madman
Super Moderator
Erectile dysfunction from mechanisms to medicines with a focus on the application of topical Minoxidil (2023)
Marziye Ranjbar Tavakoli, Pharm D, Maryam Faraji, Pharm D, Sanaz Sam, Pharm D, Ali Ghasempour, Pharm D, Masoud Rezaei, MD, Mohammad Amin Langarizadeh, Pharm D, Somayyeh Karami-Mohajeri, PhD
Abstract
Introduction
Erectile dysfunction (ED), for multifactorial reasons, is one of the biggest current quandaries among men worldwide and results in other complications such as reduced quality of life of the patient and his sexual partner, impotence, and psychiatric problems.
Objectives
Understanding disease etiology, penile anatomy, erectile physiology, therapeutic mechanisms, and effective molecular pathways all play key roles in determining a therapeutic approach. This project is based on the study of topical minoxidil’s effectiveness in treating ED.
Methods
To perform a comprehensive overview of the subject, we performed a triple-keyword combination search to assess recent studies of ED.
Results
The most common formulation used in these studies was a 2% minoxidil solution. Except for cases studied in paralytic patients, topical treatment with minoxidil appears to elicit a mild erectile response; however, this finding is insufficient to confirm the effectiveness of this topical treatment.
Conclusions
Although evidence to confirm the therapeutic properties of minoxidil in ED is limited, combination therapy and the use of modern formulations of minoxidil are promising options for treating ED in the future.
Introduction
Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection adequate to have satisfactory sexual intercourse, according to the National Institutes of Health (NIH) Consensus Development Conference on Impotence.1 By definition, ED is a more precise term than impotence, because in ED only the ability to attain and maintain an erection is lost, while sexual desire and the ability to reach orgasm and ejaculation may remain intact.2 Erectile dysfunction can be classified into 2 main subgroups, (1) primary ED, which occurs from early puberty, prevents the experience of regular sexual activity from the beginning of sexual maturity, and (2) secondary ED, due to various reasons, which may occur at different ages and prevents the patient from having regular sexual activity as before.
Because ED is usually temporary and related to emotional conditions and life problems, it may disappear as these issues are resolved, without the need to visit a doctor and be examined. However, the complete cure of ED depends on the underlying causes. Patients who experience longer-lasting ED, for example, for several months, should be evaluated medically and treated if necessary.3 Although ED is not considered a fatal morbidity, it is closely correlated to many underlying diseases, including cardiovascular disease, and may adversely affect psychosocial health. Thus, ED may have a significant impact on the quality of life of patients and their partners.4
In this study, we aimed to update clinical research into the pathophysiology of erectile dysfunction and the underlying treatments. This review also includes a discussion of the application of minoxidil as a popular topical drug for treating ED.
Results and discussion
Physiology of erection
Penile erection is the consequence of neurological and vascular events that coordinate with hormonal and psychological triggers. Eventually, penile rigidity occurs due to increased intracorporal pressure from corporal smooth muscle relaxation and increased blood flow in the arteries.5–7 Penile erection can be triggered by direct stimulation of the genital organ (reflex parasympathetic erection) or through stimulation of central pathways (psychogenic erection).8 The thalamus regulates psychogenic erection and limbic system, which control the spinal sympathetic (Tl-L2) and parasympathetic (S2-S4) centers.7
Cholinergic and nonadrenergic-noncholinergic nerves relax the smooth muscles of the corpus cavernosum by pro-erectile neurotransmitters such as nitric oxide (NO), intestinal vasoactive peptide (VIP), and prostaglandins.7 NO, which plays a more prominent role than other neurotransmitters in relaxing smooth muscles, is synthesized by NO synthase (NOS) and released from endothelial cells, and activates the enzyme guanylate cyclase (GC), producing cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP).9
VIP is injected intracavernosally for the treatment of ED and has a synergistic effect in concomitant administration with acetylcholine.7 VIP activates the enzyme adenylate cyclase (AC) and produces cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP).10–12 Both cGMP and cAMP lead to hyperpolarization of smooth muscle cells by activating the sodium-potassium channel, thereby reducing the intracellular calcium concentration and relaxing the smooth muscle corpus cavernosum.11,12 As the enzyme 5- phosphodiesterase breaks down cGMP, a primary therapeutic goal in patients with ED is to regulate the function of this enzyme. Details of the mentioned molecular pathways are shown in Figure 1.
Other pro-erectile neurotransmitters include the following.
1. Acetylcholine does not directly affect the corpus cavernosal smooth muscle cells but modulates the release of NO from endothelial cells in the relaxation process.7,13,14
2. CGRP is released from the ends of neurons leading to the corpus cavernosum and directly affects smooth muscle relaxation. Intracavernosal injection of CGRP combined with alprostadil (prostaglandin E1) is one way to treat ED.7,15
3. Substance P promotes corpus cavernosum relaxation. The function of substance P depends on the endothelial release of NO.7,16
4. Pituitary adenylate cyclase–activating polypeptide (PACAP) is structurally similar to VIP and has a relaxant effect on the corpus cavernosum.7,17
5. ATP can be injected either intracavernosally or intraarterially and has a relaxant effect on the corpus cavernosum.7
6. Histamine improves erection by activating H2 receptors and can be administered by intracavernosal injection (ICI) in men with ED.18,19
7. Oxytocin, present in the hypothalamus, is released from oxytocinergic neural terminations and therefore plays a role in modulating the central neural pathway of erection.7,20
8. Dopamine, like oxytocin, plays a role in the hypothalamus’s central neural pathway of erection, which is rich in dopaminergic receptors.21
9. Serotonin (5-Hhydroxytryptamine [5-HT]) regulates and modulates the sympathetic and parasympathetic output and can be injected peripherally.7,20
On the other hand, anti erectile neurotransmitters such as noradrenaline (norepinephrine), neuropeptide Y (NPY), and γ -aminobutyric acid act as counterpoints to the neurological and hormonal factors that cause erections.7
The equilibrium between the levels of these factors plays a crucial role in creating or preventing an erection (Figure 2).
Pathophysiology of ED and risk factors
Organic and nonorganic ED
The normal function of the smooth muscle of penile blood vessels and corpus cavernosum depends on the intactness of all neurological, vascular, and hormonal factors.22 Although the function of the peripheral nervous system in erection has been thoroughly examined, the role of the central nervous system has not been completely clarified. Regions of the frontal and limbic cortex modulate sexual response along with direct or intermediate stimulation of the septal area.23 In the evaluation of some men with epilepsy and ED, the nature of the disorder, primarily in penile stiffness, suggests a neurogenic rather than vasogenic origin and is better identified by assessing both nocturnal penile tumescence and stiffness.24
At the National Institutes of Health (NIH) Consensus Development Conference on Impotence in December 1992, organic etiologies were reported in approximately 75% of ED cases.10,25,26 Organic ED primarily results from cardiovascular diseases, spinal cord injury, and neurodegenerative disorders, which lead to impairment of blood flow and nerve messages to the penis.27 Central neurological disorders, including Parkinson's disease, epilepsy, Alzheimer's disease, and stroke defects, can also lead to ED.22,28
Other nonorganic causes of ED are diabetes mellitus, hypercholesterolemia, drug side effects, and poor lifestyle habits such as smoking, obesity, stationary lifestyle, and drug and alcohol addiction.6,10 Psychological disorders such as depression, anxiety, lack of self-confidence, etc., are the most prevalent causes of nonorganic causes of ED.2,3,29 Diabetic neuropathy and localized nerve damage due to injury or surgery are among the peripheral neurological diseases that lead to an increase in the stimulus threshold of the penis and, thus, a decrease in its sensitivity.2
Age-related ED
Erectile dysfunction was previously thought to be an inevitable consequence of aging, so little attention was paid to this sexual problem of the elderly.30 The prevalence of ED in men younger than 50 years is 9%-39% and in men older than 70 years is 40%-80%.3 However, increased recognition of the importance of sexual satisfaction in elderly patients and their complaints about not having and maintaining a normal erection have led to more attention and research in this field. Sexual problems are relatively common in elderly patients and are frequently related to general health issues or specific sexual disorders. Andropause or androgen deficiency occurs in elderly patients through decreases in glandular function and testosterone production, along with an increase in the blood concentration of sex hormone–binding globulin (SHBG), which reduces the bioavailability of testosterone and leads to impotence, decline in penile sensitivity, and ED.
Testosterone is involved in libido, penile tissue integrity, and NOS expression. The incidence of hypogonadism in older men is 30% of men in their 60s and 80% in their 80s and 90s.22,31
In addition to aging, alcoholism may cause hormonal changes and eventually ED by upsetting the androgen-estrogen balance.22,31 Chronic age-related diseases that impair sexual function include cardiovascular events such as hypertension, hyperlipidemia, and atherosclerosis; chronic neurological disorders including stroke, dementia, and depression;22,31 hormonal disturbance and hypogonadism due to testicular failure (primary hypogonadism) or hypothalamic and pituitary insufficiency (hypogonadotropic hypogonadism);29 and diabetes, a disease that leads to multiorgan dysfunctions. Because older people take many medications, side effects of some medicines may cause iatrogenic ED, especially psychiatric drugs, thiazides, and beta-blockers. If possible, erectile function can be restored in these cases by changing the class or dose of the medication.22,31
Drug-related ED
Medications can affect sexual ability in several ways,4 such as the following.
1. Antidepressants such as tricyclic antidepressants, MAOIs (monoamine oxidase inhibitors), lithium, SSRIs (selective serotonin reuptake inhibitors), and benzodiazepines indirectly cause ED by reducing libido,
2. Antihypertensive drugs, including diuretics, beta-blockers, methyldopa, clonidine, reserpine, guanethidine, and verapamil affect cardiovascular function.
3. Drugs such as phenothiazines, antipsychotic drugs (risperidone, olanzapine, and clozapine), and H2 antagonists (cimetidine and ranitidine) that cause hyperprolactinemia, which lead to ED, impotence, breast enlargement, testicular dysfunction, and infertility in men.
4. Endocrine hormones, such as antiandrogens, H2 antagonists (cimetidine), estrogens, and testosterone.
Management steps for treatment of ED
Basic measures
In the first step of ED treatment management, psychosocial counseling, lifestyle modification, sexual relationship evaluation, and a thorough medical evaluation of other underlying causes might be helpful. Patients who complain of ED should also be examined for corresponding diseases associated with the induction of ED.2,3,32 Studies have shown that lifestyle modification and elimination of ED risk factors by the patient can reduce the risk of ED by up to 70%.2–4,28,29 According to complaints of medication-induced ED, changes in medication may help patients regain the ability to have a normal erection.3,29 Sometimes the patient is in perfect physical health but has depression or conflict with his partner and therefore cannot achieve a full erection until these problems are resolved.2,3,29
Oral medication
Oral therapy is the most common way to take ED medications, including phosphodiesterase type 5 (PDE5) inhibitors. NO donors, such as minoxidil and nitroglycerin (NTG), increase cGMP and cAMP production by increasing the activity of guanylate cyclase and adenosine cyclase.11
Nonoral medication
The next steps in ED treatment include transurethral therapy, intravenous injection, topical therapy, and the application of medical devices (such as vacuums and rings)
Surgery
The last step in ED treatment is the use of invasive treatments, including penile prostheses and penile vascular surgeries.2,37,38
In the following information, among the cases mentioned in the second line of treatment, we focus on the local effects of non-PDEI vasoactive agents, including topical minoxidil.
Non-PDEI vasoactive topical medicines
Alternative routes of administration of vasoactive drugs for treating ED that are less threatening than injection therapy are explored in this section. Agents approved by the FDA for other indications or other ways of administration, including alprostadil, organic nitrates, minoxidil, papaverine, and yohimbine, have been tested via topical administration on the glans penis or penile shaft. Although the FDA does not currently approve these therapies, they may be effective, as well as other medications.2,4,39,40 The challenge with topical therapy is to reach complete absorption, ie, agents applied on penile skin must permeate fascial layers and the tunica albuginea, which means thick layers of collagen.3,41 Organic nitrate, minoxidil, aminophylline, co-dergocrine mesylate, and vasoactive intestinal polypeptide have previously been described as topical cavernosal smooth muscle relaxants with varying degrees of success and rate of side effects.42 To protect the partner, condoms are recommended with the use of aminophylline, co-dergocrine mesylate, minoxidil cream, or the NO donor isosorbide dinitrate are used.22,43 The use of glycerol trinitrate, minoxidil, and papaverine gel has been investigated in various studies, with the results that were variable but mainly disappointing.44 In the following section, we address and examine each of these agents separately.
Prostaglandin E1
Notwithstanding the achievement of PDE5Is, prostaglandin E1 (PGE1, also known as alprostadil) has been tested with various dosing methods as an alternative therapy for ED, predominantly for patients who had unsatisfactory results with PDE5Is medication .45 Topical alprostadil is the most commonly administered synthetic PGE1 for ED. PGE1 promotes corporal smooth muscle laxity, preponderantly by activation of adenylate cyclase and the pursuant agglomeration of 3 5 - cAMP. This process is independent of the NO-cGMP pathway and does not require preliminary sexual stimulation.46 The cream formulation of PGE1 (Vitaros/Virirec) incorporates the advantages of alprostadil with a formulation that is convenient to use.47 Alprostadil cream is a particular combination containing alprostadil as the active pharmaceutical ingredient, a penetration booster (dodecyl-2-N, N-dimethylamino propionate [DDAIP]), and an ester of N-dimethylalanine and dodecanol called HCl. The mentioned penetration-enhancing complex provisionally slackens tight junctions located in the dermal epithelial cells, subsequent to its interplay on the plasma membrane with the hydrophilic zone of the phospholipid bilayer.48 Numerous studies have also been reported that have investigated transdermal strategies for treating ED, including transdermal conveyance of NTG, PDEIs, phentolamine, and papaverine.
Testosterone
Testosterone is a pivotal androgen in men that is produced in the testicles and adrenal cortex. Recently, the direct effects of different testosterone levels on the structural, biochemical, and physiological characteristics of the penis and the pathways associated with erection have become apparent. Animal findings and studies of castrated individuals have shown that lowering testosterone levels not only directly affects the NO pathway but also changes the hemodynamics of the penis as well as smooth muscle tone in a way that makes ED inevitable.49 Monotherapy with gel-formulated testosterone restored erectile function but its effect is limited in hypogonadal men,49 ie, the most efficacious approach for sexual impairment in hypogonadal males is testosterone therapy. It operates by re-establishing erections as commonly evaluated with International Index of Erectile Function (IIEF) scores. This effect will be more tangible in these patients if the gel is used concomitantly with oral sildenafil.50 Numerous assessments have illustrated the advantages of merged testosterone and sildenafil therapy in generating acceptable erectile reactions in hypogonadal males who did not react to sildenafil monotherapy.51
Papaverine
Topical transmission of papaverine through the penile shaft would be a superb substitutive and lower-priced therapy for patients undergoing long-term medication for ED.52 Transdermal papaverine gel does not seem to cause severe adverse effects after administration to the penile shaft. A 15%-20% formulation of papaverine elevates intracorporal pressure due to the increased blood flow to the penis. The outcome of transdermal papaverine in altering blood flow to the phallus is dose-dependent. However, topical therapy with papaverine is not as beneficial as an intracavernous medication injection. Nevertheless, transdermal formulations of papaverine may have promising outcomes at higher concentrations or in amalgamation with diverse skin penetration boosters. Transdermal administration avoids many difficulties related to ICI medication, and the represented outcomes on boosting penile arterial flow via transdermal administration of locally acting papaverine gel formulation warrant further evaluation.53
Nitroglycerine
Transdermal NTG is a feasible and practical strategy for treating impotence and ED, and NTG-treated patients exhibited erections sufficient for regular sexual intercourse.54 After sexual stimulation, topical NTG works by increasing blood flow in the cavernous arteries, causing an increase in factors related to erection, such as stiffness and diameter of the penis. This effect was observed in a group study by Nunez and Anderson, in which 3 impotence patients were successfully treated with NTG ointment.47
Minoxidil
Topical minoxidil formulations, which influence follicular cells, have been utilized for hair regrowth in recent decades, Elevated fenestration in the follicular capillary membrane around anagen bulbs was illustrated by electron microscopy after administration of topical minoxidil 4% solution.55 This affirmative outcome of topical minoxidil stimulation of hair regrowth is chiefly attributable to its active metabolite, minoxidil sulfate, which is converted by sulfotransferase.55 However, minoxidil might generate undesirable vascular outcomes. As a direct-acting peripheral vasodilator, minoxidil decreases blood pressure in systolic and diastolic sessions by decreasing peripheral vascular resistance.56 Minoxidil also provokes PGE2 synthesis by switching on prostaglandin endoperoxide synthase-1 and suppressing prostacyclin generation. Furthermore, minoxidil increases the expression of the PGE2 receptor, which is the most upregulated in the beta-catenin pathway of dermal papilla cells.55 Minoxidil can accelerate nail growth with proven vasodilatory characteristics.57 As an alpha-adrenergic antagonist, minoxidil is a potent vasodilator and antihypertensive agent used in refractory hypertension. Because minoxidil relaxes vascular and other smooth muscle cells, it was also tested topically on the glans penis to treat ED5,7,58 and was also suggested for use in the long-term treatment of organic impotence.59
Minoxidil in treatment of ED
Mechanism of action
The primary mechanism of action of minoxidil is opening potassium channels in the membrane of vascular smooth muscle cells.12 Minoxidil does not have a direct vasodilatory effect; however, its metabolite minoxidil O-sulfate does have an immediate vasodilatory impact on arterial smooth muscle, causing a reduction in peripheral resistance and blood pressure. Nevertheless, the detailed mechanism of action of minoxidil in ED treatment is not completely clear. Topical minoxidil is a prodrug, which means that to be effective, it would have to be metabolized through the liver and then recirculated to the penis.60,61 In 1999, a study showed that NO significantly affected penile smooth muscle relaxation and erectile function. Minoxidil is considered a donor of NO. Topical minoxidil as a nitric acid donor increases cGMP, relaxing smooth muscle. Therefore, topical minoxidil was expected to positively affect ED.10,11,22 Such topical activity of minoxidil contrasts with the hypothesis that this prodrug requires hepatic metabolism to become vasoactive.62 In a study by Kim and McVary on minoxidil and NTG, it was found that the penis can absorb these substances and that their effects on the hemodynamics of the penis are direct and local (Figure 3).63
*Formulation, dosing, and effectiveness
*Side effects
*Combination of minoxidil with other ED therapies
Conclusion
Recently, topical and transdermal therapies have become increasingly crucial for treating ED due to fewer side effects, interactions, and contraindications to systemic medications. Meanwhile, minoxidil as a peripheral vasodilator has shown a doubtful role in the topical treatment of ED. There is a balance of data confirming success and reports of minoxidil’s ineffectiveness as a topical treatment agent in ED. Reasons for this equilibrium include the lack of clear transparency of the drug’s functional pathway, multiple physical barriers in the structure of the penis preventing drug uptake, uncontrolled physicochemical properties of the drug, and the lack of study of minoxidil in modern formulations such as nanoemulsions, transferosomes, bilosomes, nanoliposomes, centrosomes, nanoethosomes, liposomes, optimized multilayer vesicles (MLVs), and nanosized colloidal systems such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). Almost all of the findings regarding topical treatment of ED with minoxidil were limited to the classic formulations. If topical minoxidil is evaluated in newer formulations, it may have completely different and surprising effects due to improved local absorption.
Coadministration of intracavernosal therapies (such as papaverine, phentolamine, prostaglandin E1, yohimbine, or an adrenoceptor-antagonist), systemic medications (such as PDE5Is), or other transdermal agents (such as NTG, PGE1, papaverine, and PDE5Is) with topical minoxidil may produce a better erectile response in comparison with monotherapy. Further studies are needed on combination therapies and modern formulations to confirm the efficacy of topical minoxidil in treating ED.
Our discussion in this article includes the use of minoxidil alone as a topical treatment for ED. However, studies have shown that combination therapy and different medications are more effective than monotherapy.
Marziye Ranjbar Tavakoli, Pharm D, Maryam Faraji, Pharm D, Sanaz Sam, Pharm D, Ali Ghasempour, Pharm D, Masoud Rezaei, MD, Mohammad Amin Langarizadeh, Pharm D, Somayyeh Karami-Mohajeri, PhD
Abstract
Introduction
Erectile dysfunction (ED), for multifactorial reasons, is one of the biggest current quandaries among men worldwide and results in other complications such as reduced quality of life of the patient and his sexual partner, impotence, and psychiatric problems.
Objectives
Understanding disease etiology, penile anatomy, erectile physiology, therapeutic mechanisms, and effective molecular pathways all play key roles in determining a therapeutic approach. This project is based on the study of topical minoxidil’s effectiveness in treating ED.
Methods
To perform a comprehensive overview of the subject, we performed a triple-keyword combination search to assess recent studies of ED.
Results
The most common formulation used in these studies was a 2% minoxidil solution. Except for cases studied in paralytic patients, topical treatment with minoxidil appears to elicit a mild erectile response; however, this finding is insufficient to confirm the effectiveness of this topical treatment.
Conclusions
Although evidence to confirm the therapeutic properties of minoxidil in ED is limited, combination therapy and the use of modern formulations of minoxidil are promising options for treating ED in the future.
Introduction
Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection adequate to have satisfactory sexual intercourse, according to the National Institutes of Health (NIH) Consensus Development Conference on Impotence.1 By definition, ED is a more precise term than impotence, because in ED only the ability to attain and maintain an erection is lost, while sexual desire and the ability to reach orgasm and ejaculation may remain intact.2 Erectile dysfunction can be classified into 2 main subgroups, (1) primary ED, which occurs from early puberty, prevents the experience of regular sexual activity from the beginning of sexual maturity, and (2) secondary ED, due to various reasons, which may occur at different ages and prevents the patient from having regular sexual activity as before.
Because ED is usually temporary and related to emotional conditions and life problems, it may disappear as these issues are resolved, without the need to visit a doctor and be examined. However, the complete cure of ED depends on the underlying causes. Patients who experience longer-lasting ED, for example, for several months, should be evaluated medically and treated if necessary.3 Although ED is not considered a fatal morbidity, it is closely correlated to many underlying diseases, including cardiovascular disease, and may adversely affect psychosocial health. Thus, ED may have a significant impact on the quality of life of patients and their partners.4
In this study, we aimed to update clinical research into the pathophysiology of erectile dysfunction and the underlying treatments. This review also includes a discussion of the application of minoxidil as a popular topical drug for treating ED.
Results and discussion
Physiology of erection
Penile erection is the consequence of neurological and vascular events that coordinate with hormonal and psychological triggers. Eventually, penile rigidity occurs due to increased intracorporal pressure from corporal smooth muscle relaxation and increased blood flow in the arteries.5–7 Penile erection can be triggered by direct stimulation of the genital organ (reflex parasympathetic erection) or through stimulation of central pathways (psychogenic erection).8 The thalamus regulates psychogenic erection and limbic system, which control the spinal sympathetic (Tl-L2) and parasympathetic (S2-S4) centers.7
Cholinergic and nonadrenergic-noncholinergic nerves relax the smooth muscles of the corpus cavernosum by pro-erectile neurotransmitters such as nitric oxide (NO), intestinal vasoactive peptide (VIP), and prostaglandins.7 NO, which plays a more prominent role than other neurotransmitters in relaxing smooth muscles, is synthesized by NO synthase (NOS) and released from endothelial cells, and activates the enzyme guanylate cyclase (GC), producing cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP).9
VIP is injected intracavernosally for the treatment of ED and has a synergistic effect in concomitant administration with acetylcholine.7 VIP activates the enzyme adenylate cyclase (AC) and produces cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP).10–12 Both cGMP and cAMP lead to hyperpolarization of smooth muscle cells by activating the sodium-potassium channel, thereby reducing the intracellular calcium concentration and relaxing the smooth muscle corpus cavernosum.11,12 As the enzyme 5- phosphodiesterase breaks down cGMP, a primary therapeutic goal in patients with ED is to regulate the function of this enzyme. Details of the mentioned molecular pathways are shown in Figure 1.
Other pro-erectile neurotransmitters include the following.
1. Acetylcholine does not directly affect the corpus cavernosal smooth muscle cells but modulates the release of NO from endothelial cells in the relaxation process.7,13,14
2. CGRP is released from the ends of neurons leading to the corpus cavernosum and directly affects smooth muscle relaxation. Intracavernosal injection of CGRP combined with alprostadil (prostaglandin E1) is one way to treat ED.7,15
3. Substance P promotes corpus cavernosum relaxation. The function of substance P depends on the endothelial release of NO.7,16
4. Pituitary adenylate cyclase–activating polypeptide (PACAP) is structurally similar to VIP and has a relaxant effect on the corpus cavernosum.7,17
5. ATP can be injected either intracavernosally or intraarterially and has a relaxant effect on the corpus cavernosum.7
6. Histamine improves erection by activating H2 receptors and can be administered by intracavernosal injection (ICI) in men with ED.18,19
7. Oxytocin, present in the hypothalamus, is released from oxytocinergic neural terminations and therefore plays a role in modulating the central neural pathway of erection.7,20
8. Dopamine, like oxytocin, plays a role in the hypothalamus’s central neural pathway of erection, which is rich in dopaminergic receptors.21
9. Serotonin (5-Hhydroxytryptamine [5-HT]) regulates and modulates the sympathetic and parasympathetic output and can be injected peripherally.7,20
On the other hand, anti erectile neurotransmitters such as noradrenaline (norepinephrine), neuropeptide Y (NPY), and γ -aminobutyric acid act as counterpoints to the neurological and hormonal factors that cause erections.7
The equilibrium between the levels of these factors plays a crucial role in creating or preventing an erection (Figure 2).
Pathophysiology of ED and risk factors
Organic and nonorganic ED
The normal function of the smooth muscle of penile blood vessels and corpus cavernosum depends on the intactness of all neurological, vascular, and hormonal factors.22 Although the function of the peripheral nervous system in erection has been thoroughly examined, the role of the central nervous system has not been completely clarified. Regions of the frontal and limbic cortex modulate sexual response along with direct or intermediate stimulation of the septal area.23 In the evaluation of some men with epilepsy and ED, the nature of the disorder, primarily in penile stiffness, suggests a neurogenic rather than vasogenic origin and is better identified by assessing both nocturnal penile tumescence and stiffness.24
At the National Institutes of Health (NIH) Consensus Development Conference on Impotence in December 1992, organic etiologies were reported in approximately 75% of ED cases.10,25,26 Organic ED primarily results from cardiovascular diseases, spinal cord injury, and neurodegenerative disorders, which lead to impairment of blood flow and nerve messages to the penis.27 Central neurological disorders, including Parkinson's disease, epilepsy, Alzheimer's disease, and stroke defects, can also lead to ED.22,28
Other nonorganic causes of ED are diabetes mellitus, hypercholesterolemia, drug side effects, and poor lifestyle habits such as smoking, obesity, stationary lifestyle, and drug and alcohol addiction.6,10 Psychological disorders such as depression, anxiety, lack of self-confidence, etc., are the most prevalent causes of nonorganic causes of ED.2,3,29 Diabetic neuropathy and localized nerve damage due to injury or surgery are among the peripheral neurological diseases that lead to an increase in the stimulus threshold of the penis and, thus, a decrease in its sensitivity.2
Age-related ED
Erectile dysfunction was previously thought to be an inevitable consequence of aging, so little attention was paid to this sexual problem of the elderly.30 The prevalence of ED in men younger than 50 years is 9%-39% and in men older than 70 years is 40%-80%.3 However, increased recognition of the importance of sexual satisfaction in elderly patients and their complaints about not having and maintaining a normal erection have led to more attention and research in this field. Sexual problems are relatively common in elderly patients and are frequently related to general health issues or specific sexual disorders. Andropause or androgen deficiency occurs in elderly patients through decreases in glandular function and testosterone production, along with an increase in the blood concentration of sex hormone–binding globulin (SHBG), which reduces the bioavailability of testosterone and leads to impotence, decline in penile sensitivity, and ED.
Testosterone is involved in libido, penile tissue integrity, and NOS expression. The incidence of hypogonadism in older men is 30% of men in their 60s and 80% in their 80s and 90s.22,31
In addition to aging, alcoholism may cause hormonal changes and eventually ED by upsetting the androgen-estrogen balance.22,31 Chronic age-related diseases that impair sexual function include cardiovascular events such as hypertension, hyperlipidemia, and atherosclerosis; chronic neurological disorders including stroke, dementia, and depression;22,31 hormonal disturbance and hypogonadism due to testicular failure (primary hypogonadism) or hypothalamic and pituitary insufficiency (hypogonadotropic hypogonadism);29 and diabetes, a disease that leads to multiorgan dysfunctions. Because older people take many medications, side effects of some medicines may cause iatrogenic ED, especially psychiatric drugs, thiazides, and beta-blockers. If possible, erectile function can be restored in these cases by changing the class or dose of the medication.22,31
Drug-related ED
Medications can affect sexual ability in several ways,4 such as the following.
1. Antidepressants such as tricyclic antidepressants, MAOIs (monoamine oxidase inhibitors), lithium, SSRIs (selective serotonin reuptake inhibitors), and benzodiazepines indirectly cause ED by reducing libido,
2. Antihypertensive drugs, including diuretics, beta-blockers, methyldopa, clonidine, reserpine, guanethidine, and verapamil affect cardiovascular function.
3. Drugs such as phenothiazines, antipsychotic drugs (risperidone, olanzapine, and clozapine), and H2 antagonists (cimetidine and ranitidine) that cause hyperprolactinemia, which lead to ED, impotence, breast enlargement, testicular dysfunction, and infertility in men.
4. Endocrine hormones, such as antiandrogens, H2 antagonists (cimetidine), estrogens, and testosterone.
Management steps for treatment of ED
Basic measures
In the first step of ED treatment management, psychosocial counseling, lifestyle modification, sexual relationship evaluation, and a thorough medical evaluation of other underlying causes might be helpful. Patients who complain of ED should also be examined for corresponding diseases associated with the induction of ED.2,3,32 Studies have shown that lifestyle modification and elimination of ED risk factors by the patient can reduce the risk of ED by up to 70%.2–4,28,29 According to complaints of medication-induced ED, changes in medication may help patients regain the ability to have a normal erection.3,29 Sometimes the patient is in perfect physical health but has depression or conflict with his partner and therefore cannot achieve a full erection until these problems are resolved.2,3,29
Oral medication
Oral therapy is the most common way to take ED medications, including phosphodiesterase type 5 (PDE5) inhibitors. NO donors, such as minoxidil and nitroglycerin (NTG), increase cGMP and cAMP production by increasing the activity of guanylate cyclase and adenosine cyclase.11
Nonoral medication
The next steps in ED treatment include transurethral therapy, intravenous injection, topical therapy, and the application of medical devices (such as vacuums and rings)
Surgery
The last step in ED treatment is the use of invasive treatments, including penile prostheses and penile vascular surgeries.2,37,38
In the following information, among the cases mentioned in the second line of treatment, we focus on the local effects of non-PDEI vasoactive agents, including topical minoxidil.
Non-PDEI vasoactive topical medicines
Alternative routes of administration of vasoactive drugs for treating ED that are less threatening than injection therapy are explored in this section. Agents approved by the FDA for other indications or other ways of administration, including alprostadil, organic nitrates, minoxidil, papaverine, and yohimbine, have been tested via topical administration on the glans penis or penile shaft. Although the FDA does not currently approve these therapies, they may be effective, as well as other medications.2,4,39,40 The challenge with topical therapy is to reach complete absorption, ie, agents applied on penile skin must permeate fascial layers and the tunica albuginea, which means thick layers of collagen.3,41 Organic nitrate, minoxidil, aminophylline, co-dergocrine mesylate, and vasoactive intestinal polypeptide have previously been described as topical cavernosal smooth muscle relaxants with varying degrees of success and rate of side effects.42 To protect the partner, condoms are recommended with the use of aminophylline, co-dergocrine mesylate, minoxidil cream, or the NO donor isosorbide dinitrate are used.22,43 The use of glycerol trinitrate, minoxidil, and papaverine gel has been investigated in various studies, with the results that were variable but mainly disappointing.44 In the following section, we address and examine each of these agents separately.
Prostaglandin E1
Notwithstanding the achievement of PDE5Is, prostaglandin E1 (PGE1, also known as alprostadil) has been tested with various dosing methods as an alternative therapy for ED, predominantly for patients who had unsatisfactory results with PDE5Is medication .45 Topical alprostadil is the most commonly administered synthetic PGE1 for ED. PGE1 promotes corporal smooth muscle laxity, preponderantly by activation of adenylate cyclase and the pursuant agglomeration of 3 5 - cAMP. This process is independent of the NO-cGMP pathway and does not require preliminary sexual stimulation.46 The cream formulation of PGE1 (Vitaros/Virirec) incorporates the advantages of alprostadil with a formulation that is convenient to use.47 Alprostadil cream is a particular combination containing alprostadil as the active pharmaceutical ingredient, a penetration booster (dodecyl-2-N, N-dimethylamino propionate [DDAIP]), and an ester of N-dimethylalanine and dodecanol called HCl. The mentioned penetration-enhancing complex provisionally slackens tight junctions located in the dermal epithelial cells, subsequent to its interplay on the plasma membrane with the hydrophilic zone of the phospholipid bilayer.48 Numerous studies have also been reported that have investigated transdermal strategies for treating ED, including transdermal conveyance of NTG, PDEIs, phentolamine, and papaverine.
Testosterone
Testosterone is a pivotal androgen in men that is produced in the testicles and adrenal cortex. Recently, the direct effects of different testosterone levels on the structural, biochemical, and physiological characteristics of the penis and the pathways associated with erection have become apparent. Animal findings and studies of castrated individuals have shown that lowering testosterone levels not only directly affects the NO pathway but also changes the hemodynamics of the penis as well as smooth muscle tone in a way that makes ED inevitable.49 Monotherapy with gel-formulated testosterone restored erectile function but its effect is limited in hypogonadal men,49 ie, the most efficacious approach for sexual impairment in hypogonadal males is testosterone therapy. It operates by re-establishing erections as commonly evaluated with International Index of Erectile Function (IIEF) scores. This effect will be more tangible in these patients if the gel is used concomitantly with oral sildenafil.50 Numerous assessments have illustrated the advantages of merged testosterone and sildenafil therapy in generating acceptable erectile reactions in hypogonadal males who did not react to sildenafil monotherapy.51
Papaverine
Topical transmission of papaverine through the penile shaft would be a superb substitutive and lower-priced therapy for patients undergoing long-term medication for ED.52 Transdermal papaverine gel does not seem to cause severe adverse effects after administration to the penile shaft. A 15%-20% formulation of papaverine elevates intracorporal pressure due to the increased blood flow to the penis. The outcome of transdermal papaverine in altering blood flow to the phallus is dose-dependent. However, topical therapy with papaverine is not as beneficial as an intracavernous medication injection. Nevertheless, transdermal formulations of papaverine may have promising outcomes at higher concentrations or in amalgamation with diverse skin penetration boosters. Transdermal administration avoids many difficulties related to ICI medication, and the represented outcomes on boosting penile arterial flow via transdermal administration of locally acting papaverine gel formulation warrant further evaluation.53
Nitroglycerine
Transdermal NTG is a feasible and practical strategy for treating impotence and ED, and NTG-treated patients exhibited erections sufficient for regular sexual intercourse.54 After sexual stimulation, topical NTG works by increasing blood flow in the cavernous arteries, causing an increase in factors related to erection, such as stiffness and diameter of the penis. This effect was observed in a group study by Nunez and Anderson, in which 3 impotence patients were successfully treated with NTG ointment.47
Minoxidil
Topical minoxidil formulations, which influence follicular cells, have been utilized for hair regrowth in recent decades, Elevated fenestration in the follicular capillary membrane around anagen bulbs was illustrated by electron microscopy after administration of topical minoxidil 4% solution.55 This affirmative outcome of topical minoxidil stimulation of hair regrowth is chiefly attributable to its active metabolite, minoxidil sulfate, which is converted by sulfotransferase.55 However, minoxidil might generate undesirable vascular outcomes. As a direct-acting peripheral vasodilator, minoxidil decreases blood pressure in systolic and diastolic sessions by decreasing peripheral vascular resistance.56 Minoxidil also provokes PGE2 synthesis by switching on prostaglandin endoperoxide synthase-1 and suppressing prostacyclin generation. Furthermore, minoxidil increases the expression of the PGE2 receptor, which is the most upregulated in the beta-catenin pathway of dermal papilla cells.55 Minoxidil can accelerate nail growth with proven vasodilatory characteristics.57 As an alpha-adrenergic antagonist, minoxidil is a potent vasodilator and antihypertensive agent used in refractory hypertension. Because minoxidil relaxes vascular and other smooth muscle cells, it was also tested topically on the glans penis to treat ED5,7,58 and was also suggested for use in the long-term treatment of organic impotence.59
Minoxidil in treatment of ED
Mechanism of action
The primary mechanism of action of minoxidil is opening potassium channels in the membrane of vascular smooth muscle cells.12 Minoxidil does not have a direct vasodilatory effect; however, its metabolite minoxidil O-sulfate does have an immediate vasodilatory impact on arterial smooth muscle, causing a reduction in peripheral resistance and blood pressure. Nevertheless, the detailed mechanism of action of minoxidil in ED treatment is not completely clear. Topical minoxidil is a prodrug, which means that to be effective, it would have to be metabolized through the liver and then recirculated to the penis.60,61 In 1999, a study showed that NO significantly affected penile smooth muscle relaxation and erectile function. Minoxidil is considered a donor of NO. Topical minoxidil as a nitric acid donor increases cGMP, relaxing smooth muscle. Therefore, topical minoxidil was expected to positively affect ED.10,11,22 Such topical activity of minoxidil contrasts with the hypothesis that this prodrug requires hepatic metabolism to become vasoactive.62 In a study by Kim and McVary on minoxidil and NTG, it was found that the penis can absorb these substances and that their effects on the hemodynamics of the penis are direct and local (Figure 3).63
*Formulation, dosing, and effectiveness
*Side effects
*Combination of minoxidil with other ED therapies
Conclusion
Recently, topical and transdermal therapies have become increasingly crucial for treating ED due to fewer side effects, interactions, and contraindications to systemic medications. Meanwhile, minoxidil as a peripheral vasodilator has shown a doubtful role in the topical treatment of ED. There is a balance of data confirming success and reports of minoxidil’s ineffectiveness as a topical treatment agent in ED. Reasons for this equilibrium include the lack of clear transparency of the drug’s functional pathway, multiple physical barriers in the structure of the penis preventing drug uptake, uncontrolled physicochemical properties of the drug, and the lack of study of minoxidil in modern formulations such as nanoemulsions, transferosomes, bilosomes, nanoliposomes, centrosomes, nanoethosomes, liposomes, optimized multilayer vesicles (MLVs), and nanosized colloidal systems such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). Almost all of the findings regarding topical treatment of ED with minoxidil were limited to the classic formulations. If topical minoxidil is evaluated in newer formulations, it may have completely different and surprising effects due to improved local absorption.
Coadministration of intracavernosal therapies (such as papaverine, phentolamine, prostaglandin E1, yohimbine, or an adrenoceptor-antagonist), systemic medications (such as PDE5Is), or other transdermal agents (such as NTG, PGE1, papaverine, and PDE5Is) with topical minoxidil may produce a better erectile response in comparison with monotherapy. Further studies are needed on combination therapies and modern formulations to confirm the efficacy of topical minoxidil in treating ED.
Our discussion in this article includes the use of minoxidil alone as a topical treatment for ED. However, studies have shown that combination therapy and different medications are more effective than monotherapy.
