Scientific and Regulatory Policy Committee Best Practices: Documentation of Sexual Maturity by Microscopic Evaluation in Nonclinical Safety Studies

Abstract

The sexual maturity status of animals in nonclinical safety studies can have a significant impact on the microscopic assessment of the reproductive system, the interpretation of potential test article–related findings, and ultimately the assessment of potential risk to humans. However, the assessment and documentation of sexual maturity for animals in nonclinical safety studies is not conducted in a consistent manner across the pharmaceutical and chemical industries. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology convened an international working group of pathologists and nonclinical safety scientists with expertise in the reproductive system, pathology nomenclature, and Standard for Exchange of Nonclinical Data requirements. This article describes the best practices for documentation of the light microscopic assessment of sexual maturity in males and females for both rodent and nonrodent nonclinical safety studies. In addition, a review of the microscopic features of the immature, peripubertal, and mature male and female reproductive system and general considerations for study types and reporting are provided to aid the study pathologist tasked with documentation of sexual maturity.

Spontaneous Findings in the Reproductive System of Sexually Mature Male Cynomolgus Macaques

“…In animals approaching full sexual maturity, incomplete spermatogenesis, increased cellular debris and fewer sperm in the epididymides, and decreased accessory sex OW are expected. 9,14,15 Therefore, the diagnoses of hypospermatogenesis in the testes, reduced sperm in the epididymides, and atrophy in the accessory sex organs are likely inappropriate as these are features of normal pubertal development and it is recommended to designate these animals as "peripubertal" in the individual animal data as described in Vidal et al 17 As such, the study pathologist should use a weight of evidence approach when assessing sexual maturity including semen analysis, TBW, and OW along with the microscopic examination. Ideally, age would be a part of the weight of evidence as it is possible that some of the smaller animals in this project could be sexually mature subordinate animals with suppression of the endocrine axis due to social hierarchy-induced stress and subsequent decreased testicular size.…”

Biology and postnatal development of organ systems of cynomolgus monkeys (Macaca fascicularis)

“…1 CMs have considerable individual variations in the age of onset and duration of puberty where sexual dimorphism and secondary sex characteristics develop 9 . In general, females achieve reproductive maturity earlier than males 1,38,39 . Intense endocrine activity during puberty also affects musculoskeletal, nervous, immune, and other organ system development.…”

“…The presence of menses in the vaginal swab of females and spermatozoa in male semen confirms sexual maturity. Age, body weight, testicular volume, semen analysis, menstrual cycle, and/or sex hormones are useful for maturity evaluation 38,56,58–60 . Age or body weight alone is not a reliable indicator of sexual maturity status for CMs due to the variable onset and long duration of puberty.…”

“…Age or body weight alone is not a reliable indicator of sexual maturity status for CMs due to the variable onset and long duration of puberty. Microscopic assessment of the ovarian cycle, testicular spermatogenesis, and other reproductive tissue changes can be definitive, but it is retrospective 38,56 . It is critical to integrate all available information to assess sexual maturity using a weight of evidence approach.…”

“…A combination of age, body weight, testicular size, and serum testosterone levels facilitates the identification of sexually mature males when histological evaluation and semen analyses are unavailable 29,56,57,59 . Spermatogenesis occurs during early puberty in response to testosterone and follicle‐stimulating hormone (FSH) 38,56,59 . Spermarche may occur from 2.8 years of age in Mauritian male CMs and 3.9 years of age in Asian male CMs based on spermatozoa in the semen sample 61 …”