Impotence is a common clinical condition that mainly affects men over the age of 40. The common causes of impotence include diabetes and hypertension, as well as obesity, physical inactivity and lower urinary tract syndrome. There is definite evidence that impotence is associated with cardiovascular disease. Patients with impotence are susceptible to coronary heart disease, and therefore, cardiovascular disease risk assessment is recommended. In-depth studies on the pathophysiological mechanisms of impotence have led to the successful development of effective oral drugs such as phosphodiesterase 5 inhibitors in humans. However, phosphodiesterase 5 inhibitors have their limitations, and new therapeutic approaches, including new therapies based on genetic and cellular technologies, are being investigated with a view to treating the persistent disease of impotence.
Preface
Impotence is a male disease in which the penis does not lift during sexual intercourse, does not hold firm or does not hold firm for long, leading to failure of intercourse. 5000 years ago, this disease was described in ancient Egyptian literature, which shows the long history of impotence. History will remember that in 1998, Pfizer developed the first effective oral drug for impotence in the history of mankind, cetiramorphine citrate (Viagra, also known as Viagra). Cetiramorphine is a selective phosphodiesterase 5 inhibitor that releases nitric oxide (NO) to relax the smooth muscle of the penile corpus cavernosum, allowing erection. the involvement of NO in penile erection has spawned a great deal of research on male sexual dysfunction.
Epidemiology
Impotence is a common clinical condition that mainly affects men over the age of 40. A recent study showed that the incidence of impotence in men under 40 years of age was 1-10%, in men 40-49 years of age it was 2-9%, in men 60-69 years of age it increased to 20-40%, and in men over 70 years of age it was as high as 50-100%. The Massachusetts Male Aging Study shows that the incidence of impotence is 26/1000 person-years and increases with age, and the incidence of impotence in men aged 60-69 years is 46/1000 person-years. Worldwide, 322 million impotence patients are predicted by 2025. Impotence has now become a serious health problem in the aging population.
Cross-sectional studies as well as longitudinal studies have shown that impotence is associated with diabetes, hypertension, hyperlipidemia, metabolic syndrome, depression, and lower urinary tract disorders. Epidemiological studies have shown that impotence is a precursor to cardiovascular disease, and a meta-analysis of 12 prospective studies showed a strong association with cardiovascular disease, as well as with coronary heart disease, stroke, and all-cause mortality. Other studies suggest that certain environmental factors and lifestyle practices, such as smoking, obesity, and lack of exercise, may also be important in the development of impotence; dietary changes and encouragement of exercise may improve impotence.
Physiological mechanisms of penile erection
The release of NO from vascular endothelial cells and parasympathetic nerve endings is the main neurotransmitter involved in penile erection; NO relaxes the smooth muscle of the penile corpus cavernosum, resulting in compression of the small veins under the penile peritoneum and local obstruction of venous return, leading to penile erection. The activation of adrenergic receptors on the surface of the cavernous arteries and smooth muscles causes a decrease in arterial blood inflow and collapse of the cavernous cavity; the resistance to the return of the small penile cavernous veins decreases, the cavernous cavity is underfilled with blood, and penile weakness occurs.
Pathophysiology and causes
Normal sexual function is a process influenced by physiological, psychological and social factors, involving psychological, endocrine, vascular and neurological synergies. Impotence can be divided into three types: psychogenic, organic and mixed, with mixed impotence being the most common.
Psychogenic impotence
A significant proportion of patients with impotence is caused by psychological factors or by a combination of psychological and organic factors. An important psychological factor associated with impotence is intercourse anxiety (fear of failure to have intercourse). Historical theories explaining the psychological factors of impotence suggest that developmental, cognitive, emotional, and interpersonal factors make men susceptible to impotence. It is now believed that impotence due to psychological factors is mainly associated with a group of predisposing, aggravating, and maintaining factors.
Neurogenic impotence
Certain neurological disorders are associated with impotence, such as multiple sclerosis, temporal lobe epilepsy, Parkinson’s disease, stroke, Alzheimer’s disease, and spinal cord injury. Radical pelvic surgery, such as prostatectomy patients, can result in damage to the cavernous nerves and subsequent neurogenic impotence. Recent advances in surgical techniques have dramatically reduced the incidence of post-pelvic surgery impotence.
Endocrine impotence
Androgens play an important role in enhancing libido and maintaining adequate sleep-related erections, but have a limited role in the visible induction of erectile function. In addition, testosterone plays an important role in the regulation of NO synthase and phosphodiesterase 5 expression in the penis. Recent studies have shown that testosterone deficiency or hypogonadism is associated with lethality and disability in cardiac and blood disorders. The sexual dysfunction caused by hyperprolactinemia is the result of decreased testosterone concentration. Increased prolactin inhibits gonadotropin-releasing hormone, and decreased gonadotropin-releasing hormone reduces the secretion of luteinizing hormone, which is dependent on testosterone secretion.
Vascular impotence
Arteriosclerosis, hypertension, hyperlipidemia, smoking, diabetes mellitus, and radical pelvic surgery can all cause impaired penile artery function. The immediate cause of vascular impotence is vascular endothelial dysfunction. Studies have shown that the incidence of impotence in patients with hypertension is as high as 68%. Impotence can be improved with dietary control or statin therapy to lower total and LDL cholesterol levels. Diabetes, hypertension, dyslipidemia, obesity and smoking are all strong risk factors for coronary heart disease and impotence.
The current Princeton III consensus identifies impotence as a risk factor for cardiovascular disease, particularly coronary heart disease. The association between cardiovascular disease and impotence was confirmed in patients at high risk for cardiovascular disease. inman and colleagues screened a random sample of 1,400 men (with regular sexual partners and no coronary disease) residents for impotence every 2 years for a total of 10 years of follow-up and found that 11% of the men developed coronary heart disease, of which 15% had myocardial infarction, 79% had coronary artery malformation, and 6% had sudden death. The cumulative incidence of coronary heart disease was influenced by the age of the patients. In patients without impotence, the density of coronary heart disease occurrence/1000 person-years was 0.94 (40-49 years), 5.09 (50-59 years), 10.72 (60-69 years) and 23.30 (>70 years), respectively.
In contrast, in patients with impotence, the density of coronary heart disease occurrence/1000 person-years was 48.52 (40-49 years), 27.15 (50-59 years), 23.97 (60-69 years), and 29.63 (>70 years), respectively. The most important finding of this study is that the risk of future cardiac events is significantly higher in men under 60 years of age with impotence, compared to those without impotence; however, its predictive value is less in men over 60 years of age. Inman and colleagues suggest that impotence, like coronary artery disease, shares a common pathophysiological alteration: dysfunction of the vascular endothelium.
Other explanations include abnormalities in the L-serotonin NO pathway, increased peripheral sympathetic activity, altered vascular structure causing restricted vasodilatory function, and increased specific inflammatory mediators. montorsi and colleagues suggest that this phenomenon may be related to the size of the internal diameter of the vessels. The diameter of the penile artery is about 1-2 mm, and the diameter of the proximal segment of the anterior descending cardiac vessels is about 3-4 mm. Atheromatous plaques of the same size occurring in the thinner penile artery have a more pronounced effect on blood flow, and thus early patients complain of impotence rather than angina. Reduced resistance to venous return is another important cause of impotence, such as large venous diameters diverting blood from the cavernous tissue.
Drug-induced impotence
Psychotropic drugs and antidepressants are the most likely causes of impotence. Patients taking antidepressants, such as selective 5hydroxytryptamine reuptake inhibitors and vanafloxacin, have a high incidence of impotence. The antipsychotic drugs risperidone and olanzapine were most likely to cause pharmacological impotence. Thiazides, followed by b-blockers, were the antihypertensive drugs most likely to cause impotence, while a-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers were the antihypertensive drugs least likely to cause impotence. The most common drugs that cause impotence are listed in Table 3.
Common drugs that cause impotence
Anti-androgen drugs
Gonadotropin-releasing hormone antagonists (leuprolide, goserelin, leuprolide acetate, and norethindrone)
Chemotherapy (cyclophosphamide and leucovorin)
Flutamide
Ketoconazole
Spironolactone
H2 receptor blockers
Cimetidine
Anti-hypertensive drugs
Thiazide diuretics
b-blockers
Calcium channel blockers
Anti-arrhythmic drugs
Digoxin
Cordarone
Propiamine
Statins
The effect of atorvastatin on erectile function is controversial
Psychotropic drugs
Tricyclic antidepressants
Selective 5hydroxytryptamine reuptake inhibitors
Phenothiazines
Phenylbutazone
Drugs
Cannabis
Opiates
Nicotine
Alcohol
Impotence due to aging, lifestyle and systemic diseases
Epidemiological studies have shown that age is a major risk factor for impotence. The incidence and severity of impotence increases with age. The Massachusetts Aging Study showed that 39% of men older than 40 years of age had varying degrees of impotence, with the incidence of impotence increasing progressively to 67% by age 70. Two other independent studies with large samples, one of 2,476 Spanish men and the other of 1,464 men in the Middle East, also confirmed the relationship between impotence and age.
Type 2 diabetes is another common risk factor for impotence, with 50-57% of diabetics having impotence. Impotence is three times more common in diabetics than in non-diabetics, and impotence is the first symptom in 12% of diabetics. Sedentary lifestyle, smoking, alcohol, drug use, sleep disorders, obesity, and metabolic syndrome are all associated with impotence. In addition, long-term bedridden diseases such as chronic kidney disease, liver disease, and lung disease are also associated with impotence.
Risk factors for impotence
Age
Physical inactivity and mental illness
Lifestyle
Sedentary lifestyle
Obesity
Smoking
Alcohol addiction
Drug use
Metabolic factors and metabolic syndrome
Diabetes
Hypertension
Dyslipidemia
Hypogonadism
Diagnosis
Currently, guidelines recommend a goal-oriented approach to evaluating patients for impotence: to clarify whether the impotence is true; to determine the cause of the impotence; and to identify risk factors for impotence and potentially life-threatening conditions associated with impotence.
Medical history taking
Diagnosis of impotence is mainly based on detailed history taking and intercourse. During the initial consultation, the receiving physician should learn more about the patient’s psychosocial condition, the patient’s evaluation of his or her sexual function, and his or her general attitude and knowledge about sex. It is best to ask about the sexual partner as well. Sometimes, the history can reveal complex psychological problems such that a psychologist is needed.
In some cases, the patient may have premature ejaculation. Impotence, on the other hand, is weakness that occurs before orgasm. Weakness due to premature ejaculation cannot be called impotence. It is important to know whether the cause of impotence is organic or psychological. If you wake up in the morning or have an erection at night, or if you have an erection during sexual fantasy, the impotence is mostly due to psychological factors. If impotence occurs suddenly, in intermittent episodes or within a short period of time, it is also mostly due to psychological factors. On the contrary, impotence that appears gradually, progressively or for a long time is mostly due to organic factors. Drug-related impotence includes alcoholism, smoking, drug use, and decreased or altered libido. Past history and surgical history should also be described in detail.
Standardized scales are often used to confirm the diagnosis of impotence and to evaluate its severity. These scales are also used to evaluate the efficacy of the treatment. Two scales are most commonly used: the International Index of Penile Erectile Function and the Men’s Sexual Health Database.
Recent studies have found that impotence is a strong predictor of coronary heart disease, and impotence often predicts that patients may have a cardiovascular event 2-3 years later, so the risk of cardiovascular disease in patients with impotence needs to be critically assessed. Patients with impotence should be treated as cardiac patients even in the absence of any cardiac manifestations, unless definitive evidence can rule out cardiac disease. After a thorough medical evaluation, patients with impotence need to be risk stratified for cardiovascular disease risk. (Table 1).
After cardiovascular disease risk stratification, it is important to assess the patient for the presence of occult coronary artery disease, (Figure 3), and this assessment is particularly important in men <60 years of age with low and intermediate risk of cardiovascular disease risk stratification. An ECG should be routinely performed, and if abnormal, an exercise ECG is recommended. If abnormalities persist, an in-depth examination is recommended and referral to a cardiologist is possible. Evaluation of coronary risk in specific populations also includes waist circumference, body mass index, coronary artery calcification score, carotid intima-media thickness, peripheral arterial tone, and serum asymmetric adhesion molecules.
Physical examination
All patients with impotence should undergo a general physical examination and a locally targeted physical examination. Table 5 lists the major items of the physical examination. The localized physical examination also provides a good opportunity for physician education of the patient.
Laboratory evaluation
Fasting glucose and testosterone levels are two mandatory tests, and lipid testing is also important because impotence is a strong predictor of vascular disease. Hormone levels, including luteinizing hormone and lactogen, should be evaluated if total or free testosterone levels are low. After the initial evaluation of impotence by the primary care physician, many complex organic and psychological problems may be faced that require further comprehensive evaluation, often by specialists. Table 6.
Special tests
Understanding whether impotence is reversible is also part of the treatment for some patients with impotence, especially younger men and their partners. In addition, some impotence may be associated with potentially life-threatening cardiovascular disease. The routine use of invasive tests to diagnose impotence is not recommended because even if a patient undergoes an invasive test, it is not relevant to treatment planning adjustments. Table 2 lists the most common specific diagnostic tests for impotence, their advantages and shortcomings. Techniques to evaluate penile endothelial function based on research purposes are penile NO release test, Endo-PAT200079, detection of serum and cellular markers such as endothelin-1, C-reactive protein and endothelial cell progenitor cells.
Treatment
Overall, phosphodiesterase 5 inhibitors are the primary drug of choice for the treatment of impotence. Other treatments include lifestyle changes, penile devices, and psychotherapy. Figure 4.
Psychosexual, spousal, and partner therapy
Psychosexual therapy is appropriate for those with psychological factors causing impotence. Psychosexual treatment techniques include arousal, sex education, and interpersonal therapy. The effectiveness of these treatment techniques is uncertain.
Lifestyle changes
Recent basic and clinical studies have shown that lifestyle changes such as quitting smoking, abstaining from alcohol, losing weight, and increasing exercise can significantly improve impotence. mannino and colleagues found a lower incidence of impotence in those who quit smoking compared to smokers (2% vs. 3.7%). guay and colleagues found significant improvement in impotence in patients who quit smoking after 30 packs of years.
The relationship between alcohol consumption and impotence is not clear from the available data.
A landmark study found that 110 obese patients with impotence were randomized to a weight loss group and a verbal education group. 2 years of follow-up found significant improvement in impotence in the weight loss group, but not in the verbal education group. Subsequent studies further confirmed this finding, and in 2011 Cupta and colleagues meta-analyzed six randomized trials of 740 patients with impotence to evaluate the effects of lifestyle changes and cardiovascular risk reduction on impotence, showing that both significantly improved impotence, independent of the use of phosphodiesterase 5 inhibitors.
Mechanisms by which weight loss and exercise improve impotence include improvements in endothelial function, insulin resistance, and inflammatory response.
Although the available research data suggest that lifestyle changes can significantly improve impotence, the conclusions are not very conclusive due to the lack of rigorously designed, prospective, controlled trials with large sample sizes. Moreover, the available studies suggest that it takes at least 2 years to improve impotence through lifestyle change, which is a considerable period of time. In contrast, improvements in impotence were seen after 3 months of lifestyle change with a phosphodiesterase 5 inhibitor. It is unlikely that an immediate treatment for impotence can be abandoned in favor of a lifestyle change that takes a long time.
Oral phosphodiesterase 5 inhibitors
Oral phosphodiesterase 5 inhibitors are the first treatment for impotence. These drugs promote penile erection by inhibiting phosphodiesterase 5. Phosphodiesterase 5 specifically degrades cGMP in cavernous smooth muscle, and its inhibitors prolong cGMP activity and further reduce intracellular calcium concentration, keeping smooth muscle relaxed and thus causing erections. Currently, there are 5 oral phosphodiesterase 5 inhibitors on the market: Viagra (Pfizer, USA), tadalafil (Eli Lilly and Company, USA), Vardenafil (Bayer), Udenafil (Dong-A Pharmaceuticals, Korea), and mirodenafil (SK, Korea).
The first 3 drugs are available worldwide. Other phosphodiesterase 5 inhibitors in development are avanafil, lodenafil, and SLx-2101. The five phosphodiesterase 5 inhibitors currently on the market have similar duration of action, duration of duration, and effectiveness in impotence. Physicians should consider trying all five types of phosphodiesterase 5 inhibitors to find out which drug is most effective with the fewest side effects. It takes at least four trials to determine whether a drug is effective or ineffective.
Several studies have shown that long-term or daily use of phosphodiesterase 5 inhibitors in patients with impotence can help improve endothelial function and may lead to a cure for impotence. The potential benefits of daily phosphodiesterase 5 inhibitors are to save phosphodiesterase 5 inhibitor dependent individuals, significantly improve impotence, and promote natural sexual function. Disadvantages include high price, uncertain long-term safety, and a mechanism of action that is still not fully understood.
The main advantage of phosphodiesterase 5 inhibitors is that they improve sexual function but increase sexual desire. In young men or those who are physically strong, phosphodiesterase 5 may shorten the period of inactivity and allow for better control of ejaculation. Phosphodiesterase 5 inhibitors should not be taken by people who use nitrates, as the combination of the two can cause severe hypotension. Phosphodiesterase 5 inhibitors do not increase the incidence of myocardial infarction and death, nor do they exacerbate myocardial ischemia in patients with coronary artery disease or hemodynamic abnormalities in patients with heart failure.
Phosphodiesterase 5 inhibitors should be used with caution in patients with severe cardiovascular disease, such as poorly controlled blood pressure, unstable angina, and in patients taking a-blockers to control blood pressure. They are well tolerated in combination with calcium channel blockers. Vardenafil is contraindicated in patients taking Class IA (e.g., quinidine or procainamide) or Class III (e.g., sotalol or amiodarone) antiarrhythmic drugs, and in patients with congenital long QT interval syndrome.
The side effects associated with phosphodiesterase 5 inhibitors are usually mild and well tolerated by patients. The most common side effects include headache and facial flushing, and Tadalafil can cause myalgia. There are few reports of sustained erections in patients with oral phosphodiesterase 5 inhibitors. A direct relationship between phosphodiesterase 5 inhibitors and and non-arteritic ischemic optic neuropathy has not been confirmed. There are reports that phosphodiesterase 5 inhibitors, particularly Viagra, may cause hearing impairment.
Despite the fact that phosphodiesterase 5 inhibitors are the first line of treatment for impotence, 35% of impotence patients taking this drug are still ineffective. The main reasons for drug ineffectiveness are diabetes, severe neurological or vascular disease. There is no consensus on how to define ineffective phosphodiesterase 5 inhibitors, but it is currently believed that phosphodiesterase 5 inhibitors can be considered ineffective if you are unable to complete sexual intercourse at least four times despite taking such drugs. Further management of patients who have failed to respond to oral phosphodiesterase 5 inhibitors depends on the cause of impotence. This may include taking another history, switching to another phosphodiesterase 5 inhibitor, intracavernosal injection, intraurethral administration, combination therapy, or referral to another specialist for further evaluation. Some patients with impotence who have had no success with any medication may consider penile implant surgery.
Testosterone
Testosterone plays an important role in maintaining penile erection, but has a limited role in the treatment of impotence. Testosterone replacement therapy is recommended for patients with impotence who have reduced testosterone concentrations. A meta-analysis including 16 studies found that testosterone administration in hypogonadal individuals significantly improved impotence (57% vs. 16.7%). Some older patients with low testosterone levels who initially did not respond to phosphodiesterase 5 inhibitors showed significant improvement in sexual function with the combination of the two drugs.
Intracavernosal injections and transurethral therapy
This type of treatment is the second-line therapy for impotence and has the main advantage of reliable and rapid results. Men learn penile injections with a 28-30 gauge needle. erection occurs within 10 minutes, independent of libido. Intracavernous injections can be used to treat impotence in patients who do not like taking phosphodiesterase 5 inhibitors or for whom oral medications are ineffective, as well as in patients with spinal cord injury and after radical prostatectomy. Commonly used drugs include prostaglandin E1, papaverine, phentolamine, and vasoactive intestinal polypeptides.
A combination of drugs can also be used for intracavernosal injections. Prostaglandin E1 alone is effective up to 70% of the time, and up to 90% if all three drugs are used in combination. Side effects of intracavernous injections include persistent penile erection and penile fibrosis, but these side effects can be avoided through patient education and monitoring. Penile pain is mostly associated with prostaglandin E1 injections. There are also prostaglandin E1 pills on the market that are administered intraurethrally. The efficacy rate is 43-69%. Side effects include penile pain, urethral pain or burning sensation, hypotension, syncope, and persistent penile erection.
Vacuum constriction device
The vacuum constriction device causes an erection by creating a constant negative pressure in the penis to draw blood from the corpus cavernosum and an elastic band at the root of the penis to block blood flow back to the penis. This device is inexpensive and cost-effective. The disadvantage is that the erection created by this method is not natural but mechanically induced and therefore the penis is cold and unsatisfactory for half of the patients. Vacuum tightening devices are used in patients with stable sexual partners who are often ineffective on phosphodiesterase 5 inhibitors and refuse to use invasive methods such as intracavernous injections or penile prosthesis implants. Side effects include petechiae, penile stiffness, and delayed ejaculation.
Penile prosthesis implantation
Penile prosthesis implantation is the third-line treatment for impotence and one of the few effective surgical treatments for impotence. When all other methods fail, penile prosthesis implantation is the last resort for impotence. Once a penile prosthesis is implanted, the cavernous tissue is irreversibly altered and the smooth muscle tissue can no longer be relaxed. There are two types of penile prostheses. Semi-rigid prostheses are usually easy to implant and last well. However, semi-rigid prostheses do not allow for full erection and are more difficult to conceal. Inflatable prostheses often consist of two or three parts, including two penile-like pillars plus a scrotal pump for inflation. The scrotal pump pumps fluid behind the d-bone into the column, allowing the penis to become erect. Bending the middle of the penis allows the prosthesis to deflate, causing weakness.
Penile prosthetic implants are the most popular in the United States, with satisfaction rates as high as 70-90 percent. The most common complication is infection, with an incidence of 2-4%. Other surgical procedures to treat impotence include arterial bypass grafting (in patients with trauma to the penile arteries) and venous ligation (in young patients with congenital venous fistulas), although few people perform these procedures today.
Outlook
The advent of phosphodiesterase 5 inhibitors is undoubtedly a major advance in the treatment of impotence, but there are a number of drawbacks. For example, a proportion of patients still take them ineffectively, do not have automatic erections, and need to take them for life. Currently, drugs are being developed that aim to target not only the phosphodiesterase 5 action segment. Several ornithine cyclase activators are undergoing preclinical studies with promising results. Other drugs still in the experimental phase are potassium channel inhibitors, Rho kinase inhibitors, and melanocortin activators.
Stenting for ischemic cardiomyopathy is a revolutionary invention. A study showed that the degree of coronary artery stenosis was related to the stenosis of the pubic arteries, with 52% stenosis of the right pubic artery and 60% stenosis of the left pubic artery. Preliminary studies have shown that percutaneous pubic artery stenting is effective in treating three patients with impotence. This treatment still needs to address patient selection, long-term efficacy and safety, and potential complications before it can be replicated in the clinic. In addition, low-intensity extracorporeal shockwave therapy has been successfully used to treat vasogenic impotence. This treatment is already in clinical use in Israel and Canada, but rigorously designed, double-blind, multicenter, long-term controlled study data are needed to make it a standard treatment for impotence.
Other new approaches to treating impotence include gene therapy. The penis is one of the few human organs suitable for gene therapy because of its ease of access, thin tissue, ease of infusion of gene transfectants, and excellent diffusion. Successful preclinical gene therapy studies include vasoactive intestinal peptide, brain-derived neurotrophic factor, and superpotassium channels, etc. A breakthrough clinical study using superpotassium channel gene therapy was published in 2006. The only drawback was the small sample size of 14 cases, the absence of a control group, and the low statistical power of this study, which did not allow for a definitive conclusion that gene therapy for impotence was effective. Still, this groundbreaking study opens a new horizon for impotence treatment. Other hot topics of research include the application of specific factors to stimulate endogenous neurogenic factor production, and cellular therapy.
Conclusion
In-depth studies on the physiology of erection and the pathophysiological mechanisms of impotence led to the development of the first effective oral drug for impotence, the DD phosphodiesterase 5 inhibitor. Impotence is now considered to be a predictor of coronary heart disease. Despite the tremendous progress in the treatment of impotence, there is still a need to find more effective and longer-lasting therapeutic drugs. New strategies of gene therapy and cellular therapy are encouraging in their promise to cure impotence.