Crocetto F. et al., 2026: Erectile Dysfunction: A Comprehensive Review of Pathophysiology, Diagnosis and Contemporary Management.

Crocetto F, Amicuzi U, Musone M, Imbimbo C, Tammaro S, Napolitano L, Reccia P, De Luca L, Del Giudice F, Stizzo M, Olivetta M, Lieto DD, Mauro MD, Mattiello G, Puca G, Della Rosa G, Magliocchetti M, Giugliano M, Capoluongo R, Coppola M, Imperatore S, Madonna A, Capone F, Del Biondo D, Barone B.
Medicina (Kaunas). 2026 Apr 30;62(5):854. doi: 10.3390/medicina62050854

Abstract

Erectile dysfunction (ED) is a common multifactorial condition with significant physical, psychological and relational consequences. While historically associated with aging, its rising prevalence among younger men underscores the need for updated diagnostic and therapeutic frameworks. This narrative review synthesizes contemporary evidence on the pathophysiology, diagnostic workup and management of ED, with emphasis on guideline-directed care and emerging treatment modalities. A comprehensive literature search was conducted, with evidence synthesized from key clinical guidelines, landmark trials and recent peer-reviewed studies. Lifestyle optimization remains the foundational step, followed by first-line pharmacotherapy with phosphodiesterase type 5 inhibitors (PDE5is), which demonstrate high efficacy and safety across diverse patient populations. For patients with inadequate PDE5is response, second-line options include alprostadil (intracavernosal, with approximately 70% success rates or intraurethral), vacuum erection devices and penile prosthesis surgery, with patient and partner satisfaction exceeding 95% for the latter when performed in experienced centers. Psychosexual therapy is an integral adjunct, particularly in psychogenic or mixed etiologies. Regenerative approaches such as low-intensity extracorporeal shockwave therapy (Li-SWT) and platelet-rich plasma (PRP) injections are under investigation; current evidence supports their use only in experimental settings due to limited long-term data. A multidisciplinary, individualized strategy-incorporating pharmacologic, surgical and psychosocial interventions-remains the cornerstone of modern ED management. This review critically distinguishes well-established evidence from ongoing clinical debates and translates findings into practical guidance for daily practice. Ongoing technological advances may further refine diagnostic accuracy and treatment personalization, but high-quality studies are needed to establish the role of regenerative and digital tools.

Comment Jens Rassweiler

This article is a narrative review on erectile dysfunction (ED), focusing on what is well established, what remains controversial, and how clinicians can translate current evidence into daily practice.

Introduction

Erectile dysfunction is presented as a common, multifactorial condition involving vascular, neurologic, hormonal, psychogenic, metabolic, and relational factors. Although traditionally associated with aging, ED is increasingly recognized in younger men and may serve as an early warning sign of cardiovascular disease. The review emphasizes that ED often precedes coronary artery disease by two to five years, making cardiovascular risk assessment essential in men presenting with unexplained ED.

The article explains that normal erection depends on nitric oxide release, cyclic GMP signaling, cavernosal smooth muscle relaxation, endothelial function, neural input, and pelvic floor muscle activity. Disruption of any of these mechanisms can lead to ED. Obesity, especially central or visceral obesity, is highlighted as a major modifiable risk factor because it promotes inflammation, oxidative stress, endothelial dysfunction, and testosterone suppression. Waist circumference is recommended as a practical clinical measure because it correlates more strongly with ED severity than BMI alone.

Diagnosis

Diagnosis should begin with a detailed medical, sexual, and psychosocial history, supported by validated tools such as the International Index of Erectile Function, especially the IIEF-5. Physical examination should assess cardiovascular status, genital anatomy, secondary sexual characteristics, BMI, and waist circumference. Recommended initial laboratory tests include fasting glucose or HbA1c, lipid profile, and morning total testosterone. Prolactin and thyroid testing are not recommended routinely for all patients but may be useful when clinical suspicion exists, especially in young men with unexplained ED.

Advanced tests such as penile Doppler ultrasound and nocturnal penile tumescence testing are reserved for selected cases, especially when first-line therapy fails, when the diagnosis is unclear, or before invasive treatment. The review argues that penile Doppler should not be ordered routinely before empirical first-line therapy.

Management

Lifestyle optimization is considered foundational. Weight loss, aerobic exercise, smoking cessation, metabolic control, improved sleep, stress reduction, and a Mediterranean-style diet can improve erectile function and enhance response to medication. Weight reduction of 5–10% can meaningfully improve erectile function, and bariatric surgery may normalize erectile function in some obese men.

Phosphodiesterase type 5 inhibitors, including sildenafil, tadalafil, vardenafil, and avanafil, remain first-line pharmacologic therapy. They have strong evidence for efficacy and cardiovascular safety, with success rates of approximately 70–80% in the general ED population. They should not be used with organic nitrates, and clinicians should be cautious with alpha-blockers and strong CYP3A4 inhibitors. Daily tadalafil may be particularly useful for men with frequent sexual activity or lower urinary tract symptoms related to benign prostatic hyperplasia.

For patients who do not respond to PDE5 inhibitors, the article stresses the importance of first checking proper use: correct timing, adequate dose, adherence, sexual stimulation, and absence of contraindicating factors. Second-line options include intraurethral or intracavernosal alprostadil, vacuum erection devices, testosterone replacement in confirmed hypogonadism, and psychosexual therapy when psychological or relational contributors are present.

Penile prosthesis implantation is described as the definitive treatment for refractory ED. Modern inflatable and malleable devices have high patient and partner satisfaction, especially when implanted by experienced surgeons. Infection and mechanical failure rates have decreased substantially due to improved surgical techniques and antibiotic-coated devices. The article argues that prosthesis surgery should not be viewed merely as a last resort but as a reliable option for appropriately selected patients.

Regenerative Medicine

Regenerative therapies, particularly low-intensity shockwave therapy and platelet-rich plasma injections, are critically evaluated. Although commercially popular, current evidence is insufficient to recommend routine use. Low-intensity shockwave therapy has shown modest improvements in some studies, but results are inconsistent, protocols are heterogeneous, sham-controlled trials are conflicting, and long-term durability is unproven. PRP evidence is even weaker, with limited standardization and lack of strong randomized sham-controlled data. The review concludes that these therapies should be considered investigational and preferably offered only in clinical trials or after careful counseling.

Role of Li-ESWT

The article presents Li-ESWT as one of the most promising emerging therapies for erectile dysfunction, particularly because it aims to address the underlying vascular mechanisms of ED rather than simply producing a temporary erectile response. Unlike PDE5 inhibitors, which mainly enhance erectile function during sexual stimulation, Li-ESWT is described as a potentially restorative treatment that may improve penile blood flow and endothelial function.

Li-ESWT is especially relevant in cases of vasculogenic erectile dysfunction, where impaired blood supply to the penis is a major contributing factor. The therapy is thought to work by delivering low-intensity acoustic waves to penile tissue, which may stimulate angiogenesis, improve microvascular circulation, enhance nitric oxide signaling, and promote tissue repair. Because of this mechanism, Li-ESWT is discussed as part of a broader shift in ED management from symptom control toward disease modification.

The article likely positions Li-ESWT as an attractive option for men who respond poorly to PDE5 inhibitors or who want a treatment that may reduce dependence on medication. It may also be considered for men with mild to moderate vasculogenic ED, particularly when ED is linked to cardiovascular risk factors, metabolic dysfunction, or endothelial impairment.

However, the article also emphasizes that Li-ESWT remains investigational or not fully established in many clinical guidelines. Although studies have reported encouraging improvements in erectile function scores, important uncertainties remain. These include the lack of standardized treatment protocols, differences in shockwave devices and energy settings, variable patient selection criteria, unclear durability of benefit, and limited long-term safety and efficacy data.

Therefore, the role of Li-ESWT in the article is best understood as promising but not definitive. It represents a potential regenerative or restorative therapy within modern ED care, but the evidence is not yet strong enough to make it a universal first-line treatment. The article likely argues that Li-ESWT should be used cautiously, ideally in appropriately selected patients and with clear counseling that outcomes may vary and that further high-quality research is needed.

Jens Rassweiler