CPD 39: ERECTILE DYSFUNCTION Biography - Paul Knox graduated in 2000 from Trinity College Dublin, and completed his pre-regristration in Unicare Pharmacy, Kilkenny. He the Managing Pharmacist of Cloughjordan Pharmacy from 2001-07 during which time he garnered a higher diploma (in community pharmacy) with distinction from TCD. Paul is currently completing a PhD from TCD, and recently appointed Managing Pharmacist of Coffeys Pharmacy in Roscrea.
Module 1 June 2012
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Erectile Dysfunction DEFINITION OF ERECTILE DYSFUNCTION According to the American Psychiatric Association Diagnositc and Statistical Manual of Mental Disorders IV (DSM-IV), erectile dysfunction can be defined as follows:
EPIDEMIOLOGY OF ERECTILE DYSFUNCTION
60 Second Summary
Erectile dysfunction is highly prevalent, with 5-20% of European men having moderate to severe ED.[ii] In 2002, it was estimated that 152 According million men worldwide had an erection problem, Sheehan et al reportedtoin 1996 that the estimated cost of Introduction the American 1.Persisent or recurrent inablity to attain, or to but this is expected to reach 322 million by pain for 95 patients to the Irish Health Services when added Psychiatric maintain until completion of the sexual activity, 2025.[iii] Pain is one of the commonest reasons for patients to seek Association an adequate erection; to the amount of Social Welfare payments received and 1 Diagnositc survey has shown that as many medical attention. A recentDIAGNOSIS OF ERECTILE DYSFUNCTION the lost earnings of each patient amounted to 1.9 million and Statistical 2.The disturbance causes distress or to primary care physicians in Ireland as marked 8.3 visits per year Manual of referral.6 The recent data from PRIME pounds at the time of interpersonal difficulty; A multi-faceted approach must be taken to 2 were due to symptoms of pain. scaleofsurvey carried Mental Disorders obtainAa large diagnosis ED, incorporating Medical survey showIVthat the mean cost per chronic pain patient (DSM-IV), erectile 3.The erectile dysfuncion is in not15 better andand Sexual physical examination, out European countries Israelhistory, in 2006, screening is estimated at €5,665 per year dysfunction can be across all grades of pain, accounted for by another Axis 1 disorder laboratory and psychosocial 46,394 and respondents that thetests, prevalence of chronic examination. defined as follows: (other than sexual dysfunction) is not duereported [iv] [v] These are described in more detailwhich below: was extrapolated to €5.34 billion or 2.86% of Irish of moderate to severe intensity in adult Europeans was exclusively to the direct pain physiological effects of 1.7Persisent or recurrentan inablity to need attain,for or cost to per year. This demonstrates urgent Sexual History - a detailed descriptionGDP of the 3 a substance (e.g a drug 19%. of abuse, medication) maintain until completion of the sexual problem, including the duration of symptoms effective strategies to manage chronic pain effectively. or a general medical condition activity, an adequate erection; and original precipitants, should be obtained. Moresought recenttosurvey data from another study, carried out The updated DSM-V (2013) 2. The disturbance causes marked distress or Concurrent medical, psychiatric and surgical improve the definition, and madepeople the following interpersonal diffipain culty; in 2,019 with chronic pain and 1,472 primary Understanding chronic history should also be recorded, as should provisions – care physicians across 15 European have the currentcountries, relationship status, history of 3. The erectile dysfuncion is not better Chronic pain isaccounted defined asfor pain that outlasts healing by another Axis 1normal disorder sexual partners and relationships. • To improve precision regarding duration demonstrated thatand chronic previous pain affects 12-54% of adult (other than sexual dysfunction) and is not time (usually three to six months), and is most frequently Issues of sexual orientation 2and gender identity severity criteria and to reduce the likelihood Europeans, and its prevalence in Ireland up to 13%. Thethe subject exclusively to the direct physiological should also beisidentified. Lastly, of over-diagnosis, all of the DSM-V sexual associated withdue musculoskeletal disorders such as low effects of a substance (e.g a drug of abuse, PRIME (Prevalence, Impactofand Cost ofalcohol Chronic Pain) study, drug use smoking, and recreational dysfunctions (except substance/medication back pain and arthritis. However, it canmedical also becondition. associated medication) or a general should be broached. – induced sexual dysfunction) on thenow otherrequire hand,adetermined the prevalence of chronic with other disorders such as depression or metabolic minimum of approximately six months and Erectile dysfunction is highly prevalent, with 4 in The diagnostic processstudy can be bolstered by pain to be as high as 35.5% Ireland. The PRIME more precise sexual difficulties. These changes of European mensuch having disorders or 5-20% neurologic conditions as moderate multiple to validated questionnaires, such was designed to investigateincorporating the prevalence of chronic pain serve to provide useful thresholds for making severe ED.[ii] In 2002, it was estimated that as The International Index of Erectile Function sclerosis. a diagnosis and distinguish transient sexual the psychological and physical health 152 million men worldwide had an erection in Ireland; compare (IIEF) or the validated shorter version of the dysfunction from more persistent sexual problem, but this is expected to reach 322 SHIM (Sexual Health Inventory for Men). profiles of those with and without chronic pain; and explore Pain (acute or chronic) can be categorised as nociceptive dysfunction; million by 2025. pain-related disability.4 Responses to survey Patients should questions undergo awere full physical or neuropathic. Nociceptive caused by anensure active The primary goal pain of EDistreatment is to • Subtypes for all sexual disorders include examination, recording any genital pain, obtained 1,204 people. that the individual or couple can associated enjoy a illness, injury and/or inflammatory process with only ‘lifelong versus acquired’ andfrom ‘generalised acute or chronic; deviation of the penis during satisfactory sexual experience. This holistic versus situational’. The sub-type pertaining to actual or potential tissue damage i.e. Nociceptive pain tumescence; hypogonadism; and any other approach incorporates identifying any organic Despite the magnitude problem, chronic pain is ‘psychological versus combined factors’ has of the urological symptoms results from activity in neural secondary to actual contributor to ED;pathways initiating lifestyle changes been deleted. 2,5 both under-recognised and undertreated in primary care. and risk factor modifi cation; providing relevant A digital rectal examination (DRE) of the or potential tissue damage. Nociceptive pain is mediated counselling to patients and their partners. Indeed, updegree to 38% reported being inadequately • To indicate the presence of and ofof patients prostate is not mandatory in ED but should be receptors by pain located in skin, musculoskeletal system, 2 medical and other non-medical correlates, conducted the presence managed in primary care for their paininsymptoms. In of genito-urinary or ED is8 a complex, multifactorial condition. Its bone, and joints. Neuropathic pain, on thecondition other hand, the following features are described in protracted secondary ejaculatory symptoms. position as an isolated medical is people with chronic pain reported waiting up to the accompanying text –addition, partner factors; however debatable – anecodotal evidence results from direct injury to a peripheral or central sensory Blood heart relationship factors; individual vulnerability 2.2 years between seekinghelp andpressure, diagnosis, andrate, 1.9 waist suggests that the incidence of ED has risen by nerve; the affected nerves do not produce transduction at circumference and weight should be measured. factors; cultural or religious factors; medical 250% since the advent of Viagra in 1998. years beforeand their pain was adequately managed.2 factors.[i] nociceptors.8 Pain characteristics and associated conditions
for both types of pain are shown in Table 1. use by Healthcare Professionals in the Republic of Ireland only Learning, Evaluation,For Accredited, Readers, Network | www.learninpharmacy.ie © Copyright 2012 Pfizer Healthcare Ireland Date of Preparation: Module 1 June 2012 EPBU/2012/XXX
CPD 39: ERECTILE DYSFUNCTION
THE CAUSES OF ERECTILE DYSFUNCTION
• The choice of investigations depends on the individual circumstances of the patient. Serum lipids and fasting plasma glucose should be measured in all patients. Module 1
The contributory factors to erectile dysfunction can be categorised as psychogenic or oragnic[vii]
• Hypogonadism is a treatable cause of ED that may render men less responsive, or nonresponsive to phosphodiesterase type 5 (PDE5) sionals inhibitors. in IrelandIn this regard, all men with ED should have serum testosterone measured on a blood sample taken in the morning between 8am and 11am.
anagement in specific primary • Serum prostate antigen care (PSA) should be considered if clinically indicated. It should certainly be measured before commencing testosterone therapy and at regular intervals during testosterone therapy. DIAGNOSIS INCORPORATING THE CARDIOVASCULAR SYSTEM • Coronary heart disease (CHD) is associated with many of the same risk factors as ED. Coronary artery disease (CAD) is often just one affected site in a generalised arteriopathy that is also likely to affect the arterial flow into the corpora cavernosum of the penis.
• ED in an otherwise asymptomatic man may be a marker for underlying CAD. All men unexplained ED should have a thorough ehan et with al reported in 1996 that the estimated cost of evaluation and any risk factors for CHD that are n for 95 patients the Irish Services when added identifiedtoshould be Health addressed. In fact, a man with should be considered cardiac patient he amount ofED Social Welfare paymentsareceived and until proven otherwise.5
lost earnings of each patient amounted to 1.9 million 6 • Current guidance recommends that all nds at the time of NICE referral. The recent data from PRIME men with type 2 diabetes be asked annually vey show that the mean cost per chronic pain patient about ED, assessed, and offered oral treatment stimatedwith at €5,665 per yearwith across grades of pain, the medication the all lowest acquisition cost.[vi] ch was extrapolated to €5.34 billion or 2.86% of Irish 7 P per year. anprovide urgent for need for cost TheThis NICEdemonstrates guidelines also those who may require specialised investigations – ctive strategies to manage chronic pain effectively. 1. Young patients who have always had difficulty
in obtaining and/or sustaining an erection; derstanding chronic pain 2. Patients with a history of trauma;
onic pain is defined as pain that outlasts normal healing Where genital abnormality is evident upon e (usually3.three to asix months), and is most frequently examination; ociated with musculoskeletal disorders such as low 4. Patients to medical k pain and arthritis.unresponsive However, it can also betherapies. associated h other disorders such as depression or metabolic PSYCHOGENIC ERECTILE DYSFUNCTION orders or neurologic conditions such as multiple ARTERIOGENIC, NEUORGENIC, AND rosis. ENDOCRINE CAUSES OF ED
Arteriogenic causes of ED n (acute or chronic) can be categorised as nociceptive europathic. Nociceptive pain is caused by an active 1. Hypertension ss, injury and/or inflammatory process associated with 2. Smoking ual or potential tissue damage i.e. Nociceptive pain 3. Diabetes ults from activity in neural pathways secondary to actual Peripheral vascular diseasepain is mediated otential 4. tissue damage. Nociceptive pain receptors in or skin, musculoskeletal system, 5. Bluntlocated perineal pelvic trauma 8 e, and joints. Neuropathic 6. Pelvic irradiation pain, on the other hand, ults from direct injury to a peripheral or central sensory Neurogenic causes of ED ve; the affected nerves do not produce transduction at Lesions of medial preoptic nucleus, conditions iceptors.•8 Pain characteristics and associated paraventicular nucleus, hippocampus both types of pain are shown in Table 1.
Normal waking and nocturnal erections erections
Reduced or absent waking and nocturnal
Normal erection with masturbation
No erection with masturbation
Life event Anxiety, fear and depression • Spinal trauma
TREATMENT OF ED
• Myelodisplasia (Spina bifida)
The primary goal of ED treatment is to ensure that the individual or couple can enjoy a satisfactory sexual experience. This holistic approach incorporates identifying any organic contributor to ED; initiating lifestyle changes and risk factor modification; providing relevant counselling to patients and their partners.5
• Pelvic surgery/radiotherapy • Multiple Sclerosis • Intervertebral disc lesion • Peripheral neuropathies – alcohol, diabetes, and HIV in particular Endocrine causes of ED • Hypogonadism – Low testosterone; raised sex hormone-binding globulin (SHBG); raised prolactin • Thyroid disease DRUGS ASSOCIATED WITH ED Table 1 – Drugs associated with ED DRUGS ASSOICATED WITH ED Anti-hypertsivesives • Thiazides
Lifestyle modifications can greatly reduce the risk of ED, and should accompany any specific pharmacotherapy or psychological therapy. However, pharmacotherapy should not be withheld on the basis that lifestyle changes have not been made. Psychosexual therapy should also be considered, taking the following into account 1.Regardless of the cause of ED, the patient will develop psychosexual issues that will contribute to performance anxiety. 2.Sensate focus exercises may be employed[viii], in accordance with 3.Relationship counselling
CONTEMPORARY PHARMACOTHERAPY FOR ED
• Centrally acting drugs
PDE5 Inhibitors (Phosphodiesterase type 5 inhibitors)
o Tricyclics o MAO inhibitors o SSRIs Anticholinergics • Atropine Antipsychotics • Phenothiazines Anxiolytics • Benzodiazepines Psychotropic Drugs • Alcohol • Opiates • Amphetamines • Cocaine
Part of the physiological process of erection involves the release of nitric oxide (NO) in the vasculature of the corpus cavernosum as a result of sexual stimulation. NO activates the enzyme guanylate cyclase that results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum, resulting in increased blood flow and an erection.[ix] PDE5 inhibitors inhibit the degradation of cGMP by phosphodiesterase type 5 (PDE5), increasing blood flow to the penis during sexual stimulation. This mode of action infers that PDE5 inhibitors are ineffective without sexual stimulation.5 It is currently recommended that patients should receive eight doses of a PDE5 inhibitor with sexual stimulation at maximum dose before classifying a patient as a non-responder.
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CPD 39: ERECTILE DYSFUNCTION FIGURE 1 - METHOD OF ACTION OF PDE5 INHIBITORS
Educational distance learning content for healthcare LOW RISK INTERMEDIATE RISKprofessionals in Ireland
Chronic Pain – assessment and management in SEXUAL primary care ACTIVITY
MANAGE ED IN PRIMARY CARE SETTING
DEFERRED UNTIL CARDIAC
RISK FACTORS AND CHD EVALUATION, TREATMENT AND FOLLOW-UP FOR ALL PATIENTS WITH ED Reproduced from Carson C,Holmes S,Kirby R. Fast Facts-Erectile Dysfunction. Oxford: Health Press Limited; 2002 TABLE 2 - LIST OF ORAL THERAPIES LICENSED FOR ED
Sildenafil (Viagra) 4 hours 25mg, 50mg, 100mg Introduction Tadalafil (Ciails) 10mg, 20mg Tadalafil (Cialis) 5mg Vardenafil (Levitra) 5mg, 10mg, 20mg
Window for sexual activity
1 hour before sexual activity
4-6 hour window Absorption delayed Sheehan et al reported in 1996 themeal. estimated cost of by that a fatty pain for 95 patients to the Irish Health Services when added 36 windowof Social Welfare Absorption not affected to hour the amount payments received and by food. the lost earnings of each patient amounted to 1.9 million 6 n/a affected pounds at the time of referral.Absorption The recentnot data from PRIME by survey show that the mean costfood per chronic pain patient is estimated at €5,665 per year across alldelayed grades of pain, 4-6 hour window Absorption by a fatty which was extrapolated to €5.34 billionmeal. or 2.86% of Irish GDP per year.7 This demonstrates an urgent need for cost effective strategies to manage chronic pain effectively. • Visual disturbance
Pain is17 one of the commonest reasons for patients to seek hours 30 minutes before shown that as many medical attention.1 A recent survey has sexual activity as 8.3 visits per year to primary care physicians in Ireland 17 hours May be taken daily were due to symptoms of pain.2 A large scale survey carried out in 15 European countries and Israel in 2006, screening hours 30-60 minutesof chronic 46,3944 respondents reported that the prevalence before sexual activity pain of moderate to severe intensity in adult Europeans was 19%.3
• Nasal Congestion More recent survey data from another study, carried out • Facial flushing • Dizziness • Priapism in 2,019 people with chronic pain and 1,472 primary Understanding chronic pain care physicians across 15 European countries, have • Headache • Dyspepsia • Non-arteritic anterior ischaemic Chronic pain optic is defined as pain that outlasts normal healing neuropathy7 demonstrated that chronic pain affects 12-54% of adult time (usually three to six months), and is most frequently Europeans, and its prevalence in Ireland is up to 13%.2 The associated with musculoskeletal disorders such as low TABLE 3 - PDE5 CONTRAINDICATIONS AND DRUG-INTERACTIONS PRIME (Prevalence, Impact and Cost of Chronic Pain) study, back pain and arthritis. However, it can also be associated on the other hand, determined the prevalence of chronic other disorders such as depression or metabolic PDE5 Contraindications PDE5 Drugwith Interactions pain to be as high as 35.5% in Ireland.4 The PRIME study disorders or neurologic conditions such as multiple was designed to investigate the prevalence of chronic Nitrates pain Recent cardiovascular event sclerosis. in Ireland; compare the psychological and physical health • Glyceryl trinitrate, isorbide mono or dinitrate • Chest pain after taking sildenafil/vardenafil no nitrates for 24 profiles of those with and without chronic pain; and explore Pain (acute or chronic) can be categorised as nociceptive hours, taldalfil 48 hour interval 4 pain-related disability. Responses to survey questions were or neuropathic. • Recreational amyl nitrateNociceptive pain is caused by an active obtained from 1,204 people. illness, injury and/or inflammatory process associated with Nitrate treated angina CyP450 inhibitors actual or potential tissue damage i.e. Nociceptive pain Despite the magnitude of the problem, chronic pain is • Protease kinase inhibitors – Ritonavir • Cimetidine, Ketoconazole, grapefruit juice to actual results from activityErythromycin, in neural pathways secondary both under-recognised and undertreated in primary care.2,5 or potential tissue damage. Nociceptive pain is mediated Hypotension Alpha Blockers Indeed, up to 38% of patients reported being inadequately Anatomical deformity by pain receptors located in skin, musculoskeletal system, managed in primary care disease for their pain symptoms.2 In • Angulation, cavernosal fibrosis, Peyronie’s bone, and joints.8 Neuropathic pain, on the other hand, addition, people with chronic pain reported waiting up to Predispostion to prolonged erection results from direct injury to a peripheral or central sensory • Sickle cell disease 2.2 years between seeking help and diagnosis, and 1.9 nerve; the affected nerves do not produce transduction at • Multiple myeloma years before their pain was adequately managed.2 • Leukemia nociceptors.8 Pain characteristics and associated conditions for both types of pain are shown in Table 1. SIDE EFFECTS OF PDE5 INHIBITORS
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CPD 39: ERECTILE DYSFUNCTION VACUUM ERECTION DEVICES
These are highly effective in inducing erections regardless of the aetiology of the ED. They exert their effect by trapping blood in the intracorporal and extra-corporal compartments of the penis.7 An erection can be maintained Module 1 for a maximum of 30 minutes with varying June 2012 satisfaction rates of 35-85%; anecdotal evidence suggests that if a man is satisfied with a vacuum pump, he will continue to use it on a long term basis. Adverse effects of vacuum sionals devices in Ireland include bruising, cyanosis, oedema, local pain and failure to ejaculate. Partners sometimes complain that the penis feels cold.5 Serious side effects such as skin necrosis have been reported, but are rare.
anagement in primary care SECOND LINE TREATMENT
Prostaglandin E1 (PGE1), Alprostadil, intracavernosal injection – Caverject, Viridal • Works independently of intact nervous system • Administration requires manual dexterity, adequate vision, and training
1998. What is without question is how indelibly linked ED is to the masuclinity and self esteem of the man. A season 1 episode of Friends in 1994 has the character Joey reveal that being impotent was a fate worse than death - “If little-Joey is dead, then I’ve got no reason to live.” Such melodrama aside, there is conflicting evidence that ED can precipitate depression, but it can certainly exacerbate depression;[iii] and new evidence has suggested that the emasculating effect of ED can be slightly overstated. A European study of 30,000 men confounds the stereotype of men’s perception of masculinity. Men reported that being seen as ‘honourable, self-reliant and respected by friends’ were the most important determinants of self-perceived masculinity – having an active sex life was seen as an important construct of masuculinty by only 3% of participants, regardless of whether they reported erectile difficulties.[iv] The study also highlighs that ED may matter to the man because of the impact on the valued partnered relationship, rather than any predicted, perceived personal slight. ED AND SOCIETY
• Contraindications include bleeding disorders, sickle cell anaemia, multiple myeloma, and leukemia.
ED is a complex, multifactorial condition. Its position as an isolated medical condition is however debatable – anecodotal evidence suggests that the incidence of ED has risen • The side effects include penoscrotal pain, by 250% since the advent of Viagra in 1998. hematoma, fibrosis tat injuection site and Never before has a drug seeped into the priapism. public consciousness, achieved such market Papaverine, phentolamine, aviptadil (vasopenetration, or become so synonymous with a ehan et intestinal al reported in 1996 thatbeen the estimated cost of medical condition, than Viagra. However, the peptide) have used as sole agents ortointhe combination Alprostadil n for 95 patients Irish Healthwith Services when added positive impact of the drug is far reaching. Men with comorbidities requiring polypharmacy he amount of Social Intraurethral Welfare payments received and Alprostadil devices simply require one more tablet to alleviate an lost earnings each patient to 1.9 million embarrassing, and in some cases, debilitating Museof (125mg, 250mg,amounted 500mg, 1g) nds at the time of referral.6 The recent data from PRIME function of their illness. While the drug is open This requires administration of a pellet into to abuse, this does not seem to be prevalent, vey showthe that the mean per chronic pain patient urethra usingcost an applicator. The penis is and PDE5 inhibitors have ensured that almost massaged to aid stimatedsubsequently at €5,665 per year across all absorption. grades of pain, no man is deprived a healthy sex life. Side effects include penile pain, dizziness and ch was extrapolated to €5.34 billion or 2.86% of Irish CONCLUSION priapism.
P per year.7 This demonstrates an urgent need for cost THIRD LINE TREATMENT ctive strategies to manage chronic pain effectively. Penile prosthesis
This formchronic of treatment should be offered derstanding pain
to those patients who are unresponsive to,
or second line onic painorisunwilling defined to as consider pain thatfirst outlasts normal healing treatments. All patients and their partners e (usuallyshould three to months),pre-operatively, and is most frequently besix counselled have ociated with musculoskeletal disorders such as low access to inspect all the available devices and, where appropriate, engage other k pain and arthritis. However, it can alsowith be associated patients who have undergone the procedure. h other disorders such as depressionsuitable or metabolic This treatment is particularly for those severe organic ED,such especially if the cause orders orwith neurologic conditions as multiple rosis. is Peyronie’s Disease. All patients should be
given a choice of either a malleable or inflatable prosthesis. The risks of this approach include n (acute or chronic) can be categorised as nociceptive – infection; compromise or destruction of the corpora cavernosa; and by extrusion; and europathic. Nociceptive painerosion is caused an active failure.7 process associated with ss, injurymechanical and/or inflammatory
ED is a worldwide, indiscriminate condition, affecting hundreds of million of men. It has many components and is rarely seen without other comorbidites. The advent of PDE5 inhibitors have offered a short-term treatment for the condition but further investigation for an underlying cause, psychogenic or organic must be undertaken. REFERENCES 1
Highlights of Changes from DSM-IV-TR to DSM-5” (PDF). American Psychiatric Association. May 17, 2013
Hatzimouratidis K et al Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation Eur Urol 2010, doi 10.1016/jeururo2010.02.02
Mc Vary KT Erectile Dysfunction New England Journal of Medicine; 357: 2472814 The American Urological Foundation Diagnosing Erectile Dysfunction 2009 Fact Sheet Press Release
ERECTILE DYSFUNCION AND MASCULINITY ual or potential tissue damage i.e. Nociceptive pain ults from Erectile activity dysfunction in neural pathways secondary actual or impotence, as it to was known, has beenpain affecting men otential perjoratively tissue damage. Nociceptive is mediated since time immemorial. Angus McLaren in 4 pain receptors located in skin, musculoskeletal system, his book, Two Millennea of Impotence Cures 8 e, and joints. Neuropathic pain, the on ages, the other charts ED cures through fromhand, Anicent Rome Greece (leek, asparagus and, not ults from direct and injury to a peripheral or central sensory 5 surpisingly perhaps, the genitalia of various ve; the affected nerves do not produce transduction at animals) to the 13th century (a roasted wolf 8 iceptors.penis), Pain characteristics and associatedviagra conditions all the way to the revolutionary in both types of pain are shown in Table 1.
British Society for Sexual Medicine Guidelines on the management of erectile dysfunction 2009: 279-283 NICE guidelines – Erectile Dysfunction updated July 2013
Ewan J “Erectile Dysfunction” Powerpoint Presentation uploaded October 2012
Van Hasselt, Vincent B.; Michel Hersen (1996). Sourcebook of psychological treatment manuals for adult disorders. Springer. pp. 348–351
Ning, Hongxiu et al. “Effects of icariin on phosphodiesterase-5 activity in vitro and cyclic guanosine monophosphate level in cavernous smooth muscle cells”. Urology 2006; 68 (6): 1350–4
Tsertsvadze A et al. “Diagnosis and treatment of erectile dysfunction” Agency for Healthcare Research and Quality (US) 2009: 1-9
10 Harte C, Meston C “Recreational use of erectile dysfunction medications in undergraduate men in the US: characteristics and associated risk factors.” Archives of Sexual Behaviour 2011; 40: 597-606 11 Harte C, Meston C “Recreational use of erectile dysfunctions and its adverse effects on erectile function in young healthy men: the mediating role of confidence in erectile abilty.” Journal of Sexual Medicine 2012; 9(7): 1852-9 12 Seidman S et al. “The relationship between depression and erectile dysfunction.” Current Psychiatry Reports 2000; 2: 201-205 13 Sand MS et al. “Erectile dysfunction and constructs of masculinity an quality of life in the Multinational Men’s Attitude to Life Events and Sexuality (MALES) study.” Journal of Sexual Medicine 2008; 5: 583-594
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