Physiology and Endocrinology of the Ovarian Cycle in Macaques

Abstract

Macaques provide excellent models for preclinical testing and safety assessment of female reproductive toxicants. Currently, cynomolgus monkeys are the predominant species for (reproductive) toxicity testing. Marmosets and rhesus monkeys are being used occasionally. The authors provide a brief review on physiology and endocrinology of the cynomolgus monkey ovarian cycle, practical guidance on assessment and monitoring of ovarian cyclicity, and new data on effects of social housing on ovarian cyclicity in toxicological studies. In macaques, cycle monitoring is achieved using daily vaginal smears for menstruation combined with cycle-timed frequent sampling for steroid and peptide hormone analysis. Owing to requirements of frequent and timed blood sampling, it is not recommended to incorporate these special evaluations into a general toxicity study design. Marmosets lack external signs of ovarian cyclicity, and cycle monitoring is done by regular determinations of progesterone. Cynomolgus and marmoset monkeys do not exhibit seasonal variations in ovarian activity, whereas such annual rhythm is pronounced in rhesus monkeys. Studies on pair- and group-housed cynomolgus monkeys revealed transient alterations in the duration and endocrinology of the ovarian cycle followed by return to normal cyclicity after approximately six months. This effect is avoided if the animals had contact with each other prior to mingling. These experiments also demonstrated that synchronization of ovarian cycles did not occur.

Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques

“…We also observed a marked difference in variability between the X and autosomal chromosomes (Supplementary Section 4), which could have resulted from male-driven gene flow. One likely contributing factor to the restricted gene flow from CR macaque females to CE macaque males is that CR macaque females exhibit marked ovarian seasonality and only copulate during ovulation, whereas CE macaque females do not exhibit distinct reproductive seasonality and remain sexually receptive throughout the year 10 . Additionally, given that dispersal is primarily male-driven in macaques owing to Figure 1 Single nucleotide divergence between macaque species/subspecies.…”

The Macaque Endometrium, with Special Reference to the Cynomolgus Monkey (Macaca fascicularis)

“…During puberty the endometrium again comes under the influence of (endogenous) ovarian hormones. In macaques, this process happens between two and one half and four years of age (see paper by Weinbauer et al 2008). After the mucosa develops under the influence of the increasing level of estradiol produced in the first maturating follicles, cyclic changes gradually start.…”

“…The cycle-related changes gradually appear and disappear, and no sharp distinction between the different subphases can be made. The fact that we used mature, naturally cyclic animals instead of ovariectomized females with artificial hormone-induced synchronized cycles is a strength of this report but also a source of variation, since the length of the menstrual cycle in macaques varies substantially (see Weinbauer et al, 2008). Therefore it is often difficult to characterize the morphological changes in the endometrium of the cynomolgus monkey on a day-by-day basis, as was done by DallenbachHellweg (1987) for the changes during the luteal phase of the human menstrual cycle.…”

“…On average, the follicular phase starts on cycle day 4. The major morphologic characteristics of the different subsequent phases in the macaque endometrium in relation to the cyclic fluctuating (pituitary and) ovarian hormone levels are depicted in Figure 28 (see also Weinbauer et al, 2008).…”

Review on Ovarian Cryopreservation in Large Animals and Non-Human Primates

“…The benefit of these experimental animals is that the physiology and anatomy are similar to the human (Stevens, 1997;Weinbauer et al, 2008), although the ovarian size of the most studied cynomolgus monkey is considerably smaller (0.258+/-0.159 cm 3 ) (Jones et al, 2010) as compared to the human. Even if a lot of procedures are introduced in the human without appropriate tests in non-human primate species, it is advisable to include these animal models in preclinical research.…”