beliefs and values, and motivation. Particularly in postmenopausal women, drive fades and is no longer the initial step in a woman's sexual response (if it ever was) (Eden & Wylie 2009, 385-96.).

List of disorders Physical or psychological sexual disorders under the DSM The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders lists the following sexual dysfunctions: 15

- Hypoactive sexual desire disorder - Sexual aversion disorder: avoidance of or lack of desire for sexual intercourse - Female : failure of normal lubricating arousal response - Male erectile disorder - Female orgasmic disorder - Male orgasmic disorder - Premature ejaculation - Dyspareunia - Vaginismus

Additional DSM sexual disorders that are not sexual dysfunctions include: - - PTSD (Post-traumatic stress disorder) due to genital mutilation or childhood

Other sexual problems - Sexual dissatisfaction (non-specific) - Lack of sexual desire - - Impotence - Delay or absence of ejaculation, despite - Sexually transmitted diseases adequate stimulation - Inability to control timing of - Inability to relax vaginal muscles ejaculation enough to allow intercourse - Inadequate vaginal lubrication - Burning pain on the or in the preceding and during intercourse vagina with contact to those areas - Unhappiness or confusion related to - Post SSRI Sexual Dysfunction sexual orientation - Persistent sexual arousal syndrome - Hyper-sexuality - - All forms of Female genital cutting

Peyronie's disease Peyronie's disease or Peyronie disease, also known as induration penis plastic or chronic inflammation of the tunica albuginea (CITA), is a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the penis affecting 5% of men. Specifically, scar tissue forms in the tunica albuginea, the thick sheath of tissue surrounding the corpora cavernosa causing pain, abnormal curvature, erectile dysfunction, indentation, 16 loss of girth and shortening. A variety of treatments have been used, but none have been especially effective (Levine et al. 2003, 27-32.).

Signs and symptoms: A certain degree of curvature of the penis is considered normal, as many men are born with this benign condition, commonly referred to as congenital curvature. The disease may cause pain, hardened, big, cord-like lesions (scar tissue known as "plaques"), or abnormal curvature of the penis when erect due to chronic inflammation of the tunica albuginea (CITA). Although the popular conception of Peyronie's Disease is that it always involves curvature of the penis, the scar tissue sometimes causes divots or indentations rather than curvature (Carrieri et al. 1998, 511). The condition may also make sexual intercourse painful and/or difficult, though many men report satisfactory intercourse in spite of the disorder. Although it can affect men of any race and age, it is most commonly seen in Caucasian males above the age of 40, especially those of blood type (A+), but has been seen in men as young as 18. The disorder is confined to the penis, although a substantial number of men with Peyronie's exhibit concurrent connective tissue disorders in the hand, and to a lesser degree, in the feet. About 30 percent of men with Peyronie's Disease develop fibrosis in other elastic tissues of the body, such as on the hand or foot, including Dupuytren's contracture of the hand. An increased incidence in genetically related males suggests a genetic component (Carrieri et al. 1998, 511).

Causes: The underlying cause of Peyronie's Disease is not well understood, but is thought to be caused by trauma or injury to the penis usually through sexual activity although many patients often are unaware of any traumatic event or injury. Some drugs list Peyronie's disease as a possible side effect (Carrieri et al. 1998, 511).

Diagnosis: A urologist can diagnose the disease and suggest treatment, although it is easily diagnosed by general practitioners or family doctors. An ultrasound can provide conclusive evidence of Peyronie's disease, ruling out congenital curvature or other disorders (Amin et al. 1993, 398-402).

Peno-scrotal webbing (Webbed penis) Webbed penis, also called penis palmatus, peno-scrotal fusion is an acquired or congenital condition in which the scrotal skin extends onto the ventral penile shaft. Penile 17 shaft is buried in or tethered to scrotal midline by a fold or web of skin. The urethra and erectile bodies are usually normal. Webbed penis is usually asymptomatic, but the cosmetic appearance is often unacceptable. This condition may be corrected by surgical techniques (Abbate et al. 1994, 139-42). In the congenital form, the deformity represents an abnormality of the attachment between the penis and the scrotum, the penis, the urethra, and the remainder of the scrotum are typically normal (Bergeson et al. 1993, 794-9). Webbed penis may also be acquired (Iatrogenic) after circumcision or other penile surgery, resulting from excessive removal of ventral penile skin, the penis can retract into the scrotum, resulting in secondary (trapped penis) (Medina López et al. 1999, 68-9). The scrotum in some men extends up the underside of the penis, creating an indistinct junction between the penis and scrotum. This peno-scrotal webbing makes the penis appear short on its undersurface. It can also cause discomfort with intercourse or difficulty using a . The web may be congenital or due to removal of too much skin from a circumcision. A mild web is eliminated by rearranging the tissues at the peno-scrotal junction, leaving a zigzag incision (Z-plasty) (Alter 2014). A more severe web is eliminated by excision of the web and closure with a linear scar and Z-plasty. Simple web excision by leaving a linear scar may result in tightening and worsening of the web. This procedure is relatively simple (Alter 2014).

Treatment for males Several decades ago, the medical community believed the majority of sexual dysfunction cases were related to psychological issues. Although this may be true for a portion of men, the vast majority of cases have now been identified as having a physical cause or correlation. If the sexual dysfunction is deemed to have a psychological component or cause, can help. Situational anxiety arises from an earlier bad incident or lack of experience. This anxiety often leads to development of fear towards sexual activity and avoidance. In return evading leads to a cycle of increased anxiety and desensitization of the penis. In some cases, erectile dysfunction may be due to marital disharmony. counseling sessions are recommended in this situation (Jarow et al. 1996, 1609-12). Lifestyle changes such as discontinuing smoking, drug or alcohol abuse can also help in some types of erectile dysfunction. Several oral medications like Viagra, Cialis and Levitra have become available to help people with erectile dysfunction and have become first line therapy. These medications provide an easy, safe, and effective treatment solution for 18 approximately 60% of men. In the rest, the medications may not work because of wrong diagnosis or chronic history (Rodríguez et al. 1998, 291-319).

Another type of medication that is effective in roughly 85% of men is called intra- cavernous pharmacotherapy and involves injecting a vasodilator drug directly into the penis in order to stimulate an erection. This method has an increased risk of priapism if used in conjunction with other treatments, and localized pain (Diaz Jr & Close 2010, 473-89).

When conservative therapies fail, are unsatisfactory treatment options, or are contraindicated for use, the insertion of a penile prosthesis, or , may be selected by the patient. Technological advances have made the insertion of a penile prosthesis a safe option for the treatment of erectile dysfunction, which provides the highest patient, and partner satisfaction rates of all available ED treatment options (Rajpurkar & Dhabuwala 2003, 159-63).

Treatment for females Although there are no approved pharmaceuticals for addressing female sexual disorders, several are under investigation for their effectiveness. A vacuum device is the only approved medical device for arousal and orgasm disorders. It is designed to increase blood flow to the and external genitalia. Women experiencing pain with intercourse are often prescribed pain relievers or desensitizing agents. Others are prescribed lubricants and/or hormone therapy. Many patients with female sexual dysfunction are often also referred to a counselor or therapist for psychosocial counseling (Allahdadi et al. 2009, 260-69).

19

Chapter 2

Erectile dysfunction Introduction Inadequate penile erection, otherwise known as erectile dysfunction, is defined as the inability to attain or maintain a penile erection sufficient for successful vaginal intercourse. This clinical disorder was described in early historical records, with descriptions of poor penile erection in men found in ancient Egyptian scriptures that are more than 5000 years old. 1998 marked the milestone introduction of the first effective oral drug treatment, sildenafil citrate (Viagra, Pfizer, New York, NY, USA), for the treatment of erectile dysfunction. Sildenafil belongs to a group of well-characterized drugs that are called selective phosphodiesterase type 5 inhibitors (PDE5-Is). These drugs were all developed on the basis of a conceptual understanding of the fundamental role of nitric oxide (NO) smooth muscle relaxation in penile cavernous tissues. Recognition of the important part NO plays in signaling smooth muscle relaxation in penile tissue led to a dramatic expansion of research focused on sexual dysfunction in men (Kouvelas et al. 2009, 3464–75).

Epidemiology Introduction Erectile dysfunction is a common medical disorder that primarily affects men older than 40 years of age. A recent extensive analysis of published work on the prevalence of erectile dysfunction, reported by the International Consultation Committee for Sexual Medicine on Definitions/Epidemiology/Risk Factors for Sexual Dysfunction, showed that the prevalence of erectile dysfunction was 1-10% in men younger than 40 years (Lewis et al., 2010, 1598-607). Prevalence of erectile dysfunction ranges from 2% to 9% in men between the ages of 40 and 49 years. It then increases to 20-40% in men aged 60-69 years. In men older than 70 years, prevalence of erectile dysfunction ranges from 50% to 100%. In a long-term follow-up investigation of the landmark population-based study, the Massachusetts Male Aging Study, the crude incidence of erectile dysfunction was 26 per 1000 man-years. This number increased with age, reaching 46 per 1000 man-years for men aged 60-69 years. Moreover, the worldwide prevalence of erectile dysfunction has been predicted to reach 322 million cases by the year 2025. Clearly, erectile dysfunction is now regarded as a major health problem for the increasingly healthy ageing population (Nicolosi et al. 2005, 609–14). 20

Findings from several cross-sectional and longitudinal studies have linked the development of erectile dysfunction to diabetes mellitus, hypertension, hyperlipidemia, metabolic syndrome, depression, and lower urinary tract symptoms. Several epidemiological studies reported that erectile dysfunction is a marker of cardiovascular disease (CVD). A 2011 meta-analysis of 12 prospective cohort studies provided strong evidence that erectile dysfunction is indeed significantly and independently associated with an increased risk of, not only CVD, but also coronary heart disease, , and all-cause mortality. Findings from other studies have shown that certain environmental and lifestyle factors, such as smoking, obesity, and limited or an absence of physical exercise, might also be important predictors of erectile dysfunction. In several studies, an extensive alteration of lifestyle habits, through modification of diet and encouragement to exercise, led to improvement of erectile dysfunction (Dong et al. 2011, 1378–85).

Erectile dysfunction in Arab countries; Prevalence and correlates Introduction Erectile dysfunction (ED) is a highly prevalent health problem that affects ≤30 million men in the USA. It is a common worldwide clinical problem, with tens of thousands of new cases per year. Worldwide, the affected population is predicted to increase from 152 million in 1995 to 322 million in 2025. Unfortunately, in Arab, countries there are no firm data on the true prevalence of ED, but anecdotal reports have shown a high incidence among different age groups and in patients with different comorbidities (Feldman et al. 1994, 54–61). Due to the increasing life span and the high incidence of ED in this ageing population, a further increase in patients with ED can be expected. As ED is associated with ageing, many of the assumed causes and clinical correlates of ED will be likewise associated with age-related disorders, include vascular insufficiency, hormonal derangement, interruption of neuronal pathway and medical comorbidities (United States Bureau of Census 1992, 19).

The characteristics of ED have been reported in many studies but they are not yet well investigated in the Arab region. This prompted several investigators in Arab countries to conduct research to identify the magnitude of the problem in this region. The objective of this review is to address the published data in the last 10 years for the prevalence of ED and its correlates in Arab countries (El-Sakka 2012, 97-103).

21

Prevalence of ED, and its risk factors and medical co-morbidities a) General population In cross-sectional office-based studies of > 1500 male patients visiting an andrology clinic, El-Sakka showed that ED was very prevalent and ED risk factors were also very common in this community. In all, 92.6% of the patients had ED, 50.8% had premature ejaculation, and 7.6% had low sexual desire. Furthermore, 20% of the patients had psychogenic while 80% had organic causes of ED. Of the patients, «10% had mild, 40% had moderate and 50% had severe ED. There was a significant association between the increasing severity of ED and increased values in the cavernous veins of end-diastolic velocity (EDV), decreased values of peak systolic velocity (PSV), resistive index (RI) and penile rigidity meter values (P < 0.001 for each) (El-Sakka 2007, 1691-700). In a more recent study, Shaeer and Shaeer explored epidemiological aspects of male sexuality using an online survey. They found that among Arab-speaking Internet users, the overall prevalence of ED was 45.1%, strongly correlating with various risk factors studied, including age, diabetes mellitus (DM), hypertension under treatment, depression, concerns over genital size, interpersonal distress, premature ejaculation, low libido, and subjective reports of penile deviation (Shaeer & Shaeer 2011, 2152–60).

In another study from Upper Egypt, Zedan et al. showed that of 658 men with ED, 17.3% had hypertension, 21.4% had DM and 40.1% were smokers. The prevalence of these risk factors was 2.8%, 3.7% and 28.7%, respectively, among controls, and they concluded that hypertension (odds ratio 5.4), DM (odds ratio 5.4) and smoking (odds ratio 3.1) were significant risk factors for ED (Zedan et al. 2010, 281-5). Ghalayini et al. reported that the prevalence of all degrees of ED was estimated at 49.9% in 905 men from Jordan aged P 18 years. In this group of men, the degree was mild in 25%, moderate in 13.5% and severe in 11.4%. The prevalence of severe ED increased from 2.7% in men in their twenties to 38.6% in their sixties and 46% in those aged P70 years. They concluded that age is the single most significant risk factor. Other important risk factors included lower household income, physical inactivity, obesity, and smoking, and DM, hyper- tension and ischemic heart disease (Ghalayini et al. 2010, 196-203). Elbendary et al. analyzed risk factors in 434 Egyptian patients with organic ED age of <40 years and 272 age-matched controls. They concluded that smoking and the use of recreational drugs are the most significant risk factors for organic ED in patients aged <40 years (Elbendary et al. 2009, 520-21). 22

Al-Helali et al. described the pattern of ED in men in Jeddah city. They investigated all patients newly diagnosed with ED (388 men) who attended six andrology and urology clinics within a period of 3 months. The mean (SD, range) age was 43.23 (12.56, 20-86) years; 73% were married with one wife, 23.5% married with two wives, and 8% were single. About a half (43%) had received less than secondary education. Retired men constituted 13% of all patients. Lack of exercise was the most frequent risk factor (82%) among patients, followed by smoking (56%), use of regular medication (44%), DM (30%), hypertension (15%), history of pelvic surgery (14%) (13%), and drug addiction (8%) (Al Helali et al. 2001, 34-8). In a cross-sectional community-based random sample of Egyptian men, Seyam et al. reported on the prevalence of ED and its correlates in Egypt. They found that there was a fair correlation between ED and increasing age (P ≤ 0.001). Men with complete ED comprised 13.2% of the sample, 26% of men in their 50s, 49% of men in their 60s and 52% of those aged ≥ 70 years. The state of better erection correlated moderately with sexual desire and sexual satisfaction (P ≤ 0.01). ED was associated with living in rural areas and lower socio- economic level (P ≤ 0.01), with smoking, DM, heart disease, hypertension, liver disease, arthritis, peptic ulcer and renal disease (P ≤ 0.05). ED was negatively associated with a good health-related quality of life (HRQL) (P ≤ 0.001) (Seyam et al. 2003, 237-45).

Shaeer et al. reported on the prevalence of ED and its correlates among men attending primary-care clinics in Pakistan, Egypt and Nigeria. They found that the age-adjusted prevalence rates of ED were 57.4% in Nigeria, 63.6% in Egypt, and 80.8% in Pakistan. Older age, DM, peptic ulcers, prostate disease, depression-related symptoms, and caffeine consumption were independently associated with an increased prevalence of ED, whereas being moderately active to very active at work (hard physical labor) and during leisure time (strenuous exercise) was associated with half the prevalence of moderate-to-complete ED (Shaeer et al. 2003, S8-S14). Abdulmohsen et al. investigated physicians' knowledge, attitude and practice towards ED in Saudi Arabia. They concluded that male physicians scored significantly higher than females. Urologists scored the highest, followed by andrologists. Surprisingly, physicians with higher qualifications scored lower than those with intermediate qualifications, and even less than general practitioners. Those who had practiced for P 10 years scored better than those with <10 years of practice (Abdulmohsen et al. 2004, 648-54). 23

Furthermore, Abolfotouh and al-Helali reported on the effect of ED on HRQL. ED was rated as mild (21%), moderate (60%) or severe (19%) in patients and was strongly associated with age. About two-thirds of the patients had a poor HRQL; severe ED was the only significant predictor. This factor could also affect prevalence and severity of ED (Abolfotouh & Al-Helali 2001, 510-18).

b) DM El-Sakka and Tayeb reported that, of all patients with type 2 DM, 86.1% had various degrees of ED, including mild in 7.7%, moderate in 29.4% and severe in 49.1%. The prevalence of ED was 25% in patients aged <50 years, which increased to 75% in those aged >50 years. Of those without ED, 70% were aged <50 years and 30% were >50 years (P < 0.001). Patients with a history of DM for >10 years were three times more likely to report ED than those with a history of <5 years. Men with poor metabolic control were 12.2 times more likely to report ED than those with good metabolic control. Of diabetic patients with ED 53% had one or more diabetic-related complications compared with 20.5% with no ED (P < 0.001) (El-Sakka & Tayeb 2003, 1043-47).

El-Rufaie et al. investigated sexual dysfunction among men with type II DM in a controlled study in the United Arab Emirates. The estimated high prevalence rate of sexual dysfunction among the diabetic group (89.2%) was significantly greater than in the hypertensive group (43.6%), and the apparently healthy group (16.7%). The commonest clinical presentations of sexual dysfunction among the diabetic men were impaired morning and spontaneous , erectile weakness, and ejaculatory disturbances. Less common presentations were reduced sexual interest and complete erectile failure (El-Rufaie et al. 1997, 605-12).

Al-Hunayan et al. found that of 323 men with newly diagnosed type 2 DM, 31% had ED; comparing potent men and men with ED, there were statistically significant differences for smoking, duration of smoking, hypertension, education level, body mass index and serum glycosylated hemoglobin level (Al-Hunayan et al. 2007, 130-34).

Khatib et al. in a study that investigated prevalence and severity of ED and its correlations among Jordanian men with DM concluded that the overall prevalence of ED was 62%; of these men, 30.3% had severe ED. The prevalence increased with age from 26.5% (13 24 of 49) of patients aged <40 years to 91% (87 of 96) in those aged P 70 years. Age, glycemic control, hypertension, coronary artery disease (CAD), retinopathy and neuropathy were inde- pendent risk factors for ED (Khatib et al. 2006, 351-56).

El-Sakka reported a study on the association between DM and changes in penile Doppler ultrasonography and axial penile rigidity variables in patients with ED. There was a statistically significant association between the presence of DM and a poor response to intra- corporeal injection and decreasing PSV values and Rigidometer values (P < 0.001 for each). In diabetic patients, there was a statistically significant association between a longer duration of DM, poor control of DM, and the presence of more than one DM-related complication, and a decreasing response to intra-corporeal injection, decreasing values of PSV, RI, and Rigidometer, and increasing values of EDV (P < 0.05 for each) (El-Sakka 2003, 525-31).

In another study assessing the relation between DM and other sexual problems, El- Sakka and Tayeb evaluated the prevalence of Peyronie's disease (PD) in patients with type 2 DM who were screened for ED. Of a total of 1133 male diabetic Saudi patients, 8.1% were diagnosed as having PD. Penile plaque and curvature were the most common findings. About 75% of the patients had a long duration and progressive course of their complaint. Significant associations between PD and both ED and longer duration of ED were detected (El-Sakka & Tayeb 2005, 1026-30). There were also significant associations between PD and age, obesity, smoking, duration and number of cigarettes smoked per day. Dyslipidemia, psychological disorders and the presence of at least one risk factor were significantly associated with PD. There were significant associations between a longer duration and poor metabolic control of DM and PD ((El-Sakka & Tayeb 2005, 1026-30). In the same domain, El-Sakka and Tayeb also assessed the impact of type 2 DM and PD, solely and together, on impairment of the vascular status of erection in patients with ED. They found that the means of the Erectile Function (EF) domain of the International Index of Erectile Function, and Questions 3 and 4, were significantly lower in patients with both DM and PD than in patients with either of the conditions alone. Patients with DM only had significantly lower means in the EF domain, Q3 and Q4 than patients with PD only. The means of PSV and RI were significantly lower, and the mean EDV was significantly higher in patients with both DM and PD than in patients with either of the conditions alone. They concluded that type 2 DM and PD solely and together negatively affect the vascular status of 25 erection. Type 2 DM had the principle effect, but the presence of PD has an additive impairment effect on erection and Doppler variables (El-Sakka & Tayeb 2009, 1736-42).

In other related factors for the relation between DM and androgen alteration, El-Sakka et al. assessed the prevalence and impact of the control of DM on the androgen pattern in men with type 2 DM-associated ED. Of all patients, 25.8%, 6.3% and 30.2% had low total testosterone, low dehydroepiandrosterone sulphate, and hyper-insulinemia, respectively, at the baseline visit. There were significant increases in the mean (SD) total testosterone levels, from 4.2(1.9) to 4.7(2.1) and 5.3 (2.2) ng/mL, and significant decreases in insulin level, from 23.7 (17.4) and 22.8 (15.3) and 17.8 (13.9) IU/mL at the 3- and 6-month visits, respectively. There were significant associations between a good control of DM or decreased fasting blood sugar and normal levels of total testosterone at the 3- and 6-month visits. The prevalence of patients with normal testosterone levels and severe ED was significantly increased at the 3- and 6-month visits (El-Sakka et al. 2008 and 2009, 602-8 and 552-60).

c) CAD, hypertension and stroke El-Sakka et al. evaluated risk factors for CAD in patients with ED. They found that of these patients, 26.9% had different degrees of ischemic heart disease (IHD), of whom 84.8% were aged >50 years. There was a significant association between age and IHD. There were significant associations between IHD and the increased severity and progressive course of ED. Furthermore, higher degrees of IHD were significantly associated with severe ED. DM, hypertension, dyslipidemia and psychological disorders were present in 75.1%, 39.3%, 45.6% and 8.2% of the patients, respectively. Overall, 92.1% of the patients with ED had one or more coronary artery risk factors. The presence of at least one risk factor was significantly associated with ED in patients with IHD (El-Sakka et al. 2004, 346-50).

El-Sakka and Morsy, in a diagnostic study, assessed the role of measuring cavernosal artery blood flow as a screening tool for IHD in patients with ED. There was a statistically significant association between the presence of IHD and arteriogenic causes of ED, a poor response to intra-corporal injection, poor rigidity in the Digital Inflection Rigidometer, and low PSV in the cavernous arteries. There was a statistically significant association between a higher grade of IHD and a decreasing PSV value. They concluded that the results of that study established that a reduced PSV of the cavernous artery is associated with IHD. 26

Determining the PSV could be a reliable screening tool for detecting IHD in patients with ED (El-Sakka & Morsy 2004, 251-54).

Shamloul et al. reported on the correlation between penile duplex ultrasonography findings and stress electrocardiography in men with ED. In all, 12 patients were diagnosed with positive IHD. Their mean PSV was 19.58 cm/s. In patients not diagnosed with IHD the mean PSV was 36.21 cm/s, the difference being statistically significant. The authors concluded that the PSV of cavernous arteries is a reliable measure for predicting IHD in patients with vasculogenic ED. Patients with a PSV of <35 cm/s should be referred for a cardiological assessment as they have a real risk of having 'silent' IHD (Shamloul et al. 2004, 235-37).

Mittawae et al. evaluated the incidence of ED, its severity, and other sexual function domains, in 800 Egyptian patients with hypertension. Of these patients, 92.3% had regular sexual activity (once to twice per week) and 43.2% had ED. Of these men, 5%, 12% and 26.2% had mild, moderate or severe ED, respectively. There was a highly statistically significant correlation between the duration of hypertension and the duration of weak erections (Mittawae et al. 2006, 575-78).

Bener et al. investigated the prevalence of ED and its severity in men in Qatar who had had a stroke, and assessed the comorbidities and risk factors associated with ED. Their findings showed a greater prevalence of ED in stroke patients in the population of Qatar. The most important comorbid factors for ED in stroke patients were DM, hypertension and hypercholesterolemia, and the risk factors were smoking and obesity. The same group of authors also investigated the prevalence of ED, its severity, and other sexual function domains in hypertensive and normotensive Qatari men, and estimated the association between hypertension and predictors of ED. They concluded that the prevalence of ED was significantly higher in Qatari hypertensive men than in normotensive men. Age, level of education, DM, occupation and duration of hypertension were considered statistically significant predictors of ED (Bener et al. 2007; 2008, 870-8; 701-8).

Yassin et al. reported in their review that cardiovascular diseases and ED are two faces of the coin of androgen deficiency. They concluded that it is now clear that ED is an expression of endothelial dysfunction. Testosterone deficiency is associated with an increased 27 incidence of cardiovascular disease and DM. The latter is often the sequel of the metabolic syndrome. Visceral obesity, a pivotal characteristic of the metabolic syndrome, suppresses the hypothalamic-pituitary-testicular axis, leading to diminished testosterone production. Conversely, substantial androgen deficiency leads to signs and symptoms of metabolic syndrome. It is erroneous not to include testosterone measurements in the progress of the cardiovascular disease, DM and ED. These conditions correlate strongly with testosterone deficiency (Yassin et al. 2011, 1-8).

Jackson et al. evaluated the link between ED and CAD, and provided a consensus report on the evaluation and management of ED associated with CAD. They stated that ED can arise before CAD becomes symptomatic, with a time window of 3-5 years. ED and CAD share the same risk factors, and endothelial dysfunction is the common denominator. Treating ED in cardiac patients is safe, provided that their risks are properly evaluated (Jackson et al. 2010a; b, 1608-26).

El-Sakka et al. recently assessed the association between the severity of ED and left ventricular diastolic dysfunction (LVDD) in patients with no overt cardiac complaint; 77.4%, 74.8%, 80% and 66.1% had an abnormal E/A ratio, deceleration time, and isovolumic relaxation time (IVRT) and mitral E velocity/tissue Doppler imaging E velocity (E/Em) ratio, respectively. Only the means of the IVRT and E/Em ratio had significant associations with an increased severity of ED (P < 0.001 for each).

There were significant associations between an increased severity of ED and the following categorical echo variables; grade 1 and 2 of E/A ratio, deceleration time, IVRT, and grades 1, 2 and 3 of the E/Em ratio (P < 0.05 for each). They concluded that LVDD is prevalent among patients with ED-associated medical comorbidities but no overt cardiac complaint. There were significant associations between increased severity of ED and the presence of LVDD in those patients (El-Sakka et al. 2011, 2590-7).

d) Other conditions: LUTS, chronic renal failure, PD, post-renal transplantation and lead exposure El-Sakka, in a risk-analysis study, evaluated ED risk factors in patients with LUTS; 22.8% had mild, 42% had moderate and 35.2% had severe grades of ED. There were significant associations between LUTS and both the longer duration and the increased 28 severity of ED. There were also significant associations between LUTS and the following ED risk factors; age, obesity, DM, hypertension and IHD. The presence of at least one risk factor was significantly associated with LUTS in patients with ED (El-Sakka 2006, 144-49).

In another related study, El-Sakka investigated the underlying vascular association between LUTS and ED. Of these patients, 80.7% had different degrees of LUTS. There was a significant association between the presence of LUTS and arteriogenic and neurogenic causes of ED, poor response to intra-corporeal injection, poor rigidity in the Rigidometer test, and a low PSV of the cavernous arteries (P < 0.05 for each) (El-Sakka 2005, 319-25).

There was no significant association between the presence of LUTS and increasing values of EDV or decreasing values of RI of the cavernous arteries (P > 0.05 for each). There was a significant association between the higher degrees of LUTS and decreasing values of PSV (P < 0.05).

Ali et al. investigated ED in patients with chronic renal failure undergoing hemodialysis in Egypt. They found that the prevalence of ED among these patients was 82.5%, compared to 30% among controls. The prevalence of ED in this group was significantly higher than in controls. The prevalence of ED in patients aged <50 years was 80%, and it was 88% in those aged P 50 years, while the prevalence of ED among controls was 28% and 69.8%, respectively. Age (r = -0.3368, P < 0.01), serum urea level (r = - 0.5974, P < 0.001), and creatinine level (r = -0.5804, P < 0.001) had a significant negative correlation with the presence of ED among these patients (Ali et al. 2005, 180-85).

In a study that assessed prevalence of PD among patients with ED, El-Sakka reported on a total of 1440 men with ED who were enrolled in this study; 7.9% of them had PD. There were significant associations between PD and both the longer duration and the increased severity of ED. There were also significant associations between PD and the following socio- demo-graphic risk factors for ED; age, obesity, smoking, duration and number of cigarettes smoked per day. Concomitant diseases and medical comorbidities such as DM, dyslipidemia, psychological disorders and the presence of at least one risk factor were significantly associated with PD in patients with ED (El-Sakka 2006, 144-49).

29

In their study, El-Bahnasawy et al. reported on 400 male renal transplant recipients; erectile function compared to that before the transplant was improved, deteriorated or remained static in 44%, 12.5% and 43.5% of the recipients, respectively. Age, hemoglobin level and presence of DM and/or peripheral neuropathy had significant and independent negative effects on erectile function. They concluded that renal transplantation has varying effects on erectile function (El-Bahnasawy et al. 2004, 521-6).

Anis et al. reported on the possible hazardous effect of chronic lead exposure on erectile function, and the deposition of lead in the cavernous tissue, and concluded that chronic lead exposure might be associated with ED (Anis et al. 2007, 1428-34).

e) Summary and conclusion In summary, male sexual potency and ED are not new issues in the Arab region. Shokeir and Hussein, in their review, reported on sexual life in Pharaonic Egypt (Shokeir & Hussein 2004, 385-8).

In Pharaonictimes, the Egyptians described impotence and recorded several methods to increase sexual power. The prevalence of ED is 20-90% among patients with different risk factors and medical comorbidities in Arab region countries. The most common risk factors and medical comorbidities were smoking, obesity, type 2 DM, hypertension, dyslipidemia, CAD and depression.

A long list of additional risk factors was reported in different studies, which included liver disease, arthritis, peptic ulcer, prostate disease, LUTS, history of pelvic surgery, chronic renal failure, PD, lead exposure, lower household income, physical inactivity, caffeine con- sumption, use of recreational drugs, alcoholism, and drug addiction. The high prevalence of severe ED in patients in this region could be attributed to: (1) the high prevalence of risk factors; (2) the poor control of those risk factors; (3) the delay in seeking medical advice; and (4) the non-compliance with treatment.

Physiology of penile erection NO, released from the endothelium and the parasympathetic nerve terminals, is the primary neurotransmitter involved in penile erection, although other transmitters can also be involved. NO-dependent relaxation of the cavernosal smooth muscles leads to compression of 30 the subtunical small veins, occluding local venous return and resulting in an erection (figure: 1). Penile detumescence begins with activation of the adrenergic receptors on the cavernous arteries and trabecular smooth muscles, leading to a reduction in arterial inflow and a collapse of lacunar spaces. Decompression of the drainage venules from the cavernous bodies occurs, allowing venous drainage of the lacunar spaces and relief of the erection (Prieto 2008, 17–29).

Figure (1): Microscopic mechanisms underlying penile smooth muscle relaxation NO is the primary mediator of penile smooth muscle relaxation. After sexual stimuli, NO concentration is significantly increased because of its release from the cholinergic and non- noradrenergic, non-cholinergic fibers and the endothelium. NO works via the GTP/cGMP pathway to decrease intracellular calcium leading to trabecular smooth muscle relaxation. PDE5 enzyme regulates cGMP-dependent penile erection by stimulating hydrolysis of cGMP itself. Another mechanism that can decrease intracellular calcium concentrations is mediated by cAMP. Drugs that enhance erection include PDE5 inhibitors and prostaglandin E1. PGF2α=prostaglandin F2α. Abbreviations: PGE1: prostaglandin E1. GTP: guanosine triphosphate. cGMP: cyclic guanosine monophosphate. NO: nitric oxide. eNOS: nitric oxide synthase. PDE5: phospodiesterase type 5. ATP: adenosine triphosphate. AMP: adenosine monophosphate. GPCR: G-protein-coupled receptor. (Adopted from: Shamloul & Ghanem 2013, 153-65)

31

Pathophysiology and cause Introduction Normal sexual function has been described as a bio-psychosocial process that involves the coordination of psychological, endocrine, vascular, and neurological sys-tems.38 Erectile dysfunction is classified as psychogenic, organic (i.e., neurogenic, hormonal, arterial, cavernosal, or drug induced), or mixed psychogenic and organic (panel 1). Erectile dysfunction is usually of a mixed psychogenic and organic nature (Shamloul & Ghanem 2013, 153-65). Psychogenic erectile dysfunction Psychological factors are involved in a significant number of cases of erectile dysfunction alone or in combination with organic causes. An important psychogenic factor related to erectile dysfunction is performance anxiety (fear of failure during intercourse). Historical theories explaining psychological factors in erectile dysfunction have described multiple developmental, cognitive, affective, and interpersonal factors that predispose men to sexual dysfunction. At present, psychogenic erectile dysfunction is thought to be primarily related to a group of predisposing, precipitating, and maintaining factors (panel 2) (Carson et al. 2006, 26).

Panel (1): Main organic causes of erectile dysfunction Neurogenic  Central (cerebral or spinal cord); for example, cerebral insult, multiple sclerosis, and spinal cord injury  Peripheral; afferent (sensory neuropathy, e.g., diabetes mellitus and polyneuropathy of various other causes)  Efferent (autonomic neuropathy or after radical pelvic surgery)

Endocrinological  Diabetes mellitus, , and hyperprolactinemia

Vasculogenic  Arterial: macro or micro-angiopathy (e.g., atherosclerosis and trauma)  Venous: failure of the corporal veno-occlusive mechanism  Sinusoidal: failure to relax (e.g., fibrosis)

Drug-induced depression  Drugs; for example, some antihypertensives, antidepressants, anti-androgens, and major tranquillizers 32

 Cigarette smoking, alcoholism, and recreational drug use (e.g., marijuana and heroin)

Systemic diseases and general ill health  For example, liver, renal, respiratory, and cardiovascular disease

Local penile (cavernous) factors  For example, cavernous fibrosis after priapism or due to other reasons, Peyronie‟s disease, and

Adopted from (Shamloul & Ghanem 2013, 153-65) Panel (2): Factors related to the development of psychogenic erectile dysfunction Predisposing factors  Traumatic past experiences  Strict upbringing  Inadequate  Physical and problems

Precipitating factors  Acute relationship problems  Family or social pressures  Major life events, such as pregnancy, , or loss of a job

Maintaining factors  Relationship problems  Physical or mental health problems  Absence of knowledge of availability of various treatment options

Note: religious and cultural differences might influence the factors that affect the development of psychogenic erectile dysfunction. Adopted from (Carson et al. 2006, 26)

Neurogenic erectile dysfunction Certain neurological disorders are frequently associated with erectile dysfunction, including multiple sclerosis, temporal lobe epilepsy, Parkinson's disease, stroke, Alzheimer's disease, and spinal cord injury. Patients undergoing radical pelvic surgeries (e.g., radical prostatectomy) have an especially high risk of cavernous nerve injury and subsequent neurogenic erectile dysfunction. However, recent advances in surgical techniques have significantly lowered the incidence of post-pelvic-surgery erectile dysfunction (Mulhall 2008, 613-20). 33

Endocrinological erectile dysfunction Androgens play important parts in enhancing sexual desire and maintaining adequate sleep-related erections but have a limited effect on visually induced erections. Additionally, testosterone is important in the regulation of the expression of NO synthase (NOS) and PDE5 inside the penis. Testosterone deficiency or hypogonadism has been recently associated with cardiovascular morbidity and mortality. Hyperprolactinemia leads to sexual dysfunction, due to low testosterone concentrations. Increased prolactin concentration leads to the inhibition of gonadotropin-releasing , which, in turn, decreases the secretion of luteinizing hormone, which is responsible for testosterone secretion (Corona et al. 2011, 687-701).

Vasculogenic erectile dysfunction Several frequent risk factors are associated with penile arterial insufficiency, including atherosclerosis, hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, and pelvic irradiation. Endothelial dysfunction is the common denominator to many vascular risk factors that can lead to arteriogenic erectile dysfunction. Other studies have confirmed a significantly higher incidence and prevalence of erectile dysfunction in patients with hypertension, which can reach up to 68%. Erectile dysfunction improved when the concentrations of elevated total and low-density lipoproteins, as well as cholesterol, were either lowered, by dietary measures or administration. In addition, diabetes mellitus, hypertension, dyslipidemia, obesity, and smoking are all strong risk factors for coronary artery disease (CAD) and erectile dysfunction (Jackson 2007, 463-66). The present Princeton III consensus guidelines, an expert opinion report, now recognize erectile dysfunction as a strong predictor of CVD and, in particular, CAD. This association between CVD and erectile dysfunction was confirmed in a study that reported that erectile dysfunction is a potent predictor of adverse cardiovascular events in high-risk cardiovascular patients (Nehra et al. 2012, 766-78). In a landmark study, Inman and colleagues biennially screened a random sample of more than 1400 community-dwelling men who had regular sexual partners and no known CAD for the presence of erectile dysfunction over a 10-year period. Overall, their data show that new incident CAD developed in 11% of men over the 10-year follow-up period, in which about 15% were due to myocardial infarction, 79% to angiographic anomalies, and 6% to sudden death. The cumulative incidence of CAD was strongly influenced by patient age. CAD incidence densities per 1000 person-years for men without erectile dysfunction were 0-94 (age 40-49 years), 5-09 (age 50-59 years), 10-72 (age 60-69 years), and 23-30 (age 34

70 years and older). For men with erectile dysfunction, the CAD incidence densities per 1000 person-years were 48-52 (age 40-49 years), 27-15 (age 50-59 years), 23-97 (age 60-69 years), and 29-63 (age 70 years and older). The most significant finding of this study is that when erectile dysfunction occurs in men younger than age 60 years, it is associated with a marked increase in the risk of future cardiac events compared with men with no erectile dysfunction; however, it has less predictive significance in older men. There is no definite explanation of why this phenomenon happens in younger men (Inman et al. 2009, 108-13). Inman and colleagues suggested that erectile dysfunction shares the same risk factors as CAD, with endothelial dysfunction being an important underlying pathological change in both diseases. Other potential mechanisms involved in the development of endothelial dysfunction that can lead to erectile dysfunction and CAD include a dysfunctional L-arginine NO pathway, increased peripheral sympathetic activity, vascular structural alterations leading to decreased vascular dilatation capacity, and increased specific inflammatory mediators (Inman et al. 2009, 108-13). Montorsi and colleagues suggested that this phenomenon might be related to the caliber of the blood vessels. Whereas the penile artery has a diameter of 1-2 mm, the proximal left anterior descending coronary artery is 3-4 mm in diameter (Montorsi et al. 2003, 352-54). Thus, an equally sized atherosclerotic plaque developing in the smaller penile arteries would more likely compromise flow, presenting itself as an erectile dysfunction complaint much earlier than if the same amount of plaque developed in the larger coronary artery, causing angina. Inadequate venous occlusion is another important cause of vasculogenic erectile dysfunction. Inadequate venous occlusion can occur as a result of the development of large venous channels draining the cavernous tissue. It might also be caused by severe degenerative, functional, or anatomical changes in the tunica albuginea, such as those that occur in Peyronie's disease (Dean and Lue 2005, 379–95).

Drug-induced erectile dysfunction Psychotropic drugs and antihypertensives are among the most common drug classes involved in the development of erectile dysfunction. Antidepressants are the most common psychotropic drugs associated with significant rates of erectile dysfunction, including the selective serotonin reuptake inhibitors and venlafaxine. Antipsychotics such as risperidone and olanzapine have the highest likelihood of all psychotropic drugs of causing erectile dysfunction. Thiazides, followed by P blockers, are the most common groups of 35 antihypertensive drugs that cause erectile dysfunction, whereas a blockers, angiotensin- converting enzyme inhibitors, and angiotensin receptor blockers are the least likely of these drugs to cause erectile dysfunction. have also been implicated in the development of erectile dysfunction. Panel (3) lists the most common groups of drugs that can cause erectile dysfunction (Serretti and Chiesa 2011, 130-40).

Erectile dysfunction due to ageing, lifestyle factors, and systemic diseases Findings from epidemiological studies confirm that age is the primary risk factor for erectile dysfunction. The prevalence and severity of erectile dysfunction increases with age. In the Massachusetts Male Aging study, 39% of men had some degree of erectile dysfunction by the age of 40 years. The prevalence of erectile dysfunction gradually increased, reaching 67% for men by the age of 70 years. The relation between increased age and increased prevalence and severity of erectile dysfunction was confirmed by two other independent, large-scale studies, which included 2476 Spanish men58 and 1464 Middle Eastern men (Lewis et al. 2010, 1598-607). Panel (3): Drugs and recreational substances commonly associated with erectile dysfunction Anti-androgens  Gonadotropin-releasing hormone agonists (Leuprolide, Goserelin, Lupron, and Zoladex)   Chemotherapy (cyclophosphamide and busulfan)  Ketoconazole  H2 blockers Antihypertensive drugs Thiazide diuretics, β-blockers and Calcium channel blockers Anti-arrhythmic agents Digoxin, Amiodarone and Disopyramide Statins There is controversial evidence about the effects of atorvastatin on erectile function Psychotropic drugs  Tricyclic antidepressants  Selective serotonin reuptake inhibitors  Phenothiazines and Butyrophenones Recreational substances Alcohol, Cocaine, Marijuana, Nicotine and Opiates Adopted from (Shamloul and Ghanem, 2013) Diabetes mellitus type 2 is the second most common risk factor for erectile dysfunction, which in turn develops in 50-75% of diabetics. Erectile dysfunction also occurs three times more frequently in diabetics than non-diabetics (49-3% vs15-6%, respectively). Erectile dysfunction was the first sign of diabetes mellitus in 12% of patients. A sedentary 36 lifestyle, smoking, alcohol or drug misuse, sleep disorders, obesity, and metabolic syndromes have all been associated with erectile dysfunction (panel 4). In addition, persistent debilitating medical disorders, including chronic kidney, liver, and pulmonary diseases, have all been associated with erectile dysfunction (Holden et al. 2010, 96).

Diagnosis Introduction At present, the scientific consensus has been to adopt a goal-directed approach during the assessment of patients complaining of erectile dysfunction. The main goals of assessment of erectile dysfunction are to establish whether the disorder is truly erectile dysfunction, to identify the cause of the disorder, and to ascertain risk factors and potentially life-threatening comorbid disorders associated with erectile dysfunction (Hatzimouratidis et al. 2010, 337– 48). Panel (4): Risk factors and comorbidities associated with erectile dysfunction  Age  Alcohol misuse  Lifestyle factors  Sedentary lifestyle  Obesity  Cigarette smoking  Poor physical and psychological health  Diabetes mellitus  Metabolic risk factors and metabolic  Recreational drug use (e.g., marijuana syndrome and heroin)  Hypertension  Dyslipidemia  Hypogonadism

History taking The mainstay in the diagnosis of erectile dysfunction is adequate and comprehensive sexual and medical history taking (figure: 2). During the initial visit, the primary-care physician should attempt to obtain a detailed psychosocial history from the patient, focusing on the patient's assessment of his own sexual performance and his general attitude and knowledge about sex. Interviewing the patient's partner during the erectile dysfunction assessment is also usually advisable. Occasionally, a medical history might reveal complex psychological problems, prompting psychiatric referral (Shamloul and Ghanem 2013, 153- 65). 37

Patients who complain of weak erections might be actually suffering from premature ejaculation. In erectile dysfunction, erection loss occurs before orgasm, while with premature ejaculation, it happens afterwards. Assessment of whether the main cause of erectile dysfunction is organic or psychogenic is also important. The presence of rigid morning or night erections, or rigid erections at any sexual thought suggests a mainly psychogenic cause (Montorsi et al. 2010, 3572-88).

Figure (2): Algorithm for the diagnosis of erectile dysfunction Adopted from (Shamloul and Ghanem, 2013) Erectile dysfunction with a sudden onset, intermittent course, or short duration also suggests psychogenic factors. Conversely, erectile dysfunction with a gradual onset, 38 progressive course, or long duration suggests a predominantly organic cause. Relevant drug history, including alcohol, tobacco, or illicit drug use, and decreased or altered sex desire should also be reviewed. Past medical and surgical disorders should be thoroughly detailed (Montorsi et al. 2010, 3572-88). Standardized questionnaires are frequently used to confirm that the disorder is truly erectile dysfunction and to measure its severity. They are also valuable research aids that help assess the response to different treatments. Several questionnaires are available. Two of the most practical and easily administered ones are the International Index of Erectile Function and the Sexual Health Inventory for Men (Ghanem and Shamloul 2008, 1582–89). Recent findings that erectile dysfunction is a strong predictor of CAD and that the development of symptomatic erectile dysfunction might precede the occurrence of a cardiovascular event by 2-3 years have led to stricter measures during the assessment of patients who present with poor erections. A strong recommendation is that all men with erectile dysfunction who are free from any cardiac symptoms should be considered to be cardiac (or vascular) patients until proven otherwise. After a full medical assessment, the patient's cardiovascular risk should be assessed with stratification to high, medium, or low risk levels (table: 1) (Vardi et al. 2009, 979-85). Table (1): Risk stratification and treatment of men with erectile dysfunction and cardiovascular disease Low risk (asymptomatic after moderate-intensity Sexual activity can be continued exercise):asymptomatic and less than three major risk and oral PDE5-Is can be given factors-controlled hypertension, mild valvular disease, LVD (NYHA class I), and NYHA class II Intermediate or indeterminate risk: asymptomatic and In-depth cardiovascular assessment at least three coronary artery disease risk factors-mild to re-categories the patient is stable angina pectoris, asymptomatic after MI (>6–8 needed before treatment of erectile weeks), moderate stable angina pectoris, MI for over dysfunction 2 weeks but less than 6 weeks, LVD or CHF (NYHA class III)peripheral arterial disease, history of stroke, or transient ischemic attack High risk: unstable or refractory angina, uncontrolled Sexual activity stopped. Stabilize hypertension, CHF(NYHA class IV), recent MI (<2 cardiovascular condition first then weeks), high-risk arrhythmias, obstructive proceed to treatment for erectile hypertrophic cardiomyopathies, or moderate-to- dysfunction severe valve disease MI; myocardial infarction. LVD; left ventricular disease. NYHA; New York heart classification. CHF; congestive heart failure. PDE5-Is; phosphodiesterase type 5 inhibitors. Adopted from (Nehra et al. 2012, 766-87) 39

After cardiovascular risk stratification, further assessment for the presence of silent CAD is of major importance (figure: 3). This assessment is particularly important in young men (<60 years old), who are at low risk of developing CVD, and in other patients with intermediate risk. In these men, a resting electrocardiogram (ECG) test should be done and, if abnormal, a further exercise ECG test is recommended. If abnormal, more in-depth cardiovascular assessment (e.g., angiography) with referral to a cardiologist is the logical next step. Other useful measurements of CAD in this specific population might include waist circumference, body mass index, and coronary artery calcification scoring, as measured by electron-beam CT, carotid intima-media thickness, peripheral arterial tonometry, and serum asymmetric vascular molecules (Miner 2011, 125–34).

Figure (3): Algorithm for coronary risk assessment in erectile dysfunction Adopted from (Montorsi et al. 2006, 721–31)

40

Physical examination General and more focused local examinations are recommended for all cases of erectile dysfunction. Panel 5 lists the main components of a physical examination. The local examination is a good opportunity for the physician to educate the patient, if necessary, on normal penile size and to explore any misconceptions the patient might have about the relation between penile length, masculinity, and erectile dysfunction (Shamloul and Ghanem 2013, 153-65).

Laboratory assessment Assessments of fasting blood sugar and total testosterone are the two basic laboratory investigations that should be done. However, because erectile dysfunction is a strong predictor of vascular disease, physicians could discuss with the patient the importance of also checking their lipid profile and other tests. Low concentrations of free or total testosterone necessitate further hormonal assessment, including that of luteinizing hormone and prolactin. After the initial erectile dysfunction assessment, the primary-care physician might be faced with complex organic or psychological findings, or both, that warrant extensive assessment, which is preferably done by a specialist (panel 6) (Shamloul and Ghanem 2013, 153-65).

Panel (6): Indications for referral to a specialist in erectile dysfunction  Deep-rooted psychiatric problems  CNS disorders  Complex endocrine disorders  Severe cardiovascular disease  Lifelong erectile dysfunction  Penile fibrosis (Peyronie‟s disease or post-priapism)  Congenital penile anomalies (e.g., hypospadias)  Failure to respond to phosphodiesterase type 5 inhibitors Adopted from: (Shamloul and Ghanem 2013, 153-65)

Specific investigations and imaging  Introduction For many patients, especially young men and their partners, knowing whether or not the disorder is reversible is part of the treatment. Additionally, certain types of erectile dysfunction might be associated with potentially life-threatening cardiovascular disorders. The routine use of investigative procedures in erectile dysfunction is generally not advisable, 41 because patients might be subjected to expensive invasive procedures that will not alter the management plan. Table (2) lists the most common specific diagnostic tests for erectile dysfunction and their benefits and limitations. Recent research-based techniques that attempt to assess penile endothelial dysfunction include the penile NO release test and Endo- PAT200079 and the measurement of specific serum (e.g., endothelin-1 and C-reactive protein) and cellular (circulating endothelial progenitor cells) markers (Esposito et al. 2009, 107–14).  Ultrasound Ultrasound examination can be utilized to examine penile structure and vasculature with penile Doppler sonography (PDS), allowing for the examination of the cavernosal and dorsal penile arteries. These drugs cause smooth muscle relaxation, vasodilatation and increased inflow of blood into the corpora cavernosa, leading to tumescence. Therefore, penile Doppler sonography can be reserved for those patients with little or no response to these first-line medications, and in whom arterial or venous insufficiency is suspected. In addition, PDS may be of use in anatomical delineation for patients with post-traumatic/post- surgical abnormalities where curative/reconstructive surgery is being considered (Patel et al. 2012, 69-78).

At ultrasound, penile anatomy is readily demonstrated. The corpora cavernosa are depicted as longitudinally orientated vascular beds of mixed echogenicity, with the tunica albuginea visualized as a thin echogenic envelope, usually <2 mm thick. In the absence of cavernosal fibrosis, the interface between the tunica and the underlying cavernosal tissue is quite distinct. The spongiosum is visualized on the ventral surface and is of slightly higher reflectivity than the cavernosa. The cavernosal arteries can be identified within the corpora cavernosa at ultrasound as parallel hyper-echoic lines (figure: 4). Variants in arterial anatomy exist in up to 20% (figure: 5), but their relevance to clinical practice is not established (Patel et al. 2012, 69-78). 42

Table (2): Uses and limitations of commonly used specific erectile dysfunction investigations Main benefits Limitations Easy to administer, well tested, and Questionnaires validated. Assess presence and severity of Do not define the cause of erectile dysfunction erectile dysfunction Rapid and easy. Can assess severity of Intra-cavernosal injection Risk of prolonged erection, priapism, and faulty injection erectile dysfunction Tested against a historical gold standard Less reliable in diagnosing venogenic erectile dysfunction. (pharmaco-arteriography) to diagnose Incomplete smooth muscle relaxation due to anxiety or Color Doppler Ultrasound arteriogenic erectile dysfunction. Might sympathetic overtone might lead to false-positive results. Re- suggest other vascular disease (e.g., coronary dosing and retesting are frequently needed artery disease) Outlines arterial anatomy before arterial Pharmaco-Arteriography surgery in post-traumatic and congenital Invasive. Affected by methodology and timing cases Suggests venogenic erectile dysfunction. Pharmaco-Cavernosometry Moderately invasive. Incomplete smooth muscle relaxation due to Delineates site of leak and cavernosal or Cavernosography anxiety or sympathetic overtone might lead to false-positive results abnormalities Does not directly assess autonomic nerve function. No universally Neurological testing Assess somatic pathways accepted and reproducible criteria. Complex and time consuming Nocturnal erections might be regulated by different pathways. Does not detect sensory deficit impotence. False-positive results Closest to a gold standard in differentiating Nocturnal Penile can occur if patients do not sleep well. Physical disorders might between psychogenic and organic erectile Tumescence Testing alter nocturnal penile tumescence testing. Assesses only radial not dysfunction axial rigidity. Does not correlate well with International Index of Erectile Function domain scores Adopted from (Shamloul and Ghanem 2013, 153-65) 43

Adopted from (Patel et al. 2012, 69-78) Figure (4): Longitudinal ultrasound image of left cavernosal artery (arrow) within corpus cavernosum in an un-stimulated penis

Adopted from (Patel et al., 2012) Figure (5): Transverse ultrasound image of right cavernosal artery (white arrow) branching to supply left cavernosum (red arrow) in an un-stimulated penis

44

a) Ultrasound method PDS aims to examine the cavernosal arteries and the response of their spectral Doppler waveforms following intra-cavernosal injection of a pharmaco-stimulant agent, commonly a prostaglandin E1 derivative such as alprostadil. The fundamental principle is repeated sampling of these waveforms in a stepwise manner until maximal peak systolic and minimal diastolic velocities have been reached (Wilkins et al. 2003, 514–23). Owing to the nature of the problem under investigation, a quiet, private and comfortable environment is essential for satisfactory PDS. Many patients will be anxious, and a detailed explanation of the procedure is required prior to commencing. Informed consent should be obtained, especially with regard to the low risk of priapism following intra- cavernosal injection (Gontero et al. 2004, 922–6). The patient is positioned supine upon the examination bed and an initial injection of alprostadil is tailored according to the patient. If the patient is pharmacologically naive, then a small dose (5 µg of alprostadil) is initially given. If there has been a poor response to the PDE5 agents previously, then up to the full dose (20 µg) may be given at the outset. The injection is gently massaged into one of the corpora cavernosa. The authors' standard approach is dorsal, although ventral scanning may also be undertaken. Initially transverse views are obtained, utilizing a high-frequency linear probe, and once tumescence commences an oblique-longitudinal approach may be necessary. Angulation of 20-30° cephalad in the transverse plane enables visualization of the cavernosal artery at its root, running towards the probe, and the artery can be insonated at a Doppler angle of 0°. As usual, angle correction is essential and should be implemented. A velocity gradient exists within the artery from the base to the tip, and reproducible and accurate measurements are best obtained at the penile base towards the peno-scrotal junction (Kim et al. 1994, 591–4). 2-3 min after injection, the cavernosal arteries should become more visible, and spectral measurement and image acquisition should begin at this stage. In addition, the quality of the erection should be assessed both objectively by the operator and subjectively by the patient, and recorded. If the quality of erection is insufficient, repeated injection can be made. Other authors advocate self- or visual stimulation (Montorsi et al. 1996, 536–40). Repeated Doppler measurements should occur at 5-min intervals until the maximal peak systolic velocity (PSV) and end-diastolic velocity (EDV) are judged to have been reached. The PSV is normal if it is >35 cm s-1 and EDV is usually normal if negative or close to 0 cm s-1. The PDS waveform during erection is multiphasic (figures: 6 and 7). Following injection of pharmaco-stimulant, initial waveforms display elevation of velocities, especially 45 the diastolic velocity, which reflects smooth muscle relaxation (Phase: 2, figure: 6). The PSV then usually stabilizes after this and is sustained for at least 5 min. After this, intra- cavernosal pressure (IP) increases, reflected by a steady reduction in the end-diastolic velocity as increasing sinusoidal distension elevates IP and impedes venous outflow (Phase: 3, figure: 6). As the IP continues to rise, the diastolic velocity diminishes and the systolic waveform narrows. When IP exceeds diastolic pressure, the diastolic waveform will reverse (Phase 4, figure 6). As maximal penile rigidity is achieved in the final phase, the IP is equal to or greater than systolic, producing further narrowing of the systolic peak. In some cases, the systolic velocity may reduce to such an extent that there is a transient interruption to systolic flow (Patel et al. 2012, 69-78).

Figure (6): Diagrammatic representation of multiphasic Doppler waveforms encountered during normal erection in the cavernosal arteries. Phase 1: initial low flow arterial waveform. Phase 2: elevation of systolic and diastolic velocities, approximately 5 min following injection. Phase 3: reduction in end-diastolic velocity as sinusoidal distension causes increased intra- cavernosal pressure and reduction in venous outflow. Phase 4: reversal in diastolic waveform as intra-cavernosal pressure exceeds diastolic pressure. Phase 5: intra-cavernosal pressure exceeds systolic pressure at maximal tumescence, causing reduction in the systolic velocity and narrowing of the systolic peak Adopted from (Patel et al., 2012)

When the minimal diastolic velocity is attained, the Doppler study is complete, although subsequent examination of the vessel course should be undertaken to exclude distal stenosis and appreciate any variations in the vascular supply. Standard greyscale imaging is then used to examine for the presence of non-vascular abnormalities such as plaques, fibrosis or tunica albuginea defects (Patel et al. 2012, 69-78).

46

b) Diagnostic values Threshold values for the diagnosis of arterial insufficiency (figure 8) vary in the literature, with values of 25-35 cm s-1 suggested. A PSV of <25 cm s-1 has been correlated with severe arterial disease on angiographic imaging. PDS not only enables the arterial waveform to be analyzed but also allows for visualization of stenosis, damped waveforms and high-velocity "jets" that may occur as a result of a proximal stenosis elsewhere (Wilkins et al. 2003, 514–23). 47

Figure (7): (a) Longitudinal Doppler image showing cavernosal artery at base of penis (seen in longitudinal section) prior to stimulation. Note the barely recordable arterial flow.

(b) The same cavernosal artery race a few minutes following injection. Note the elevated systolic (28.9 cm s–1) and diastolic (6.7 cm s–1) velocities.

(c) Later in the same study, the systolic velocity has peaked (66.9 cm s–1), indicating excellent arterial inflow with a narrowing of the systolic trace. A dicrotic notch is visible (long arrow).

(d) Late in the study, diastolic flow reversal can be observed (short arrow). This signifies an intact venous occlusion mechanism. Later still, in a normal study a significant reduction in the systolic velocities may also be observed (not shown).

Adopted from (Patel et al. 2012, 69- 78)

48

Figure (8): Arterial insufficiency Patient with a pelvic fracture and subsequent erectile dysfunction who underwent intra- cavernosal injection of pharmaco-stimulant; image at 10 min following injection. The pre- stimulation Doppler waveform is not shown. Throughout the study, the PSV was below the threshold value of 35 cm s–1 with a wide systolic trace, indicating inadequate arterial inflow to produce rigidity. The persistently elevated end-diastolic flow seen throughout the examination is felt to be a consequence of the arterial insufficiency preventing full sinusoidal dilation (which would normally occlude venous outflow). The patient achieved only soft tumescence. Note only the right cavernosal artery is shown Adopted from (Patel et al. 2012, 69-78)

49

Venous incompetence can cause ED through failure of cavernosal engorgement. On PDS this is manifested by persistent diastolic flow and elevated end-diastolic velocity. Again, various threshold EDV values have been suggested between 5 and 7 cm s-1 as diagnostic of venous incompetence. However, such threshold values for EDV can be misleading if arterial insufficiency is present. In these cases, resistive indices (RI) <0.75 may be helpful in predicting venous leakage (figure: 9), although measurement of RI is not usually undertaken in our practice (Naroda et al. 1996, 1231–5).

c) Further ultrasound findings Ultrasound can demonstrate alternative pathologies that may cause ED. In our practice, the penis is assessed for the presence of non-vascular abnormalities such as plaques, areas of fibrosis and defects in the tunica albuginea once full tumescence has been achieved. Peyronie's disease is a localized benign connective tissue disorder with an unknown etiology that results in fibrous thickening of the penile tunica albuginea. An association with Dupuytren's contracture has been established. The disorder has a prevalence reported to be up to 3%, and typical features include pain upon erection, penile curvature, loss of girth and ED. At ultrasound, it is manifested by hyperechoic-thickened plaques of the tunica albuginea, which may be calcified (figure: 10) (Golijanin et al. 2007, 43–8).

50

Figure (9): Venous leak. (a) Un-stimulated Doppler trace of cavernosal artery.

(b) Systolic velocities indicating adequate arterial inflow with elevated diastolic flow (6.2 cm s– 1) following intra-cavernosal injection of pharmaco-stimulant.

(c, d) As the study progresses, the diastolic flow remains abnormally persistently elevated (7.4 cm s–1), signaling venous leak.

Adopted from (Patel et al. 2012, 69-78) 51

Figure (10): (a) Longitudinal ultrasound image showing highly fibrogenic plaque in Peyronie’s disease (long arrow) measuring 1.6 cm. The plaque is principally dorsal in location, contributing in this patient to failure of the veno-occlusion mechanism, with normal arterial inflow but elevated diastolic velocities throughout. (b) Longitudinal ultrasound image showing typical calcified plaque (short arrow) encountered in Peyronie‟s disease.

Adopted from (Patel et al. 2012, 69-78)

52

In the early stage of the disease, inflammation predominates and lasts for 12-18 months, causing erectile discomfort and unstable curvature. In this early phase, hyperperfusion can be demonstrated around the plaques by power Doppler. A more chronic phase follows with stable deformity and plaque size. Up to 80% of patients with Peyronie's will suffer from ED, although the association is multi-factorial, with pain and psychological factors also recognized. In addition, many authors have postulated that ED in Peyronie's is secondary to vascular abnormalities, with both arterial incompetence and venous leakage documented (Weidner et al. 1997, 325–8). Penile fractures can result in the long-term complication of ED through the development of fibrous plaque formation, similar to those encountered in Peyronie's disease. In addition, venous leakage and arterial insufficiency can be encountered as a further long- term complication of penile trauma, as can defects in the tunica albuginea. These have been reported to lead to herniation of the adjacent cavernosum, causing venous leakage (Mondaini et al. 2002, 971). Penile fibrosis may be encountered in association with Peyronie's disease, but also following trauma, prolonged priapism and after penile prosthesis surgery. On ultrasound, it is manifest as focal, often linear, hyper-reflective areas within the corpora cavernosa (figure: 11). Mondor's disease (figure: 12) refers to thrombophlebitis of the superficial dorsal vein of the penis. The vein is felt as a painful cord and the thrombosed lumen will be clearly seen on ultrasound. It is self-limiting and not a cause of ED, but as the pain is more notable during erection, the patient may present for PDS (Kirkham et al. 2008, 837–53).

53

Figure (11): Longitudinal ultrasound image displaying hyperechogenic fibrotic thickening (arrow) at base of un-stimulated penis in-patient with erectile dysfunction and history of previous penile trauma Adopted from (Patel et al. 2012, 69-78)

 Angiography/Cavernosography In our practice, formal catheter angiography (figures: 13 and 14) is reserved for those patients with a suspected stenotic or occlusive lesion causing arterial insufficiency. It is considered a second-line technique utilized as an adjunct to ultrasound. Catheterization of the internal pudendal artery allows formal documentation of arterial supply to the penis, and will demonstrate the extent and location of any arterial lesion as preparation for bypass surgery/revascularization (Patel et al. 2012, 69-78).

54

Figure (12): Mondor’s disease affecting distal dorsal superficial penile vein. (a) Longitudinal ultrasound image displaying focal area of thrombosis (arrow) in distal dorsal superficial penile vein. The cavernosa are normal bilaterally. (b) Longitudinal color Doppler ultrasound image showing lack of flow within thrombosed segment of vein (arrow). Adopted from (Patel et al. 2012, 69-78)

55

Cavernosography is a technique utilizing injection of contrast medium into the cavernosa as a means of primarily detecting defects in the veno-occlusive mechanism that are causing leaks. It can be combined with manifests as a hypo-intense structure surrounding the corpora, and in some cases the suspensory ligament can also be identified. Some authors advocate the use of MRI in combination with pharmaco-stimulant injection to demonstrate tunical dehiscence and cavernosal fibrosis (figure: 15). In addition, Peyronie's disease plaques and hematoma resulting from penile trauma/fracture can also be well visualized. MRI, in our ED practice, is utilized almost exclusively as a second-line ''problem-solving'' modality in those cases where structural abnormality has been demonstrated but requires further characterization (Uder et al. 2002, 113–20).

 MRI MRI readily demonstrates penile anatomy with both the cavernosa and spongiosum displaying intermediate to high signal on T1weighted sequences and high signal on T2 weighted sequences. The tunica albuginea manifests as a hypo-intense structure surrounding the corpora, and in some cases the suspensory ligament can also be identified. Some authors advocate the use of MRI in combination with pharmaco-stimulant injection to demonstrate tunical dehiscence and cavernosal fibrosis (figure: 15). In addition, Peyronie‟s disease plaques and hematoma resulting from penile trauma/fracture can also be well visualized. MRI, in our ED practice, is utilized almost exclusively as a second-line „„problem solving‟‟ modality in those cases where structural abnormality has been demonstrated but requires further characterization (Patel et al. 2012, 69-78). 56

Figure (13): Right internal iliac digital subtraction angiogram showing normal penile arterial anatomy (black arrow, internal pudendal artery; short white arrow, cavernosal artery; long white arrow, dorsal penile artery) Adopted from (Patel et al. 2012, 69-78)

57

Figure (14): Left internal iliac digital subtraction angiogram in patient with erectile dysfunction. Study confirms the prior ultrasound findings of lack of flow within left cavernosal and dorsal penile arteries Adopted from (Patel et al. 2012, 69-78)

58

Figure (15): T2 weighted MRI images displaying extensive low signal fibrosis (arrows) within both corpora of penile crura in patient with erectile dysfunction and history of previous penile trauma (same patient as in figure: 11). (a) Axial small-field-of view MR image. (b) Sagittal MR image Adopted from (Patel et al. 2012, 69-78) 59

Treatment Introduction Overall, oral PDE5-Is, are the mainstay of treatment of erectile dysfunction. Other treatment modalities include lifestyle modification, injection therapies, testosterone therapy, penile devices, and psychotherapy (Hatzichristou et al. 2010, 337–48).

Psychosexual, couple, and partner therapy Psychosexual therapy is indicated particularly where significant psychological problems are recognized. It is best used in men with predominantly psychogenic erectile dysfunction. Techniques of psychosexual therapy include sensate focus, sex education, and interpersonal therapy. Data regarding the efficacy of such techniques are largely inconclusive (Eardley et al. 2010, 524-40).

Lifestyle modification Findings from recent basic and clinical studies have shown that targeting several life style factors commonly associated with erectile dysfunction, such as smoking, alcohol consumption, obesity, and limited physical activity, can have significant effects on improvement of erectile function. Mannino and colleagues88 reported that men who quit smoking had a lower erectile dysfunction rate compared with present smokers (2-0% vs 3- 7%) (Maio et al. 2010, 2201–08).

Guay and colleagues reported a significant and rapid improvement in erectile function upon smoking cessation in patients who had smoked over 30 pack-years (calculated by multiplying the number of cigarette packs a person smokes per day by the total number of years this person smoked; i.e., 30 pack-years means the person smoked a pack of cigarettes every day for 30 years). The present published work is not absolutely clear on whether or not alcohol consumption adversely affects erectile function (Chew et al. 2009, 1386–94). In a landmark study, 110 obese men with erectile dysfunction were randomly assigned to either an extensive weight loss programme with dietary counseling and exercise advice or to educational guidance on weight loss only. 2 years later, the former group weighed significantly less, practiced more physical activities and had a significant improvement in their erectile dysfunction scores compared with the latter group. These data were further confirmed by later studies (Esposito and Giugliano 2011, 293–301). 60

Furthermore, in 2011 Gupta and colleagues reported data on their meta-analysis of six randomized controlled trials (740 participants) assessing the effects of lifestyle modification and reduction of cardiovascular risk factors on the severity of erectile dysfunction. Their findings suggest that of lifestyle modifications and cardiovascular risk factor reduction can provide incremental benefits on erectile function regardless of PDE5-I use (Gupta et al. 2011, 1797–803). Suggested mechanisms by which weight reduction and increased physical exercise can improve erectile function include interference with endothelial dysfunction, insulin resistance, and the low-grade inflammatory state already associated with diabetes mellitus and metabolic disease, which are all well-known risk factors for erectile dysfunction (Gupta et al. 2011, 1797–803). Even though the present evidence suggests that modifying certain lifestyle factors can lead to significant improvements in men with erectile dysfunction, solid conclusions cannot be reached without several properly designed, prospective, and large-scale controlled studies. In addition, present research suggests that lifestyle modification can positively affect erectile function but after at least 2 years, a considerably long time. Conversely, a combined approach of oral PDE5-Is and lifestyle modification can improve the results after 3 months. Finally, successful available treatments for erectile dysfunction should not be suspended awaiting lifestyle modification (Maio et al. 2010, 2201–08).

Oral PDE5-Is Oral PDE5-Is are now regarded as the first-line treatment for erectile dysfunction. These drugs facilitate erection by inhibiting the PDE5 enzyme, which is specifically responsible for the degradation of cyclic guanosine monophosphate (cGMP) in the cavernous smooth muscles. This inhibition results in the prolonged activity of cGMP, which further decreases intracellular calcium concentrations, maintains smooth muscle relaxation and, hence, results in rigid penile erections (Konstantinos and Petros 2009, 3540–51). There are now five commercially available oral PDE5-Is, which are sildenafil (Viagra; Pfizer, New York, NY, USA), (Cialis; Lilly, Indianapolis, IN, USA), (Levitra, Staxyn; Bayer, West Haven, CT, USA), udenafil (Zydena; Dong-A PharmTech, South Korea), and (Mvix; SK Chemical, South Korea). The first three drugs are available worldwide. Other PDE5-Is under investigation for the treatment of erectile dysfunction include avanafil, , and SLx-2101 (Andersson 2011, 811–59). 61

All five commercially available PDE5-Is have an appropriate onset of action and duration and a success rate of at least 65% (table: 3). Physicians should consider trying all available PDE5-Is until it is known which one has the best effects on the patient's erections with the least overall side effects. These drugs should be tried at least four times before deeming them successful or not (Carson 2007, 507–15). Findings from several studies have shown that chronic or daily use of PDE5-Is in erectile dysfunction can significantly improve endothelial dysfunction with the potential for a cure. Tadalafil 5 mg is the only PDE5-I clinically approved for daily use in the treatment of erectile dysfunction. Potential benefits of daily use of PDE5-Is include salvage of on-demand PDE5-I non-responders, apparent disease modification, and development of a more natural sexual function. Disadvantages are limited to the high cost compared with on-demand use, absence of long-term safety profile data, and incomplete understanding of the mechanisms of action (Wrishko et al. 2009, 2039–48).

62

Table (3): Characteristics of commercially available phosphodiesterase type 5 inhibitors Sildenafil Vardenafil Tadalafil Udenafil Mirodenafil Dosage 25, 50, and 100 mg. 2.5, 5, 10, and 20 mg. 2.5, 5, 10, and 20 mg. 100 mg. 50 or 100 mg. Usually start with 50 Usually start with 10 Usually start with 10 mg. mg. mg. Maximum dose 100 Maximum dose 20 Maximum dose 20 Maximum dose 200 Maximum dose 100 mg daily mg daily mg daily mg daily mg daily Onset 30–60 min 30 min 45 min 30–60 min 30–60 min Duration 4–8 h 4–8 h Up to 36 h 12 h 6–12 h Efficacy > 65% > 65% > 65% > 65% > 65% Side-effects Headache, flushing, As for sildenafil Flushing, back pain, flushing, nasal Facial flushing, and dyspepsia and general congestion, ocular headache, nausea, and hyperemia, and eye redness headache Contraindications Nitrate-containing As for sildenafil, but As for sildenafil As for sildenafil As for sildenafil compounds, recent also class 1 or 3 anti- serious cardiovascular arrhythmic drugs and events, non-arteritic congenital prolonged ischemic optic QT syndrome neuropathy, and α blockers Food and alcohol Interacts with food, Interacts with food, No food or alcohol No food or alcohol Food interaction: no interaction administer while administer while interaction interaction available data fasting. fasting. No alcohol interaction No alcohol interaction No alcohol interaction

Adopted from (Brant et al. 2007, 465–79; Andersson 2011, 811–59; Setter et al. 2005, 1286–95; Carson 2007, 507–15) 63

The main advantage of PDE5-Is lies in improvement of sexual performance and not libido. In young and potent men, PDE5-Is can lead to shortening of the refractory period (a temporary period of physiological erectile flaccidity immediately after ejaculation during which a man cannot be sexually aroused) and better ejaculatory control. Concomitant PDE5-I use is contraindicated in nitrate users because it increases the risk of severe hypotension (Gruenwald et al. 2009, 969–76). There was no increase in the rates of myocardial infarction or death, nor did PDE5-I use worsen ischemia or cardiac upon exercise testing in patients with CAD or heart failure. However, PDE5-Is should be used with caution in patients with serious CVDs, such as uncontrolled hypertension and unstable angina, and in patients taking a blockers for blood pressure control. The concurrent use of other antihypertensive drugs, such as calcium- channel blockers, is well tolerated by men taking any of the available PDE5-Is. Vardenafil is not recommended in patients who take class-lA (e.g., quinidine or procainamide) or class-3 (e.g., sotalol or amiodarone) anti-arrhythmics or in patients who have congenital prolonged QT syndrome (Morganroth et al. 2004, 1378–83). Side effects related to PDE5-Is are generally mild and well tolerated. The most common is headache, followed by flushing. Tadalafil can cause myalgia and pain at different body sites (table: 3). PDE5-I-related priapism has been reported in a few case reports (King et al. 2005, 432). A direct link between PDE5-Is and non-arteritic ischemic optic neuropathy could not be established. Patients using PDE5-Is should be also warned about a possible link between PDE5-I use, especially sildenafil, and occurrence of hearing impairment (McGwin 2010, 488–92).

Although PDE5-Is, are a good first-line treatment, up to 35% of patients with erectile dysfunction may fail to respond to this treatment. Common causes of this response failure are diabetes mellitus and severe neurological or vascular diseases. Although there is no consensus on how to define the failure of PDE5-Is, the inability to attain or maintain adequate penile erection during sexual intercourse on at least four consecutive occasions, in spite of optimum drug dosing, is an acceptable definition.103 Management of PDE5-I failure is mostly dependent on the cause and can include proper patient counselling, switching to another PDE5-I, intra-cavernosal injection, intraurethral drug administration (MUSE [Vivus, CA, USA]), combination therapy, and referral to a specialist for further assessment. Patients

64 not responding to any of the medical treatment options for erectile dysfunction might be candidates for penile implant surgery (Shamloul and Ghanem 2013, 153-65).

Testosterone Although testosterone has important actions in maintaining adequate erectile function, its role in the treatment of erectile dysfunction is limited. Testosterone-replacement therapy is recommended in men with erectile dysfunction who have confirmed low concentrations of bioavailable testosterone. In a meta-analysis of 16 studies, improvement in erectile dysfunction was significantly more common in men with hypogonadism who were treated with testosterone than in those who received placebo (57-0% vs 16-7%). Testosterone has also been used as part of a successful combination therapy with PDE5-Is in elderly men (age > 65 years) with low testosterone concentrations who were initially unresponsive to PDE5-Is (Shabsigh et al. 2008, S97–102).

Intra-cavernosal injection and transurethral therapy Regarded as a second-line treatment for erectile dysfunction, the main advantage of this type of treatment is that the erection achieved is predictable and occurs rapidly. Men or their partners, or both, learn to inject the penis, after adequate training, with small 28-30- gauge needles. Erection usually occurs in less than 10 min, independent of sexual desire. Intra-cavernosal injection is usually prescribed to men who disliked or failed oral treatment and those with spinal cord injuries or post-radical prostatectomy. Commonly used drugs include alprostadil (prostaglandin E1), papaverine, phentolamine, and vasoactive intestinal polypeptide. Intra-cavernosal mixture treatment with two or more vasoactive drugs can also be used. Although alprostadil has a high efficacy rate, reaching up to 70%, the trimix solution has a 90% success rate. Side-effects associated with intra-cavernosal injections are priapism and penile fibrosis, but these can be avoided with proper patient education and monitoring. Penile pain is commonly associated with alprostadil injection. High rates (>50%) of injection dropouts occur primarily because of inconvenience. Alprostadil is also available as an intraurethral pellet (MUSE). Success rates are between 43% and 69%. Side effects include penile pain, urethral pain or burning, hypotension, syncope, and priapism (Perimenis et al. 2006, 21924). Vacuum constrictive devices

65

Vacuum constrictive devices operate by applying continuous negative pressure to the shaft of the penis, which helps to draw blood inside the corpora cavernosa, which is further retained by an elastic band at the base of the penis. These devices are inexpensive and have very limited drawbacks. However, the erections created using this method are unnatural, being mechanical with a cold penis sensation, and nearly half of patients are not satisfied with this method. Vacuum constrictive devices are usually reserved for patients with stable relationships, who failed oral PDE5-Is, and who have refused other more invasive options such as intra-cavernosal injection or penile prosthesis implantation. Side effects include petechiae, penile numbness, and (Wessels 2006, 323–29).

Penile prostheses The third-line treatment for erectile dysfunction is one of the few successful surgical treatments for erectile dysfunction. Implantation of a penile prosthesis is usually the last resort for treatment of erectile dysfunction, when other modalities have failed or are not preferred by the patient. Once the penile prosthesis surgery is done, the corporal tissue is irreversibly changed and no further smooth muscle relaxation is possible. There are two main types of penile prostheses. The semi-rigid prosthesis is usually easy to implant and lasts longer than the inflatable one. However, a semi-rigid prosthesis cannot produce a fully erect penis, and the device is difficult to conceal. Inflatable prostheses are usually made of two or three parts, including two penile cylinders with a scrotal pump for inflation. The scrotal pump is used to transfer fluid from a retro-pubic reservoir into the cylinders, thus creating a rigid erection. The device can be deflated by bending the penis mid-shaft (Shamloul and Ghanem 2013, 153-65). The hydraulic three-piece implant is the most popular penile prosthesis in the USA. Satisfaction rates of patients with penile implants and their partners are high, reaching up to 70% and 90%, respectively. The most common complication of penile prostheses is infection, which occurs in 2-4% of cases. Other surgical treatments for erectile dysfunction include arterial bypass procedures, which are specifically indicated for traumatic injuries of penile arteries (and can potentially lead to cure of the erectile dysfunction), and venous ligation surgery for young men with congenital abnormal venous leakage; however, vascular surgery is rarely done nowadays (Selph and Carson 2011, 227–35).

Future perspectives

66

Although PDE5-Is, are undoubtedly a huge step forward in the management of erectile dysfunction, they are far from flawless. Well-known shortcomings of PDE5-Is, are their non-universal success rate, absence of spontaneity, and life-long drug commitment. At present, specific treatments that target more than just the inhibition of the PDE5 enzyme is being developed. For example, several guanylate cyclase activators have already undergone preclinical trials and promising results have been reported. Other potential drugs undergoing experimental research include potassium channel inhibitors, Rho kinase inhibitors, and melanocortin system activators (Martin et al. 2002, 71–79). The invention of the coronary artery stent has revolutionized the treatment of men with ischemic heart disease. In the Pelvic Angiography in Non-responders to Phosphodiesterase-5 Inhibitors (PANPI) pilot study, the stenosis in the coronary arteries typically mirrored that of the pudendal arteries, which ranged from a mean of 52% in the right internal pudendal artery to 60% in the left internal pudendal artery. The zotarolimus- eluting peripheral stent system for the treatment of erectile dysfunction in males with suboptimal response to PDE5 inhibitors (ZEN) trial, which was initiated in 2009, is the first feasibility safety trial in human beings. A concurrent study, the Incidence of Male Pudendal Artery Stenosis in Suboptimal Erections Study (IMPASSE; NCT01341483), was designed to assess the angiographic patterns of atherosclerosis in erectile-related arteries in men with suspected or known CAD or peripheral artery disease undergoing diagnostic angiography. In a preliminary study, percutaneous treatment of pudendal artery stenosis with endovascular stents provided significant benefit to three patients with erectile dysfunction and peripheral arterial disease (Babaev and Jhaveri 2012, 236–40). Several issues with patient selection, long-term efficacy and safety, and potential complications in this study should be addressed before peripheral vascular stents are recognized as a valid treatment option for erectile dysfunction. In addition, low intensity extracorporeal shockwave therapy has been used successfully to treat vasculogenic erectile dysfunction in a highly selected group of patients (Vardi et al. 2012, 1769–75). However, although this technology is available for clinical use (e.g., in Israel and Canada), confirmatory data from well-designed, double blind, and multi-center, long-term comparative studies are essential before it can be incorporated as a standard therapeutic option for erectile dysfunction. An interesting new method for the treatment of erectile dysfunction is the application of gene therapy principles. The penis is one of the few organs that provide an ideal location for gene therapy because of its ease of access and homogeneous parenchymatous content,

67 which enable the convenient delivery and spread of transfected genetic material. After many studies successfully used preclinical genetic approaches-with molecules such as vasoactive intestinal peptide, brain-derived neurotrophic factor, and the maxi-K (calcium-sensitive potassium) channel-a breakthrough clinical study using the latter molecule was published in 2006 (Melman et al. 2006, 1165–76). Unfortunately, the small number of patients involved in this study (n=14), the absence of a control arm, and the low statistical power prevent a definitive conclusion on the efficacy of gene therapy for erectile dysfunction treatment from being reached. However, this landmark study does open new horizons in the specialty, giving researchers new hope for a potentially successful long-term treatment plan or cure for erectile dysfunction. Other hot areas of research include application of specific factors to stimulate endogenous neuropathic factors and cell-based therapy (Xie et al. 2008, 23–27).

68

Chapter 3

METHODOLOGY Study design Clinic-based, descriptive, cross-sectional study.

Study area The study was conducted at our Andrology clinics, located in three different areas, covering almost all of Egypt as follows; Clinic location Areas covered Cairo Cairo, Giza Desouk City Delta governorates Damanhour City Delta governorates, Alexandria, North Coast

The clinics provide broad services including assessment of patients for anthropometric measurements, other relevant quick assessment depending on patient presentation. Each clinic has adequate space to carry out its services; there are more than three separate rooms, which are sufficient for providing privacy between patients and the doctor. About four doctors and three nurses are present at each of clinics. There are four days of each clinic per week, for randomization purposes, this study included only patients attending two days of each clinic working days.

1. Study population and participants The study population was men attending our Andrology clinics, at different locations as previously mentioned. All booked and newly registered patients attending the clinics who satisfied inclusion criteria were eligible for the study. 2. Inclusion criteria The study participants included male patients attending our Andrology clinics, with the following criteria  Age ≥ 16 years  Duration of erectile dysfunction ≥ 6 months  Both type 1 and 2 diabetic mellitus, hypertensive and cardiovascular patients were included  Consenting to participate in the study

69

3. Exclusion criteria  The very sick patients for purpose of this study were defined as Patients with unstable vital signs/mental status e.g. in diabetic ketoacidosis or hyperosmolar hyperglycemic state, confused, or in septicemia as in infected diabetic foot. 4. Grouping Subjects were grouped into 2 groups according to presence or absence of erectile dysfunction, as follows:  Group 1: with erectile dysfunction.  Group 2: without erectile dysfunction. 5. Sample size 4014 subjects of different age groups were recruited and included in the study from the three different locations previously described, 2810 subjects were recruited from Cairo clinic, 803 subjects were recruited from Desouk clinic and 401 were recruited from Damanhour clinic. 6. Study period The study was carried out from February, 2009 to February, 2014. 7. Data Collection Technique (Procedures) 7.1. Socio-demographic sheet and the IIEF-5 questionnaire The participants were interviewed using a standard structured questionnaire, which included socio-demographic data, to assess the different sexual domains; the abridged version of the International Index of Erectile Function (IIEF-5) Questionnaire was used. The IIEF-5 was translated into Arabic language. The IIEF-5 is a brief, reliable and valid self-administered questionnaire containing five domains. It has been used widely in many countries to detect the presence and severity of ED. The erectile function was classified based on the scores on IIEF into severe 0-7; moderate 8-11; mild to moderate 12-16; 17-21, mild (17-31) ED and 22-25, no dysfunction. 7.2. Anthropometric measurements Weight: The individual„s body weight was measured by standardized (AXIOM, AX – 120) scales without heavy clothing and shoes, and recorded to the nearest 0.5kg Height: The study participant„s height was measured with a firm measure against a vertical wall, and the height was measured to the nearest 0.5cm The body mass index (BMI) was calculated using the formula Kg/m2; where Kg is body weight in kilograms and m is squared height in meters.

70

The BMI will be classified according to World Health Organization into underweight: BMI< 18.5; Normal weight: BMI 18.5-24.9; overweight: BMI 25.0-29.9; obesity: BMI>30 (WHO 1995, 854). The research assistants were trained on how to take the anthropometric measurements prior to the commencement of data collection. 7.3. Blood pressure (BP) measurements The patients‟ blood pressure was measured by trained research assistants. After a 10- minutes rest, the patients BP was measured with a standard manual mercury sphygmomanometer while in the sitting position. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements was determined by the 1st and 5th Korotokoffs sounds respectively. The BP was measured twice, with interval of 5 minutes; the average of the two BP measurements was considered as the patient‟s BP. Hypertension was defined as SBP ≥140mmHg and/or DBP≥90mmHg or known hypertensive on treatment (WHO 1999, 151-83). 8. Data processing and analysis The results of the study were analyzed using the Statistical Package for Social Sciences (SPSS 17.0). Comparisons of categorical data were done using the chi-square test. The p-value of equal to or less than 0.05 was used to determine the level of statistical significance.

71

Chapter 4

RESULTS

Of the 4014 participants recruited into the study, 520 (13 %) were aged 16 – 25 years; 1375 (34.3 %) between 26 and 35 years; 841 (21 %) between 36 and 45 years; 691 (17.2 %) were aged 46 – 55 years; 480 (12 %) were between 56 and 65 years; 95 (2.4 %) were aged 66 – 75 years; while 12 (0.3 %) were aged between 76 and 82 years. Table (1) shows the comparison between the studied groups according to the age distribution. None of the studied subjects was classified as underweight (< 18.5 Kg/M2) in both groups, normal weight accounted for 1152 (28.7 %) of group 1 subjects and 727 (18.1 %) of group 2 subjects, overweight accounted for 876 (21.8 %) of group 1 subjects and 523 (13 %) of group 2 subjects; while obesity accounted for 456 (11.4 %) group 1 subjects and 280 (7 %) of group 2 subjects (Table: 2). 1693 (42.2 %) respondents were married; 1160 (28.9 %) were single; while 1161 (28.9 %) were separated, divorced or widowed (Table: 3).A total of 969 (24.1 %) were illiterates; while 946 (23.6 %) were able to read and write and 1062 (26.5 %) had pre- university education; while 1037 (25.8 %) had university education (Table: 4). 2008 (50 %) subjects were employed and 2006 (50 %) were unemployed (Either self-employed, a peasant or totally unemployed) (Table: 5). A total of 2016 (50.2 %) participants resided in rural areas; while 1998 (49.8 %) lived in the rural areas(Table: 6).

Table (7) shows the smoking status of the participants, 2034 (50.7 %) of the subjects were smokers and 1980 (49.3 %) were non-smokers.

Table (8) shows the distribution of various health conditions associated with ED among the respondents. Of the 4014 patients seen in the clinics during the period, 2484 (61.8 %) had ED, and 1530 (38.2 %) had no dysfunction. 297 (34.9 %) of the 2484 respondents with ED suffered from hypertension and were on medications; 892 (35.9 %)suffered from diabetes and were on medications; 250 (10.1 %) from cardiovascular disease and were on a combination of medications; 116 (4.7 %) were previously operated upon; while 61 (2.5 %) suffered from undiagnosed medical conditions and were reportedly on complimentary/alternative medications.

72

Table (9) shows the distribution of erectile dysfunction among different age groups in group 1 (With erectile dysfunction) respondents, 158 (6.4 %) of the 2484 subjects were between 16 – 25 years, 722 (29.1 %) were 26 – 35 years, 546 (22 %) were 36 – 45 years, 555 (22.3 %) were 46 – 55 years, 404 (16.3 %) were 56 – 65 years, 91 (3.7 %) were 66 – 75 years and 8 (0.3 %) were 76 – 82 years.

Table (10) shows the distribution of other correlates in relation to the age of erectile dysfunction group, a total of 1314 (52.9 %) had premature ejaculation, 488 (19.6 %) had small-sized penis, 40 (1.6 %) had an-ejaculation and 330 (13.3 %) had impotence.

Table (11) shows the degree of ED among the respondents with relation to the health conditions. A total of 119 (4.8 %) of ED resulting from hypertension and its medications were mild; 60 (2.4 %) mild-moderate; 39 (1.6 %) and 79 (3.2 %) were moderate and severe respectively. Similarly, 351 (14.1 %) of ED resulting from diabetes and its medications were mild; 177 (7.1 %) mild-moderate; 118 (4.8 %) moderate; while 246 (9.9 %) were severe. 250 (10 %) of ED resulted from cardiovascular diseases and their medications, 89 (3.6 %) were mild; 52 (2.1 %) mild-moderate; 44 (1.8 %) moderate; while 65 (2.6 %) were severe. Previous surgeries contributed to 116 (4.6 %) of ED, of which 50 (2%) were mild; 22 (0.9 %) mild-moderate; while 13 (0.5%) were severe.

73

Table (4): Comparison between the studied groups as regards the age (Years) Group 2 (Without ED; n= Age Group 1 (With ED; n= 2484) 1530) P (Years) No. % Mean ± SD No. % Mean ± SD 16 - 25 158 3.9 362 9.0 26 - 35 722 18.0 653 16.3 36 - 45 546 13.6 295 7.3 46 - 55 555 13.8 42.9 ± 13.4 136 3.4 33.6 ± 11.5 0.001* 56 - 65 404 10.1 76 1.9 66 - 75 91 2.3 4 0.1 76 - 82 8 0.2 4 0.1

Table (5): Comparison between the studied groups as regards the BMI (Kg/M2) Group 2 (Without ED; n= BMI Group 1 (With ED; n= 2484) 1530) P (Kg/M2) No. % Mean ± SD No. % Mean ± SD < 18.5 0 0.0 0 0.0 18.6 - 25 1152 28.7 727 18.1 25.6 ± 4.1 25.5 ± 4.1 0.4 25.1 - 30 876 21.8 523 13.0 > 30 456 11.4 280 7.0 < 18.5; Underweight. 18.6 – 25; Normal weight. 25.1 – 30; overweight. > 30; Obese

Table (6): Comparison between the studied groups as regards the marital status Group 1 (With ED; Group 2 (Without ED; Marital status n= 2484) n= 1530) X2 P No. % No. % Single 660 16.4 500 12.5 Married 1199 29.9 494 12.3 372.37 0.001* Divorced, separated, 625 15.6 536 13.4 widowed

74

75

76

77

Table (7): Comparison between the studied groups as regards the educational level Group 1 (With ED; n= Group 2 (Without ED; n= Educational 2484) 1530) X2 P level No. % No. % Illiterate 598 14.9 371 9.2 Read and write 613 15.3 333 8.3 60.99 0.001* Pre-university 650 16.2 412 10.3 University 623 15.5 414 10.3

Table (8): Comparison between the studied groups as regards the occupation Group 1 (With ED; n= Group 2 (Without ED; n= Occupation 2484) 1530) X2 P No. % No. % Employed 1250 31.1 758 18.9 Un- 158.66 0.001* 1234 30.7 772 19.2 employed

Table (9): Comparison between the studied groups as regards the residence Group 1 (With ED; n= Group 2 (Without ED; n= Residence 2484) 1530) X2 P No. % No. % Rural 1276 31.8 740 18.4 190.97 0.001* Urban 1208 30.1 790 19.7

Table (10): Comparison between the studied groups as regards the smoking Group 1 (With ED; Group 2 (Without ED; n= Smoking n= 2484) 1530) X2 P No. % No. % Smoker 1282 31.9 752 18.7 118.56 0.001* Non-smoker 1202 29.9 778 19.4

78

79

80

81

82

Table (11): Comparison between the studied groups as regards the medical co- morbidities Group 1 (With ED; Group 2 (Without Co-morbidities n= 2484) ED; n= 1530) X2 P No. % No. % Healthy 868 34.9 1044 68.2 256 0.9 Hypertension & 297 12.0 140 9.2 7.33 0.006 antihypertensives Diabetes & anti-diabetics 892 35.9 230 15.0 204.4 0.001* Cardiovascular disease 250 10.1 86 5.6 24.37 0.001* Previous surgery 116 4.7 30 2.0 1.31 0.1 Undiagnosed medical 61 2.5 0 0.0 0 0 condition

Table (12): Relation of erectile dysfunction to the age of erectile dysfunction group (n= 2484) Age (Years) No. % 16 - 25 158 6.4 26 - 35 722 29.1 36 - 45 546 22.0 46 - 55 555 22.3 56 - 65 404 16.3 66 - 75 91 3.7 76 - 82 8 0.3

Table (13): Distribution of other correlates in relation to age of erectile dysfunction group (n= 2484) PE SSP An-ejaculation Impotence Age (Years) No. % No. % No. % No. % 16 - 25 136 5.5 229 9.2 4 0.2 0 0 26 - 35 541 21.8 187 7.5 16 0.6 12 0.5 36 - 45 319 12.8 40 1.6 8 0.3 47 1.9 46 - 55 188 7.6 24 1.0 4 0.2 120 4.8 56 - 65 114 4.6 4 0.2 8 0.3 107 4.3 66 - 75 16 0.6 0 0.0 0 0.0 36 1.4 76 - 82 0 0.0 4 0.2 0 0.0 8 0.3 PE: Premature ejaculation; SSP: Small-sized penis

83

84

85

86

87

Table (14): Distribution of co-morbidities and degree of erectile dysfunction (n= 2484) Mild Mild-Moderate Moderate Severe Co-morbidities No. % No. % No. % No. % Hypertension & 119 4.8 60 2.4 39 1.6 79 3.2 antihypertensives Diabetes & antidiabetics 351 14.1 177 7.1 118 4.8 246 9.9 Cardiovascular disease 89 3.6 52 2.1 44 1.8 65 2.6 Previous surgery 50 2.0 22 0.9 13 0.5 31 1.2 Undiagnosed medical condition 20 0.8 10 0.4 14 0.6 17 0.7

88

89

Chapter 5

DISCUSSION

Erectile dysfunction (ED) is currently one of the most common sexual dysfunctions in men worldwide. This serious health problem has been the focus of public attention in recent times. It ranges from partial decrease in penile rigidity to a complete erectile failure. The National Institutes of Health (NIH) defines it as the consistent inability to maintain a penile erection, sufficiently for satisfactory sexual intercourse (Ariba et al. 2007, 9).

The estimated global prevalence has been on the increase. It is projected that the number of men with this condition will rise to 322 million by the year 2025. Erectile dysfunction is usually underestimated in many developing countries including Egypt. This is because it is not a life threatening condition and due to associated stigma, men with the problem rarely seek help. There is also the problem of early detection and management of factors responsible for the development of erectile dysfunction. The impact of ED could be devastating because evidence has shown that sexual function is one of the important indices of quality of life (Quek et al. 2008, 70-76).

The dysfunction could affect all levels of intimacy, like emotional, social, sexual, recreational and intellectual intimacy. Previous studies have reported significant poor health-related quality of life (HRQOL) in men with ED. This has been found to affect both general and disease-specific health-related quality of life (HRQOL). Therefore, there is need to address this social health problem (Olarinoye et al. 2006, 291-6).

The causes of ED until recently, were mainly thought to be due to psychogenic factors. However, various studies have shown that the causes of ED may be multifactorial. Organic factors such as chronic medical conditions including hypertension, diabetes mellitus, as well as adverse effects of therapies used for these conditions are known to constitute major causes of ED (Garko et al. 2005, 46-51).

90

Evidence suggests that there is a strong association between age and ED. This is because cardiovascular risk factors are associated with increasing age, and since penile erection is primarily a vascular event, it may be impaired in conditions in which degenerative changes result in endothelial dysfunction. Furthermore, the physiological alterations related to hormonal changes and sedentary lifestyle have been implicated in the causes of ED. It is also reported that psychological problems such as depression, performance anxiety, and relationship problems could be both complications and risk factors of ED (Billups et al. 2008, 236-242).

It is important to take cognizance of the various adverse health conditions that probably contribute to its development. This study attempts to add to the pool of information currently available from the developing world on the prevalence and risk factors of ED. It is hoped that the findings would increase awareness amongst men with ED and enhance positive attitude to care (Idung et al. 2012, 237-245).

The findings of this study show that ED is common in our environment. The findings are similar and in agreement to the reports in previous studies (Berrada et al. 2003, S3-7; Shaeer et al. 2003, S8-S14; Billups et al. 2008, 236-242; Moreira et al. 2002, 49-54; Seyam et al. 2003, 237-45). Although, the rate of 61.8 % found in this study is lower compared to the findings in previous studies, this is significant in view of the fact that men with ED do not always confide in other people or readily seek medical attention. Considering the limited healthcare facilities and poor services in some areas, the present rate seems to suggest that there is a problem. Therefore, efforts must be made to improve our healthcare services, to be able to detect and intervene early in some of the treatable medical conditions responsible for ED.

In line with the reports in previous studies, our findings have shown that erectile dysfunction was more in men who were older (Piores et al. 2007, 16-29; Berrada et al. 2003, S3-7; Moreira et al. 2002, 49-54; Seyam et al. 2003, 237-45). Several reasons including changes in the and age-related decline in male sex hormones have been adduced for the increasing incidence of ED in older men. The degenerative and the fact that older men are known to be more worried about sexual performance are some of the other factors commonly associated with ED (Shabsigh and Anastaiadis 2003, 153-68; Garko et al. 2005, 46-51).

91

In our study, erectile dysfunction was also found in 29.9 % of married and 31.7 % of educated men. The high incidence in married men may be attributable to the frequency of sexual activity. This in turn may be due to the cultural expectation on procreation in marriage.

These findings may seem to suggest that married men are more sexually active and more prone to ED than the unmarried ones. However, the fact that there is also a significant proportion of ED among men who are not married in this study shows that the problem is multifactorial in nature.

There is no proof to demonstrate that married men indulge in more sexual activities than the unmarried ones. On the other hand, education is a major determinant of social class, and could influence the lifestyle of individuals. Although there have been divergent opinions on the impact of socioeconomic factors on sexual functions, individuals in a higher socio-economic class are more prone to stress. This is because of their status and lifestyles, which have the tendency to predispose them to cardiovascular risk factors (Billups et al. 2008, 236-242; Pinnock et al. 1999, 353- 357).

Significantly, our study also shows a high frequency of erectile dysfunction among respondents who were either separated or divorced. This is not surprising and life events could be a possibility. The loss of self-esteem, decreased libido and erectile dysfunction could be due to pressure and frustration in relationships. In addition to adverse lifestyle, this could predispose respondents to major psychological distress including depression (Okulate et al. 2003, 209-213; Fatusi et al. 2003, 79-85). There is increasing evidence that emotional and relationship problems could be both the complications and risk factors of ED (Seidman et al. 2001, 1623-30).

Although the present study did not focus specifically on alcohol abuse/dependence, it is a well-known fact that alcohol and other substance use including smoking are the major risk factors of ED. It may be interesting to note that in Niger Delta region, alcohol in the form of palmwine, local gin and liquor is a locally produced substance with long historical and traditional importance (Omigbodun and Babalola 2004, 111-115).

92

Therefore, its use in various ceremonies/celebrations such as traditional , and naming ceremonies is not restricted. This is common among both low and higher socio-economic classes, and could account for the high incidence of ED in educated and unemployed men.

The findings of this study also highlight the risk factors for ED in our environment. In line with previous studies, our study shows that hypertension and diabetes with their medications are still the major risk factors of ED. This strongly corroborates the findings in earlier studies (Shaeer et al. 2003, S8-S14; Moreira et al. 2002, 49-54; Seyam et al. 2003, 237-45; Safarine Jad 2003, 246-52).

Although it is reported that sexual dysfunction in males with hypertension presents in a variety of ways, it has been found that the problem tends to occur more frequently in patients receiving antihypertensive medications (Garko et al. 2005, 46- 51; Mikhailidis et al. 2000, 31-36).There is also increasing evidence that ED is three times greater in patients treated for diabetes (Penson 2004, 225-230).

The association between medications and ED is confounded by the underlying medical conditions and the drug-related effect is difficult to distinguish from the effect of the diseases (Naya et al. 2003, 532-36). Therefore, it may not be unreasonable to argue that the control of these medical conditions could reduce significantly the incidence of erectile dysfunction in our environment.

We also found that 2.5 % of erectile dysfunction in this study was due to undiagnosed medical conditions and complementary and/or alternative medications. This is an indication that ED is multifactorial in nature.

Although ED is known to have a strong organic component, it has been found that erectile dysfunction could be due to psychogenic factors especially in men less than 35 years of age (Rosen 2001, 269-78). Studies have also shown that 10% of ED in men above 50 years is psychogenic in origin. It has also been reported that men with organic ED could as well develop a psychogenic component (Usta et al. 2001, 758-62).

93

The use of complementary/alternative medications to treat ED in our environment may not be unconnected with the social stigma, cultural perception on etiology and the perceived response to indigenous herbs. Our study also demonstrates that previous surgical exposures were associated with ED in men. The implication is that extreme care must be taken during surgical procedures to prevent unnecessary health hazards.

94

Glossary of Terms CVD Cardiovascular Disease CITA Chronic Inflammation of the Tunica Albuginea CAD Coronary Artery Disease cGMP Cyclic Guanosine Monophosphate DM Diabetes Mellitus ECG Electrocardiogram EDV End-Diastolic Velocity ED Erectile Dysfunction EF Erectile Function HRQL Health-Related Quality of Life HRT Hormone Replacement Therapy IHD Ischemic Heart Disease IVRT Isovolumic Relaxation Time LVDD Left Ventricular Diastolic Dysfunction LUTS Lower Urinary Tract Symptoms MRI Magnetic Resonance Imaging NO Nitric Oxide NOS NO Synthase PSV Peak Systolic Velocity PD Peyronie's Disease PDE5-Is Phosphodiesterase Type 5 Inhibitors PSSD Post-Ssri Sexual Dysfunction PTSD Post-Traumatic Stress Disorder RI Resistive Index SSRIs Selective Serotonin Reuptake Inhibitors

95

List of Tables 1 Risk stratification and treatment of men with erectile dysfunction 39 and cardiovascular disease 2 Uses and limitations of commonly used specific erectile 43 dysfunction investigations 3 Characteristics of commercially available phosphodiesterase type 5 63 inhibitors 4 Comparison between the studied groups as regards the age (Years) 75 5 Comparison between the studied groups as regards the BMI 75 (Kg/M2) 6 Comparison between the studied groups as regards the marital 75 status 7 Comparison between the studied groups as regards the educational 79 level 8 Comparison between the studied groups as regards the occupation 79 9 Comparison between the studied groups as regards the residence 79

10 Comparison between the studied groups as regards the smoking 79 11 Comparison between the studied groups as regards the medical co- 84 morbidities 12 Relation of erectile dysfunction to the age of erectile dysfunction 84 group (n= 2484) 13 Distribution of other correlates in relation to age of erectile 84 dysfunction group (n= 2484) 14 Distribution of co-morbidities and degree of erectile dysfunction 89 (n= 2484)

96

List of Graphs 1 Microscopic mechanisms underlying penile smooth muscle 31 relaxation 2 Algorithm for the diagnosis of erectile dysfunction 38 3 Algorithm for coronary risk assessment in erectile dysfunction 40 4 Longitudinal ultrasound image of left cavernosal artery (arrow) 44 within corpus cavernosum in an un-stimulated penis 5 Transverse ultrasound image of right cavernosal artery 44 6 Diagrammatic representation of multiphasic Doppler waveforms 46 encountered during normal erection in the cavernosal arteries 7 Longitudinal Doppler image showing cavernosal artery at base of penis 48 8 Arterial insufficiency 49 9 Venous leak 51 10 Longitudinal ultrasound image showing highly fibrogenic plaque in 52 Peyronie‟s disease 11 Longitudinal ultrasound image displaying hyperechogenic fibrotic 54 thickening 12 Mondor‟s disease affecting distal dorsal superficial penile vein 55 13 Right internal iliac digital subtraction angiogram 57 14 Left internal iliac digital subtraction angiogram in patient with 58 erectile dysfunction 15 T2 weighted MRI images displaying extensive low signal fibrosis 59

97

References Abbate B, Danti DA, Pancani S and Pampaloni A. 1994. "Congenital anomalies of the penis in children, a few consideration about 92 cases". Minerva Pediatr.; 46(4):139-42. Italian.

Abdulmohsen MF, Abdulrahman IS, Al-Khadra AH, Bahnassy AA, Taha SA, Kamal BA, Al-Rubaish AM and Ai-Elq AH. 2004. "Physicians' knowledge, attitude and practice towards erectile dysfunction in Saudi Arabia". East Med Health J; 10: 648-54.

Abolfotouh MA and al-Helali NS. 2001. "Effect of erectile dysfunction on quality of life". East Med Health J; 7: 510-8.

Al Helali NS, Abolfotouh MA and Ghanem HM. 2001. "Pattern of erectile dysfunction in Jeddah city". Saudi Med J; 22: 34-8.

Al-Hunayan A, Al-Mutar M, Kehinde EO, Thalib L and Al-Ghorory M. 2007. "The prevalence and predictors of erectile dysfunction in men with newly diagnosed with mellitus". BJU Int; 99: 130-4.

Ali ME, Abdel-Hafez HZ, Mahran AM, Mohamed HZ, Mohamed ER, El-Shazly AM, Gadallah AM and Abbas MA. 2005. "Erectile dysfunction in chronic renal failure patients undergoing hemodialysis in Egypt". Int J Impot Res; 17: 180- 5.

Allahdadi KJ, Tostes RC and Webb RC. 2009. "Female sexual dysfunction: therapeutic options and experimental challenges". Cardiovasc Hematol Agents Med Chem.; 7(4): 260-9.

Alter GJ. Penoscrotal Webbing. Retrieved 11-6-2014. (http://www.altermd.com/Penis%20Enhancement/penoscrotal_webbing.htm).

Amin Z, Patel U, Friedman EP, Vale JA, Kirby R and Lees WR. 1993. "Colour Doppler and duplex ultrasound assessment of Peyronie's disease in impotent men". Br J Radiol.; 66(785): 398-402.

Andersson KE. 2011. "Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction". Pharmacol Rev; 63: 811–59.

Anis TH, ElKaraksy A, Mostafa T, Gadalla A, Imam H, Hamdy L and Abu el-Alla O. 2007. "Chronic lead exposure may be associated with erectile dysfunction". J Sex Med; 4: 1428-34.

98

Ariba AJ, Oladopo OT, Iyaniwura CA and Dada OA. 2007."Management of erectile of dysfunction: Perception and practices of Nigerian Primary care clinicians". South African Family Practice, 49:9, 16-16d.

Ayta IA, McKinlay JB and Krane RJ. 1999. "The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences". BJU Int.; 84(1): 50-6.

Babaev A and Jhaveri RR. 2012. "Angiography and endovascular revascularization of pudendal artery atherosclerotic disease in patients with medically refractory erectile dysfunction". J Invasive Cardiol; 24: 236–40.

Bener A, Al-Ansari A, Al-Hamaq AO, Elbagi IE and Afifi M. 2007. "Prevalence of erectile dysfunction among hypertensive and nonhypertensive Qatari men". Medicina (Kaunas); 43: 870-8.

Bener A, Al-Hamaq AO, Kamran S and Al-Ansari A. 2008. "Prevalence of erectile dysfunction in male stroke patients, and associated co-morbidities and risk factors". Int Urol Nephrol; 40: 701-8.

Bergeson PS, Hopkin RJ, Bailey RB Jr, McGill LC and Piatt JP. 1993. "The inconspicuous penis". Pediatrics; 92(6): 794-9.

Berrada S, Kadiri N, Mechakra-Tahiri S and Nejjari C. 2003. "Prevalence of erectile dysfunction and its correlates: a population- based study in Morrocco". Int J Impot Res.; Apr; 15 Suppl 1: S3-7.

Billups KL, Bank AJ, Padma-Nathan H, Katz SD and Williams RA. 2008. "Erectile dysfunction as a harbinger for increased cardio-metabolic risk". Int. J Impot Research.; 20: 236-242.

Brant WO, Bella AJ and Lue TF. 2007. "Treatment options for erectile dysfunction". Endocrinol Metab Clin North Am; 36: 465–79.

Carrieri MP, Serraino D, Palmiotto F, Nucci G and Sasso F. 1998. "A case-control study on risk factors for Peyronie's disease". .J Clin Epidemiol.; 51(6): 511-5.

Carson C, Dean J and Wylie M. 2006. "Management of erectile dysfunction in clinical practice". New York: Springer Medical Publishing, P: 26.

Carson CC. 2007. "3rd Phosphodiesterase type 5 inhibitors: state of the therapeutic class". Urol Clin North Am; 34: 507–15.

Chew KK, Bremner A, Stuckey B, Earle C and Jamrozik K. 2009. "Alcohol consumption and male erectile dysfunction: an unfounded reputation for risk?". J Sex Med; 6: 1386–94.

99

Coretti G and Baldi I. 2007. "The Relationship Between Anxiety Disorders and Sexual Dysfunction". Psychiatric Times; 24(9): 58-59.

Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, Forti G, Mannucci E and Maggi M. 2011. "Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study". Eur J Endocrinol; 165: 687–701.

Dean RC and Lue TF. 2005. "Physiology of penile erection and pathophysiology of erectile dysfunction". Urol Clin North Am; 32: 379–95.

Diaz VA Jr and Close JD. 2010. "Male sexual dysfunction". Prim Care; 37(3): 473- 89, vii-viii.

Dong JY, Zhang YH and Qin LQ. 2011. "Erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies". J Am Coll Cardiol; 58: 1378–85.

Dougherty CM. Priapism in Emergency Medicine. eMedicine. Retrieved 11-6-2014.

Eardley I, Donatucci C, Corbin J, El-Meliegy A, Hatzimouratidis K, McVary K, Munarriz R and Lee SW. 2010. "Pharmacotherapy for erectile dysfunction". J Sex Med; 7: 524-40.

Eden KJ and Wylie KR. 2009. "Quality of sexual life and menopause". Womens Health (Lond Engl); 5(4): 385-96.

El-Bahnasawy MS, El-Assmy A, El-Sawy E, Ali-El Dein B, Shehab El-Dein AB, Refaie A and El-Hammady S. 2004. "Critical evaluation of the factors influencing erectile function after renal transplantation". Int J Impot Res; 16: 521-6.

Elbendary MA, El-Gamal OM and Salem KA. 2009. "Analysis of risk factors for organic erectile dysfunction in Egyptian patients under the age of 40 years". J Androl; 30: 520-1.

El-Rufaie OE, Bener A, Abuzeid MS and Ali TA. 1997. "Sexual dysfunction among type II diabetic men: a controlled study". J Psychosom Res; 43: 605-12.

El-Sakka AI, Morsy AM, Fagih BI and Nassar AH. 2004. "Coronary artery risk factors in patients with erectile dysfunction". J Urol; 172: 251-4.

El-Sakka AI, Morsy AM and Fagih BI. 2011. "Severity of erectile dysfunction could predict left ventricular diastolic dysfunction in patients without overt cardiac complaint". J Sex Med; 8: 2590-7.

100

El-Sakka AI and Morsy AM. 2004. "Screening for ischemic heart disease in patients with erectile dysfunction, the role of penile Doppler ultrasonography". Urology; 64: 346-50.

El-Sakka AI, Sayed HM and Tayeb KA. 2009. "Androgen pattern in patients with type 2 diabetes associated erectile dysfunction: impact of metabolic control". Urology; 74: 552-60.

El-Sakka AI, Sayed HM and Tayeb KA. 2008. "Diabetes-associated androgen alteration in patients with erectile dysfunction". Int J Androl; 31: 602-8.

El-Sakka AI and Tayeb KA. 2003. "Erectile dysfunction risk factors in non-insulin dependent diabetic Saudi patients". J Urol; 169: 1043-7.

El-Sakka AI and Tayeb KA. 2005. "Peyronie's disease in diabetic patients being screened for erectile dysfunction". J Urol; 174: 1026-30.

El-Sakka AI and Tayeb KA. 2009. "Vascular impairment of erection in patients with diabetes and Peyronie's disease: Is that accumulative?". J Sex Med; 6: 1736- 42.

El-Sakka AI. 2007. "Association of risk factors and medical comorbidities with male sexual dysfunctions". J Sex Med; 4: 1691–700.

El-Sakka AI. 2012. "Erectile dysfunction in Arab countries. Part I: Prevalence and correlates". Arab Journal of Urology; 10: 97–103.

El-Sakka AI. 2006. "Lower urinary tract symptoms in patients with erectile dysfunction: analysis of risk factors". J Sex Med; 3: 144-9.

El-Sakka AI. 2005. "Lower urinary tract symptoms in patients with erectile dysfunction: is there a vascular association?". Eur Urol; 48: 319-25.

El-Sakka AI. 2003. "Penile axial rigidity and Doppler ultrasonography parameters in patients with erectile dysfunction: association with type 2 diabetes". Urology; 62: 525-31.

El-Sakka AI. 2006. "Prevalence of Peyronie's disease among patients with erectile dysfunction". Eur Urol; 49: 564-9.

Esposito K and Giugliano D. 2011. "Lifestyle/dietary recommendations for erectile dysfunction and female sexual dysfunction". Urol Clin North Am; 38: 293– 301.

Fatusi AO, IJadunola KT, OJofeitimi EO, Adeyemi MO and Adewuyi AA. 2003. "Assessment of Andropuase Awareness and Erectile Dysfunction among married men in Ile-Ife, Nigeria". Aging Male. Jun; 6(2): 79-85.

101

Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ and Mckinlay JB. 1994. "Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study". J Urol; 151: 54–61.

Garko B, Ogunsina MO and Danbauchi SS. 2005. "Sexual dysfunction in hypertensive patients.Implications for therapy". Ann Afr med; 4: 46-51.

Ghalayini IF, Al-Ghazo MA, Al-Azab R, Bani-Hani I, Matani YS, Barham AE, Harfeil MN and Haddad Y. 2010. "Erectile dysfunction in a Mediterranean country: results of an epidemiological survey of a representative sample of men". Int J Impot Res; 22: 196-203.

Ghanem H and Shamloul R. 2008. "An evidence-based perspective to commonly performed erectile dysfunction investigations". J Sex Med; 5: 1582–89.

Golijanin D, Singer E, Davis R, Bhatt S, Seftel A and Dogra V. 2007. "Doppler evaluation of erectile dysfunction". Int J Impot Res; 19: 43–8.

Gontero P, Sriprasad S, Wilkins CJ, Donaldson N, Muir GH and Sidhu PS. 2004. "Phentolamine re-dosing during penile dynamic color Doppler ultrasound: a practical method to abolish a false diagnosis of venous leakage in patients with erectile dysfunction". Br J Radiol; 77: 922–6.

Gruenwald I, Leiba R and Vardi Y. 2009. "Effect of sildenafil on middle-aged sexually active males with no erectile complaints: a randomized placebo- controlled double-blind study". Eur Urol; 55: 969–76.

Gupta AK, Chaudhry M and Elewski B. 2003. "Tinea corporis, tinea cruris, tinea nigra, and piedr"a. Dermatol Clin.; 21(3): 395-400.

Gupta BP, Murad MH, Clifton MM, Prokop L, Nehra A and Kopecky SL. 2011. "The effect of lifestyle modification and cardiovascular risk factor reduction on erectile dysfunction: a systematic review and meta-analysis". Arch Intern Med; 171: 1797–803.

Hatzichristou D, Rosen RC, Derogatis LR, Low WY, Meuleman EJ, Sadovsky R and Symonds T. 2010. "Recommendations for the clinical evaluation of men and women with sexual dysfunction". J Sex Med; 7: 337–48.

Holden CA, McLachlan RI, Pitts M, Cumming R, Wittert G, Ehsani JP, de Kretser DM and Handelsman DJ. 2010. "Determinants of male disorders: the Men in Australia Telephone Survey (MATeS)". BMC Public Health; 10: 96.

102

Idung AU, Abasiubong F, Ukott IA, Udoh SB and Unadike BC. 2003. "Prevalence and risk factors of erectile dysfunction in Niger delta region, Nigeria". African Health Impot.Res.; 15: 237-245.

Inman BA, Sauver JL, Jacobson DJ, McGree ME, Nehra A, Lieber MM, Roger VL and Jacobsen SJ. 2009. "A population-based, longitudinal study of erectile dysfunction and future coronary artery disease". Mayo Clin Proc; 84: 108–13.

Jackson G, Montorsi P, Adams MA, Anis T, El-Sakka A, Miner M, Vlachopoulos C and Kim E. 2010a. "Cardiovascular aspects of sexual medicine". J Sex Med; 7: 1608-26.

Jackson G. 2007. "The importance of risk factor reduction in erectile dysfunction". Curr Urol Rep; 8: 463–66.

Jarow JP, Nana-Sinkam P, Sabbagh M and Eskew A. 1996. "Outcome analysis of goal directed therapy for impotence". J Urol.; 155(5): 1609-12.

Kaplan HS. 1974. "The New : Active Treatment of Sexual Dysfunctions". New York: Brunner/Mazel, Inc.: 255.

Khatib FA, Jarrah NS, Shegem NS, Bateiha AM, Abu-Ali RM and Ajlouni KM. 2006. "Sexual dysfunction among Jordanian men with diabetes". Saudi Med J; 27: 351-6.

Kim SH, Paick JS, Lee SE, Choi BI, Yeon KM and Han MC. 1994. "Doppler sonography of deep cavernosal artery of the penis: variation of peak systolic velocity according to sampling location". J Ultrasound Med; 13: 591–4.

King SH, Hallock M, Strote J and Wessells H. 2005. "Tadalafil-associated priapism". Urology; 66: 432.

Kingsberg SA. 2002. "The impact of aging on sexual function in women and their partners" .Arch Sex Behav.; 31(5): 431-7.

Kirkham AP, Illing RO, Minhas S, Minhas S and Allen C. 2008. "MR imaging of non-malignant penile lesions". Radiographics; 28: 837–53.

Konstantinos G and Petros P. 2009. "Phosphodiesterase-5 inhibitors: future perspectives". Curr Pharm Des; 15: 3540–51.

Kouvelas D, Goulas A, Papazisis G, Sardeli C and Pourzitaki C. 2009. "PDE5 inhibitors: in vitro and in vivo pharmacological profile". Curr Pharm Des; 15: 3464–75.

103

Laan E, van Driel EM and van Lunsen RH. 2008. "Genital responsiveness in healthy women with and without sexual arousal disorder". J Sex Med. Jun; 5(6): 1424- 35.

Landén M, Högberg P and Thase ME. 2005. "Incidence of sexual side effects in refractory depression during treatment with or ". .J Clin . Jan; 66(1): 100-6.

Laumann EO, Nicolosi A, Glasser DB, Paik A, Gingell C, Moreira E and Wang T. GSSAB Investigators' Group. 2005. "Sexual problems among women and men aged 40-80y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors". Int J Impot Res.; 17(1): 39-57.

Levine LA, Estrada CR, Storm DW and Matkov TG. 2003. "Peyronie disease in younger men: characteristics and treatment results". J Androl.; 24(1) :27-32.

Lewis RW, Fugl-Meyer KS, Corona G, Hayes RD, Laumann EO, Moreira ED Jr, Rellini AH and Segraves T. 2010. "Definitions/epidemiology/risk factors for sexual dysfunction". J Sex Med.; 7: 1598-607.

Maio G, Saraeb S and Marchiori A. 2010. "Physical activity and PDE5 inhibitors in the treatment of erectile dysfunction: results of a randomized controlled study". J Sex Med; 7: 2201–08.

Martin WJ, McGowan E, Cashen DE, Gantert LT, Drisko JE, Hom GJ, Nargund R, Sebhat I, Howard AD, Van der Ploeg LH and MacIntyre DE. 2002. "Activation of melanocortin MC(4) receptors increases erectile activity in rats ex copula". Eur J Pharmacol; 454: 71–79.

Maurice W. 2007. "Sexual Desire Disorders in Men". In: Leiblum S (Editor). Principles and Practice of Sex Therapy (4th edition). The Guilford Press. New York. 2007.

McGwin G Jr. 2010. "Phosphodiesterase type 5 inhibitor use and hearing impairment". Arch Otolaryngol Head Neck Surg; 136: 488–92.

Medina L, pez RA, Campoy Martnez P, Jiménez del Valle U, Hernendez Soto R, Ramerez Mendoza A and Soltero Gonzalez A. 1999. "The webbed penis" .A report of a new case. Arch Esp Urol.; 52(1): 68-9. Spanish.

Melman A, Bar-Chama N, McCullough A, Davies K and Christ G. 2006. "hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial". Hum Gene Ther; 17: 1165–76.

104

Michetti PM, Rossi R, Bonanno D, Tiesi A and Simonelli C. 2006. "Male sexuality and regulation of emotions: a study on the association between and erectile dysfunction (ED)". Int J Impot Res.; 18(2): 170-4.

Mikhailidis DP, Khan MA, Milionis HJ and Morgan RJ. 2000. "The treatment of hypertension in patient with erectile dysfunction". Curr.Med. Res. Opin.; 16 (suppl.1): 31-36

Miner MM. 2011. "Erectile dysfunction: a harbinger or consequence: does its detection lead to a window of curability?". J Androl; 32: 125–34.

Mittawae B, El-Nashaar AR, Fouda A, Magdy M and Shamloul R. 2006. "Incidence of erectile dysfunction in 800 hypertensive patients: a multicenter Egyptian national study". Urology 2006; 67: 575-8.

Mondaini N, Sriprasad S, Hopster D, Sidhu PS and Muir GH. 2002. "Congenital herniation of cavernous tissue through the tunica albuginea with osseous metaplasia of the penis". Br J Urol Int; 89: 971.

Montague DK, Jarow JP, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, Milbank AJ, Nehra A and Sharlip ID. 2005. "Erectile Dysfunction Guideline Update Panel. Chapter 1: The management of erectile dysfunction: an AUA update". J Urol.; 174(1): 230-9.

Montorsi F, Adaikan G, Becher E, Giuliano F, Khoury S, Lue TF, Sharlip I, Althof SE, Andersson KE, Brock G, Broderick G, Burnett A, Buvat J, Dean J, t A, Buvat J, Dean J, Donatucci C, Eardley I, Fugl-Meyer KS, Goldstein I, Hackett G, Hatzichristou D, Hellstrom W, Incrocci L, Jackson G, Kadioglu A, Levine L, Lewis RW, Maggi M, McCabe M, McMahon CG, Montague D, Montorsi P, Mulhall J, Pfaus J, Porst H, Ralph D, Rosen R, Rowland D, Sadeghi-Nejad H, Shabsigh R, Stief C, Vardi Y, Wallen K and Wasserman M. 2010. "Summary of the recommendations on sexual dysfunctions in men". J Sex Med; 7: 3572–88.

Montorsi F, Guazzoni G, Barbieri L, Galli L, Rigatti P, Pizzini G and Miani A. 1996. "The effect of intra-corporeal injection plus genital and audiovisual sexual stimulation versus second injection on penile color Doppler sonography parameters". J Urol; 155: 536–40.

Montorsi P, Montorsi F and Schulman CC. 2003. "Is erectile dysfunction the “tip of the iceberg” of a systemic vascular disorder?". Eur Urol; 44: 352–54.

Montorsi P, Ravagnani PM, Galli S, Salonia A, Briganti A, Werba JP and Montorsi F. 2006. "Association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient". Eur Urol; 50: 721–31.

105

Moreira ED, Bestance WJ, Bartolo EB and Fittipaldi JA. 2002. "Prevalence and determinants of erectile dysfunction in Santos, South eastern Brazil". Sao Paulo Med. J., 120 (2): 49-54. .

Morganroth J, Ilson BE, Shaddinger BC, Dabiri GA, Patel BR, Boyle DA, Sethuraman VS and Montague TH. 2004. "Evaluation of vardenafil and sildenafil on cardiac repolarization". Am J Cardiol; 93: 1378–83, A6.

Mulhall JP. 2008. "Penile rehabilitation following radical prostatectomy". Curr Opin Urol; 18: 613–20.

Naroda T, Yamanaka M, Matsushita K, Kimura K, Kawanishi Y, Numata A, Yuasa M, Tamura M and Kagawa S. 1996. "Clinical studies for venogenic impotence with color Doppler ultrasonography-evaluation of resistance index of the cavernous artery". Nihon Hinyokika Gakkai Zasshi; 87: 1231–5.[In Japanese].

Naya Y, Mizutani Y, Ochiai A, Soh J, Kawauchi A and Fujito A. 2003. "Preliminary report of association of chronic diseases and erectile dysfunction in middle- aged men in Japan". Urology; 65: 532-536.

Nehra A, Jackson G, Miner M, Billups KL, Burnett AL, Buvat J, Carson CC, Cunningham GR, Ganz P, Goldstein I, Guay AT, Hackett G, Kloner RA, Kostis J, Montorsi P, Ramsey M, Rosen R, Sadovsky R, Seftel AD, Shabsigh R, Vlachopoulos C and Wu FC. 2012. "The Princeton III consensus recommendations for the management of erectile dysfunction and cardiovascular disease". Mayo Clin Proc; 87: 766–78.

Nicolosi A, Glasser DB, Kim SC, Marumo K and Laumann EO, for the GSSAB Investigator's Group. 2005. "Sexual behavior and dysfunction and help- seeking patterns in adults aged 40–80 years in the urban population of Asian countries". BJU Int; 95: 609–14.

NIH Consensus Conference. Impotence. 1993. "NIH Consensus Development Panel on Impotence". JAMA.; 270(1): 83-90.

Nolen-Hoeksema S. 2014. "". 2 Penn Plaza, New York, NY 10121: McGraw-Hill. pp. 366–367. ISBN 978-1-259-06072-4.

Okulate G, Olayinka O and Dogunro AS. 2003. "Erectile dysfunction and relationship to depression alcohol abuse and panic disorders". General Hospital Psychiatry; 25(3): 209-213.

Olarinoye JK, Kuranga SA, Katibi IA, Adeniran OS, Jimoh AAG and Sanya EO. 2006. "Prevalence and determinants of erectile dysfunction among people with type 2 diabetes in Ilorin, Nigeria". Niger Postgrad Med J.; 13(4): 291-6.

106

Omigbodun OO, Babalola. 2004. "Psychosocial dynamics of psychoactive substance misuse among Nigerian Adolescents". Annals of African Medicine; 3(3): 111- 115.

Patel DV, Halls J, Patel U. Investigation of erectile dysfunction.Br J Radiol.2012; 8 5:69-78.

Penson DF. 2004. "Erectile Dysfunction in Diabetic Patients". Diabetes Spectrum.; 17: 225-230.

Perimenis P, Konstantinopoulos A, Perimeni PP, Gyftopoulos K, Kartsanis G, Liatsikos E and Athanasopoulos A. 2006. "Long-term treatment with intra- cavernosal injections in diabetic men with erectile dysfunction". Asian J Androl; 8: 21924.

Pinnock CB, Stapleton AM and Marshall VR. 1999. "Erectile dysfunction in the Community: a prevalence Study". Med J.; 171: 353-357.

Piores OM, Jimeno CA and Acampado LT. 2007. "Erectile Dysfunction Among Diabetes Men At UP-PGH Outpatient Department: Prevalence And Risk Factors". Phil. J Pract.; 49(9): 16-29.

Prieto D. 2008. "Physiological regulation of penile arteries and veins". Int J Impot Res; 20: 17–29.

Quek F, Sallam AA, Ng CH and Chua CB. 2008. "Prevalence of sexual problems and its association with social, psychological and physical factors among men in a Malayzian population". J Sex Med. Jan; 5(1): 70-6.

Rajpurkar A and Dhabuwala CB. 2003. "Comparison of satisfaction rates and erectile function in patients treated with sildenafil, intra-cavernous prostaglandin E1 and penile implant surgery for erectile dysfunction in urology practice". J Urol.; 170(1): 159-63.

Rodriguez Vela L, Moncada Iribarren I, Gonzalvo Ibarra A and Saenz de Tejada y Gorman I. 1998. "Treatment of erectile dysfunction using intracavernous pharmacotherapy". Actas Urol Esp.; 22(4): 291-319. Spanish.

Rosen RC, Cappelleri JC, Smith MD, Lipsky J and Peña BM. 1999. "Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction". Int J Impot Res.;11(6): 319-26.

107

Rosen RC. 2001. "Psychogenic erectile dysfunction, Classification and management". Urol. Clin North Am.; 28: 269-78.

Safarine Jad MR. 2003. "Prevalence and Risk factors for erectile dysfunction in a population–based study in Iran". Int. J Impot Res.; 15: 246-252.

Seidman SN, Roose SP, Menza MA, Shabsigh R and Rosen RC. 2001. "Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo- controlled with sildenafil citrate". Am J Psychiatry; 158(10): 1623-30.

Selph JP and Carson CC. 2011. "Penile prosthesis infection: approaches to prevention and treatment". Urol Clin North Am; 38: 227–35.

Serretti A and Chiesa A. 2011. "A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics". Int Clin Psychopharmacol; 26: 130–40.

Setter SM, Iltz JL, Fincham JE, Campbell RK and Baker DE. 2005. "Phosphodiesterase 5 inhibitors for erectile dysfunction". Ann Pharmacother; 39: 1286–95.

Seyam RM, Albakry A, Ghobish A, Arif H, Dandash K and Rashwan H. 2003. "Prevalence of erectile dysfunction and its correlates in Egypt: a community- based study". Int J Impot Res; 15: 237-45.

Shabsigh R and Anastaiadis AG. 2003. "Erectile Dysfunction". Annu.Rev Med.; 54: 153-68.

Shabsigh R, Kaufman JM, Steidle C and Padma-Nathan H. 2008. "Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone". J Urol; 179: S97– 102.

Shaeer KZ, Osegbe DN, Siddiqui SH, Razzaque A, Glasser DB, Jaguste V. 2003. "Prevalence of erectile dysfunction and its correlates among men attending primary care clinics in three countries, Pakistan, Egypt, and Nigeria". Int J Impot Res Suppl; 1: S8-S14.

Shaeer O and Shaeer K. 2011. "The Global Online Sexuality Survey (GOSS), erectile dysfunction among Arabic-speaking Internet users in the Middle East". J Sex Med; 8: 2152–60.

Shamloul R and Ghanem H. 2013. "Erectile dysfunction". Lancet; 381(9861): 153-65.

108

Shamloul R, Ghanem HM, Salem A, Elnashaar A, Elnaggar W, Darwish H and Mousa AA. 2004. "Correlation between penile duplex findings and stress- electrocardiography in men with erectile dysfunction". Int J Impot Res; 16: 235-7.

Shokeir AA and Hussein MI. 2004. "Sexual life in Pharaonic Egypt: towards a urological view". Int J Impot Res; 16: 385-8.

Uder M, Gohl D, Takahashi M, Derouet H, Defreyne L, Kramann B and Schneider G. 2002. "MRI of penile fracture: diagnosis and therapeutic follow-up". Eur Radiol; 12: 113–20.

United States Bureau of Census. 1992. "Statistical abstract of the United States".112th ed. Washington, DC; P: 19.

Usta MF, Erdogru T, Tefekli A, Koksa, T, Yucel B and Kadioglu A. 2001. "Honeymoon impotence: psychogenic or organic in origin?". Urology; 57: 758-62.

Vardi Y, Appel B, Kilchevsky A and Gruenwald I. 2012. "Does low intensity extracorporeal shock wave therapy have a physiological effect on erectile function? Short-term results of a randomized, double-blind, sham controlled study". J Urol; 187: 1769–75.

Vardi Y, Dayan L, Apple B, Gruenwald I, Ofer Y and Jacob G. 2009. "Penile and systemic endothelial function in men with and without erectile dysfunction". Eur Urol; 55: 979–85.

Weidner W, Schroeder-Printzen I, Weiske WH and Vosshenrich R. 1997. "Sexual dysfunction in Peyronie‟s disease: an analysis of 222 patients without previous local plaque therapy". J Urol; 157: 325–8.

Wessels H. 2006. "Vacuum erection devices". In: Mulcahy J (Editor). Male sexual function, a guide to clinical management. Totowa, NJ: Humana Press: 323–29.

WHO. 1999. "International Society of Hypertension guidelines for the management of hypertension". J Hypertens., 17: 151-83.

WHO. 1995. "Physical status, the use and interpretation of anthropometry". Report of a WHO Expert Committee. WHO Technical Report, Geneva, Series 854.

Wilkins CJ, Sriprasad S and Sidhu PS. 2003. "Colour Doppler ultrasound of the penis". Clin Radiol; 58: 514–23.

Wrishko R, Sorsaburu S, Wong D, Strawbridge A and McGill J. 2009. "Safety, efficacy, and pharmacokinetic overview of low-dose daily administration of tadalafil". J Sex Med; 6: 2039–48.

109

Xie D, Annex BH and Donatucci CF. 2008. "Growth factors for therapeutic angiogenesis in hyper-cholesterolemic erectile dysfunction". Asian J Androl; 10: 23–27.

Yassin AA, Akhras F, El-Sakka AI and Saad F. 2011. "Cardiovascular diseases and erectile dysfunction: the two faces of the coin of androgen deficiency". Andrologia; 43 :1-8.

Zedan H, Hareadei AA, Abd-Elsayed AA and Abdel-Maguid EM. 2010. "Cigarette smoking, hypertension and diabetes mellitus as risk factors for erectile dysfunction in upper Egypt". East Med Health J; 16: 281-5.