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An overview of the history, current strategies, and potential future treatment approaches in erectile dysfunction: a comprehensive review (2023)
Mohammad Amin Langarizadeh, PharmD, Amirhossein Salary, PharmD, Marziye Ranjbar Tavakoli, PharmD, Behnam Ghorbani Nejad, PhD, Shirin Fadaei, PharmD, Zahra Jahani, PharmD, Hamid Forootanfar, PhD
Abstract
Introduction
Erectile dysfunction (ED) is one of the most common urologic problems in men worldwide, with an approximately high incidence rate, significantly affecting patients’ quality of life and their sexual partners.
Objectives
Due to the association of this disorder with essential diseases such as cardiovascular disease and diabetes, its prevention and treatment are vital for overall human physiologic and psychological health. Along with reviewing the history of treatment and current methods, we seek new approaches to curb this issue in the future.
Methods
In this review, investigations were based on the focus of each section’s content or conducted on an ad hoc basis. Searches were performed in Scopus and PubMed.
Results
In recent years, many treatments for ED have been reported besides oral administration of phosphodiesterase 5 inhibitors such as sildenafil and tadalafil (approved by the Food and Drug Administration). Common oral medications, intracavernous injections, herbal therapies (eg, herbal phosphodiesterase 5 inhibitors), and topical/transdermal medications are routine ED treatment approaches. Moreover, some novel medications are innovative candidates for completing ED’s treatment protocols: stem cell injection, low-intensity extracorporeal shock wave therapy, platelet-rich plasma injection, gene therapy, amniotic fluid matrices, rho-kinase inhibitors, melanocortin receptor antagonists, maxi-K channel activators (ie, large-conductance calcium-activated potassium channels), guanylate cyclase activators, and nitric oxide donors.
Conclusion
Due to the importance of this complicated problem in men’s society, a faster course of treatment trends toward new methods is needed to increase efficiency. Combining the mentioned treatments and attentively examining their efficacy through programmed clinical trials can be a big step toward solving this global problem.
Introduction
The most commonly studied sexual illness is erectile dysfunction (ED). The inability to achieve and/or sustain a sufficient penile erection for sexual activity is defined as ED.1 Several therapies for ED are currently available. According to current findings, the pathophysiology of ED is linked to several factors, including underlying comorbidities, past surgery, and psychosocial issues, according to recent findings.2
Penile erection is a remarkably complicated process primarily controlled by a peripheral neurovascular, nonadrenergic, noncholinergic mechanism, as well as the central nervous system. Sympathetic reactions regulate detumescence by releasing norepinephrine, which causes smooth muscle contraction, vasoconstriction, and penile flaccidity.3 The tone of the penile smooth muscle determines the hemodynamic events that sustain penile flaccidity or induce erection. Smooth muscle tone is increased in the flaccid penis. Penile erection, however, necessitates a reduction in penile smooth muscle tone. The balance and interaction of relaxant and contractile factors determine the outcome of penile smooth muscle tone. Smooth muscle contraction depends on a relatively quick rise in intracellular free calcium concentration and the contractile machinery’s sensitivity to calcium.4
The tunica albuginea, ligaments, and muscles bind the 3 cylindrical structures of the human penis. The urethra is housed in the paired corpora cavernosa and a single corpus spongiosum. Penile erection and detumescence depend on the complex but closely controlled interplay among these erectile tissues, vessels, and nerves. The ischiocavernosus muscle surrounds the paired corpora cavernosa, spongy cylinders containing erectile tissues encircled by the stern, flexible tunica albuginea. During an erection, contraction of these muscles at the crus blocks venous outflow even further, leading to greater rigidity and higher intracavernous pressures. Blood gently diffuses from central to peripheral sinusoids in the flaccid state. During an erection, however, central and peripheral sinusoidal blood gas levels approach those of arterial blood due to accelerated penetration of arterial blood.5 The smooth muscles of the arteriolar and artery walls and the cavernous smooth musculature play an essential part in the erectile process. These smooth muscles are tonically contracted in flaccid conditions, permitting just a minimal amount of artery flow for nutritional needs. The release of neurotransmitters from the cavernous nerve terminals is triggered by sexual stimulation, resulting in smooth muscle relaxation.6 The health of the penile vascular tissues, as well as the perineal and ischiocavernosus muscles that support the proximal penis, is essential for normal erectile function.7
Nitric oxide (NO) is generally considered the critical mediator in penile erection, which is a complicated process combining neurogenic, psychogenic, and hormonal factors.8 Sexual stimuli cause NO release in the nitrergic nerve and relaxed corpus cavernosal smooth muscle in the penis, resulting in an erection. NO activates guanylate cyclase in the corpus cavernosum’s smooth muscle cells, increasing cyclic guanosine monophosphate (cGMP) levels and causing smooth muscle relaxation. The enzyme phosphodiesterase 5 (PDE5) converts cGMP to guanosine 5 -monophosphate.9 NO raises the levels of 3,5 -cGMP via activating soluble guanylyl cyclase (sGC). cGMP, a second messenger molecule, affects the relaxation of corpus cavernosum smooth muscle by regulating the activation of calcium channels and intracellular contractile proteins.
ED is caused by a reduction in NO bioactivity, which is a primary pathogenic factor.3
Specific essential symptoms, such as decreased muscle tissue mass, increased body fat mass, reduced bone density, osteoporosis, depression, and ED, are also associated with reduced testosterone. A dynamic interplay of psychological, neurologic, vascular, and endocrine factors is required for regular male sexual activity. In general, androgens enhance libido and the duration of sexual activities, but there is no proof that altered androgen levels cause ED.10 Since puberty, men with androgen deficiency have lower bone mineral density, muscle mass, stamina, sexual activity, and hematocrit, as well as a smaller prostate gland, as compared with healthy men. Testosterone is a significant androgen needed for male sexual characteristics to grow and maintain. Androgens can regulate penile erection in the central nervous system.11
According to published statistical data, the global prevalence of ED is 3% to 76.5%. An exponential increase in the occurrence of ED is associated with aging. Some males have several times greater rates of incidence (eg, those with diabetes, alcoholism, ischemic coronary heart disease, and renal illnesses).12
The evaluation of ED in these patients is evolving, with the use of evoked potentials technology in somatic and autonomic nerve testing, as well as functional magnetic resonance imaging. Neurogenic reasons can be determined via electrophysiologic testing. These techniques allow for the classification of neurologic lesions as well as the assessment of the patient’s prognosis.13 The quality of sexual function should be considered to prevent depression and failed marriages. In the first step, psychosocial counseling, lifestyle modification, sexual relationship evaluation, and a thorough medical evaluation of other underlying causes might be helpful.14,15 Then, PDE5 inhibitors (PDE5Is), which have developed as a safe and effective oral treatment for ED,16 are the most common treatments worldwide. Intracavernous and intraurethral vasoactive injections are other valuable approaches to curb ED. Penile prostheses and penile vascular surgery are other invasive treatments. Each therapy modality’s efficacy and safety are determined by the unique neurologic disease.
In addition to these methods, nonpharmacologic treatments, such as continuous positive airway pressure in patients with ED and obstructive sleep apnea, can elevate the International Index of Erectile Function 5 (IIEF-5) score.17 Different methods have been used in various studies to evaluate the improvement of ED. While validated patient questionnaires (eg, Erection Hardness Score, IIEF-5, or Global Assessment Questionnaire) have been routinely employed, the changes related to the size of the penis are assessed by length measuring tools. In addition to these methods, tools such as RigiScan,18 real-time ultrasonic shear wave elastography,19, and penile Doppler sonography20 are now used for measuring erectile hardness.
Publication of the first promising clinical findings on the application of the orally active PDE5I sildenafil to treat ED was characterized by increased investigations of cavernous intracellular signal transmission and phosphodiesterase characterization based on molecular biology as well as protein chemistry. The safety and effectiveness of numerous next-generation PDE5Is for treating male ED are now being studied in vitro and in vivo. 21
In the following, we examine different approaches for curbing this global problem.
*ED medications
-Oral medications
-Side effects and contraindications of PDE5Is
*Intracavernous medications
*Testosterone replacement therapy
*Herbal medications
-Tribulus terrestris (TT)
-Yohimbine
-Coleus forskohlii
-Berberine
-Maca (Lepidium meyenii)
-Ginseng
-Eurycoma longifolia
-Zhongcao
-Catuama—Paullinia cupana, Trichilia catigua, Zingiber officinale, and Ptychopetalum olacoides
-Moringa oleifera
-Ficus capensis
-French maritime pine bark (Pinus pinaster)
-Pycnogenol
-Ashvattha kshirpaka
-Ashwagandha (Withania somnifera or winter cherry)
-Tradamix (alga Ecklonia bicyclis, TT, and glucosamine oligosaccharide)
-VigRX Plus, a proprietary polyherbal preparation
-Cappra
*Herbal PDE5Is
*Novel treatments
-Stem cell therapy
-Low-intensity extracorporeal shock wave therapy
-Platelet-rich plasma
-Gene therapy
-Amniotic fluid matrices
-Rho-associated inhibitors
-Melanocortin receptor agonists
-Maxi-K channel activators
-Guanylate cyclase activators
-NO donors: L-arginine and glyceryl trinitrate
Conclusion
As mentioned earlier, ED is a troublesome tribulation for men, and despite the tremendous advances in urology in recent decades, many people still struggle with this disorder. The high prevalence of this disorder in the present era, alongside dissatisfaction with its current treatment methods (due to adverse effects, interactions, or contraindications), is substantial evidence that an adequate solution has not been established for it. However, proper sexual activity is not only a factor for the preservation of generations; it also affects physical and mental health in various ways. All of this leads to the conclusion that one should establish a complete and comprehensive treatment approach to sufficiently curb ED by relying on such protocols. Based on our review of the various ED treatments, examining these methods in binary or even trinary combination therapies can be very helpful. For example, combining novel treatment methods (as detailed in the previous section) is worthy of clinical trials. In addition, traditional therapies and herbal compounds can synergize with the current treatment routine (including oral PDE5Is and ICI methods). Low-risk topical and transdermal methods, such as alprostadil cream, tadalafil nanoemulsion, or testosterone gel, can also be used parallel with any of these treatments. The design of such protocols could provide a bright future for treating this global problem.
Mohammad Amin Langarizadeh, PharmD, Amirhossein Salary, PharmD, Marziye Ranjbar Tavakoli, PharmD, Behnam Ghorbani Nejad, PhD, Shirin Fadaei, PharmD, Zahra Jahani, PharmD, Hamid Forootanfar, PhD
Abstract
Introduction
Erectile dysfunction (ED) is one of the most common urologic problems in men worldwide, with an approximately high incidence rate, significantly affecting patients’ quality of life and their sexual partners.
Objectives
Due to the association of this disorder with essential diseases such as cardiovascular disease and diabetes, its prevention and treatment are vital for overall human physiologic and psychological health. Along with reviewing the history of treatment and current methods, we seek new approaches to curb this issue in the future.
Methods
In this review, investigations were based on the focus of each section’s content or conducted on an ad hoc basis. Searches were performed in Scopus and PubMed.
Results
In recent years, many treatments for ED have been reported besides oral administration of phosphodiesterase 5 inhibitors such as sildenafil and tadalafil (approved by the Food and Drug Administration). Common oral medications, intracavernous injections, herbal therapies (eg, herbal phosphodiesterase 5 inhibitors), and topical/transdermal medications are routine ED treatment approaches. Moreover, some novel medications are innovative candidates for completing ED’s treatment protocols: stem cell injection, low-intensity extracorporeal shock wave therapy, platelet-rich plasma injection, gene therapy, amniotic fluid matrices, rho-kinase inhibitors, melanocortin receptor antagonists, maxi-K channel activators (ie, large-conductance calcium-activated potassium channels), guanylate cyclase activators, and nitric oxide donors.
Conclusion
Due to the importance of this complicated problem in men’s society, a faster course of treatment trends toward new methods is needed to increase efficiency. Combining the mentioned treatments and attentively examining their efficacy through programmed clinical trials can be a big step toward solving this global problem.
Introduction
The most commonly studied sexual illness is erectile dysfunction (ED). The inability to achieve and/or sustain a sufficient penile erection for sexual activity is defined as ED.1 Several therapies for ED are currently available. According to current findings, the pathophysiology of ED is linked to several factors, including underlying comorbidities, past surgery, and psychosocial issues, according to recent findings.2
Penile erection is a remarkably complicated process primarily controlled by a peripheral neurovascular, nonadrenergic, noncholinergic mechanism, as well as the central nervous system. Sympathetic reactions regulate detumescence by releasing norepinephrine, which causes smooth muscle contraction, vasoconstriction, and penile flaccidity.3 The tone of the penile smooth muscle determines the hemodynamic events that sustain penile flaccidity or induce erection. Smooth muscle tone is increased in the flaccid penis. Penile erection, however, necessitates a reduction in penile smooth muscle tone. The balance and interaction of relaxant and contractile factors determine the outcome of penile smooth muscle tone. Smooth muscle contraction depends on a relatively quick rise in intracellular free calcium concentration and the contractile machinery’s sensitivity to calcium.4
The tunica albuginea, ligaments, and muscles bind the 3 cylindrical structures of the human penis. The urethra is housed in the paired corpora cavernosa and a single corpus spongiosum. Penile erection and detumescence depend on the complex but closely controlled interplay among these erectile tissues, vessels, and nerves. The ischiocavernosus muscle surrounds the paired corpora cavernosa, spongy cylinders containing erectile tissues encircled by the stern, flexible tunica albuginea. During an erection, contraction of these muscles at the crus blocks venous outflow even further, leading to greater rigidity and higher intracavernous pressures. Blood gently diffuses from central to peripheral sinusoids in the flaccid state. During an erection, however, central and peripheral sinusoidal blood gas levels approach those of arterial blood due to accelerated penetration of arterial blood.5 The smooth muscles of the arteriolar and artery walls and the cavernous smooth musculature play an essential part in the erectile process. These smooth muscles are tonically contracted in flaccid conditions, permitting just a minimal amount of artery flow for nutritional needs. The release of neurotransmitters from the cavernous nerve terminals is triggered by sexual stimulation, resulting in smooth muscle relaxation.6 The health of the penile vascular tissues, as well as the perineal and ischiocavernosus muscles that support the proximal penis, is essential for normal erectile function.7
Nitric oxide (NO) is generally considered the critical mediator in penile erection, which is a complicated process combining neurogenic, psychogenic, and hormonal factors.8 Sexual stimuli cause NO release in the nitrergic nerve and relaxed corpus cavernosal smooth muscle in the penis, resulting in an erection. NO activates guanylate cyclase in the corpus cavernosum’s smooth muscle cells, increasing cyclic guanosine monophosphate (cGMP) levels and causing smooth muscle relaxation. The enzyme phosphodiesterase 5 (PDE5) converts cGMP to guanosine 5 -monophosphate.9 NO raises the levels of 3,5 -cGMP via activating soluble guanylyl cyclase (sGC). cGMP, a second messenger molecule, affects the relaxation of corpus cavernosum smooth muscle by regulating the activation of calcium channels and intracellular contractile proteins.
ED is caused by a reduction in NO bioactivity, which is a primary pathogenic factor.3
Specific essential symptoms, such as decreased muscle tissue mass, increased body fat mass, reduced bone density, osteoporosis, depression, and ED, are also associated with reduced testosterone. A dynamic interplay of psychological, neurologic, vascular, and endocrine factors is required for regular male sexual activity. In general, androgens enhance libido and the duration of sexual activities, but there is no proof that altered androgen levels cause ED.10 Since puberty, men with androgen deficiency have lower bone mineral density, muscle mass, stamina, sexual activity, and hematocrit, as well as a smaller prostate gland, as compared with healthy men. Testosterone is a significant androgen needed for male sexual characteristics to grow and maintain. Androgens can regulate penile erection in the central nervous system.11
According to published statistical data, the global prevalence of ED is 3% to 76.5%. An exponential increase in the occurrence of ED is associated with aging. Some males have several times greater rates of incidence (eg, those with diabetes, alcoholism, ischemic coronary heart disease, and renal illnesses).12
The evaluation of ED in these patients is evolving, with the use of evoked potentials technology in somatic and autonomic nerve testing, as well as functional magnetic resonance imaging. Neurogenic reasons can be determined via electrophysiologic testing. These techniques allow for the classification of neurologic lesions as well as the assessment of the patient’s prognosis.13 The quality of sexual function should be considered to prevent depression and failed marriages. In the first step, psychosocial counseling, lifestyle modification, sexual relationship evaluation, and a thorough medical evaluation of other underlying causes might be helpful.14,15 Then, PDE5 inhibitors (PDE5Is), which have developed as a safe and effective oral treatment for ED,16 are the most common treatments worldwide. Intracavernous and intraurethral vasoactive injections are other valuable approaches to curb ED. Penile prostheses and penile vascular surgery are other invasive treatments. Each therapy modality’s efficacy and safety are determined by the unique neurologic disease.
In addition to these methods, nonpharmacologic treatments, such as continuous positive airway pressure in patients with ED and obstructive sleep apnea, can elevate the International Index of Erectile Function 5 (IIEF-5) score.17 Different methods have been used in various studies to evaluate the improvement of ED. While validated patient questionnaires (eg, Erection Hardness Score, IIEF-5, or Global Assessment Questionnaire) have been routinely employed, the changes related to the size of the penis are assessed by length measuring tools. In addition to these methods, tools such as RigiScan,18 real-time ultrasonic shear wave elastography,19, and penile Doppler sonography20 are now used for measuring erectile hardness.
Publication of the first promising clinical findings on the application of the orally active PDE5I sildenafil to treat ED was characterized by increased investigations of cavernous intracellular signal transmission and phosphodiesterase characterization based on molecular biology as well as protein chemistry. The safety and effectiveness of numerous next-generation PDE5Is for treating male ED are now being studied in vitro and in vivo. 21
In the following, we examine different approaches for curbing this global problem.
*ED medications
-Oral medications
-Side effects and contraindications of PDE5Is
*Intracavernous medications
*Testosterone replacement therapy
*Herbal medications
-Tribulus terrestris (TT)
-Yohimbine
-Coleus forskohlii
-Berberine
-Maca (Lepidium meyenii)
-Ginseng
-Eurycoma longifolia
-Zhongcao
-Catuama—Paullinia cupana, Trichilia catigua, Zingiber officinale, and Ptychopetalum olacoides
-Moringa oleifera
-Ficus capensis
-French maritime pine bark (Pinus pinaster)
-Pycnogenol
-Ashvattha kshirpaka
-Ashwagandha (Withania somnifera or winter cherry)
-Tradamix (alga Ecklonia bicyclis, TT, and glucosamine oligosaccharide)
-VigRX Plus, a proprietary polyherbal preparation
-Cappra
*Herbal PDE5Is
*Novel treatments
-Stem cell therapy
-Low-intensity extracorporeal shock wave therapy
-Platelet-rich plasma
-Gene therapy
-Amniotic fluid matrices
-Rho-associated inhibitors
-Melanocortin receptor agonists
-Maxi-K channel activators
-Guanylate cyclase activators
-NO donors: L-arginine and glyceryl trinitrate
Conclusion
As mentioned earlier, ED is a troublesome tribulation for men, and despite the tremendous advances in urology in recent decades, many people still struggle with this disorder. The high prevalence of this disorder in the present era, alongside dissatisfaction with its current treatment methods (due to adverse effects, interactions, or contraindications), is substantial evidence that an adequate solution has not been established for it. However, proper sexual activity is not only a factor for the preservation of generations; it also affects physical and mental health in various ways. All of this leads to the conclusion that one should establish a complete and comprehensive treatment approach to sufficiently curb ED by relying on such protocols. Based on our review of the various ED treatments, examining these methods in binary or even trinary combination therapies can be very helpful. For example, combining novel treatment methods (as detailed in the previous section) is worthy of clinical trials. In addition, traditional therapies and herbal compounds can synergize with the current treatment routine (including oral PDE5Is and ICI methods). Low-risk topical and transdermal methods, such as alprostadil cream, tadalafil nanoemulsion, or testosterone gel, can also be used parallel with any of these treatments. The design of such protocols could provide a bright future for treating this global problem.
