The Shifting Role and Regulation of the Corpus Luteum in Vertebrate Reproduction: A Synthetic Review

A hallmark of eutherian pregnancy is its dependency on elevated progesterone levels for its entire length. This fact substantially affected the evolution of pregnancy and even the life history of eutherians. Progesterone synthesis by the ovarian corpus luteum, however, long predates all origins of vertebrate viviparity, which requires reconsidering the role of the corpus luteum and progesterone before and beyond placental mammals. Pregnancy originated repeatedly by co-opting the ancestral luteal phase of the ovarian cycle. Therefore, it represents a physiological equivalent and “serial homolog” of the nonpregnant luteal phase. Because of this relationship, we argue that understanding the origin and evolution of pregnancy can substantially benefit from examining the evolution and regulation of the corpus luteum during nonpregnancy. In the first part of this paper, we investigate what is known about the evolution of the corpus luteum and its changing regulation and function across vertebrates, covering both pregnant and nonpregnant cycles wherever possible. Studying pregnancy in the context of the nonpregnant cycle reveals the key evolutionary innovation that facilitated the characteristically long eutherian pregnancies: the regulatory decoupling of the pregnant and nonpregnant cycle, that is, the evolution of maternal recognition of pregnancy. Only after the two cycles became separately modifiable, could gestation length increase without deleteriously extending the time to the next fertile phase. In this review, we argue that, assuming selection for body size increase, the origin of MRP led to a punctuated increase of gestation length, which could imply that we overestimate pregnancy length in the eutherian ancestor when using conventional phylogenetic inference methods. Mechanistically, decoupling between cycles means that the progesterone-dominated phase in pregnancy is extended beyond that of nonpregnancy. In eutherians, this is achieved by extending the lifespan of progesterone-producing corpus luteum, providing additional corpora lutea, extraovarian sources of progesterone, or a combination of these. Alternatively, it can also be accomplished by shortening the nonpregnant cycle. The differences in underlying mechanisms for decoupling among the major eutherian lineages suggest that they originated independently, which leads us to conclude that eutherian gestation consists of parts that are not homologous across eutherians. Consequently, eutherian gestation length is not a homologous trait that can be productively compared across species directly. Finally, we find no evidence for an increase in gestational length due to maternal-fetal conflict. Rather, as long appreciated, body size explains a major portion of the variation in gestation length in eutherians. This suggests that the increase in eutherian gestation length was driven by the need to accommodate an increasing body size, a well-documented trend (Cope’s rule), once independent evolution of pregnant and non-pregnant cycles became possible.