What causes erectile dysfunction and what can be done to treat it? | Peter Attia & Mohit Khera

Khera explicitly prefers this approach over the on-demand strategy for most of his patients. He cites the Aversa study showing that men who took daily tadalafil for four weeks had persistent improvement in brachial artery flow-mediated dilation and inflammatory markers (IL-6, CRP) versus men on on-demand dosing — suggesting systemic vascular conditioning beyond the penile tissue. The triple approval (ED plus BPH plus pulmonary hypertension) at the same 5 mg/day dose makes this one of the most bang-for-buck medications in preventive urology.

Khera frames improving HbA1c as particularly high-leverage. Attia cites his clinical experience: a patient who reduces HbA1c from 5.9 to 5.0 — roughly a 25 mg/dL reduction in average blood glucose — moves from needing Cialis for every erection to needing none. Khera's four-pillar framework (diet, exercise, sleep, stress) each have independent effects, and any one of them in isolation produces measurable IIEF improvement. The Mediterranean diet specifically is endorsed by Khera based on its evidence base for endothelial protection.

Khera also uses the SEP2 and SEP3 questions (Sexual Encounter Profile) as validated diagnostic anchors: SEP2 asks whether the patient was able to insert the penis (sufficient erection for penetration); SEP3 asks whether the erection was maintained through orgasm. Any no to either constitutes ED by definition — even if it happens only once in nine encounters. The number-one presentation is men who can achieve but not maintain erection, which indicates venous leak as the first pathologic change. Men who can neither achieve nor maintain have more advanced disease or a neurogenic component.

Khera notes that the penile Doppler ultrasound — showing normal hemodynamics — is itself therapeutically powerful in these patients: seeing that everything is anatomically intact is anxiolytic. Some patients improve after the diagnostic procedure alone. Daily Cialis at 5 mg then reinforces this with consistently better erectile responses in the early attempts, building the positive expectation track record that gradually overwrites the negative one.

Khera explains the anatomy driving the diagnostic logic: the Tunica albuginea surrounds two corpora cavernosa. Subtunical veins sit just under the Tunica. When the cavernosal muscle is healthy and fills with arterial blood, it expands against the Tunica and physically compresses the subtunical veins, preventing outflow — a passive occlusion mechanism. As the muscle atrophies and fibrosizes with aging or testosterone deficiency, it cannot generate sufficient pressure against the Tunica, and the venous outflow persists during erection. EDV above 5 mL/s documents this persistent outflow.

Khera demonstrates the argument with biopsy data from his penile prosthesis lab: tissue taken at time of prosthesis implantation shows high androgen-receptor density. As androgens decline, those receptors signal atrophy. The two-factor model is: testosterone provides the hormonal substrate for cavernosal muscle mass; regular erection (via sexual activity or nocturnal cycles) provides the mechanical stimulus. Remove either factor and atrophy accelerates. Post-prostatectomy patients lose both nerve-driven spontaneous erections and often experience testosterone suppression — making aggressive penile rehabilitation essential.

Khera uses intracavernosal injection both therapeutically (trimix for refractory ED) and diagnostically (to induce a pharmacological erection before Doppler ultrasound). Commercially, alprostadil (brand: Edex) is available without compounding; trimix requires a compounding pharmacy and is the most potent and popular clinical option. The injection site at the base of the penis (2 or 10 o'clock, not the urethra) is well-tolerated due to lower nerve density at that location.

Khera frames it clearly: the risk factor profiles for ED and cardiovascular disease are almost identical columns — hypertension, smoking, obesity, diabetes, insulin resistance all appear on both lists. The common mechanistic link is endothelial dysfunction. Cardiologists had already demonstrated that improving endothelial function can reverse cardiovascular disease; urologists are now applying the same principle. Treating organic ED as a metabolic and vascular disease rather than a plumbing problem changes the entire clinical approach: the goal is not just the erection — it is cardiovascular risk reduction.

Khera explains the dosing math: daily 5 mg tadalafil produces a tissue-level equivalent of approximately 8 mg (multiplier of 1.6) — less than the 20 mg on-demand dose, but still sufficient for most men. Crucially, the tissue is being continuously maintained rather than just temporarily perfused. A study by Aversa also showed that men on daily Cialis had persistent improvement in endothelial function markers (IL-6, CRP, brachial artery flow-mediated dilation) even after stopping the drug — suggesting an endothelial conditioning effect beyond simple PDE5 inhibition.

Khera's driving analogy captures the mechanism: looking where you don't want to go is exactly where you're going. The same neural principle applies — focusing on maintaining an erection during sex is the most reliable way to lose it. Daily Cialis at 5 mg for these patients serves as an anxiolytic scaffold: it demonstrably improves erection quality, which breaks the expectation of failure, which removes the anxiety loop. Once confidence is restored, the medication can often be weaned entirely. Telehealth has made sex therapy access dramatically easier, which Khera now uses as an adjunct.

Khera explains that the ideal PDE5 inhibitor would be perfectly selective for type 5 with zero cross-reactivity — and that avanafil comes closest today, though it is not yet available as a generic and remains expensive. Generic tadalafil (Cialis) is now available for roughly $0.19 per pill at HEB or GoodRx compared to the original $400+ for a 30-day supply of brand Cialis. Khera notes mild concern about consistency across generic manufacturers but has not seen clinically meaningful potency differences with PDE5 inhibitors specifically.

Khera's four lifestyle pillars for sexual dysfunction are diet, exercise, sleep, and stress reduction. All four independently improve erectile quality, and all four operate through the same endothelial and metabolic pathways. He specifically highlights that improving hemoglobin A1c — Attia cites a real patient going from 5.9 to 5.0 HbA1c (roughly minus 25 mg/dL average glucose) — can take a man from needing Cialis for every erection to needing none. Stopping smoking and controlling blood pressure address the endothelium directly (chemical disruption vs. mechanical disruption respectively).

Khera performs these studies routinely in his office. The procedure — injecting trimix at the penile base — sounds alarming to most men, but is well-tolerated due to the anesthetic properties of the local anatomy. The ultrasound findings directly map to the inflow/outflow model: if peak systolic velocity (inflow) is too low, arterial insufficiency is present; if end-diastolic velocity (outflow) is too high, the venous occlusion mechanism is failing. This is venous leak. EDV above 5 mL/s documents this persistent outflow.