Testicular Development in Cynomolgus Monkeys

Abstract

The testes from 136 male cynomolgus monkeys were examined histopathologically in order to investigate the relationship between the development of spermatogenesis and testis weight, age, and body weight. At Grade 1 (immature), Sertoli cells and spermatogonia were the only cell classes in the testis. At Grade 2 (pre-puberty), no elongated spermatids were observed in the testis, although a few round spermatids and small lumen formation were observed. At Grade 3 (onset of puberty), all classes of germ cells were observed in the testis, although seminiferous tubule diameters and numbers of germ cells were small. Slight debris in the epididymis was observed in almost all animals. At Grade 4 (puberty), almost complete spermatogenesis was observed in the seminiferous tubules and it was possible to ascertain the spermatogenesis stage as described by Clermont, although tubule diameters and numbers of germ cells were small. There was less debris in the epididymis than at Grade 3. At Grade 5 (early adult), complete spermatogenesis was observed in the seminiferous tubules. At Grade 6 (adult), complete spermatogenesis in the seminiferous tubules and a moderate or large number of sperm in the epididymis were observed. Moreover, sperm analysis using ejaculated sperm was possible. Logistic regression analysis showed that testis weight is a good indicator of testicular maturity.

Comparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System

“…The inability to closely align these temporal stages of development with microscopic changes in the testes is due to the quiescent period that occurs during one or more of these early stages, and to the large degree of inter‐animal variability (discussed below). Rather than use this temporal staging scheme used in rats and humans, the monkey testis has been evaluated microscopically based on a grade 1 (immature) through grade 6 (adult) scheme (Haruyama et al, ). In an attempt to draw parallels between rat and NHP, Table compares the microscopic findings at the various grade levels in the NHP with those microscopic findings at the temporal developmental stages (in rats).…”

“…The timing of the quiescent period in cynomolgus monkeys has not received significant attention. Part of this reason is that most publications in the cynomolgus monkey focus on the timing of sexual maturity (Smedley et al, ; Haruyama et al, ; Luetjens and Weinbauer, ), because preclinical toxicity studies ideally require the examination of sexually mature males. Accordingly, the microscopic details of the neonatal, infantile, or quiescent periods have been largely ignored.…”

“…Comparison between species is difficult because different developmental stage schemes are used for different species. Six developmental stages (grades 1–6) are used in publications on the NHP (Haruyama et al, ), while four stages (from neonatal to peripubertal) are used in the rat (Ojeda et al, ), and three stages (immature, peripubertal/transitional, and mature) are often used in pigs (Evans et al, ). Moreover, these stage schemes are not specific for any one system, and, therefore, may fail to correspond to gross or microscopic changes in the male reproductive tract.…”

Non‐clinical safety evaluation of repeated intramuscular administration of the AS15 immunostimulant combined with various antigens in rabbits and cynomolgus monkeys

“…At necropsy, prostate weights were higher in the vaccine group (and correlated with epithelial cell hypertrophy) and lower in the AS15 group, in comparison to controls. Organ weights for male reproductive organs such as prostate, seminal vesicles or testes usually correlate with age and weight but can be also influenced by other factors, such as sexual maturity of the individual, prostatic hypertrophy or other pathological conditions, social ranking or state of repletion (Chapin and Creasy, 2012; Haruyama et al ., 2012; Ku et al ., 2010). In this study, terminal prostate volume correlated well with terminal body weight.…”

Scientific and Regulatory Policy Committee Points to Consider Review

“…This can be a challenging exercise, even for pathologists experienced in the evaluation of the reproductive tract, due to the small number of animals used and the high variability among individuals. Publications describing testicular development (Picut et al , 2015b, Haruyama et al , 2012, Campion et al , 2013), common spontaneous histologic features of the testes during the process of sexual maturation (Goedken et al , 2008, Rehm, 2000, Sato et al , 2012a, Sato et al , 2012b, Thuilliez et al , 2014), and ovarian development (Picut et al , 2015a, Picut et al , 2014) represent excellent references for this topic.…”