Efficacy and safety of PDE5 inhibitors in middle-aged and old patients with and without hypogonadism

Abstract

Purpose

Although several reviews have evaluated the use of PDE5 inhibitors (PDE5i) for treating erectile dysfunction (ED), their specific use in middle-aged and old patients has not been fully evaluated. Given that elderly patients with ED often have a complex combination of systemic and sexual health risk factors, the safety and efficacy of PDE5i in such a context are hereby reviewed.

Materials and methods

A thorough examination of existing literature has been conducted on PubMed.

Results

PDE5i has good safety and efficacy, but the situation is more complex for patients with hypogonadism than those with normal testosterone levels, with reduced responsiveness to PDE5i. In this case, combination therapy with testosterone is recommended, safe and effective

Conclusions

Eliminating or reducing reversible risk factors and controlling or slowing the development of irreversible factors is an important foundation for using PDE5i to treat ED in all patients, especially middle-aged and elderly ones.

Keywords:

• Phosphodiesterase type 5 (PDE5) inhibitors
• erectile dysfunction (ED)
• hypogonadism
• efficacy
• safety

Introduction

Erectile dysfunction (ED) is the inability to obtain or maintain sufficient penile erection to complete satisfactory sexual intercourse [1]. ED is a common male sexual dysfunction in today’s society [2,3], with a global prevalence ranging from 3 to 76.5% [3–5]. Such discrepancy arises from using different screen tools and according to the age of the sample [3]. Increasing age is the variable most strongly associated with ED [6–8]: indeed, an overall prevalence of approximately 50% has been reported in middle-aged and elderly men, according to several epidemiological studies [5,9,10]. The classification of ED includes predominantly organic and predominantly non-organic types [1]. Common risk factors for ED include systemic health risk factors, such as cardiovascular, respiratory, metabolic, hormonal, neurological, and urological, as well as iatrogenic, psychological, and psychosexual risk factors [1].

ED can be often the manifestation of another common clinical condition being male hypogonadism, which is the inability to produce physiological concentrations of testosterone and/or several normal sperm cells [11]. The etiology of hypogonadism can involve testicular disease, hypothalamic-pituitary unit dysfunction, and aging [11]. The decline in testosterone concentrations associated with aging is referred to as late-onset hypogonadism (LOH) [12]. The diagnosis of male hypogonadism primarily relies on laboratory testing (low testosterone concentrations at least twice in morning serum) as well as related symptoms and signs [11]. The threshold for what actually constitutes a “low testosterone concentration” has often been questioned, and no definition is currently universally viable. Accordingly, the prevalence of LOH ranges from 2.1 to 40% [13–20], with significant variation in prevalence primarily due to: (1) non-uniform criteria for defining LOH; (2) differences in the population studied.

Male hypogonadism is closely related to ED [14,21–25]. Indeed, testosterone plays a crucial role in the production and maintenance of sexual desire and erectile function, acting either at the central nervous system level or locally in the penile corpora cavernosa [22]. As a matter of fact, among the manifestations of testosterone deficiency, low libido, and ED are found [22]. In addition, ED is the most sensitive and specific symptom for identifying LOH [14]. Male hypogonadism is also closely related to metabolic diseases [26]. For instance, the bidirectional relationship between diabetes and hypogonadism is well known, and the emotional distress caused by chronic disease in diabetes patients can also lead to, or worsen, ED [27]. Moreover, the reduced sexual activity caused by ED is related to a reversible decrease in testosterone levels [28,29].

The emergence of PDE5 inhibitor (PDE5i), i.e. sildenafil, has opened a new era for the treatment of ED [30]. The mechanism of action of PDE5i is to inhibit the degradation of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum tissue by inhibiting the PDE5 enzyme. This increases the concentration of cGMP in the corpus cavernosum tissue, leading to a decrease in intracellular calcium ion concentration, smooth muscle relaxation, and increased arterial blood flow, which further leads to compression of the venous plexus and, ultimately, penile erection [31–33]. Tadalafil, vardenafil, and avanafil are three other PDE5i that have been licensed worldwide for the treatment of ED [34].

PDE5i are currently the gold standard for treating ED and have become recognized as first-line therapy [1,30,34–36]. However, there is still a nearly 30–35% inefficacy rate when using PDE5i alone to treat ED [37], partly due to the frequent, concurrent presence of hypogonadism [38]. This occurs particularly among middle-aged and elderly men with ED, 15% of whom are also hypogonadal [23]. To date, although several review articles have discussed the safety and efficacy of PDE5i [30,34–36], middle-aged and elderly patients with ED have not been thoroughly evaluated for this purpose.

Eugonadal and hypogonadal patients could be, in fact, considered two distinct populations when considering indications and contraindications to ED treatments. First, testosterone deficiency can reduce responsiveness to PDE5i among ED patients [38]. Second, hypogonadism can interact with other risk factors contributing to ED [27]. Third, combined treatment with testosterone supplementation therapy and PDE5i can significantly improve erectile function in patients with hypogonadism [39]. These three points collectively indicate the unique characteristics of patients with concomitant hypogonadism. Hence, we will comprehensively discuss the safety and efficacy of using PDE5i to treat middle-aged and elderly patients with ED with or without concurrent hypogonadism, summarizing the current research status on this issue, providing critical insights into previous literature, and attempting to pave the way on future research.

The safety and efficacy of PDE5 inhibitors in middle-aged and elderly patients with ED and without hypogonadism

Compared to young patients with ED, middle-aged and elderly patients are more likely to bear a combination of multiple risk factors for ED [40]. The efficacy of PDE5i largely depends on the severity and risk factors of ED [41]. Therefore, when discussing the safety and efficacy of PDE5i, it is still necessary to analyze various risk factors first.

Reversible risk factors

Smoking and heavy alcohol consumption are closely related to ED [42,43] (Figure 1), and smokers have a 51% increased risk of developing ED compared to non-smokers [44]. Smoking can cause vascular inflammation, vascular dysfunction, and oxidative stress, ultimately leading to chronic anatomical damage [45,46]. Smoking cessation and alcohol intake reduction have beneficial effects on restoring erectile function [47]. Therefore, theoretically, the efficacy of PDE5i in the treatment of ED may benefit from quitting smoking and stopping alcohol dependence. For those who find it challenging to change their habits, such as smoking and alcohol consumption, harm reduction strategies can reduce the harms associated with these behaviors: examples of such strategies include moderate drinking, the use of heat-not-burn devices, and nicotine replacement therapy [48].

Figure 1. The common systemic and sexual health risk factors related to ED and the differences in responsiveness to PDE5i between ED patients with and without hypogonadism. ED: erectile dysfunction; PDE5-is: phosphodiesterase type 5 inhibitors; RP: radical prostatectomy; PPRF: psychological and partner relationship factors; LUTS: lower urinary tract symptoms; DM: diabetes mellitus. “…” represents classification of risk factors of ED. “.-.-.” represents treatment. “——” represents causal relationship.

In addition, several medications may worsen ED [49–54], the most studied ones being listed in Table 1. These drugs can affect erectile function through various mechanisms, including altering blood flow, producing endocrine derangements, or influencing neurotransmitter activity [55]. Some commonly encountered categories of drugs known to contribute to ED include antihypertensive medications such as beta-blockers, especially non-selective ones (e.g. metoprolol, etc.) [56] and diuretics (e.g. hydrochlorothiazide, spironolactone) [52]. Additionally, psychiatric medications like selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (e.g. paroxetine, venlafaxine) are known to have the potential for causing sexual side effects, including ED [57]. Hormonal therapies, such as androgen deprivation therapy (ADT) for prostate cancer, can significantly impact testosterone levels and contribute to ED [58]. Furthermore, substances like recreational drugs (e.g. cocaine, marijuana), opioids (e.g. morphine, oxycodone), and even some over-the-counter antihistamines can have adverse effects on erectile function [59].

Table 1. An overview of common drugs which may affect erectile function.

Classification	Pharmacotherapeutic group	Common drugs
Cardiovascular drugs	Beta-blockers Thiazide diuretics Anti-mineralocorticoid diuretics Dihydropyridine derivatives HMG-CoA reductase inhibitors	Metoprolol, carvedilol, atenolol, propranolol Hydrochlorothiazide, chlortalidone Spironolactone Amlodipine Simvastatin, atorvastatin
Antiandrogens	Gonadotropin-releasing hormone agonists Alpha-reductase inhibitors	Leuprolide Finasteride, dutasteride
Psychotropic drugs	Selective serotonin reuptake inhibitors Other antidepressants	Paroxetine, fluoxetine, citalopram Venlafaxine, duloxetine, clomipramine
Other drugs	α-Adrenoreceptor antagonists Biguanides Proton pump inhibitors Centrally acting sympathomimetics	Tamsulosin Metformin Omeprazole Methylphenidate

When using PDE5i to treat ED resulting from, or worsened, by the use of other concomitant drugs, several important considerations must be taken into account. Firstly, a comprehensive medical history and medication review should be conducted to identify potential contributors to ED and assess the necessity of these medications. Open communication between the patient and healthcare provider is vital to discuss concerns, expectations, and any potential side effects of PDE5i. It is crucial to monitor blood pressure, especially when using PDE5i alongside antihypertensive medications, as there may be interactions that affect blood pressure regulation. Dose adjustments may be required based on the severity of ED and the specific drug interactions involved, as well as the patient’s comorbidity (i.e. reduced kidney function). In cases where altering the medication regimen or discontinuing the causative drug is feasible, healthcare providers should consider such options in collaboration with the patient’s primary care physician or specialist. Overall, the management of drug-induced ED with PDE5i should be individualized and monitored closely to ensure both efficacy and patient safety.

Concomitant and underlying risks

Metabolic disorders

Diabetes mellitus (DM) is one of the most common chronic diseases characterized by elevated blood sugar levels, which can cause multi-organ damage. ED is the most important sexual dysfunction in male diabetic patients, with a prevalence rate of over 50% [60]. The mechanism of ED in diabetes is complex. High blood sugar and low-grade chronic inflammation can cause endothelial damage, leading to atherosclerosis and, ultimately to hemodynamic abnormalities [27,61]. High blood sugar can also cause peripheral neuropathy, impairing penile sensory function [7]. Long-term chronic disease may generate psychological distress, playing a role in the development of ED [27]. In addition, DM often accompanies other clinical conditions, such as obesity and gout, which also play a role in the occurrence and development of ED [62,63].

In patients with DM who had a disease duration of 12 years and ED duration of 5.6 years (mean age 57 years), 56% of the patients reported improvement in erectile function with sildenafil treatment, and adverse events related to treatment occurred in approximately 16% of the patients, with the most common adverse reactions being headache, gastrointestinal reactions, and respiratory reactions [64]. In diabetic patients (mean age 56 years) treated with tadalafil 10 and 20 mg for 12 weeks, 56% and 64% of the patients reported improvement in erectile function, respectively, and adverse events occurred in over 3% of the patients, mainly including indigestion, headache, and muscle pain [65]. In diabetic patients (mean age approximately 57 years) treated with vardenafil for 12 weeks, 57% (10 mg dose) and 72% (20 mg dose) of the patients showed improvement in erectile function, and adverse events related to treatment occurred in over 5% of the patients, mainly including headache, flushing, and rhinitis [66]. In diabetic patients with ED (mean age 58 years) treated with avanafil 100 and 200 mg, successful sexual attempts were achieved in 34.4 and 40% of the patients, respectively, and 33.3% of the patients experienced adverse events, mainly including headache, nasopharyngitis, and flushing [67].

In summary, PDE5i has good efficacy and safety in treating ED associated with DM. However, it is important to consider that DM can worsen erectile function through various complex mechanisms [27]. Therefore, when using PDE5i to treat ED, reasonable control of blood glucose, treatment of relevant complications, active attention to mental and psychological health, and partner relationships are key factors to increase treatment efficacy and safety. On the other hand, among the new hypoglycemic agents, GLP1-receptor analogs and sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been shown to have beneficial effects that go far beyond blood glucose control [68,69]. Research involving GLP1-receptor analogs indeed demonstrated favorable outcomes concerning body weight and testosterone levels in men who have low testosterone levels and are affected by obesity, whether or not they have type 2 diabetes [68]. Moreover, it has been shown that SGLT2is can reduce patients’ body weight, raise testosterone levels, and improve endothelial function, all of which can further ameliorate erectile function [68].

Endocrine diseases

Jannini et al. [70] first summarized all the evidence on the relationship between thyroid hormones and sexual dysfunction in 1995, and since then, numerous studies have confirmed the impact of thyroid diseases on sexual function [71]. Macroscopic studies have found a higher prevalence of ED in patients with thyroid diseases compared to the control group [72,73]. A microscopic study has revealed the presence of thyroid hormone receptors in the corpora cavernosa [74]. Noticeable hypothyroidism is associated with anxiety and depression [75], which evidently can negatively affect male erectile function [73,76]. Additionally, hypothyroidism can lead to sexual dysfunction by regulating the hypothalamus-pituitary-thyroid axis [71]. After restoring thyroid hormone levels to normal in patients with hypothyroidism, erectile function is restored [77].

There is a close relationship between hyperprolactinemia, hypothyroidism, and ED [78]. Overt hypothyroidism is characterized by elevated levels of TSH (thyroid-stimulating hormone) and thyrotropin-releasing hormone, leading to an increase in the production of prolactin (PRL), and prolactin levels have a negative association with erection [78]. Therefore, theoretically, when thyroid hormone and prolactin levels are abnormal, if the endocrine imbalance is not corrected, the effectiveness of using PDE5i alone to treat ED may be reduced. Animal experiments have shown reduced reactivity to sildenafil following thyroidectomy [79], and it is worth noting that clinical studies exploring the safety and efficacy of PDE5i in treating ED in patients who are suffering from thyroid dysfunction are extremely scarce. One clinical study suggests that PDE5i should only be initiated for ED at least 6 months after thyroid function has been restored because thyroid dysfunction is often a primary cause of ED, making early use of PDE5i inadvisable [80]. Research on the treatment of ED combined with hyperprolactinemia using PDE5i is very scarce. A case report indicates that ED caused by pituitary prolactinoma showed a reduced response to PDE5i during treatment, but the responsiveness increased after correcting the prolactin levels [81].

The good effectiveness and safety of PDE5i may lead sexual health specialists to diminish their pursuit of the underlying causes, as the space for diagnostic and etiological treatment is diminished, particularly evident in endocrine-related conditions associated with ED [82]. Currently, both in scientific research and clinical practice, thyroid hormones and prolactin receive less attention compared to testosterone. Nevertheless, the impact of thyroid hormones and prolactin on erectile function is gradually gaining more recognition. In diagnosing and treating ED, appropriate attention should be given to these endocrine factors relevant to sexual function.

Cardiovascular disease

As of 2019, there were approximately 652 million men (aged 30–79) worldwide with hypertension [83]. Many studies have shown that hypertension is closely and complexly related to ED (Figure 1) and that hypertensive patients have a higher incidence of ED [84–88]. Endothelial damage at systemic and penile vascular levels and atherosclerosis caused by hypertension play an important role in the occurrence and development of ED [87,89].

When treating patients with hypertension, PDE5i remains the first-line therapy [90,91]. The cardiovascular safety of PDE5i has been the subject of extensive research and scrutiny. These medications, such as sildenafil, tadalafil, and vardenafil, were initially developed for the treatment of ED but have demonstrated a relatively favorable cardiovascular safety profile. After sildenafil treatment, 69.2% and 76% of patients had improved scores in questions 3 and 4 of the International Index of Erectile Function (IIEF), respectively, with only 5.7% of patients experiencing adverse effects [92]. A study has demonstrated that vardenafil exhibited favorable cardiovascular safety in hypertensive patients [93]. There were no significant changes in systolic and diastolic blood pressure or heart rate between the vardenafil group and the placebo group. Additionally, another study has shown that sildenafil has minimal impact on hemodynamic variables and can increase coronary artery blood flow reserve [94]. Numerous clinical trials and studies have explored the effects of PDE5i on the cardiovascular system, particularly due to their potential to interact with nitric oxide pathways, vasodilation, and improvement of endothelial function [95]. A meta-analysis has demonstrated that PDE5i possesses anti-ventricular remodeling properties and improves cardiac contractility, with a good safety profile [96]. While there have been occasional reports of transient cardiovascular events like mild blood pressure fluctuations, the overall consensus from research suggests that PDE5i are generally well-tolerated However, it’s worth noting that shorter-acting PDE5i appear to be safer for patients with high cardiovascular risk [1]. Therefore, it is essential for healthcare providers to exercise caution and perform a thorough assessment of patients’ cardiovascular health before prescribing these medications, especially in individuals taking nitrates or other medications that affect blood pressure, to ensure safe and appropriate usage.

Effective ED treatment relies on reasonable blood pressure control [97]. However, some antihypertensive drugs have a negative impact on erectile function, such as beta blockers and thiazide diuretics (see previous section) [49]. In clinical practice, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can be used as alternatives to the aforementioned drugs that negatively affect erectile function, as ACEIs and ARBs seem to have a positive effect on erectile function [98–103]. PDE5i do not significantly increase the risk of hypotension when combined with commonly used antihypertensive drugs [104] but are contraindicated with organic nitrates due to the potential for fatal hypotension [105]. When associated with alpha-blockers, caution should be used to prevent orthostatic hypotension, and it is advisable to start with a lower dose [106,107].

Urological risk factors

Lower urinary tract symptoms (LUTS) are a collective term for storage, voiding, and post-micturition symptoms [108], and the causes of LUTS can be varied, with benign prostatic hyperplasia (BPH) being one of the most common causes [109]. LUTS affect approximately 62.5% of men, particularly after 40 years old, and are closely related to ED [110] (Figure 1). The prevalence of ED in LUTS patients is as high as 58% [111]. The underlying mechanism between ED and LUTS is unclear. Possible mechanisms currently include pelvic ischemia and microvascular dysfunction, inflammatory pathways, activation of nitric oxide synthase (NOS/NO) and Rho-kinase pathways, autonomic nervous system overactivity, and psychological factors, and are related to sex hormones [112]. Clarifying these complex mechanisms will help to optimize the use of PDE5i in patients with LUTS. Indeed, PDE5i has significant advantages in treating patients with LUTS and ED [113]. Treatment with sildenafil for 12 weeks significantly improved the IIEF and LUTS-related scale scores, with a treatment-related adverse event rate of 14% [114]. Combination therapy with tamsulosin and PDE5i has also been shown effective in treating LUTS-ED [115]. Studies have shown that tadalafil can improve urodynamic parameters in LUTS-BPH [116]. In patients with LUTS-BPH combined with ED, tadalafil can be preferred as a first-line treatment [117]. However, it should be noted that tadalafil has not been adequately compared with other drugs used to treat LUTS in clinical trials, and whether the combination of tadalafil with other drugs (β3-adrenergic receptor agonists, 5-α reductase inhibitors, and M receptor antagonists) for treating LUTS-ED is more advantageous than using tadalafil alone remains unknown.

After radical prostatectomy

Previously, almost all patients would experience permanent ED after non-nerve-sparing radical prostatectomy [118]. Nerve-sparing radical prostatectomy (NSRP) was invented by American doctor Patrick C. Walsh and was first applied in clinical practice in 1982 [119]. The invention of this technique brought revolutionary changes to the treatment of prostate cancer patients, as it can better preserve erectile function and reduce the risk of postoperative ED [119]. Sixty to 85% of patients can eventually recover erectile function after NSRP [119]. The recovery of erectile function mainly depends on the age and quality of NSRP [120], and often a restitutio ad integrum is not possible [121]. For patients with ED after radical prostatectomy, PDE5i remains the first-line treatment. However, relatively low responsiveness is documented, being 0–15% in patients undergoing non-nerve-sparing radical prostatectomy and 35–75% in patients undergoing NSRP [120,122]. In clinical practice, the recovery of erectile function is usually slow [123], so patients may be skeptical about the recovery of their erectile function, which can also cause significant psychological pressure on them. Hence, during the recovery phase of erectile function, it is advisable for healthcare professionals to provide appropriate medical counseling and comprehensive health management to patients.

Infertility

When couples engage in sexual intercourse with the sole purpose of achieving pregnancy, the sexual activity, marked by a sense of urgency and pressure, may no longer prioritize eroticism and mutual satisfaction [124]. Additionally, sex may become scheduled rather than spontaneous. These shifts may give rise to a state of performance anxiety, characterized by a heightened focus on the outcome of the sexual encounter rather than the enjoyment of the process [124]. As individuals age, the pressure stemming from infertility may intensify, potentially exacerbating the prominence of performance anxiety. Men typically experience performance anxiety more acutely than women, owing to the observable nature of a man’s penis (whether erect or flaccid) to both himself and his partner. This heightened preoccupation with the rigidity of an erection significantly amplifies the risk of developing ED. Once both partners become concerned about ED, it can perpetuate a vicious cycle, ultimately culminating in the onset of ED.

The effects of assisted reproduction on erectile function can vary among individuals and couples. While assisted reproduction techniques, such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), offer hope to those struggling with infertility, they can also introduce psychological and emotional stress. The process often involves frequent medical appointments, hormonal treatments, and invasive procedures, which can contribute to heightened stress and anxiety [125]. This emotional burden may, in turn, impact erectile function negatively for some individuals, as stress and anxiety are known factors that can lead to or exacerbate ED. However, it is crucial to note that the effects on erectile function can be highly individualized, and not all individuals undergoing assisted reproduction will experience such issues.

In this context of erectile dysfunction, PDE5i is applicable, as previous research suggests that PDE5i not only lacks adverse effects on sperm but may even enhance certain sperm parameters, such as sperm motility [126,127]. Additionally, supportive care and counseling can be valuable resources for couples navigating both fertility treatments and potential changes in sexual function.

Loss of control over erection and ejaculation (LCEE)

Premature ejaculation (PE) patients may reduce excitement to prolong intercourse time, thereby compromising erectile function, or they may experience performance anxiety due to rapid ejaculation, impacting erectile function [128]. ED patients may increase excitement to achieve and maintain an erection, which accelerates ejaculation and results in PE, or they may experience premature ejaculation due to concerns about penile flaccidity during sexual intercourse [128]. In such cases, considering erectile and ejaculatory functions as an interconnected whole is essential, and PDE5i can be used to treat this combined disorder, LCEE.

Psychological and partner relationship factors

Similar to ejaculation function [129], erectile function is closely related to mental and psychological health [130] (Figure 1). Older men tend to suffer from depression, with a prevalence of around 30% [131], and drugs used to treat depression may significantly affect erectile function [132] (Table 1). First, a good partner relationship can increase the sexual desire and interest of older adults [133]. Intimacy, communication, and support between elderly couples can promote sexual arousal and satisfaction. In addition, mutual understanding and respect between partners can help alleviate the concerns and anxiety of elderly people about sex. Second, the partner relationship’s stability and interaction style directly impact the sexual function of the elderly [134]. Compared with young people, the elderly pay more attention to the intimacy and emotional connection between partners, which is very important for the sexual satisfaction and quality of life of the elderly. Additionally, the physical and health condition of the elderly can also affect the performance of sexual function [135], and the support and understanding of the partner relationship can alleviate the physical and emotional pressure of the elderly regarding sex. Couplepause, as a new paradigm, emphasizes the importance of seeing aging couples as a whole, considering both male and female factors in treating sexual dysfunction rather than just focusing on one partner [133]. In addition, couplepause is closely related to the lost penis syndrome, which is defined as a new clinical entity in sexual medicine characterized by weakened or even lost sensation of the penis within the vagina, a sensation that can be quite frequent among elderly couples [135].

PDE5i still has high efficacy in treating ED combined with depression [136]. After 12 weeks of treatment with sildenafil, depressed patients (mean age 56) reported improved erectile function and sexual intercourse ability in 90.9% of cases [136]. Among patients who responded to treatment, their scores on the Beck Depression Inventory and Hamilton Depression Rating Scale were significantly reduced [136]. About 47.3% of patients reported treatment-related adverse events with sildenafil [136]. A study suggested that daily use of PDE5i may even improve depressive symptoms and cognitive function [137]. Additionally, PDE5i appeared to have an anti-anxiety effect on animal models [138]. In summary, while using PDE5i to treat ED, attention should also be paid to patients’ mental health and partner relationships.

The safety and efficacy of PDE5 inhibitors in middle-aged and elderly patients with ED and hypogonadism

For elderly patients with hypogonadism, given the interaction between testosterone deficiency and several common risk factors mentioned earlier (such as diabetes), a comprehensive analysis of the risk factors related to ED should be carried out before applying PDE5i to treat ED.

Normal testosterone levels are crucial for PDE5 expression, and testosterone deficiency appears to be associated with reduced responsiveness to PDE5i [139]. Animal studies have shown that when testosterone levels were reduced, the expression of PDE5 genes and proteins decreased significantly, which could be reversed by testosterone supplementation [140]. Testosterone deficiency can reduce the responsiveness of PDE5i to PDE5, and testosterone supplementation can even enhance responsiveness [140] (Figure 1). In addition, testosterone is essential for maintaining normal endothelial cell function and benefits vascular health [141]. Testosterone deficiency can cause endothelial cell dysfunction and is closely related to decreased endothelial cells [142,143]. This provides a theoretical basis for the widely used practice of using PDE5i combined with testosterone therapy to treat ED in patients with hypogonadism [38]. However, a recent meta-analysis showed that testosterone therapy did not significantly affect endothelial function in patients with hypogonadism [144]. The negative result may be due to the inclusion of fewer relevant studies, so more prospective studies are needed in the future to explore the effect of testosterone supplementation therapy on endothelial function.

Research has indicated that when 10 mg of tadalafil is used alone for a period of four weeks to treat ED in patients with hypogonadism, only 17% of responsive patients experience improvement, and 14% of patients achieve a return to normal erectile function (IIEF-5 score ≥ 26) [145]. In patients with hypogonadism, taking sildenafil for 2 weeks at a dosage of twice a week, 50% of the patients experienced no improvement in erectile function, while the remaining 50% observed some improvement but were not satisfied with the degree of improvement [146]. This suggests that in some patients with ED combined with hypogonadism, treatment with PDE5i alone may not achieve satisfactory results [145] (Figure 1). Several other studies have also suggested that using PDE5i alone to treat ED in patients with hypogonadism may be ineffective, but there have been no reports indicating the exact rate of ineffectiveness [147–149]. More research is needed in the future to explore the non-response rate when using PDE5i alone for treatment. Using PDE5i alone to treat ED in patients with concomitant hypogonadism does not typically result in significant adverse reactions [145,146], demonstrating good safety. Furthermore, research suggests that daily consumption of 5 mg of tadalafil can elevate testosterone levels [150].

Numerous studies have shown that hypogonadal patients who do not respond to PDE5i alone can benefit from adding testosterone therapy [145,149,151–154]. A meta-analysis showed that when treating patients with a combination of PDE5i and testosterone, there is no significant increase in prostate-specific antigen levels and no significant increase in the incidence of adverse events [38]. Currently, there is no sufficient evidence to suggest that testosterone supplementation increases the risk of prostate cancer and hyperplasia [155]. In summary, testosterone can be combined with PDE5i in hypogonadal patients when the latter alone is ineffective in treating ED.

Conclusion

As research continues to deepen, we are increasingly aware that sexual health is a barometer of overall human health, which enables us to apply a holistic (systemic) approach to thoroughly understand the risk factors of ED. The efficacy of PDE5i for ED in elderly patients also depends on the management of the complex interplay involving different general and sexual health risk factors that most elderly patients often exhibit. In the presence of various systemic and sexual health risk factors, PDE5i has shown good safety, with common adverse reactions including headache, flushing, and muscle pain. Compared with individuals with normal testosterone levels, patients with hypogonadism have a more multifaceted situation and reduced responsiveness to PDE5i. Combination therapy with testosterone can effectively improve responsiveness, and adverse events are not significantly increased. In summary, eliminating reversible risk factors and slowing or controlling the development of irreversible factors are important foundations for PDE5i therapy.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

CLW is supported by the China Scholarship Council (CSC, No. 202307820010). EAJ is partly supported by PRIN grant 2017S9KTNE_002 by the Italian Ministry of University and Research. EAJ was also partially supported by #NEXTGENERATIONEU (NGEU) project funded by the National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)—A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).