Tadalafil: Erectile Dysfunction Cure? Testosterone Booster? Non-Responders? [Study 147-154 Analysis]

Main ideas and concepts

• Purpose of the video/analysis

  • Reviews eight studies (noted as the Study 147–154 range) on tadalafil (Cialis).
  • Emphasizes:
    • Mechanisms of action
    • Evidence for tadalafil’s effects on testosterone
    • Evidence for tadalafil’s effects on erectile dysfunction (ED)
    • Issues such as “non-responders” (about 30% may not benefit)

• What tadalafil is and how it works (mechanism)

  • Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor.

  • The presenter explains an erection-related pathway:

    1. Neural/endothelial signaling releases nitric oxide (NO)
    2. NO activates soluble guanylate cyclase
    3. This converts GTP → cyclic GMP (cGMP)
    4. cGMP activates PKG (protein kinase G)
    5. PKG promotes smooth muscle relaxation by:
       • Increasing myosin light chain phosphatase activity and inhibiting factors that oppose relaxation
       • Reducing calcium influx and/or calcium availability that would otherwise drive contraction
       • Increasing potassium efflux, increasing membrane negativity and supporting a relaxed state
    6. Normally, cGMP is broken down by phosphodiesterases (including PDE5), reducing PKG signaling
    7. Tadalafil inhibits PDE5, reducing cGMP breakdown → higher cGMP → more PKG activity → more blood flow → erection

• Proposed mechanism: how tadalafil might affect testosterone

  • Testosterone could theoretically increase NO production, supporting the erectile mechanism.

  • The presenter also describes a speculative/offshoot mechanism for tadalafil possibly affecting testosterone production:

    • Testosterone production in Leydig cells involves:

      • LH → GPCR → adenylyl cyclase → cAMP → PKA → CREB → steroid gene expression → testosterone

    • Some PDEs degrade cAMP (not specifically PDE5; other PDE isoforms are suggested).

    • If tadalafil (or related PDE inhibition) affects those PDE isoforms, cAMP could remain higher → potentially increasing testosterone signaling.
    • The presenter emphasizes the testosterone mechanism evidence is not fully clear and may involve off-target PDE effects.

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Methodological themes across the studies (how the evidence is critiqued)

• The presenter repeatedly critiques study designs, especially:
  • Lack of placebo/control groups
  • Lack of randomization
  • Lack of blinding
• Because of these limitations, effects on testosterone are treated cautiously—particularly when baseline testosterone is normal vs low (hypogonadal).
• For ED outcomes, the presenter highlights that subjective questionnaires (e.g., IIEF) can be influenced by expectation, making placebo important.

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Detailed findings by study (as presented)

Testosterone-focused findings

Study 147 (internal funding; tadalafil + ED/metabolic syndrome population)

• Participants: 40 men
  • Metabolic syndrome + ED
  • Mean age ~57
• Design issues:
  • Not randomized
  • No placebo and no control group
  • No blinding
  • Repeated measures: baseline vs 12 weeks after tadalafil
• Outcomes described:
  • Total testosterone: increased after 12 weeks
  • LH: decreased
• Interpretation offered:
  • Speculates LH may drop due to feedback mechanisms after testosterone rises
  • Suggests tadalafil may have stronger testosterone effects in certain subgroups

Study 148 (industry ties; ED vs non-ED comparison)

• Participants: 20 men with ED
  • Mostly normal weight
  • Mean age ~54
• Design:
  • Has a control group of age-matched non-ED individuals
  • No placebo
  • Not randomized and no blinding (groups differ by ED status)
  • 12 months long
• Outcomes described:
  • SHBG: no effect
  • Total testosterone: no statistically significant effect
  • Estradiol (estrogen): decreased
  • Testosterone-to-estrogen ratio: increased due to estrogen decrease
  • Free testosterone: no clear effect (trend suggested)
  • LH: no effect
• Presenter’s interpretation:
  • Possible subgroup differences vs Study 147 (metabolic syndrome vs normal weight)
  • Possible mediation via estrogen

Study 151 (public funding; overweight ED men; once-daily vs on-demand)

• Participants: 43 men with ED
  • Age ~40–49
  • Overweight
• Design:
  • Randomized to:
    • Once-daily tadalafil (OAD)
    • Tadalafil on demand
  • No placebo, open-label (no blinding)
  • 8 weeks on treatment
  • Follow-up after stopping (remaining effects assessed)
• Key testosterone-related outcomes described:
  • Total testosterone: no effect
  • Estrogen: decreased during treatment and reversed after stopping
  • Testosterone-to-estrogen ratio: increased during treatment and reverted after stopping
  • SHBG: no effect
  • Insulin levels: increased substantially with tadalafil, then returned toward baseline after stopping (presented as intriguing/unclear)
• Body composition add-on:
  • Some changes in lean/fat mass in specific regions (trunk/android mentioned)
  • Statistically significant in places, but described as not necessarily large in practical magnitude

Synthesis of testosterone message

• Tadalafil may increase testosterone mainly in men with lower baseline testosterone (hypogonadal range).
• Men with normal baseline testosterone more often show no increase.
• Estrogen reduction is a recurring theme, which can shift the testosterone-to-estrogen ratio even when total testosterone does not change.

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ED-focused findings

Study 147 (ED outcomes with IIEF)

• ED outcome metric: IIEF questionnaire score (higher = better erectile function)
• Finding described:
  • Large increase in IIEF from baseline (~11.3) to treatment (~19)
• Caution emphasized:
  • No placebo/control → questionnaire-based outcomes may be influenced by expectations

Study 150 (crossover; TRT + tadalafil in low-testosterone ED men)

• Conflicts: includes industry ties (as stated by presenter)
• Participants: 29 men with ED
  • Age ~57–60
  • Low testosterone
  • Normal weight (as described)
• Design:
  • Crossover, 24 weeks total
  • Each condition lasted 12 weeks
  • No randomization and no blinding
• Interventions (two crossover groups):
  • Group 1: TRT alone (12 weeks) → then TRT + tadalafil (12 weeks)
  • Group 2: TRT + tadalafil (12 weeks) → then TRT alone (12 weeks)
• Outcomes described:
  • TRT alone vs TRT + tadalafil showed no statistically significant overall improvements across most metrics
  • Some symptom scores worsened when tadalafil was removed (phase changes), including:
    • AMS score (higher = worse), especially a somatic domain score
    • IIEF score decreased when tadalafil was discontinued (within-group comparison)
• Preference data (non-blinded):
  • Most participants preferred the combined approach (TRT + tadalafil) over TRT alone

Study 151 (ED outcomes: once-daily vs on-demand)

• ED outcomes described:
  • Once-daily tadalafil (consistent use): improvement in ED-related measures including:
    • Erection capacity
    • Sexual satisfaction
  • On-demand use: also improved some measures, but less reliably
  • Stopping: regression toward baseline for at least some outcomes (not consistently statistically significant)
• Prostate/urination-related measure:
  • IPSS score improved during consistent use (lower = better)
  • On-demand showed less clear improvement

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“Non-responders” concept and how it’s addressed

• The presenter states that ~30% of people taking tadalafil/other PDE inhibitors may be non-responders for:
  • Testosterone effects
  • Erectile dysfunction effects
• The video promises (and discusses later as a planned segment):
  • Explanations for non-response
  • Ways to improve response odds
  • Optimal dosing across studies (via aggregated dosing information)

Note: The provided excerpt includes the setup for these topics, but the detailed “non-responder” dosing methodology is not shown here.

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Conclusions / overall lessons (as stated)

• Testosterone

  • Evidence is mixed and appears dependent on baseline testosterone status:
    • Hypogonadal / low testosterone: more likely to see an increase (example: Study 147)
    • Normal testosterone: often no increase (example: Studies 148, 151)
  • Estrogen tends to decrease, improving the testosterone-to-estrogen ratio even when total testosterone is unchanged.

• Erectile dysfunction

  • Tadalafil shows clinically relevant improvements on ED metrics like IIEF, especially with consistent once-daily dosing.
  • Benefits may be reduced or absent in a portion of individuals (non-responders).

• Evidence quality caution

  • Several testosterone studies lack ideal controls (placebo, randomization, blinding), limiting confidence in testosterone claims.

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Speakers / sources featured (identified in the subtitles)

• Nicholas Verhoeven — PhD candidate in molecular medicine; narrator/host of the “PhysioNet detailed study analysis” channel
• The studies referenced in the subtitles: Study 147, 148, 151, 150 (full titles/DOIs not included in the excerpt)