Symptoms & Causes of ED
The DSM-5 has identified 3 symptoms for ED1:
- Marked difficulty in obtaining an erection during sexual activity
- Marked difficulty in maintaining an erection until completion of sexual activity
- Marked decrease in erectile rigidity or hardness
What might be causing ED?2
The pathophysiology of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/or psychogenic.
- Vasculogenic conditions, for example, atherosclerosis, high BP, diabetes and high cholesterol.
- Neurogenic conditions, for example, multiple sclerosis, Parkinson’s disease or stroke.
- Hormonal conditions, for example, hypogonadism and hypo- or hyperthyroidism.
- Anatomical conditions, for example, Peyronie’s disease (a condition affecting the tissue of the penis), and hypospadias (abnormal development of the urethra).
- Drug-induced, Some medications that can cause erection problems:
- Diuretics are the most common medication causing ED
- Hormone therapy for prostate
- Recreational/illicit drugs can also cause erection problems
BP: blood pressure; DSM: Diagnostic and Statistical Manual of Mental Disorders; ED: erectile dysfunction; NCD: non-communicable disease.
- Mitchell KR, Jones KG, Wellings K, et al. Estimating the Prevalence of Sexual Function Problems: The Impact of Morbidity Criteria. J Sex Med. 2016;53(8):955-967.
- Hatzimouratidis K, Giuliano F, Moncada I, Muneer A, Salonia A, Verze P. European Association of Urology. Guidelines on erectile dysfunction, premature ejaculation, penile curvature and priapism. March 2016. Uroweb Web site https://uroweb.org/wp-content/uploads/EAU-Guidelines-Male-SexualDysfunction-2016.pdf. Accessed May, 2021.
ED as a Biomarker of NCD
Erection as the most efficient marker of the phenotypic condition of biological systems.
- ED is correlated with general health and health prognosis and may have evolved as a marker of poor phenotypic quality.1
- It is an excellent, if not the best, surrogate marker of vascular, endocrine, neurological, immunological, oncological, systemic, toxicological, psychiatric, environmental, intrapsychic and relational health.1
Management of NCD-generated ED
- Optimal pharmacologic management of diseases comorbid with ED is dependent upon long-term treatment adherence.2
- ED may contribute to poor adherence to medication use because poor-quality erectile function may be an unwanted adverse effect of some medications.2
- Therefore, diagnosis and successful treatment of concomitant ED may promote improved adherence and management of comorbid diseases.2
ED: erectile dysfunction; NCD: non-communicable disease.
- Cellerino A, Jannini EA. Male reproductive physiology as a sexually selected handicap? Erectile dysfunction is correlated with general health and health prognosis and may have evolved as a marker of poor phenotypic quality. Med Hypotheses. 2005;65(1):179-184.
- Scranton RE, Goldstein I, Stecher VJ. Erectile dysfunction diagnosis and treatment as a means to improve medication adherence and optimize comorbidity management. J Sex Med. 2013;10(2):551-561.
Prevalance of ED Comorbidities
In the “Multinational Men’s Attitudes to Life Events: and Sexuality (MALES)” study:
Men with comorbid medical conditions and risk factors all reported higher prevalence of ED.1
Prevalance of comorbidities is higher in men with ED1-4
ED, appearing in otherwise healthy men, may be an indicator of serious systemic conditions that have not yet manifested in other ways.5
ED: erectile dysfunction; NCD: non-communicable disease.
- Rosen RC, Fisher WA, Eardley I, Niederberger C, Nadel A, Sand M. The multinational Men’s Attitudes to Life Events and Sexuality (MALES) study: I. Prevalence of erectile dysfunction and related health concerns in the general population. Curr Med Res Opin. 2004;20(5):607-617.
- Awad H, Salem A, Gadalla A, El Wafa NA, Mohamed OA. Erectile function in men with diabetes type 2: correlation with glycemic control. Int J lmpot Res. 2010;22(1):36-39.
- Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA. 2004;291(24):2978-2984.
- Feldman HA, Johannes CB, Derby CA, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med. 2000;30(4):328-338.
- La Rochelle JC, Levine LA. Evaluation of the patient with erectile dysfunction. In: Male Sexual Function. Current Clinical Urology. Humana Press. 2006:253-270.
Cardiovascular Diseases & ED
Erectile Dysfunction and Comorbidities
- ED may be an early indicator for identifying men at higher risk of CVD,1 which has been demonstrated to occur on average 3 to 5 years prior to the CV event.2
- Incidence of cardiac disease tends to be higher in those with ED.1 Studies have reported an increased prevalence of ED in patients with CAD compared with men without CAD as well as an increased risk of CVD in men with ED compared with men without ED.2
- In a retrospective study of 62 men admitted to the hospital for first MI, 51.6% of patients were reported to have pre-existing ED.2
- ED and CVD share many common risk factors, including age, hypertension, diabetes, insulin resistance, smoking, increased BMI, cholesterol and lower HDL.2
- The artery size hypothesis stipulates that ED is an earlier symptom of systemic atherosclerosis.3
The artery size hypothesis. (A) Early stage of the atherosclerotic process. Significant vascular obstruction (>50% lumen artery narrowing) of penile circulation leading to ED symptoms is shown. (B) Late stage of the atherosclerotic process. Significant vascular obstruction of coronary circulation leading to angina pectoris is shown.3
The relationship between ED and CVD in various multivariate models.4
*Hazard ratio compared with men with no ED.
†Wald Chi-square test.
‡The multivariate model includes BMI (continuous) and the variables that are part of the Framingham risk score: Age, HDL cholesterol and TC (all as continuous variables), as well as current smoking (yes/no), and hypertension categorised according to BP readings by JNC-V definition (optimal, normal, high normal, Stages I-IV).4
A systematic literature review was conducted to analyse the relationship between ED and CVD, including pathological links between these conditions. A systematic literature review searching medline, embase and web of science databases was performed. The search strategy included the terms erectile dysfunction, cardiovascular disease, coronary artery disease, risk factors, pathophysiology, atherosclerosis, low androgen levels, inflammation, screening and phosphodiesterase type 5 inhibitors alone or in combination. ED and CVD should be regarded as 2 different manifestations of the same systemic disorder. ED usually precedes CVD onset, and it might be considered an early marker of symptomatic CVD.1
A systematic review discusses the role of cardiologists and urologists in the characterisation of risk and management of CVD in the setting of ED, as well as contrasting the current evaluation of CVD and ED from the standpoint of published consensus statements.2
A pathophysiologic mechanism was proposed to explain the link between ED and CAD called the artery size hypothesis. Given the systemic nature of atherosclerosis, all major vascular beds should be affected to the same extent. However, symptoms rarely become evident at the same time. This difference in rate of occurrence of different symptoms is proposed to be caused by the different size of the arteries supplying different vascular beds that allow a larger vessel to better tolerate the same amount of plaque compared with a smaller one.3
A prospective, population-based study of 1709 men (of 3258 eligible) aged 40-70 years was conducted. ED was measured by self-report. Subjects were followed for CVD for an average follow-up of 11.7 years. The association between ED and CVD was examined using the Cox proportional hazards regression model. The discriminatory capability of ED was examined using c-statistics. The reclassification of CVD risk associated with ED was assessed using a method that quantifies net reclassification improvement.4
BMI: body mass index; BP: blood pressure; CAD: coronary artery disease, CI: confidence interval; CV: cardiovascular; CVD: cardiovascular disease, ED: erectile dysfunction, HDL: high-density lipoprotein, JNC: Joint national committee on detection, evaluation, and treatment of high blood pressure; MI: myocardial infarction, NCD: non-communicable disease; TC: total cholesterol; TIA: transient ischaemic attack.
- Gandaglia G, Briganti A, Jackson G, et al. Systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol. 2014;65(5):868-968.
- Raheem OA, Su JJ, Wilson JR, Hsieh TC. The association of erectile dysfunction and cardiovascular disease: a systematic critical review. Am J Mens Health. 2017;11(3):552-563.
- Montorsi P, Ravagnani PM, Galli S, et al. The artery size hypothesis: a macrovascular link between erectile dysfunction and coronary artery disease. Am J Cardiol. 2005;96(12B):19M-23M.
- Araujo AB, Hall SA, Ganz P, et al. Does erectile dysfunction contribute to cardiovascular disease risk prediction beyond the Framingham risk score? J Am Coll Cardiol. 2010;55(4):350-356.
Diabetes & ED
- ED is one of the most common complication of diabetes mellitus. Depending on the severity and duration of diabetes, the prevalence of ED ranges from 20% to 85%1
- 83.6% of men with diabetes had some degree of ED2
- The Massachusetts Male Aging Study showed a 28% age-adjusted prevalence of ED in men with diabetes compared with 10% in men without diabetes, that is, a 3-fold increased risk1
- Prevalence of ED is higher in men with diabetes who are older than 50 years, nearly double than that in age-matched men without diabetes (45.8% vs. 24.1%)1
- An increase in the relative risk of ED was associated with increased duration of diabetes2. 50% of men with diabetes will experience ED within 10 years of diagnosis3
- Epidemiological studies suggest that both type 1 and type 2 diabetes are associated with an increased risk of ED, which is reported to occur in ≥50% of men with diabetes worldwide4
Association between diabetes and ED
- Some observational studies have shown an association between poor glycaemic control, expressed by elevated levels of glycated HbA1c, and ED4
- Hyperglycaemia, which is a main determinant of vascular and microvascular diabetic complications, may participate in the pathogenetic mechanisms of sexual dysfunction in diabetes4
- Patients with diabetes may present several clinical conditions, including hypertension, overweight and obesity, metabolic syndrome, cigarette smoking and atherogenic dyslipidaemia, which are themselves risk factors for sexual dysfunction4
- The use of several medications frequently assumed by diabetic patients, such use of antihypertensive drugs (β blockers, thiazide diuretics and spironolactone), psychotropic drugs (antidepressants) and certain fibrates, have all been associated with an additive deleterious effect on diabetic ED4
Pathogenesis of ED in diabetes
Diabetic vasculopathy concerns macroangiopathy, microangiopathy and endothelial dysfunction.4
i.Macrovascular disease in diabetes corresponds to the atherosclerotic damage in the blood vessels, which limits blood flow to the penis.4
i.Microvascular disease determines ischaemic damage in the distal circulation and autonomic and peripheral neuropathy. Both somatic and autonomic neuropathies may contribute to diabetes-induced ED due to the impairment of sensory impulses from the penis to the reflexogenic erectile centre, and reduced or absent parasympathetic activity necessary for relaxation of the smooth muscle of the corpus cavernosum.4
i.Endothelial dysfunction in diabetes is manifested as the decreased bioavailability of NO, resulting in insufficient relaxation of the vascular smooth muscle of the corpora cavernosa.4
Insulin resistance and visceral adiposity, which are both distinctive clinical traits of type 2 diabetes, are associated with a proinflammatory state that results in the decreased availability and activity of NO, leading to ED in overweight and obese diabetic men.4
To examine the association between ED and vascular disorders in the context of current knowledge regarding PDE-5 inhibitors, an electronic search was performed of articles published from January 2002 through April 2008 using the PubMed, EMBASE and MEDLINE databases. Although preference was given to randomised, blinded, controlled clinical trials, data from retrospective studies were also reviewed when appropriate.1
The study was conducted to evaluate the association of glycaemic control with risk of ED in type 2 diabetics. A self-administered questionnaire containing SHIM was obtained from 792 subjects with type 2 diabetes. Clinical data were obtained through the chart review. Better glycaemic control probably would reduce the prevalence of ED and its severity among the younger men with type 2 diabetes. For the older group, ageing was the major determinant for ED risk among this population with type 2 diabetes.2
A prospective study was conducted to evaluate 7 classic CHD risk factors (age, smoking, hypertension, diabetes, hypercholesterolaemia, hypertriglyceridemia and obesity) in 1810 men aged between 30 and 69 years from 1972 to 1974. In 1998, after an average follow-up of 25 years, surviving male participants were asked to complete the IIEF-5, which allows stratification of ED into 5 groups. Improving CHD risk factors in mid-life may decrease the risk of ED as well as CHD. ED should be included as an outcome in clinical trials of lipid-lowering agents and lifestyle modifications.3
CHD: chronic heart disease; ED: erectile dysfunction, IIEF: international index of erectile function; NCD: non-communicable disease; NO: nitric oxide; PDE5: phosphodiesterase; SHIM: Sexual Health Inventory of Men.
- Nehra A. Erectile dysfunction and cardiovascular disease: efficacy and safety of phosphodiesterase type 5 inhibitors in men with both conditions. Mayo Clin Proc. 2009;84(2):139-148.
- Lu CC, Jiann PB, Sun CC, Lam HC, Chu CH, Lee JK. Association of glycemic control with risk of erectile dysfunction in men with type 2 diabetes. J Sex Med. 2009; 6(6):1719-1728.
- Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol. 2004;43(8):1405-1411.
- Maiorino MI, Bellastella G, Esposito K. Diabetes and sexual dysfunction: current perspectives. Diabetes Metab Syndr Obes. 2014;7:95-105.
Hypertension & ED
- Hypertension is considered one of the most hazardous CV risk factors and it is a frequent comorbidity of men with ED1
- Men with hypertension are at higher risk of ED2
- The overall prevalence of ED in patients with hypertension was 61% as reported on the patient questionnaire and 67% according to the IIEF-53
- ED was more frequent among those with more antihypertensive drugs or systolic pressure over 140 mm Hg1
- ED is an early sign for hypertension4
Relationship between hypertension and ED1
- Hypertension and ED are closely intertwined diseases which have endothelium dysfunction as a common base4
- During hypertension and/or ED, disturbance of endothelium-derived factors can lead to an increase in VSM contraction4
- Hypertension can also lead to ED as a consequence of high BP or due to antihypertensive treatment4
Relationship between hypertension and ED
Depending on the class of the antihypertensive drug and its effect over endothelium mediators, the impact on ED could be positive or negative. PDE-5 inhibitors, ED’s first-line therapy, present a mechanism of action based on NO bioavailability. Continuous use of PDE-5 inhibitors proved to reverse endothelial dysfunction with positive impact on sexual function and even on BP control.1
- Studies in models of pre-clinical hypertension have suggested that high BP causes morphological modifications in the penile vascular bed, contributing to ED4
- In the vasculature, as well in the penile tissue, circulating neurotransmitters, hormones and endothelium-derived factors play a critical role in modulating the VSM tone. During hypertension, disturbance of these factors can lead to an increase in VSM tone which favours contraction4
Adapted from Javaroni V, et al. Int J Hypertens. 2012.
Adapted from Nunes KP, et al. Curr Opin Nephrol Hypertens. 2012.
Pathways involved in erectile function:
On the right, signalling pathways involved in mediating CSMC relaxation. On the left, signalling pathway involved in mediating CSMC contraction. During normal conditions, there is a balance between pro-erectile and pro-relaxation signalling pathways resulting in a normal erectile function. During hypertension, there is an increase in pro-contractile signalling and/or decrease in pro-relaxation signalling resulting in increased contractility and decreased relaxation of CSMC, therefore, resulting in ED. Treatment with hypertensive drugs resulting in either increasing CSMC relaxation (i.e. PDEi), or decreasing CSMC contractility (i.e. ACEi), which will result in improvement of CSMC function and improving or restoring erectile function.4
The MALES Phase 1 study looked at the prevalence of ED and related health concerns in the general population and included 27,839 men aged 20 to 75 years who were interviewed using a standardised questionnaire. The MALES study confirms the high prevalence rates of ED and its association with co-morbid medical conditions, such as diabetes and depression, reported in other large-scale, epidemiological studies. Despite the advent of oral PDE inhibitors, only 58% of ED sufferers consult a physician about their problem, and only 16% of men with self-reported ED maintain their use of oral therapy.2
In total, 7689 patients (mean ± SD age 58.9 ± 9.2 years), including 6719 (87%) in a stable sexual relationship were surveyed. The abbreviated 5-item version of the IIEF-5 was used to determine the presence of ED. A patient questionnaire was used to assess attitudes about ED.3
The interplay between hypertension and ED, exploring newest insights regarding hypertension-associated ED, as well as the effect of antihypertensive drugs in ED patients has been reviewed.4
Ach: acetylcholine; ACE: angiotensin-converting enzyme; ACEi: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blockers; BP: blood pressure; CBS: cystathionine-β-synthase; CSE: cystathionine gamma-lyase; CSMC: cavernosal smooth muscle cell; CV: cardiovascular; DAG: diacylglycerol; ED: erectile dysfunction; eNOS: endothelial nitric oxide synthase; GMP: guanosine monophosphate; GTP: guanosine-5'-triphosphate; H2S: hydrogen sulphide; IIEF: International Index of Erectile Function; IP3: inositol 1,4,5-trisphosphate; PDE-5: phosphodiesterase 5; PIP2: phosphatidylinositol 4,5-bisphosphate; MLC: myosin light chain; MLCK: myosin light chain kinase; NCD: non-communicable disease; NO: nitric oxide; nNOS: Neuronal nitric oxide synthase; PLC: phospholipase C; PDE: phosphodiesterase; PDEi: phosphodiesterase inhibitor; PKG: protein kinase G; sGC: soluble guanylyl cyclase; VSM: vascular smooth muscle
- Javaroni V, Neves MF. Erectile dysfunction and hypertension: impact on cardiovascular risk and treatment. Int J Hypertens. 2012;2012:627278.
- Rosen RC, Fisher WA, Eardley I, Niederberger C, Nadel A, sand M. The multinational Men's Attitudes to Life Events and Sexuality (MALES) study: l. Prevalence of erectile dysfunction and related health concerns in the general population. Curr Med Res Opin. 2004;20(5):607-617.
- Giuliano FA, Leriche A, Jaudinot EO, de Gendre AS. Prevalence of erectile dysfunction among 7689 patients with diabetes or hypertension, or both. Urology. 2004;64(6):1196-1201.
- Nunes KP, Labazi H, Webb RC. New insights into hypertension-associated erectile dysfunction. Curr Opin Nephrol Hypertens. 2012;21(2):163-170.
Lifestyle impact on ED
Obese men are at higher risk of developing ED1
The prevalence of overweight or obese men reporting symptoms of ED may be as high as 79%.2
How are obesity and ED related?
- Visceral obesity is associated with increased inflammatory responses, which contribute to endothelial dysfunction. Furthermore, obesity is also associated with reduced plasma testosterone levels, which contributes to hypogonadism and increases the risk of vascular pathology1
- Endothelial dysfunction and androgen deficiency have been linked to the pathophysiological mechanisms of ED. The underlying pathophysiological mechanisms of endothelial dysfunction and testosterone deficiency include penile vascular insufficiency as a result of the loss of NO synthase expression and activity and the loss of tissue compliance, resulting in reduced haemodynamic properties1
Randomised, single-blind trial of 110 obese men (BMI ≥30) aged 35 to 55 years, without diabetes, hypertension or hyperlipidaemia, who had ED that was determined by having a score of 21 or less on IIEF. The study was conducted from October 2000 to October 2003 at a university hospital in Italy. The objective of the study was to determine the effect of weight loss and increased physical activity on erectile and endothelial functions in obese men. Lifestyle changes are associated with improvement in sexual function in about one-third of obese men with ED at baseline.2
Men with ED may experience anxiety, depression, reduced self-esteem and a reduced quality of life.3
Prevalence of depression or anxiety in men with and without ED4
- 25% of men with ED have depression or anxiety4
Adapted from Rosen RC, et al. Curr Med Res Opin. 2004
The MALES Phase 1 study looked at the prevalence of ED and related health concerns in the general population and included 27,839 men aged 20 to 75 years who were interviewed using a standardised questionnaire. The MALES study confirms the high prevalence rates of ED and its association with co-morbid medical conditions, such as diabetes and depression, reported in other large-scale, epidemiological studies. Despite the advent of oral PDE inhibitors, only 58% of ED sufferers consult a physician about their problem, and only 16% of men with self-reported ED maintain their use of oral therapy.4
Cigarette smoking may be a cause of ED.5
The relation between smoking and ED
- The main physiological mechanism that appears to be affected includes the NO signal transduction pathway5
- Cigarette smoking can lead to CV dysfunction and is now established to be Cigarette smoking can lead to CV dysfunction and is now established to be an independent risk factor for the development of ED5
- In a specific cohort of young men <40 years of age, smoking was a significant risk factor for ED6
- In the Male Health Professionals Study, of the 22,086 men without baseline ED, the relative risk that smokers developed ED over a follow-up of 14 years was 1.4 (95% CI 1.3-1.6)5
Review details the recent literature linking cigarette smoking to ED, epidemiological associations, dose-dependency and the effects of smoking cessation on improving erectile quality.5
BMI: body mass index; CAD: coronary artery disease, CI: confidence interval; CV: cardiovascular; ED: erectile dysfunction; IIEF: International Index of Erectile Function; MALES: Multinational Men’s Attitudes to Life Events and Sexuality. NCD: non-communicable disease; NO: nitric oxide; PDE: phosphodiesterase.
- Traish AM, Feeley RJ, Guay A. Mechanisms of obesity and related pathologies: androgen deficiency and endothelial dysfunction may be the link between obesity and erectile dysfunction. FEBS J. 2009;276(20):5755-5767.
- Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA. 2004;291:2978-2984.
- Hwang TIS, Tsai T-F, Lin Y-C, Chiang H-S, Change LS. A survey of erectile dysfunction in Taiwan: use of the erection hardness score and quality of erection questionnaire. J Sex Med. 2010;7(8):2817-2824.
- Rosen RC, Fisher WA, Eardley l. Niederberger C, Nadel A, Sand M. The multinational Men's Attitudes to Life Events and Sexuality (MALES) study: I. Prevalence of erectile dysfunction and related health concerns in the general population. Curr Med Res Opin. 2004;20(5):607-617.
- Kovac J, Labbate C, Ramasamy R, Tang D, Lipshultz L. Effects of cigarette smoking on erectile dysfunction. Andrologia. 2014;47(10):1087-1092.
ED comorbidities by age
New real-world results from a database of 48 million men in the US showed that:
- Men with ED are at risk of the below comorbidities even at younger ages1
- The diagnosis of ED followed an inverted U-shaped pattern, with diagnosis peaking in patients aged 50-59 years and then declining in the older age groups1
- CVD, DM and depression had a statistically significant association with ED, and importantly this association was evident in patients as young as 30-39 years of age1
Younger men with ED should be evaluated for comorbidities even men as younger as 30 years old.1
This was a cross-sectional, non-interventional study in men aged ≥18 years using data from the Truven Health MarketScan® and Medicare Supplemental Research Databases from January 2010 to December 2015, with an observational period of January 2011 to December 2014 to allow for 12 months pre- and post-index. Comorbidity rate was compared between ED and non-ED groups by age using the χ2 (bivariate) test. Comorbidity relationship to ED after controlling for categorical variables was assessed using logistic regression analysis.1
CI: confidence interval; CVD: cardiovascular disease, DM: diabetes mellitus, ED: erectile dysfunction; IIEF: International Index of Erectile Function; NCD: non-communicable disease; NO: nitric oxide; US: United States
- Goldstein I, Chambers R, Tang W, et al. Real-world observational results from a database of 48 million men in the United States: relationship of cardiovascular disease, diabetes mellitus and depression with age and erectile dysfunction. Int J Clin Pract. 2018;72(4):e13078.