Comparative histopathology of the estrous or menstrual cycle in laboratory animals

Abstract

Accurate analysis of female reproductive toxicity requires a thorough understanding the differences in and specifics of estrous or menstrual cycles between laboratory animals. There are some species differences such as the time of sex maturation, the length of the estrous or menstrual cycle, the length of the luteal phase, the number of dominant follicles or corpora lutea, the size of follicles, processes of luteinization, and hormonal changes during the estrous or menstrual cycle. Rodents have a short estrous cycle, and their ovarian cycling features are the same in both ovaries, which contain a large number of follicles and corpora lutea. The dog estrous cycle is much longer than those of other laboratory animals, and it includes a long anestrus phase. The duration of the menstrual cycle of monkeys is roughly 30 days, and their ovarian cycling features are different between the left and right ovaries. In both rodents and dogs, the theca cells invade the early luteum, mixing with granulosa cells during luteinization. However in monkeys, the theca layer dose not mix with the granulosa cells as it invaginates only slightly into the early luteum. In addition, we found that high progesterone levels after ovulation are sustained for a much shorter duration in rodents than in dogs and monkeys due to the comparatively rapid passage of the rodent luteal phase. Based on these species differences, animal species for use in ovarian toxicology studies need to be selected appropriately.

Keywords: estrous cycle; female; gonadotropin; menstrual cycle; ovarian hormone; reproductive system.

Fig. 1.

Morphologic features of the ovary, uterus, and vagina, and pituitary and ovarian hormonal levels in each estrous phase in rats: D=diestrus, P=proestrus, E=estrus, M=metestrus.

Fig. 2.

Morphologic features of the ovary, uterus, and vagina and pituitary and ovarian hormonal levels in each estrus phase in a beagle dog.

Fig. 3.

Morphologic features of the bilateral ovaries, uterus, and vagina, and pituitary and ovarian hormonal levels in each menstrual phase in a cynomolgus monkey.

Fig. 4.

Follicle development shown by the diameter of each class of follicles in rats, beagles, and monkeys: primordial=primordial follicle, primary small=small primary follicle, primary large=large primary follicle, secondary=secondary follicle, preantral=preantral follicle, antral small=small antral follicle, antral large=large antral follicle, preovulatory=preovulatory follicle (selectable follicle), mature corpus luteum=mature (functional) corpus luteum.

Fig. 5.

Schematic description of variations in luteinization between rats, beagles, and monkeys. In the dog, folding of theca cells and the granulosa cell layer starts during pre-ovulation. In dogs and rodents, theca cells invade into the early luteum, with vessels and interstitial cells mixed together with granulosa cells. In monkeys, the theca layer slightly invaginates into the granulosa layer, but the components never mix.