madman
Super Moderator
ABSTRACT: Erectile dysfunction (ED) is a common sexual disorder in adult males and one of the most important factors affecting their quality of life and that of their partners. Although PDE5 inhibitors (PDE5is) are the first choice for improving erectile function, there is a substantial proportion of ED patients, termed PDE5i nonresponders, who do not respond to PDE5is. Because of the lack of effective therapies, these patients always have serious social and psychological problems due to ED, which should be addressed. Here, we review the available literature about ED and PDE5is and propose several strategies for mitigating ED in PDE5i nonresponders.
1. Introduction Erectile dysfunction
(ED) is a common sexual disorder in adult males and has significant biological, psychological, and social effects on the quality of life (QOL) of men with ED and their sexual partners or spouses [1-2]. Indeed, the high prevalence of ED has become a global health concern [3]. The percentages of men affected by ED are as follows: 14.3–70% of men aged ≥60 years, 6.7–48% of men aged ≥70 years, and 38% of men aged ≥80 years [4]. Many treatments are available for ED, including psychotherapy, oral medication, vacuum constriction devices (VCDs), intraurethral drugs, intracavernous drugs, and implantable prosthetics. Among them, phosphodiesterase type 5 inhibitors (PDE5is), as a first-line treatment, are recognized as the most satisfying and effective drugs for ED [5-6]. However, with the increasing administration of PDE5is in clinical practice, it has found that approximately 30–35% of ED patients cannot respond to PDE5is [7]. Although the unreasonable use of PDE5is, including the use of inadequate dosages, administration of a single dose, and lack of dosage regulation, is considered the main reason for the lack of response to PDE5is [8], 50–70% of ED patients still do not respond to PDE5is after restoring rational PDE5i use [9]. In general, the detailed mechanisms of the lack of response to PDE5is in ED remain to be clarified, and treating these patients is a challenge that urgently needs to be addressed.
ED is closely related to aging. Penile erection is a complex physiological activity involving the neuroendocrine vascular tissue system [10], and aging can not only cause tissue dysfunction related to this physiological activity, including dysfunction involving the nerves, blood vessels, cavernous tissue, and reproductive hormones but also increase the risk of penile ED [11]. Aging also increases the risk of various chronic diseases in the elderly, such as cardiovascular diseases, diabetes, metabolic syndrome, late-onset hypogonadism (LOH), and lower urinary tract symptoms (LUTSs) [11]. These chronic diseases have been recognized as risk factors for ED and can cause and/or aggravate ED [12]. It has been shown that the prevalence of ED ranges from 1– 10% for men aged under 40 years, 2–15% for men aged 40–49 years, 22–31% for men aged 50–69 years, 20–40% for men aged 60–69 years, and 50–100% for men over 70 years old [13]. Therefore, aging is an important risk factor for ED development. At the same time, the changes caused by aging will also increase the difficulty of ED treatment, which is an important factor in the lack of response to PDE5i treatment. It is worth noting that according to previous reports, approximately 15% of the global population will be over 65 years old by the year 2025 due to the increase in life expectancy [11, 14]. Therefore, sexual dysfunction, especially ED, in elderly men is a problem that cannot be ignored. Moreover, PDE5i nonresponsiveness in older men as a result of age is a major challenge that urgently needs to be addressed. Here, we propose several strategies for treating ED in PDE5i nonresponders and present a summary of the direct evidence of rescue treatment in PDE5i responders in Table 1.
2. Possible causes for ED in PDE5i nonresponders
3. Approaches to improve ED in PDE5i nonresponders
3.1 Improved pharmacotherapy with PDE5is
3.1.2 Increased PDE5i doses
3.1.3 Different dosing regimens
3.1.4 Different PDE5is
3.1.5 Combined use of long-acting and short-acting PDE5is
3.2 Non-drug therapeutic approaches with or without PDE5is
3.3 Attention to psychological factors
3.4 Focus on the comorbidities of ED
3.4.1 Selection of PDE5is with greater effects on ED
3.4.1.1 PDE5is, ED and premature ejaculation
3.4.1.2 PDE5is, ED and diabetes
3.4.1.3 PDE5is, ED and spinal injury
3.4.1.4 PDE5is, ED and RP
3.4.1.5 PDE5is, ED and other comorbidities
3.4.2 Management of medications for comorbidities of ED
3.4.2.1 Associated medication modifications
3.4.2.2 PDE5is combined with other non-PDE5i drugs
3.5 Lifestyle adjustments: a neglected issue
3.6 Patient management
4. Management of strategies for treating ED in PDE5i nonresponders
5. Conclusions
ED is a common sexual abnormality in adult men that measurably affects their psychological and physical QOL as well as that of their partners. The discovery and application of PDE5is have been revolutionary for the treatment of ED. With increasing clinical trials on PDE5is and ED, there are now many strategies for improving erectile function, as reviewed above. Regardless, ED is a very complex condition involving both psychological and physical factors. The treatment program for ED will vary among individuals, especially in patients with a poor response to PDE5is. Therefore, combinations of various strategies to enhance the response to PDE5is should be applied to improve the therapeutic efficacy according to the clinical characteristics of each patient. Additionally, PDE5i nonresponders are a unique group of ED patients, and the causes of the lack of response to PDE5is remain to be clarified. Although some studies have suggested improved strategies for PDE5i nonresponders, these studies are limited, and more related basic and clinical research is needed to help PDE5i nonresponders achieve satisfactory sexual experiences.
1. Introduction Erectile dysfunction
(ED) is a common sexual disorder in adult males and has significant biological, psychological, and social effects on the quality of life (QOL) of men with ED and their sexual partners or spouses [1-2]. Indeed, the high prevalence of ED has become a global health concern [3]. The percentages of men affected by ED are as follows: 14.3–70% of men aged ≥60 years, 6.7–48% of men aged ≥70 years, and 38% of men aged ≥80 years [4]. Many treatments are available for ED, including psychotherapy, oral medication, vacuum constriction devices (VCDs), intraurethral drugs, intracavernous drugs, and implantable prosthetics. Among them, phosphodiesterase type 5 inhibitors (PDE5is), as a first-line treatment, are recognized as the most satisfying and effective drugs for ED [5-6]. However, with the increasing administration of PDE5is in clinical practice, it has found that approximately 30–35% of ED patients cannot respond to PDE5is [7]. Although the unreasonable use of PDE5is, including the use of inadequate dosages, administration of a single dose, and lack of dosage regulation, is considered the main reason for the lack of response to PDE5is [8], 50–70% of ED patients still do not respond to PDE5is after restoring rational PDE5i use [9]. In general, the detailed mechanisms of the lack of response to PDE5is in ED remain to be clarified, and treating these patients is a challenge that urgently needs to be addressed.
ED is closely related to aging. Penile erection is a complex physiological activity involving the neuroendocrine vascular tissue system [10], and aging can not only cause tissue dysfunction related to this physiological activity, including dysfunction involving the nerves, blood vessels, cavernous tissue, and reproductive hormones but also increase the risk of penile ED [11]. Aging also increases the risk of various chronic diseases in the elderly, such as cardiovascular diseases, diabetes, metabolic syndrome, late-onset hypogonadism (LOH), and lower urinary tract symptoms (LUTSs) [11]. These chronic diseases have been recognized as risk factors for ED and can cause and/or aggravate ED [12]. It has been shown that the prevalence of ED ranges from 1– 10% for men aged under 40 years, 2–15% for men aged 40–49 years, 22–31% for men aged 50–69 years, 20–40% for men aged 60–69 years, and 50–100% for men over 70 years old [13]. Therefore, aging is an important risk factor for ED development. At the same time, the changes caused by aging will also increase the difficulty of ED treatment, which is an important factor in the lack of response to PDE5i treatment. It is worth noting that according to previous reports, approximately 15% of the global population will be over 65 years old by the year 2025 due to the increase in life expectancy [11, 14]. Therefore, sexual dysfunction, especially ED, in elderly men is a problem that cannot be ignored. Moreover, PDE5i nonresponsiveness in older men as a result of age is a major challenge that urgently needs to be addressed. Here, we propose several strategies for treating ED in PDE5i nonresponders and present a summary of the direct evidence of rescue treatment in PDE5i responders in Table 1.
2. Possible causes for ED in PDE5i nonresponders
3. Approaches to improve ED in PDE5i nonresponders
3.1 Improved pharmacotherapy with PDE5is
3.1.2 Increased PDE5i doses
3.1.3 Different dosing regimens
3.1.4 Different PDE5is
3.1.5 Combined use of long-acting and short-acting PDE5is
3.2 Non-drug therapeutic approaches with or without PDE5is
3.3 Attention to psychological factors
3.4 Focus on the comorbidities of ED
3.4.1 Selection of PDE5is with greater effects on ED
3.4.1.1 PDE5is, ED and premature ejaculation
3.4.1.2 PDE5is, ED and diabetes
3.4.1.3 PDE5is, ED and spinal injury
3.4.1.4 PDE5is, ED and RP
3.4.1.5 PDE5is, ED and other comorbidities
3.4.2 Management of medications for comorbidities of ED
3.4.2.1 Associated medication modifications
3.4.2.2 PDE5is combined with other non-PDE5i drugs
3.5 Lifestyle adjustments: a neglected issue
3.6 Patient management
4. Management of strategies for treating ED in PDE5i nonresponders
5. Conclusions
ED is a common sexual abnormality in adult men that measurably affects their psychological and physical QOL as well as that of their partners. The discovery and application of PDE5is have been revolutionary for the treatment of ED. With increasing clinical trials on PDE5is and ED, there are now many strategies for improving erectile function, as reviewed above. Regardless, ED is a very complex condition involving both psychological and physical factors. The treatment program for ED will vary among individuals, especially in patients with a poor response to PDE5is. Therefore, combinations of various strategies to enhance the response to PDE5is should be applied to improve the therapeutic efficacy according to the clinical characteristics of each patient. Additionally, PDE5i nonresponders are a unique group of ED patients, and the causes of the lack of response to PDE5is remain to be clarified. Although some studies have suggested improved strategies for PDE5i nonresponders, these studies are limited, and more related basic and clinical research is needed to help PDE5i nonresponders achieve satisfactory sexual experiences.
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