Mammalian Labor: Variations on a Theme by Amniota

Abstract

In this month’s issue of Endocrinology, Wada et al (1) report on the “Role of vascular endothelial growth factor (VEGF) in maintenance of pregnancy in mice.” It’s a beautifully written report of a carefully performed series of experiments that strongly implicate a fall in the corpus luteum production of VEGF in the onset of labor in mice. However, the most intriguing and insightful aspect is the focus within the title on pregnancy maintenance. Maintaining the fertilized egg within the reproductive tract is a key issue for all amniotes. Before the evolution of the amniote egg, most vertebrate females laid their eggs in water and fertilization was achieved by the male depositing sperm in the vicinity (2). The ability to be fully terrestrial required the evolution of the amniote egg that was covered with membranes that were impervious to water so they did not dry out, yet permeable to oxygen and carbon dioxide allowing respiration. However, the membranes and shell of the amniote egg are formed inside the reproductive tract and the formed coverings are impermeable not only to water but also to sperm. The physiological consequence of the internal creation of the egg coverings is the need also for internal fertilization before the formation of the impenetrable membranes. Movement of the ovum from the ovary to the exterior down the reproductive tract is seen in fish and amphibians in anticipation of external fertilization. This transport is effected by both peristaltic contraction and cilial motion (3). In contrast, for all amniotes, a central requirement is a female reproductive tract that allows the penetration of the sperm against the usual peristaltic and cilial transport toward the exterior. Once fertilization has occurred within the reproductive tract of the amniote, the fertilized ovum must be retained to allow formation of the membranes and in some species the shell or outer covering. A critical evolutionary step for the amniote is the development of a mechanism to retain the zygote within the reproductive tract. Although direct studies of early amniotes are impossible, the physiology of extant members of the group may provide clues. Extant amniotes include birds, reptiles, and mammals. In these diverse classes of vertebrates, the endocrinological processes that arrest contractions of the reproductive tract or uterus have been examined. In the chicken, progesterone plays a key role in retaining the egg within the oviduct. Equally, in the lizard and other reptiles, corpus luteum production of progesterone is critical (4). Within mammalia, the role of progesterone has been examined in many species. In the sheep, murides, marsupials (5), and in humans, progesterone withdrawal is associated with the onset of labor indicating a role for progesterone in reducing contractile activity of the myometrium. Therefore, progesterone as an agent for the inhibition of uterine or reproductive tract activity is found in members of all extant classes of amniotes. This is evidence that progesterone was used to maintain reproductive tract quiescence in the ancestral root amniote. This view is also supported by genome comparison studies that support the evolution of the progesterone receptor (PR) before the evolution of amniotes (6). The data indicate that progesterone allows the amniote to delay the passage of the zygote through the reproductive passage to permit additional parental investment. In some amniotes, the investment of the mother is in the form of egg yolk and the formation of a shell. In placental mammals, retention of the zygote allows additional development of the embryo and fetal growth before release into the exter-