Erectile dysfunction: a symptom or a disease? The National Institute of Health (NIH) has defined Erectile Dysfunction (ED) the inability to reach and/or maintain an erection that can assure satisfactory sexual relations (1).
ED affects millions of men throughout the world and, though it does not alter their life span, it can negatively influence their well being and quality of life (2). ED generating pathologies are many hence it must be considered a systemic or relational symptom of an organic disease that requires accurate clinical and diagnostic assessment. ED can be the first clinical expression of important systemic diseases and it is considered a possible marker of clinically misdiagnosed atherosclerotic, metabolic and neurological diseases (3). For the first time fasting glycaemic levels above normal values (4) were detected in 15% of patients with erectile dysfunction and the prevalence of undiagnosed diabetes mellitus was 12.1% (5) in individuals with ED and normal glycaemia after an Oral Glucose Tolerance Test (OGTT). Besides recently Sairan et al. (6) reported a 4.7% prevalence of undiagnosed diabetes mellitus and 8.4% high fasting glycaemic levels. In patients over 45 years with presumed vascular pathogenic ED and no cardiovascular symptoms an exercise ECG detected the appearance of ECG alterations in 15.7% of cases (7) while an ischaemic heart disease was detected in 41.9% of those whose eco-colour-Doppler scan of cavernous arteries presented a systolic peak flow below 35 cm/s (8). Lastly Billups et al. (9) reported an increase in plasma cholesterol in 60% of patients affected by erectile dysfunction. Recently marketed new drugs to treat erectile dysfunction can lead to medicate this symptom without following a correct clinical approach to the problem. Since the treatment’s feasibility and effectiveness must also consider the treated individual’s level of androgenization (10), these drugs can be usefully administered to a relevant number of patients. Besides the failure to diagnose concomitant diseases that can be potentially corrected, possible side effects subsequent to the assumption of these drugs stress the importance of a correct diagnostic approach to ED. In addition to this, the recent effective and easy to administer ED drugs involve the risk of accustoming individuals to an unnatural sexuality, imposing an unreal and hence dangerous sexual model. Drugs that can improve the quality of sexual life can improve sexuality, but they can also deeply condition the person, creating an addiction and hence a disease especially when at the basis of ED there was only a relational difficulty. The literature of recent months has presented many Consensus Conferences on ED authored by single specialist categories that have focused on the therapeutic course of individuals with ED, attaching less importance to the diagnostic course that is essential to recognize concomitant ED generating diseases (11-12). The Consensus Conference’s purpose is to agree on a clinical and investigative diagnostic approach to erectile dysfunction, together with the many specialists involved.

Epidemiology
Having used various criteria to define erectile dysfunction and select the population studied, epidemiological studies present in literature make it hard to estimate this symptom’s real prevalence. Divergent data is in fact reported with values between 12%, described by Furlow, and 52% reported by the Massachusetts Male Aging Study (MMAS) (13-17). The main Italian study published in 2000 reports a 12.8% prevalence of erectile dysfunction in a sample of 2,010 patients selected from the archives of 143 physicians specialized in general medicine. Extrapolating this data to the entire Italian population the authors conclude that about 3 million men present an erectile disorder (18). All studies present in literature and even with different data agree in stating that the prevalence of erectile dysfunction is strongly age-related, reporting a particularly significant increase from the 60th year. It is currently probable that 5 to 10% belongs to the 50th year of life, increasing to 30 - 50% in the mid 70s (13-18). Relational studies between diabetes mellitus and ED estimate the prevalence of ED between 25 and 33% of patients studied, occasionally reaching even 75% (19-22). In the MMAS the incidence of ED in diabetic patients after an 8.8-year follow-up was 50.7 new cases in 1000 patients/year compared to 25.9 % in the general population (23). In a recent Italian study the incidence of ED in diabetic patients after a 2.8-year follow-up was 68 new cases in 1000 patients/year, more than twice the amount reported in the general MMAS population (24). Other pathological conditions besides diabetes can be associated with erective problems: chronic systemic disorders (CRF, liver failure etc.), cardiovascular diseases (atherosclerosis, hypertension etc.), neuropathies (cerebrovascular incidents, multiple sclerosis etc.), psychiatric diseases (anxiety syndrome, depressive syndrome, etc.), endocrine disorders (hypogonadism, hyperprolactinaemia etc.), iatrogenic diseases (drug treatment, surgery etc.) and luxury habits (alcoholism, tabacosis etc.) (25) (Tab. I). These pathologies can give rise to an ED picture by modifying intrapenile circulation, neurological functions, the hormone structure and the corpora cavernosa and tonaca albuginea’s microstructure.

Assessing patients with erectile dysfunction
Erectile dysfunction marks the beginning of many diseases such as diabetes, dyslipidemias, hypertension and coronary heart diseases hence it must be considered a symptom. A correct diagnostic approach is of essential importance and must involve a carefully taken case history (medical, sexual and psychosocial), an accurate physical examination and precise laboratory and diagnostic investigations (25). Patient history: patient history is the basic element in the diagnostic process as it enables to highlight risk factors, directs the physician towards a possible organic and/or non organic pathogenesis and highlights the partner’s possible sexual or relational problems, thus influencing the next diagnostic course. A correct case history must comprise three aspects: medical, psychological and psychosocial. Medical history: many are the conditions that can encourage the onset of erectile dysfunction. The medical history is divided in three points: family, physiological and distant pathological history. The family history is useful to assess a patient’s tendency to develop cardiovascular diseases, diabetes, endocrine disorders etc. The physiological history enables to spot risk factors and conditions that can lead to suspect concomitant ED generating diseases. We should hence establish the patient’s habits (smoking, alcohol, drugs, Circadian rhythm, exercise, food etc.), type of work (hours, stress, managerial or subordinate activity etc.) and micturition and alvus characteristics. The distant pathological history seeks concomitant chronic diseases (diabetes, liver diseases, hypertension, CRF etc.) and precise well known cardiovascular risk factors (hypercholesterolaemia, hypertension, diabetes, pelvic irradiation etc.) that can cause ED. In the light of the population’s increased mean life span and the high degree of medicalization that has involved a high incidence of erective disorders on an iatrogenic base, it is advisable to carefully assess whether the patient is under medication (antihypertensive, anticholinergic, antipsychotic drugs etc.) (26-51) (Tab. II) and whether he reports past traumas (cranial, dorsal, pelvic etc.) or surgery (abdominal or pelvic amputation of the rectum, radical cystoprostatectomy, vascular prosthesis, surgery of the rachis etc.) that can cause ED due to neurological, vascular, psychological and relational modifications (1-52). Sexual history: After forming a clear picture of the patient’s health, the physician must take his sexual history to focus on the reason that has lead the patient to consult the doctor. In the first place he should determine the type of problem (drop in sexual desire, difficulty in reaching an erection, reduced rigidity during intercourse, ejaculation disorders etc.), the period of onset and especially the method of onset. In fact a sudden onset of ED directs towards a psychogenic form, also confirmed by spontaneous nocturnal erections or the ability to obtain valid erections during masturbation.

The disorder’s gradual and progressive onset directs us towards an organic pathogenesis. ED can also be reported with the current partner but not with other partners or vice versa. It is hence advisable to extend the interview to the partner’s health, investigating possible sexual disorders, menopause condition and the couple’s relationship (53). It is also important to assess whether the patient has a sexual life outside the couple and whether the disorders complained of concerning the couple are more or less present in his outside relationships too. Lastly the symptom’s development in time must be assessed, whether it has undermined the couple’s relationship and the situation at the moment of the consultation. Psychosocial history: knowing the patient’s experiences is essential in the diagnostic course of ED, enabling to spot psychological and relational situations that can negatively influence erection. Tiefler et al. have divided these conditions in predisposing, precipitating and maintenance (54). Predisposing conditions can be some altered family relations, early sexual traumas, an inadequate sexual education, an uncertain psychosexual role etc. Precipitating conditions can be possible bad relations within the couple, unfaithfulness, reactions to chronic pathologies, depressive syndrome, anxiety syndrome, etc. Maintenance conditions are represented by the loss of attraction towards the partner, reduced self-esteem, anxiety concerning sexual performance etc. Erectile dysfunction evaluation scales: some quantification scales can be useful to standardize the gravity of the symptoms and to supply an objective measurement of the various treatments’ effects when assessing patients with erectile dysfunction. To this end the scientific community has proposed some more or less valid questionnaires. The most used questionnaire in international literature in recent years was IIEF-5; it comprised five questions that explored the erective capacity and the patient had to fill it out on his own (55). According to the points obtained ED can be defined mild, moderate or serious. This questionnaire’s most important limit lies in its very essence; in fact the patient fills it out on his own without always succeeding in correctly interpreting the questions and choosing the appropriate answer. Besides the questionnaire interrupts the doctor-patient contact that is essential in the diagnosis of ED. Another limit is the fact that questionnaires do not consider the abovementioned anamnestic factors. Many clinicians are prone to administer the questionnaire themselves, discussing each question with the patient. The structured interview is an alternative to the questionnaire. In this case the doctor uses a previously defined method and order to ask the patient a series of questions to which he assigns a score. Akerman and D’Attilio too proposed a sort of semistructured interview (56), whose complete version does not currently appear in literature. A form of structured interview has been currently validated and it is a useful tool to pathogenetically situate the patient affected by ED (57). The interview in question is called SIEDY (Structured Interview on Erectile Dysfunction). Short, versatile and easy to carry out, it comprises 13 questions distributed on three scales that mark out three different pathogenic moments, which often coexist in ED patients. Scale 1 marks the presence of an organic component in the disorder; scale 2 marks out a relational component and scale 3 an intrapsychic component. SIEDY does not only spot these three components but also quantifies them. Besides a score > 3.5 on scale 1 marks patients affected by ED with an organic component and 68% specificity and sensitivity. Hence SIEDY is a useful tool towards the aetiopathogenic assessment of ED and does not measure the acuteness of ED. Various questionnaires such as IIEF (International Index on Erectile Dysfunction) and BMSFI (Brief Male Sexual Function Inventory for urology) can be used to quantify the gravity. Physical examination: after following a wide anamnestic approach and performing the self-assessment tests previously described, the physical examination checks what has emerged during the interview and what the patient, due to emotion or reticence, may have described confusedly or even omitted. Hence we recommend performing a general examination of the body structure (muscular mass, adipose distribution, gynaecomastia etc), measuring weight and height and calculating the body mass index, excluding evident physical signs of major diseases (tumours, hepatopathies, nephropathies etc.), seeking physical signs of concomitant diseases and their possible complications, determining, whenever possible, their degree (25,58-60). Secondary sexual characters will then be assessed (piliferous distribution, muscular trophism etc.). The physical examination will be especially targeted at assessing the cardiovascular system, the gonads and the nervous system. The cardiovascular assessment must comprise a careful physical examination of the heart (evaluation of the cardiac area and possible murmurs), measurement of arterial pressure and intensity of peripheral pulses (femoral and pedal) and the search for possible vascular murmurs (carotid, abdominal, femoral). Concerning the penis, its dimensions and shape when flaccid (length > 10 cm with the expanded penis) must be determined, assessing possible fibrosis of the corpora cavernosa, the presence of plates and the smooth movement of the prepuce on the glans penis (to exclude a phimosis, short fraenulum, skin lesions and covered mucous tissue), marking out the urethral meatus’ site and patency. Examination of the testes must highlight the presence of mono or bilateral hypotrophy, morphology, consistency, tenderness, presence of an ectasis of the pampiniform plexus and the size and tenderness of the epididymes. Rectal exploration to assess the prostate gland is of fundamental importance in the physical examination of individuals with ED and must always be performed to determine the gland’s morphology, volume, consistency and painfulness. A drop in the prostate gland’s volume greatly suggests hypogonadism. Lastly, the nervous system’s examination must involve the search for motor alterations (slackened response, tremor etc.), testing of tendon reflexes (patellar and achilles’ jerk), the cremasteric reflex (obtained by exercising pressure in the inguinal region and observing the contraction of the scrotum) and the bulbocavernous reflex (appreciating the contraction of the anal sphincter subsequent to squeezing of the glans penis). Alterations in tactile and vibrational sensitivity in the lower limbs and in the genitalia region are recognized through biotensiometry that quantitatively assesses the individual’s somatosensorial vibrational sensitivity. Normograms that enable to appreciate possible sensitive deficits have been created to this end (61). First level diagnostic approach: laboratory tests prescribed to individuals with ED are directed at determining a possible cause for the erectile problem and at spotting possible concomitant systemic pathologies of which ED can be the first expression. In particular all ED patients must be prescribed: a blood cell count to detect possible haematological pathologies, a urine test to detect glycosuria and assess indexes of diabetic decompensation and microangiopathic complications such as glycaemia, creatinaemia, total cholesterol, HDL and triglycerides (58-60). All patients must be prescribed a total testosterone test (62), besides an SHBG test in obese patients, in those aged > 60, in patients suffering from endocrine disorders and those under antiepileptic medication (63); in fact increased SHBG levels with a subsequent reduction of bioavailable testosterone can be noticed in these patients. The test must be repeated when testosterone is below 3 ng/ml, given the pulsating nature of this hormone’s secretion. Gonadotropine tests (FSH and LH) must be prescribed only following specific clinical suspicions hence they represent a second level detailed diagnostic investigation. All patients must be prescribed the prolactin (PRL) test (64); an increase in prolactin can be caused by a prolactin secreting pituitary adenoma or, more frequently, by other conditions such as drugs (butyrphenones, benzamides, phenothiazines and others), renal failure or primary hypothyroidism. Very often a slightly high PRL value is subsequent to stress caused by an injection in the vein and hence must be confirmed by many samples taken distanced in time and with the needle on site. Patients with high PRL levels usually report an ED related to a relevant drop in sexual desire. The mechanism at the basis of these symptoms seems to be reduced GnRH pulsations with subsequent hypotestosteronaemia, even though a direct PRL effect has been proved (65). We recommend prescribing the PSA test to all patients aged > 50 years, considering the high incidence of prostatic diseases (1-60). TSH need not be tested except for specific clinical suspicions (Tab. III). Second level diagnostic approach: a correctly taken first level patient history and well conducted physical examination and diagnostic approach enables us to select those patients to whom it can be useful, towards a greater diagnostic definition, to perform a second level test such as the monitoring of nocturnal erections, penile eco-colour-Doppler scans, both at rest and drug induced, and investigations that assess the neurogenic component. As these diagnostic tools must be performed in specialized centres as they are costly and not easy to perform. Monitoring nocturnal erections: it is well known that there are erective events during the REM stage of sleep. In the ’70s these were detected with the “stamp test” that consisted in placing a series of stamps around the penis and in observing whether there were cracks in the same in the morning. The “Snap gauge” was developed later. It consisted in fitting two or three strips around the penis, each of which required a different strength to tear it. The RigiScan, a computerized tool, is currently used. It comprises two rings placed one at the basis of the penis and the second at the balanopreputial sulcus. This tool measures variations in penile circumference every thirty seconds and penile rigidity every three minutes. The parameters of a normal reading reported in international literature are at least 3 erective events a night, with a duration of at least 10 minutes per episode, a circumference increase of at least 3 cm at the base of the penis and 2 cm at its tip with a rigidity >70% (66-67-68). Night recordings of erections offer the advantage of being independent from the operator, they can be performed at home, they are neither invasive nor painful and they are barely influenced by the patient’s psychological condition during the REM phase of sleep. But there are many disadvantages too: the absence of normal parameters in patients aged > 65, the lack of corroboration from other methods, the lack of clear measurements that can relate night erection with the one obtained during intercourse, the possible influence of special psychological conditions (anxiety, depression, loss of sexual desire), the first night effect, the negative influence of possible sleep anomalies (nocturnal apnea, myoclonias, anxiogenic dreams), normal recordings in case of pelvic steal syndrome and multiple sclerosis (false negatives) and inconsistent duration and intensity criteria of the erective event (69). In the light of these limitations this method must be only used to analyse normal graphs and hence to exclude the presence of organic diseases. We recommend performing this test for at least two nights in young patients (aged < 40) with probable psychogenic ED. In fact a normal graph has a reassuring significance; it can enable the symptom to solve spontaneously and help the patient to accept behavioural or drug treatment with greater conviction. It is also used before possible prosthetic surgery and for medical and legal assessments. Mini-invasive diagnostics of erectile dysfunction: it was once believed that ED had mainly a psychogenic pathogenesis. However, as time went by, many studies proved that ED is mainly of an organic nature and is caused in up to 50% of cases by alterations in vascular structures (70). Currently there exists no specific non-invasive test that can alone help to recognize the vascular origin of ED. The penobrachial index was much used in the ‘80s; it enabled to roughly assess the patency of penile arterial districts. This test consisted in measuring the ratio between arterial systolic pressure in the penis’ dorsal arteries and brachial systemic systolic arterial pressure in flaccid conditions. A normal penobrachial index close to the unit suggested penile vessel patency while a value below 0.6 indicated a possible obstruction. This test has been currently abandoned as it is not very accurate and specific, both due to the difficulty of precisely measuring the pressure of the penis’ dorsal arteries in flaccid conditions and because the correct functioning of these is not however a sign of integrity of corpora cavernosa haemodynamics during erection (71-72). Intracavernous Drug Infusion Test When an ED with a neurovascular pathogenesis is suspected it can be useful to clinically administer an intracavernous injection of alprostadil (PGE1), a prostaglandin with a high vasodilatory activity (73). The test consists in the intracavernous administration of a standard dose (10 mcg) of PGE1. A dose between 2 and 5 mcg is advised in young men and/or in the presence of severe peripheral neuropathies to avoid drug induced priapism. The response to the drug is assessed through palpation and comprises five response levels (74): ·level 0: absence of tumescence; ·level 1: partial tumescence with inadequate rigidity for sexual intercourse (inadequate response); ·level 2: penile tumescence with moderate or complete rigidity that lasts less than 20 minutes (sub-optimum response); ·level 3: complete rigidity with duration between 20 and 60 minutes (optimum response); and, ·level 4: complete rigidity and duration over 60 minutes (excessive response). The test is defined pathological in case of level 0, 1 and 2 responses, while it is normal with level 3 and 4 responses. However the test can often be positive due to autonomic hypertone induced by anxiety caused by the test that can produce false positives by altering the venocclusive mechanism (75). Besides vascular alterations can be highlighted in 20-65% of cases showing a high incidence of false negatives in the Intracavernous Drug Infusion test if other diagnostic methods are performed (i.e. eco-colour-Doppler scan, arteriograph) when there is a complete clinical response (type 3) (76-77). An alternative to this test could be the assessment “at home” of the response to phosphodiesterase inhibitors that could supply greater indications on the correct functioning of the venocclusive mechanism during sexual intercourse. The Intracavernous Drug Infusion test should be recommended when oral treatment is contraindicated or ineffective in centres that do not have eco-colour-Doppler equipment. Penile dynamic eco-colour-Doppler scan A penile Doppler scan performed in basal conditions does not allow detection of vascular alterations. The availability of erection inducing drugs such as alprostadil that can be easily administered through an intracavernous injection has lead to the advent of dynamic eco-colour-Doppler scans (78). The technique involves the use of high frequency probes (7.5-13 MHz) fitted with digital software and a colour-Doppler module. The patient is normally studied while lying on his back with the penis placed against the abdomen’s anterior wall. The presence of ecostructural alterations such as fibrosis or calcified plates is initially assessed in the context of the corpora cavernosa and tunica albuginea testis. These structures’ investigation involves transversal scans (where they appear as two circular structures with a consistent ecostructure, average intensity and separated by a septum) and longitudinal scans. Then the cavernous arteries are viewed with the colour-Doppler sonograph and basal velocimetric graphs are assessed. Some scientists have reported significant relations between basal flow levels in cavernous arteries and those obtained after the Intracavernous Drug Infusion Test (ICI test)(79). This relation would enable to predict the erective disorder’s vascular pathogenesis. Currently the vascular study of cavernous arteries is performed in dynamic conditions after the ICI test. After detecting the cavernous arteries the test is performed by administering a standard dose of 10 mcg of PGE1. Flow velocity inside the cavernous arteries generally in the penis-scrotum joint is measured at an angle that is possibly smaller than 60° and at a distance of 5-10-15-20 minutes from the injection. The time required to reach and maintain the erection is extremely variable and is influenced by interfering factors such as anxiety, cigarette smoke (80), intake of caffeine/theine and the very vessels’ degree of rigidity in relations with the age. If after 20 minutes the patient has not reached and/or has not maintained an adequate erection for penetration, the effects of these interfering factors must be reduced, when possible, by re-injecting a similar dose of PGE1 or repeating the test at a later date with a maximal dose (20 ug). During the test’s first minutes the Doppler spectrum presents a rounded systolic peak and high values of diastolic flow indicating a low resistance flow inside the sinusoid spaces. As the minutes pass the intracavernous pressure increases, the systolic flow’s velocity peak becomes more pointed and the diastolic flow gradually decreases till it completely ceases (78). Men with a normal erective response present a Systolic Peak Flow Velocity (PFV) that is higher than 30 cm/s and End Diastolic Velocity (EDV) that is lower than 5 cm/s. The corpus cavernosus’ “compliance” is calculated to assess the resistance index (RI: PFV-EDV/PFV) that must be > 0.9. This index, according to the formula’s calculations, tends towards one in case of the corpus cavernosus’ regular “compliance” (81, 82). Besides the PFV, some scientists advice evaluating other parameters such as the time of systolic rise, which in some individuals affected by erectile dysfunction would seem longer (>110 cm/s) even in the presence of high PFV values. In these cases ED could result from the cavernous arteries’ reduced dimensions, which in practice limit their flow (83) (Tab IV). A drug “reverse” should be performed to avoid surgical detumescence when the erective event tends to be prolonged (for over two-three hours). The adrenergic agonist ethylephrin is used to this end at a dose of 1-2 mg (dilution 1:10) injected directly into the corpora cavernosa with a 21G butterfly needle (83) that can antagonize the effects of vasodilatory drugs injected for the Intracavernous Drug Infusion Test.The reduction of wave amplitude and a drop in the systolic peak flow velocity (PFV) below 30 cm/sec after the induced maximum erection indicates an ED of arterial origin (83). In patients presenting a low arterial flow and aged below 50, we advise monitoring nocturnal erections and, in certain cases, performing a selective arteriograph to recognize the level and degree of obstruction in view of possible revascularization surgery. The presence of a telediastolic flow over 5 cm/sec with an RI < 0.9 after a high dosage drug stimulation of the corpus cavernosus and absence of rigid erection could indicate a dysfunction of the venocclusive mechanism. However the patient’s anxiety when he comes for the test can influence this parameter (75). Hence in some cases it could be useful to repeat an eco-colour-Doppler scan by administering a high dosage of trimix (papaverine 30 mg + phentolamine 2 mg (not marketed in Italy) + alprostadil 20 mcg) in an attempt to overcome this interference. Despite these procedures a significant percentage of patients subject to eco-colour-Doppler sonography present high diastolic flow values subsequent to a lower compliance of the corpora cavernosa due to autonomic hypertone. This possibility has been recently highlighted by Slob et al. (85) who, in individuals affected by ED, compared the results of the dynamic eco-colour Doppler scan with a psychological and physiological assessment, with the degree of response to visual sexual stimulation (VSS) and with the effectiveness of the Intracavernous Drug Infusion Test at a low dosage. The Doppler study showed the presence of EDV alterations in more than 50% of patients. When the results of the other investigations were considered, over half of these patients presented a penetrative response to ICI (response type II-III) that did not exclude the presence of a vascular disease (77). Hence, the results of the eco-colour Doppler scan must be interpreted with much caution before entering on more invasive diagnostic courses. A story of normal erectile activity (with or without drugs that encourage erection), a normal nocturnal erection value and specially an altered psychometric test should help reassess the diagnosis of the venocclusive mechanism’s insufficiency. In the presence of persistent pathological values in some cases it becomes necessary to perform a cavernosometry/graph.

Recently the use of phosphodiesterase inhibitors to substitute the ICI test has been theorized in drug induced erections during the dynamic eco-colour Doppler scan to limit its invasivity and the anxiety induced by the ICI test (86). The results were not promising since they proved that accuracy and reproducibility are high concerning the arterial flow compared to the test with PGE1, but the same does not apply to the study of the venocclusive mechanism’s correct functioning. As a matter of fact the latter requires repeated measurements (every 5’ for at least 20’) of the EDV till complete erection is reached, which on the other hand must be maintained for an adequate time. In the presence of an operator phosphodiesterase inhibitors do not guarantee that an adequate erection will be reached to perform these measurements. In conclusion, we recommend performing the basal and dynamic eco-colour Doppler scan as a 2nd level investigation to all patients whose history presents a significant cardiovascular risk (> 20%) (Tab.VII) and also in cases of induratio penis plastica (Peyronie’s disease), which frequently involves the cavernous and vascular structures (87). 3rd level investigations (NPT, cavernosometry/graph, arteriograph) must be performed when the eco-colour-Doppler scan has produced results that require detailed study. Penile angiography Arteriography of penile arteries was once considered “gold standard” in assessing patients with ED with a presumed vascular pathogenesis. Today, with the advent of eco-colour-Doppler sonography, which is less costly, less invasive and quicker, it is only advised in two specific situations: A) to see the internal pudendal, lower epigastric and intrapenile arteries in view of revascularization surgery; and, B) to diagnose high flow priapism generated by a perineal penile trauma that is often not detected from the patient’s history and is characterized by the formation of an arteriovenous fistula between the artery and sinusoid spaces. This technique enables to perform super-selective embolizations with instant closure of the fistula. The test is usually performed under local anaesthesia by catheterizing the femoral artery. The intracavernous injection of 10 ug of alprostadil to stimulate erection is followed by selective catheterization of the internal pudendal artery to view the penis’ more distal arteries. Complications are rare except for haematomas or the reported feeling of heat and indefinite perineal complaints after the infusion of the contrast medium. The test is hard to perform in case of extensive atherosclerosis of the iliac vessels and virtually impossible in case of an occlusion at the origin of the internal pudendal artery. This method provides precise anatomical data but does not allow assessments of erection-related functional changes (88). Cavernosometry/graph Cavernosometry was the first method available to quantify and map venocclusive dysfunction in patients with erectile dysfunction. However this investigation does not allow to precisely differentiate the various types of venocclusive dysfunctions. Considering its invasive nature the test is recommended only in patients who can undergo corrective surgery. These are generally young men with low resistance to venous outflow subsequent to anatomical anomalies such as ectopic veins, abnormal communications between the corpora cavernosa and spongiosa and other penile and perineal traumas. The technique involves inserting two 19G butterfly needles in the corpora cavernosa and injecting 10-20 ug of alprostadil. Later there begins the infusion of saline through one of the butterfly needles, measuring the infusion speed required to induce erection and maintain rigidity. Generally complete erection is reached with an infusion speed of 100-200 ml/sec and the maintenance flow, in case of a normal venoocclusive function, varies from 3 to 15 ml/min. The second butterfly needle enables to measure intracavernous pressure (89). The inability to reach complete erection indicates inadequate relaxation of cavernous smooth muscles to the point of not permitting the entrance in the sinusoid spaces of adequate quantities of blood required to reach an erection. If a venoocclusive dysfunction is suspected, a radio-opaque contrast medium is injected to view the site of a possible leak. If the penis is not completely rigid the contrast medium will unavoidably flow into the veins, reducing the test’s clinical reliability. The most common outflow sites are the deep dorsal and superficial veins and occasionally the crural veins. Often the anxiety caused by the test and the implant of needles in the corpus cavernosus obstacle the complete relaxation of the corpora cavernosa leading to overrate the venocclusive mechanism’s degree of dysfunction (90, 91). Neurological diagnostics Penile erection is a neurovascular event comprising two neurological erective mechanisms: psychogenic erection that begins in supraspinal centres in response to visual, auditory, olfactory and imaginary stimuli mediated by autonomic stimuli and reflex erection, encouraged by the tactile stimulation of the genitalia and mediated by the spinal reflex arc formed by afferent somatic fibres and efferent parasympathetic ones (92, 93). The autonomic nervous system plays an essential role in beginning and maintaining erection by modulating intracavernous smooth muscle fibre relaxation. The somatic nervous system is instead necessary towards the perception of sensitive stimuli for the completion of penile rigidity as it causes the ischium and bulbocavernosus muscles to contract and controls ejaculation. Lesions in the central nervous system (intracranial: in the temporal lobe, hypothalamus, lenticular loop; suprasacral: multiple sclerosis, compressive lesions, traumas; caudal: discal prolapse (protrusion), bifid spine, vascular malformations) and peripheral one (pelvic: traumas, surgery; neuropathies: diabetes, alcohol, etc.) can cause the onset of ED. Current clinical practice offers no widely accepted diagnostic protocol for neurogenic ED. To be valid and reproducible the assessment of the somatic nervous system requires neurophysiological diagnostic tools that are available only in few specialized centres. The most frequently performed tests are: a) biotensiometry: by applying an electromagnetic vibrator with a fixed vibration frequency and variable amplitude, it assesses the intrapenile vibrational sensitivity through standardized normograms that suggest the presence of a peripheral neuropathy (61-94). b) the penis’ dorsal nerve’s conduction speed: it is measured by stretching the penis and applying two electrodes to its tips. A defect in conduction detected by this test can cause difficulty in maintaining erection during sexual intercourse (94-96). c) bulbocavernosus/penile reflex: it assesses the sacral reflex arc’s latency period. It can be useful in assessing suspicious lesions in the sacral nerve, cauda equina and lesions in the spinal cord caused by multiple sclerosis, traumas, tumours and intervertebral prolapse (96). d) evoked somatosensorial potentials: electrodes are placed in the spinal cord and the cortex to assess the conduction velocity of stimuli applied at a peripheral level. It enables to determine the lesion’s site, peripheral or central (97, 98). e) perineal electromiography: it assesses possible disorders of the pudendal nerve’s motor component that can be associated with metabolic alterations or exotoxicoses such as diabetes and addiction to alcohol (99). The evaluation of the autonomic nervous system is characterized by tests that are not well standardized, which, by assessing the cardiovascular, cutaneous and urinary systems, provide non-specific, indirect measurements of abnormalities in the autonomic nervous system that controls erection. The most highly reputed tests today are: a) cardiovascular reflexes: they assess variations in cardiac frequency and pressure in response to various stimuli such as forced breathing, posture changes, Valsalva’s manoeuvre etc. Changes in cardiac frequency reflect the parasympathetic activity while pressure variations mark autonomic activity. The loss of variations in cardiac frequency and blood pressure in the absence of confusing factors such as cardiac arrhythmias, the intake of caffeine and nicotine before the test, hyper/hypovolaemia etc. mark the presence of an autonomic neuropathy (100, 102). b) electromiography of the corpora cavernosa assesses the electric activity of intracavernous smooth muscle cells. When they are flaccid the electrical silence is interrupted by synchronized, high amplitude and long duration potentials that express the autonomic contraction of smooth muscle cells. During erotic stimulation the frequency of potentials increases with a gradual reduction of amplitude till total electrical silence is reached expressing the relaxation of intracavernous smooth muscles induced by parasympathetic activity. High frequency desynchronized potentials are recorded in autonomic neuropathies with a reduced amplitude and abnormal appearance (102, 103). c) cutaneous autonomic response: it assesses potentials generated by cutaneous sweat glands after stimulation on the part of the amyelinated autonomic C-fibres in response to thermoregulating and emotional stimuli. These potentials are measured by positioning the cutaneous electrodes in regions with diverse concentrations of sweat glands (back vs. palm of the hand, back vs. plant of the foot). The patient is placed on his back in an isolated room and subject to various stimuli (light, auditory, electric, thermal) after which the potentials are measured. The absence of potentials after three stimulations or a difference in amplitude that is greater than 50% between the homolateral and opposite limb are considered abnormal. The influence of confusing factors such as adaptation to the stimuli, the application method and the recording of the stimulus, skin hydration, the density of sweat glands, skin and room temperature and a possible somatosensorial neuropathy can cause modifications in the amplitude and latency of the potentials making data hard to interpret.

The cutaneous autonomic response is probably the most reliable test among those that assess the autonomic nervous system’s functionality, even though it is performed in very few centres (102, 105). In most neurological pathologies ED is a secondary symptom hence a carefully taken patient history and an accurate physical examination that highlights the clinical symptoms of these diseases make detailed diagnostic investigations superfluous in most cases. Neurological physical examinations must evaluate motor functions (slackening of speed, tremor, poor coordination), gauge tendon reflexes (patellar and achilles’ jerk), the cremasteric reflex (obtained by manually exercising pressure on the inguinal region and observing the contraction of the scrotum) and the bulbocavernosus or penile reflex (appreciating the contraction of the anal sphincter subsequent to squeezing of the glans penis) and use biotensiometry to assess sensitivity to a light touch, acupuncture in the lower limbs and pallesthetic sensibility in genital areas. Considering the inadequate standardization and repeatability of the tests mentioned, the low number of studies on sufficiently large populations, the scarcity of sufficiently expert people, the cost of tests and the sufficient eloquence of the patient’s history and physical examination, we believe that neurological diagnostic investigations must only be resorted to for precise study protocols or in selected cases and a II-III level investigation must hence be considered and cannot be used for mass screening (105). Cardiovascular diseases and erectile dysfunction All epidemiological studies performed on ED prevalence and incidence detected the existence of close relations between this condition and cardiovascular diseases. Endothelial dysfunction without irreversible vascular stenosis and atherosclerosis with irreversible arterial stenoses are the main causes of ED. Endothelial dysfunction and atherosclerosis of the vessels that feed the penis are subsequent to the exposure to the same risk factors that affect coronary arteries, i.e. cigarette smoke, dyslipidemias, hypertension and diabetes (106). A recent meta-analysis of observational studies on relations between cigarette smoke and ED published in the past twenty years stated that the incidence of ED in patients who are smokers is 40% compared to 28% of the general population (107). In the MMAS study on individuals treated for heart diseases the probability of complete age-related ED was 56% in smokers compared to 21% in non-smokers (17). Arterial hypertension is often associated with ED to the point that Shabsigh and his collaborators report various degrees of ED (7.7% mild, 15.4% moderate and 45.2% complete) in 68.3% hypertense patients studied by them (30). High levels of total cholesterol and/or low levels of HDL cholesterol can cause atherosclerosis, leading to ED due to poor intrapenile circulation. Wei observed that every 1 mmol/l increase in total cholesterol corresponds to a 1.32 times increase in the risk of developing ED; the risk run by patients with plasma values over 6.21 mmol/l is 1.83 times greater than individuals with levels below 4.65 mmol/l, while those whose HDL cholesterol levels are over 1.55 mmol/l present a relative risk of 0.3 (108). Lastly, various studies have reported that the incidence of ED in diabetic patients is twice the amount compared to the general population (23-24). This data has recently been confirmed by an extensive epidemiological study conducted in Italy (Tab. V). The various risk factors are often associated among them, contributing to aggravate the risk of developing multiple vasculopathies and ED. An alteration of penile haemodynamics has been noticed in patients with diverse vascular diseases: in a group of men aged from 31 to 86 and affected by myocardial infarction 64% presented ED, while ED was detected in 57% of those subject to coronary by-passes (109-110). A similar increase in the percentages of ED incidence has been noticed even in patients with peripheral and cerebral vasculopathies (111-112).

It has recently been observed that in patients aged over 45 with ED with a presumed vascular pathogenesis and no cardiovascular symptoms, an exercise ECG highlighted the appearance of ECG alterations in 15.7% of cases (7) while a silent ischaemic heart disease could be detected in 41.9% of cases that presented a systolic peak flow below 35 cm/s during the eco-colour-Doppler investigation of cavernous arteries (8). These observations highlight how ED can be the first symptom of previously misdiagnosed multiple vasculopathies. In 1999 the World Health Organization and the International Society for Hypertension (WHO/ISH) (113) drafted guidelines to assess the risk of developing myocardial infarction and stroke within ten years. This study marked out four patient categories: low cardiovascular risk, corresponding to a probability below 15% of developing an ischaemic event in ten years; average risk, with a probability between 15 to 20%; high risk with a 20 to 30% probability and very high risk with a probability over 30% (Tab. VI, VII). In patients with ED and an average to low cardiovascular risk (<20%) only the physical examination and arterial pressure need be evaluated. In patients with ED and a high or very high cardiovascular risk (>20%), besides evaluating their physical examination and measuring the arterial pressure, a penile eco-colour-Doppler scan must be performed to detect possible decreased arterial flow and ischaemic heart diseases must be screened to diagnose pathologies at a preclinical stage to improve prognosis. The choice cardiovascular screening method is the exercise ECG, which is easy to perform, has a low risk and limited cost. A normal result extensively guarantees a low probability of ischaemic events in the next three years. If the test is instead pathological the next diagnostic and therapeutic course must be performed with the trusted cardiologist. Diabetes and ED (CAR 10) Relational studies between diabetes mellitus and ED rate a 25 to 33% prevalence of ED in analysed patients, occasionally reaching even 75% (19-22). The MMAS calculated that the incidence of ED in diabetic patients after an 8.8 year follow up was 50.7 new cases in 1000 patients/year compared to 25.9% in the population at large (23). In a recent Italian study the incidence of ED in diabetic patients after a 2.8 year follow-up was 68 new cases in 1000 patients/year, more than double the number reported in the MMAS general population (24). Often diabetes mellitus is asymptomatic and it has been calculated that 33-50% of patients suffering from type II diabetes is not diagnosed (114). Besides, as diabetes is meanly diagnosed 4-7 years following its onset, at the time of diagnosis many patients may have already developed the disease’s complications (115). Microvascular complications (retinopathy, nephropathy, neuropathy, alterations in helicine arteries) and macrovascular ones (coronary heart disease, peripheral vasculopathy, alterations in cerebral, pudendal and cavernous arteries) typical of diabetes can clinically appear with the onset of ED. DeWire and collaborators highlighted that for the first time fasting glycaemic levels were above normal values in 15% of patients with ED (4) while the prevalence of undiagnosed diabetes mellitus was 12.1% in individuals with ED and normal glycaemia, after performing an Oral Glucose Tolerance Test (OGTT). These factors highlight the importance of adequately screening the glucide metabolism in individuals with ED. Clinical procedures that diagnose diabetes mellitus need rarely check the Oral Glucose Tolerance Test (OGTT): when there are typical symptoms (polyuria, polydipsia, polyphagia), glycaemia > 200 mg/dl is considered diagnostic for diabetes. If symptoms are doubtful or absent, fasting glycaemia must be greater or equal to 126 mg/dl on at least two occasions to diagnose diabetes (116). If it is below 110 mg/dl diabetes mellitus can be excluded and the patient can be advised to repeat the test after about three years (114). Advice to perform the Oral Glucose Tolerance Test (75 mg of glucose administered with water and glycaemia tested at 0 and 120 min.) is limited to patients whose fasting glycaemic levels are not diagnostic (glycaemia between 110-126 mg/dl) or who present conditions that significantly increase the risk of diabetes such as a greatly positive first degree family tendency or obese hypertense patients with reduced HDL cholesterol levels and increased TGL (Metabolic syndrome) (116). Two important multi-centre studies have clearly proved that good metabolic control reduces the onset of microvascular complications (117,118) in diabetics, confirming that such complications are subsequent to hyperglycaemia in these patients. Factors that contribute to the glycaemic balance are many: exercise, diet, stress, intercurrent events and sensitivity to oral and/or insulin hypoglycaemic treatment. Glycated haemoglobin (HbA1c) is produced by non-enzymic glycation and its percentage, when compared to non-glycated haemoglobin, is related with the main glycaemic levels during the 6-8 weeks prior to the test. As it does not undergo blood sugar concentrations’ daytime fluctuations and as it is related with the onset and progress of microvascular complications, HbA1c dosage plays a key role in evaluating glycaemic balance in diabetics. A recent study has shown that every 1% increase in HbA1c corresponds to an increased risk of developing microvascular complications, while every 1% drop marks a 35% risk reduction (118). HbA1c below 6% is a sign of normal glycaemic values during the last 6-8 weeks; below 7% it marks good drug control and over 8% it suggests a change in hypoglycaemic treatment (119). In type I diabetics, who may present marked fluctuations in blood sugar levels, we advice testing HbA1c at three-monthly intervals and every six months in type II diabetics. In diabetic patients ED is mainly a symptom of macro and micro vascular alterations that may concern other body districts, hence it is best to determine the presence of the disease’s complications such as multiple vasculopathies, nephropathies, neuropathies and retinal alterations. When evaluating the possible presence of multiple vasculopathies in diabetic patients complaining of ED, besides measuring arterial pressure and assessing cardiac tones and peripheral pulses, we recommend checking the ankle / arm pressure index (Winsor’s index) and performing an eco-colour-Doppler scan of epiaortic vessels and lower limbs. In patients presenting a high cardiovascular risk (>20%) we also advise performing an ergometric test that will allow detection of coronary heart diseases that have so far been misdiagnosed. It may suffice to prescribe uraemia, creatinaemia, urine and microalbuminuria tests to assess possible renal damage in these patients. Lastly, having noticed that about 25-30% of diabetic patients suffers from peripheral neuropathies and 15% from autonomic neuropathies, we advice evaluating tendon reflexes, peripheral and penile pallesthetic sensibility (biotensiometry) and prescribing cardiovascular autonomic tests and the neurone conduction velocity test. Conclusions Besides lowering self-esteem and altering patients and their sexual partners’ quality of life, at its onset erectile dysfunction is a symptom of many diseases typical of internal medicine. Recently available effective therapeutic tools have encouraged the development of studies that have confirmed close relations between ED physiopathology and acute and chronic systemic diseases. On the basis of this data ED, underestimated in clinical practice due to outdated biases that prevent patients from spontaneously revealing the problem and doctors from investigating it, can represent the first clinical symptom in evaluating and preventing epidemiologically relevant diseases such as diabetes mellitus, atherosclerosis, blood pressure, dyslipidemias, ischaemic heart disease, neuropathies, etc. till then unrecognised by the patient. A doctor’s acquired knowledge must envisage the skill to recognize ED generating diseases in order to ask the question while taking down the case history if the patient does not report it spontaneously. If the answer is positive the doctor must also be able to propose a specific diagnostic course (Tab. VIII) that can enable to form a precise physiopathological explanation and appropriately approach possible related acute or chronic diseases. In this Consensus Conference many specialists involved in ED diagnostics agreed towards a clinical and diagnostic investigational approach to the disease to enable detection of undiagnosed systemic diseases involving both improved disease prognosis and spontaneous or specific treatment to reduce the erectile dysfunction symptom. Translated by Interpres sas