Corpus Luteum Development: Lessons from Genetic Models in Mice

https://doi.org/10.1016/S0070-2153(05)68003-9Get rights and content

The corpus luteum is a transient endocrine gland that produces essentially 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. The life span and function of the corpus luteum is regulated by complex interactions between stimulatory (luteotrophic) and inhibitory (luteolytic) mediators. Although the process of luteal formation and 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. In rodents, prolactin is the major luteotrophic hormone by maintaining the structural and functional integrity of the corpus luteum for several days after mating. Other factors involved in steroidogenesis, control of cell cycle, apoptosis, and tissue remodeling have been shown to play a role in corpus luteum development and maintenance. Especially, PGF2α seems to be the most potent luteolytic hormone. One of the most important advances in the study of mammalian genes has been the development of techniques to obtain defined mutations in mice. These tools enable us to target specific genes and to analyze the impact of their loss on cell fate and function. With these approaches, several receptors, transcription factors, enzymes, and other factors have been linked to corpus luteum development and maintenance. These models are helping to define mechanisms of reproductive function and to identify potential new contraceptive targets and genes involved in the pathophysiology of reproductive disorders.

Introduction

The corpus luteum (CL) is an endocrine gland of limited life span formed from the remaining granulosa and theca cells of the follicle after ovulation. The corpus luteum produces progesterone and, in the event of fertilization, provides the required progesterone responsible for preparing the uterus for pregnancy and, if pregnancy occurs, maintaining it until birth in rodents. It inhibits the contractile activity of the uterus and inhibits development of a new follicle. The corpus luteum also produces low amounts of estrogen. In the absence of fertilization, the life span of the corpus luteum is limited. In rodents, the corpus luteum exerts an essential role, because it is responsible for the maintenance of full pregnancy by sustaining progesterone secretion, whereas in humans it provides the required progesterone until the placenta is formed. After ovulation on the morning of estrus, the corpus luteum secretes a limited amount of progesterone, is maintained 2 days, and then involutes if mating does not occur. On estrus, mating induces the release of prolactin (PRL) from the anterior pituitary by activation of a neural network that begins at the cervix and ends in the hypothalamus (Freeman et al., 2000). This causes two daily surges of PRL to be released for 12 days (Freeman 1972, Morishige 1973); if fertilization does not occur, the corpus luteum survives then establishing the pseudopregnancy state.

Section snippets

Development of the Corpus Luteum

The preovulatory surge of gonadotrophins induces ovulation and differentiation of residual follicular cells that form the corpus luteum and begin to produce progesterone at high levels. Before this step, granulosa and theca cells of the follicle produce estrogens. Theca cells express the enzymes necessary to convert cholesterol to androgens, whereas granulosa cells can convert androgens to estradiol. Thus, androgens produced by theca cells are aromatized to estradiol by granulosa cells.

Luteolysis

Luteinized cells complete their life span by a process of structural luteolysis that includes cell fusion, apoptosis, and phagocytosis. Luteolysis is characterized by an initial decline of progesterone secretion that is commonly designated as functional luteolysis as distinct from structural luteolysis, which signifies the subsequent change in the cellular structure of the gland and its gradual involution in the ovary to form a small scar composed of connective tissue. This latter structure,

Factors Affecting the Maintenance or the Development of the Corpus Luteum: Mouse Models

One of the most important advances in the study of mammalian genes has been the development of techniques to obtain defined mutations in mice. Often, the deletion of a gene that has accepted functions from biochemical and cell biological experiments results in different kinds of phenotypes. Frequently, this takes the form of no or mild phenotypes and evokes the possibility that redundantly functioning genes exist. Efforts to define the functions of PRL and its receptor from the phenotype of

Conclusion

This chapter has reviewed the advances in our understanding of corpus luteum function that have been greatly facilitated by the analysis of many mutant mice. Targeted mutagenesis models are increasingly being used to study reproductive function and also to understand fundamental processes of development. The mechanisms by which the progesterone required for establishment and maintenance of pregnancy are regulated by the mammalian conceptus. In all cases, adequate luteal progesterone is secreted

References (112)

  • FeroM.L. et al.

    A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)‐deficient mice

    Cell

    (1996)
  • FrasorJ. et al.

    Prolactin regulation of estrogen receptor expression

    Trends Endocrinol. Metab.

    (2003)
  • IhleJ.N.

    STATs: Signal transducers and activators of transcription

    Cell

    (1996)
  • IhleJ.N. et al.

    Jaks and Stats in signaling by the cytokine receptor superfamily

    Trends Genet.

    (1995)
  • JirawatnotaiS. et al.

    Cdk4 is indispensable for postnatal proliferation of the anterior pituitary

    J. Biol. Chem

    (2004)
  • JirawatnotaiS. et al.

    The cyclin‐dependent kinase inhibitors p27Kip1 and p21Cip1 cooperate to restrict proliferative life span in differentiating ovarian cells

    J. Biol. Chem.

    (2003)
  • KiyokawaH. et al.

    Enhanced growth of mice lacking the cyclin‐dependent kinase inhibitor function of p27(Kip1)

    Cell

    (1996)
  • LiuK. et al.

    Expression pattern and functional studies of matrix degrading proteases and their inhibitors in the mouse corpus luteum

    Mol. Cell Endocrinol.

    (2003)
  • NakayamaK. et al.

    Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors

    Cell

    (1996)
  • NyT. et al.

    Matrix remodeling in the ovary: Regulation and functional role of the plasminogen activator and matrix metalloproteinase systems

    Mol. Cell Endocrinol.

    (2002)
  • OlofssonJ. et al.

    Synthesis of prostaglandin F2 alpha, E2 and prostacyclin in isolated corpora lutea of adult pseudopregnant rats throughout the luteal life‐span Prostaglandins Leukot

    Essent. Fatty Acids

    (1992)
  • Prigent‐TessierA. et al.

    Rat decidual prolactin. Identification, molecular cloning, and characterization

    J. Biol. Chem.

    (1999)
  • RahkonenO.P. et al.

    Characterization of the murine Timp4 gene, localization within intron 5 of the synapsin 2 gene and tissue distribution of the mRNA

    Biochim. Biophys. Acta

    (2002)
  • RothchildI.

    The regulation of the mammalian corpus luteum

    Recent Prog. Horm. Res.

    (1981)
  • RuiH. et al.

    Prolactin receptor triggering: Evidence for rapid tyrosine kinase activation

    J. Biol. Chem.

    (1992)
  • SilvermanE. et al.

    CCAAT enhancer‐binding protein beta and GATA‐4 binding regions within the promoter of the steroidogenic acute regulatory protein (StAR) gene are required for transcription in rat ovarian cells

    J. Biol. Chem.

    (1999)
  • SimonL.S.

    Role and regulation of cyclooxygenase‐2 during inflammation

    Am. J. Med.

    (1999)
  • SiroisJ. et al.

    Transcriptional regulation of the rat prostaglandin endoperoxide synthase 2 gene in granulosa cells. Evidence for the role of a cis‐acting C/EBP beta promoter element

    J. Biol. Chem.

    (1993)
  • SixD.A. et al.

    The expanding superfamily of phospholipase A(2) enzymes: Classification and characterization

    Biochim. Biophys. Acta

    (2000)
  • StraussJ.F. et al.

    Cholesterol metabolism by ovarian tissue

    Adv. Lipid Res.

    (1981)
  • TeglundS. et al.

    Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses

    Cell

    (1998)
  • AcostaJ.J. et al.

    Src mediates prolactin‐dependent proliferation of T47D and MCF7 cells via the activation of focal adhesion kinase/Erk1/2 and phosphatidylinositol 3‐kinase pathways

    Mol. Endocrinol.

    (2003)
  • AlbarracinC.T. et al.

    Identification of a major prolactin‐regulated protein as 20 alpha‐ hydroxysteroid dehydrogenase: Coordinate regulation of its activity, protein content, and messenger ribonucleic acid expression

    Endocrinology

    (1994)
  • AliS. et al.

    PTP1D is a positive regulator of the prolactin signal leading to b‐casein promoter activation

    EMBO J.

    (1996)
  • AscoliM. et al.

    The lutropin/choriogonadotropin receptor, a 2002 perspective

    Endocr. Rev.

    (2002)
  • AzharS. et al.

    Cholesterol uptake in adrenal and gonadal tissues: The SR‐BI and ‘selective’ pathway connection

    Front Biosci.

    (2003)
  • BinartN. et al.

    Rescue of preimplantatory egg development and embryo implantation in prolactin receptor‐deficient mice after progesterone administration

    Endocrinology

    (2000)
  • BinartN. et al.

    A short form of the prolactin receptor is able to rescue mammopoiesis in heterozygous prolactin receptor mice

    Mol. Endocrinol.

    (2003)
  • Bole‐FeysotC. et al.

    Prolactin and its receptor: Actions, signal transduction pathways and phenotypes observed in prolactin receptor knockout mice

    Endocr. Rev.

    (1998)
  • BrannstromM. et al.

    Immune regulation of corpus luteum function

    Semin. Reprod. Endocrinol.

    (1997)
  • BrugarolasJ. et al.

    Radiation‐induced cell cycle arrest compromised by p21 deficiency

    Nature

    (1995)
  • CarambulaS.F. et al.

    Caspase‐3 is a pivotal mediator of apoptosis during regression of the ovarian corpus luteum

    Endocrinology

    (2002)
  • CurryT.E. et al.

    The matrix metalloproteinase system: Changes, regulation, and impact throughout the ovarian and uterine reproductive cycle

    Endocr. Rev.

    (2003)
  • DarnellJ.E.J. et al.

    Jak‐STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

    Science

    (1994)
  • DevotoL. et al.

    Insulin and insulin‐like growth factor‐I and ‐II modulate human granulosa‐lutein cell steroidogenesis: Enhancement of steroidogenic acute regulatory protein (StAR) expression

    Mol. Hum. Reprod.

    (1999)
  • ErlebacherA. et al.

    Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system

    J. Clin. Invest.

    (2004)
  • FerraraN.

    Vascular endothelial growth factor and the regulation of angiogenesis

    Recent Prog. Horm. Res.

    (2000)
  • FreemanM.E. et al.

    Prolactin: Structure, function, and regulation of secretion

    Physiol. Rev.

    (2000)
  • FreemanM.E. et al.

    The pattern of prolactin secretion during pseudopregnancy in the rat: A daily nocturnal surge

    Endocrinology

    (1972)
  • GaoQ. et al.

    Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation

    Proc. Natl. Acad. Sci. USA

    (2004)
  • Cited by (0)

    View full text