Timing is everything for sperm assessment in fertility studies

Area of Science:

• Reproductive toxicology
• Pharmacology
• Drug safety assessment

Background:

• The International Council for Harmonisation (ICH) S5(R2) guideline recommends histopathology and mating assessments for male fertility studies.
• Current guidelines may not fully capture all potential male reproductive toxicities.
• Sperm assessment offers a complementary endpoint for evaluating male fertility.

Purpose of the Study:

• To evaluate the utility of sperm assessment as a standard endpoint in nonclinical male fertility studies.
• To determine if sperm analysis can detect effects missed by traditional histopathological endpoints.
• To assess the potential impact of a CNS-active agent (JNJ-26489112) on male rat fertility.

Main Methods:

• A male rat fertility study was conducted using the CNS-active agent JNJ-26489112.
• Standard endpoints included histopathology, mating performance, and pregnancy outcomes.
• Sperm concentration, motility, and morphology were specifically assessed in addition to standard endpoints.

Main Results:

• No significant effects were observed in histopathological endpoints, mating performance, or pregnancy outcomes.
• High-dose male rats showed reversible decreases in epididymal sperm concentration and motility.
• An increase in abnormal sperm morphology was observed in high-dose male rats.

Conclusions:

• Sperm assessment identified subtle male reproductive effects not detected by histopathology alone.
• These findings in rats suggest a potential impact on human male fertility that traditional methods might miss.
• Including semenology as a standard endpoint in nonclinical fertility studies may enhance the detection of male reproductive toxicity.