[Frontiers in Bioscience 7, d1949-1978, September 1, 2002]

THE CORPUS LUTEUM: AN OVARIAN STRUCTURE WITH MATERNAL INSTINCTS AND SUICIDAL TENDENCIES

John S. Davis 1 and Bo R. Rueda 2

1 Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3255, Veterans Affairs Medical Center, Research Service, Omaha, Nebraska 68105-1873 2 Harvard Medical School, Boston, Massachusetts and Vincent Center For Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1 Role of the corpus luteum (general perspective)
2.2. Luteolysis
2.3. Luteolysins
3. Signaling via the PGF2 alpha receptor
3.1. PGF2 alpha receptor
3.2. Activation of phospholipase C
3.3. Calcium signaling
3.4. Protein kinase C
3.5. Mitogen-activated protein kinase
3.6. Early response genes
3.7. Additional signaling mechanisms
4. Mediators of Luteal regression
4.1 Cytokine involvement
4.1.1. Fas ligand
4.1.2. Tumor necrosis factor alpha
4.1.3. Interferon gamma
4.2. Vascular contributions to luteal regression
4.3. Reactive oxygen species
4.4. Non-traditional lipid signaling (Sphingomyelin pathway)
4.5. Endothelin-1
5. Structural regression
5.1. Apoptosis
5.2. Bcl-2 family members
5.3. Caspases
5.4. Immune cells and phagocytosis
5.5. Monocyte chemoattractant pathway-1
6. Summary
7. Acknowledgements
8. References

1. ABSTRACT

The corpus luteum is a unique hormone-regulated, transient reproductive gland that produces progesterone, a required product for the establishment and maintenance of early pregnancy. In the absence of pregnancy the corpus luteum will cease to produce progesterone and the structure itself will regress in size over time. Although the process of luteal regression has been studied for several decades, many of the regulatory mechanisms involved in loss of function and involution of the structure are incompletely understood. More importantly, we are far from understanding how these complex mechanisms function in unison. The factor or factors responsible for initiating and mediating luteolysis are no doubt more complex than originally envisioned. Further, efforts to elucidate the mechanisms responsible for luteolysis have been complicated by different interpretations of what is 'luteolysis', discrepancies between in vitro and in vivo studies, and subsequent biases which are associated with the different methods of analyses. Moreover, the complexity of the mechanisms which regulate the life span of the corpus luteum are compounded by the presence of a heterogeneous population of cells which often respond differentially to the same ligand or stimuli. Attempts to isolate specific luteal cell types for the intention of defining intracellular signaling mechanisms have yielded valuable information. However, studies of a specific cell type taken out of context are often subject to criticism. The most obvious being that the cells are no longer maintained within their three dimensional environment. Evaluation of the corpus luteum in vivo, is not without its criticisms either. A subtle change evoked within a subpopulation of cells can be overlooked if measured in whole tissue or in mixed cell preparations. Furthermore, treatment in vivo with a single agent/ligand (i.e., prostaglandin F2 alpha) may induce a secondary ligand that is ultimately responsible for the biological response. All arguments are valid and cannot be ignored. There are secondary levels of complexity in the corpus luteum brought about by the pleiotropic actions of specific ligands. For example, one ligand can be luteotropic to a steroid producing cell and cytotoxic to a luteal endothelial cell. Furthermore, a specific cell type within the corpus luteum may respond differentially depending on the developmental stage of the luteal phase (i.e., early, mid, or late luteal phase) suggesting that the intracellular signaling pathways are key to defining ligand-induced biological responses. The purpose of this review is to culminate what is known regarding signal transduction pathways activated by initiator(s) and/or mediators of luteolysis. We recognize that an all-inclusive review describing the molecular mechanisms involved in the development, maintenance and regression of the corpus luteum would be impossible within the context of this review. There are a number of recent reviews that discuss luteal development, luteal maintenance and luteolysis with emphasis on neuroendocrine events (1-3). Consequently, we have focused our review primarily on potential intracellular signaling events of proposed regulators and mediators of luteal regression. Where possible we have attempted to incorporate references that represent rodents, domestic farm animals and primates.