Toxicologic Pathology Forum*: Opinion on Sexual Maturity and Fertility Assessment in Long-tailed Macaques (Macaca fascicularis) in Nonclinical Safety Studies

Abstract

If nonhuman primates represent the only relevant species for nonclinical safety evaluation of biotechnology-derived products, male and female fertility effects can be assessed in repeat dose toxicity studies given that sexually mature monkeys are used. This opinion piece provides recommendations for determining sexual maturity and when/how fertility assessments should be conducted in the cynomolgus monkey. Male sexual maturity should be proven by presence of sperm in a semen sample, female sexual maturity by at least two consecutive menstrual bleedings. As per regulatory guidance, default parameters for an indirect assessment of fertility in both sexes are reproductive organ weight and histopathology. Beyond default parameters, daily vaginal swabs are recommended for females, and for males, it is recommended to include blood collections (for potential analysis of reproductive hormones), testis volume sonography, and collection of frozen testis samples at necropsy. Only if there is a cause for concern, blood collection for potential reproductive hormone analysis should be conducted in females and semen analysis in males. In principle, adverse reproductive effects can be detected within 4 weeks of test article administration, depending on study design and reproductive end point chosen. Therefore, there are options for addressing reproductive toxicity aspects with studies of less than 3 months dosing duration. [Box: see text]

Does Geographical Origin of Long-Tailed Macaques (Macaca fascicularis) Matter in Drug Safety Assessment?: A Literature Review and Proposed Conclusion

“…Examination of reproductive toxicity in the long-tailed macaque is limited to an indirect assessment of fertility, based upon clinical and morphological endpoints in sexually mature animals. 44…”

Endocrine Disruption and Reproductive Pathology

“…Assessment of reproductive pathophysiology in female macaques is best accomplished using an integrative approach that includes in-life assessments. The strategic approaches outlined below and recommendations from the recent literature 116 should be considered. For example,…”

“…Trimming(see also 116,117 ): Ovaries and uterine tubes along their long/flat axis Uterus axially across the short axis Cervix sagitally …”

“…The more definitive landmark of sperm production in an ejaculate has recently been recommended as a screening criterion. 116…”

“…Trimming (see also 116 ): Testes: Trim in the anterior half of the testis to include rete testis Epididymides: At a minimum, trim the tail; ideally, the head, body, and tail Prostate: Cross-section of the caudal prostate Seminal vesicle: Cross-section of each gland …”