title: Timing is everything for sperm assessment in fertility studies.
abstract: The fertility study design recommended in the ICH S5(R2) Harmonised Guideline for Detection of Toxicity to Reproduction for Medicinal Products emphasizes the importance of histopathological endpoints next to a pairing assessment in evaluating male fertility. However, in a male rat fertility study with JNJ-26489112, a CNS-active agent, while there were no effects on histological endpoints, mating performance or pregnancy outcomes, sperm assessment was included. The high dose males presented with reversible decreases in epididymal, but not testicular, sperm concentration and motility and an increase in abnormal sperm morphology. In view of the differences in fertility between rats and humans, these types of sperm effects in rats suggest the potential for an impact on human male fertility that would be undetected if not for the sperm assessment. Therefore, the current example suggests that including semenology as a standard endpoint in nonclinical fertility studies may be warranted.
authors.affiliation: Preclinical Development & Safety, Janssen Research & Development, Beerse, Belgium. Electronic address: dmarien5@its.jnj.com.
authors.forename: Dirk
authors.initials: D
authors.lastname: Mariën
authors.affiliation: Preclinical Development & Safety, Janssen Research & Development, Beerse, Belgium.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Bailey
authors.affiliation: Preclinical Science & Safety, Office of the Chief Medical Officer, Johnson & Johnson, New Brunswick, NJ, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Eichenbaum
authors.affiliation: Preclinical Development & Safety, Janssen Research & Development, Beerse, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Jonghe
mesh_terms: D000818:Animals; D004146:Dioxanes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005298:Fertility / Q000187:drug effects*; D017408:Guidelines as Topic; D008297:Male; D017207:Rats, Sprague-Dawley; D013076:Sperm Count; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects*; D013449:Sulfonamides / Q000633:toxicity*; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D004146:Dioxanes; C585982:N-((6-chloro-2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)sulfamide; D013449:Sulfonamides
keywords: Epididymal toxicity; ICH S5(R2); Male fertility; Reproductive toxicity; Semenology; Sprague Dawley rat