Erectile dysfunction (ED)

What changes during this transition

Erectile dysfunction affects roughly half of men between 40 and 70 (Massachusetts Male Aging Study) and rises with age — but the clinically important framing is that ED is most often a presenting symptom of something else, not a primary disorder. Vasculogenic ED (endothelial dysfunction from hypertension, dyslipidemia, type 2 diabetes, smoking, obesity, sedentary phenotype) is the most common etiology after age 40; neurogenic ED (post-radical-prostatectomy, spinal cord injury, multiple sclerosis, diabetic autonomic neuropathy), hormonal ED (hypogonadism, hyperprolactinemia, thyroid dysfunction), anatomical ED (Peyronie's disease), and psychogenic ED (more common in younger men, often situational) fill out the differential. Mixed presentations are common. The single most important editorial point: ED predates symptomatic coronary artery disease by 3-5 years on average, which makes the workup a cardiovascular sentinel event — IIEF-5 or SHIM questionnaire, morning total testosterone + prolactin, glucose + lipids, cardiac risk stratification — not a 'try a pill and see' target. Standard-of-care first-line treatment is PDE5 inhibitors: sildenafil (Viagra, FDA-approved 1998), tadalafil (Cialis 2003, available on-demand or as 2.5/5mg daily), vardenafil (Levitra), avanafil (Stendra 2012). Response rates run ~70% across the class. The non-negotiable safety thread is the nitrate contraindication — concurrent nitrates (including amyl nitrite 'poppers') plus PDE5 inhibitors can produce life-threatening hypotension. Second-line options when PDE5i fails include intracavernosal injection (alprostadil, papaverine/phentolamine, or tri-mix; ~85% response rate) and intraurethral alprostadil (MUSE), with vacuum erection devices as a non-pharmacologic option. Third-line is penile prosthesis (inflatable or malleable), with high satisfaction rates in carefully selected patients. Adjuncts include testosterone replacement therapy where laboratory-confirmed hypogonadism is present (AUA 2018 guidelines: low morning T plus symptoms), psychosexual therapy for psychogenic components, and lifestyle modification — weight loss, exercise, smoking cessation, sleep apnea treatment, glycemic control — which is more reversibility-leveraging than most patients are told. Low-intensity shock wave therapy (Li-ESWT) and PRP injections are emerging with heterogeneous evidence; stem cell therapy remains investigational. The peptide angles surfaced here are narrower than the community framing suggests. PT-141 (bremelanotide) is the closest peptide-specific case — older male-ED trials in PDE5i non-responders showed modest signals before the development arc pivoted to female HSDD, where it landed FDA approval as Vyleesi in 2019. Kisspeptin is research-grade work (the Comninos/Dhillo program at Imperial College London) applicable to a specific subset — men whose ED has a functional-hypogonadism driver where the standard alternative would be TRT. Semaglutide and tirzepatide address ED indirectly via the metabolic-syndrome / obesity drivers that underlie vasculogenic ED in this phenotype — the mechanism chain (weight loss → reduced aromatization → improved endogenous T; weight loss + glycemic control → endothelial function recovery) is well-established but no GLP-1 trial uses ED as a primary endpoint. BPC-157 and melanotan-2 are surfaced as substrate only — not as discovery cards — because the editorial posture doesn't support elevating them. BPC-157's Peyronie's and vasculogenic-ED claims have zero human RCT support and the procedural risks of community injection protocols (especially intracavernosal use) are significant. Melanotan-2 carries the same mechanistic rationale as PT-141 but with a worse safety profile centered on MC1R-mediated melanoma risk — the more selective compound (bremelanotide) is the better-characterized conversation.