Introduction: Beyond Erection – A Question of Fertility
For millions of men worldwide, erectile dysfunction (ED) has been successfully managed through the pharmacological revolution brought by phosphodiesterase type 5 inhibitors (PDE5-Is)—notably sildenafil (Viagra) and tadalafil (Cialis). These drugs are synonymous with restored confidence and improved quality of life. However, the same biochemical pathways that support penile erection may have subtle—and clinically significant—effects on another crucial element of male reproduction: sperm motility.
While sildenafil and tadalafil are both PDE5 inhibitors, they differ in selectivity, duration of action, and affinity for other phosphodiesterase isoenzymes—particularly PDE11, an enzyme expressed in the prostate and testes. This distinction, though seemingly minor, may hold key implications for fertility in men already struggling with infertility.
A seminal study conducted by Pomara et al. (2007) explored these pharmacological nuances by examining how single doses of sildenafil and tadalafil influence sperm motility in young infertile men. The results, surprisingly divergent, remind clinicians that not all PDE5 inhibitors behave alike.
The Study Design: Science in Motion
Structure and Purpose
The investigation was a prospective, randomized, double-blind, crossover clinical trial involving 18 young infertile men under 40 years old. Each participant received:
- A single oral dose of sildenafil 50 mg, or
- A single oral dose of tadalafil 20 mg,
administered in random order, with a two-week washout between treatments to eliminate carryover effects. This elegant crossover design ensured that each subject acted as his own control—an ideal method for minimizing biological variability in semen parameters.
The primary objective was straightforward yet profound: to assess acute changes in sperm motility and seminal quality after ingestion of each drug. Semen samples were collected 1 hour after sildenafil and 2 hours after tadalafil, aligning with the known pharmacokinetics of peak plasma concentration (Cmax).
Selection and Exclusion
Participants were carefully screened to ensure a homogeneous population:
- Inclusion criteria:
- Normal erectile function
- Infertility lasting ≥2 years
- Abnormal baseline semen parameters
- No concurrent medication use or major illness
- Exclusion criteria:
- Cardiovascular disease, diabetes, endocrine disorders
- Retinitis pigmentosa
- Anatomical genital deformities
- Abnormal testosterone or prolactin levels
This rigorous selection allowed the researchers to focus on the pharmacodynamic effects of the drugs without interference from comorbidities or confounding variables.
Data Collection and Evaluation
All semen analyses were performed in accordance with World Health Organization (WHO) guidelines by the same trained biologists, ensuring inter-observer reliability. Parameters assessed included:
- Semen volume and pH
- Sperm concentration
- Rapid progressive motility (class a)
- Total progressive motility (classes a + b)
- Morphology (normal forms)
Quality control was meticulous, with less than 10% variation across repeated assessments—a gold standard for reproductive laboratory precision.
Results: Two Drugs, Two Opposite Stories
Sildenafil – The Unexpected Enhancer
After administration of sildenafil (50 mg), a significant improvement in sperm motility was observed:
- Rapid progressive motility (class a) increased from 10.5% to 18.5%.
- Total progressive motility (a + b) rose from 28.5% to 37.0%.
These gains were statistically robust (P < .01), suggesting that sildenafil exerts a stimulatory influence on sperm activity, potentially enhancing the ability of sperm to reach and fertilize the oocyte.
Interestingly, no changes were recorded in sperm count, morphology, or semen volume—indicating a targeted effect on motility mechanisms rather than on spermatogenesis itself.
Tadalafil – The Surprising Inhibitor
In sharp contrast, tadalafil (20 mg) produced the opposite effect:
- Rapid progressive motility fell from 10.5% to 6.0%.
- Total progressive motility decreased from 28.5% to 21.5%.
While the overall semen quality parameters remained unchanged, this drop in motility raised an important clinical question: could tadalafil’s dual inhibition of PDE5 and PDE11 adversely affect sperm function?
Statistical Harmony and Biological Discord
Despite being tested in the same individuals, the drugs demonstrated opposing effects, both reaching statistical significance. The results were consistent across all subjects, making the findings unlikely to be due to random variation or chance.
Thus, the conclusion was unequivocal: sildenafil acutely stimulates sperm motility, while tadalafil transiently suppresses it.
Discussion: Decoding the Mechanisms
A Molecular Tug-of-War
Both sildenafil and tadalafil inhibit PDE5, leading to increased cyclic guanosine monophosphate (cGMP) levels, vascular smooth muscle relaxation, and enhanced blood flow—mechanisms well-understood in erectile physiology. However, their influence extends beyond penile vasculature.
Sperm cells themselves express various phosphodiesterases, including PDE1, PDE4, and notably, PDE11. These enzymes regulate intracellular signaling pathways crucial for motility, capacitation, and acrosomal function. When PDE activity is inhibited, intracellular cGMP levels rise, potentially influencing flagellar movement and mitochondrial energy metabolism.
The Sildenafil Effect
Sildenafil’s action appears to enhance mitochondrial efficiency and calcium channel responsiveness, resulting in improved forward motility. It may also stimulate NO-cGMP-mediated pathways within the sperm tail, enhancing the flagellar beat frequency—a finding corroborated by Lefievre et al. and Du Plessis et al., who observed similar improvements in vitro.
Moreover, sildenafil does not significantly inhibit PDE11, preserving the delicate signaling balance within Leydig and germ cells. This selective mechanism could explain its favorable effect on sperm dynamics.
The Tadalafil Paradox
Tadalafil, however, presents a more complex pharmacodynamic profile. It is less selective, with an approximately 40-fold preference for PDE5 over PDE11, compared to sildenafil’s >1000-fold selectivity. As PDE11 is expressed in the prostate, testes, and developing germ cells, its inhibition may disrupt cellular homeostasis within the reproductive tract.
Animal studies support this theory: chronic tadalafil exposure in dogs led to degenerative changes in the seminiferous epithelium, while PDE11 knockout mice displayed reduced sperm count and motility. These findings suggest that even transient PDE11 inhibition may transiently impair sperm kinetics.
Clinical Implications: Fertility in Focus
The Dual Identity of PDE5 Inhibitors
PDE5 inhibitors were designed for erectile restoration, not fertility enhancement. Yet, their systemic pharmacology inevitably intersects with reproductive physiology. For infertile men, even small alterations in motility can have significant clinical consequences—particularly in assisted reproductive technologies (ART), where the proportion of motile sperm dictates procedural success.
Implications for Assisted Reproduction
In cases where men experience performance anxiety or temporary ED during semen collection for intrauterine insemination (IUI) or in vitro fertilization (IVF), sildenafil may offer a dual advantage: resolving ED while potentially enhancing sperm motility. Conversely, tadalafil might be less ideal in such scenarios, especially given its prolonged half-life and potential inhibitory action on PDE11.
Clinicians should therefore individualize PDE5 inhibitor selection, balancing erectile efficacy with fertility goals—a reminder that pharmacology rarely operates in isolation.
Safety Considerations
Neither sildenafil nor tadalafil demonstrated alterations in hormone levels, sperm morphology, or concentration—reassuring evidence for their general reproductive safety. Reported side effects were mild (flushing, nasal congestion, headache), self-limiting, and consistent with established safety profiles.
However, the acute motility effect observed here underscores the need for caution when prescribing tadalafil to men actively attempting conception or providing semen samples for ART.
Unanswered Questions and Future Directions
The study’s sample size (n=18) limits the generalizability of its conclusions, but its design was methodologically sound and statistically convincing. Larger, long-term investigations are needed to determine:
- Whether these acute changes persist with chronic administration.
- How PDE11 inhibition affects spermatogenesis and germ cell viability.
- Whether similar patterns exist with vardenafil or avanafil, other PDE5 inhibitors with unique selectivity ratios.
Emerging molecular research may also clarify whether these pharmacologic differences can be harnessed therapeutically—for example, using sildenafil not only to treat ED but also to support sperm function in subfertile patients.
Conclusion: A Tale of Two Inhibitors
The study by Pomara and colleagues stands as an elegant demonstration of how small molecular differences yield clinically divergent outcomes. Despite sharing a therapeutic class, sildenafil and tadalafil display opposing effects on sperm motility in young infertile men.
- Sildenafil (50 mg): Enhances rapid and total progressive motility, likely through PDE5 inhibition within sperm flagella.
- Tadalafil (20 mg): Reduces motility, possibly due to concurrent PDE11 inhibition affecting testicular or prostatic function.
These findings have practical relevance for urologists, andrologists, and reproductive specialists. In the context of male infertility, pharmacologic choice should extend beyond erectile efficacy to encompass reproductive implications.
As with much in medicine, the devil—and sometimes the solution—lies in the molecular details.
FAQ
1. Does sildenafil improve fertility in men with low sperm motility?
Sildenafil may transiently enhance sperm motility by stimulating cGMP pathways in sperm cells. While this could improve fertilization potential, it does not treat underlying infertility causes and should not be used as a standalone fertility therapy.
2. Why does tadalafil decrease sperm motility despite being in the same drug class?
Tadalafil inhibits both PDE5 and PDE11. Since PDE11 is present in the testes and prostate, its inhibition may temporarily disturb sperm function, leading to decreased motility. This effect appears acute and reversible.
3. Should men undergoing fertility treatments avoid tadalafil?
Caution is advisable. While tadalafil remains safe for general use, infertile men collecting semen for ART procedures may prefer sildenafil, which appears to enhance motility rather than suppress it.
