Reproduction in Domestic Animals

Reprod Dom Anim 43 (Suppl. 2), 57–65 (2008); doi: 10.1111/j.1439-0531.2008.01143.xISSN 0936-6768Regulation of Luteal Function and Corpus Luteum Regression in Cows: HormonalControl, Immune Mechanisms and Intercellular CommunicationDJ Skarzynski 1 , G Ferreira-Dias 2 and K Okuda 31 Department of Reproductive Immunology, Institute of Animal Reproduction and Food Research of PAS, Olsztyn, Poland; 2 C.I.I.S.A., Facultyof Veterinary Medicine, TU Lisbon, Portugal; 3 Laboratory of Reproductive Endocrinology, Graduate School of Natural Science andTechnology, Okayama University, Okayama, JapanContentsThe main function of the corpus luteum (CL) is production ofprogesterone (P4). Adequate luteal function to secrete P4 iscrucial for determining the physiological duration of theoestrous cycle and for achieving a successful pregnancy. Thebovine CL grows very fast and regresses within a few days atluteolysis. Mechanisms controlling development and secretoryfunction of the bovine CL may involve many factors that areproduced both within and outside the CL. Some of theseregulators seem to be prostaglandins (PGs), oxytocin, growthand adrenergic factors. Moreover, there is evidence that P4acts within the CL as an autocrine or paracrine regulator. Eachof these factors may act on the CL independently or maymodify the actions of others. Although uterine PGF 2a isknown to be a principal luteolytic factor, its direct action onthe CL is mediated by local factors: cytokines, endothelin-1,nitric oxide. The changes in ovarian blood flow have also beensuggested to have some role in regulation of CL development,maintenance and regression.IntroductionThe corpus luteum (CL) is a transient ovarian organthat is established by cells of a follicle after ovulation.The mammalian CL is composed of a heterogeneousmixture of cell types. There are at least two types ofsteroidogenic cells, large and small luteal cells, whichoriginate from the granulosa and thecal cells of thefollicle ruptured at ovulation, respectively. The CLconsists of not only steroidogenic luteal cells but alsonon-steroidogenic cells, i.e. vascular endothelial cells,fibroblasts, pericytes and immune cells such as lymphocytes,leucocytes and macrophages (Lei et al. 1991).Macrophages and endothelial cells infiltrate into thenewly formed CL concomitant with vascular angiogenesis(Reynolds and Redmer 1999). Most of the cellsproliferating during growth of the CL are endothelialcells under hypoxic conditions, although leucocytes havebeen shown to proliferate in CL as well (Reynolds andRedmer 1999; Towson et al. 2002). There is evidencethat steroids, protein hormones, growth factors, eicosanoidsand cytokines produced by the component cells ofthe CL play roles in establishing CL (Reynolds andRedmer 1999; Berisha and Schams 2005).Progesterone (P4), the primary product of the CL, isrequired for establishment and maintenance of pregnancy.P4 concentration in blood increases during thedeveloping luteal stage. The CL continues to secrete ahigh level of P4 until late luteal stage, and then its abilityrapidly decreases in the regressing luteal stage. Indomestic animals, luteinizing hormone (LH) releasedin a pulsatile fashion from the anterior pituitary is oneof the most potent regulators of synthesis and secretionof P4 in the CL (Niswender et al. 2007). Luteinizinghormone stimulates P4 production in small luteal cellsvia the LH receptor. In addition to pituitary hormones,intraluteal substances produced by the component cellsof the CL play important roles in regulating P4production during the luteal stages in bovine CL.Moreover, the changes in P4 concentration throughoutthe luteal phase are closely associated with blood flow aswell as steroidogenic capacity of luteal cells. Duringluteal regression, the decrease in P4 is concerned withreduced blood flow and loss of LH receptors in the CL(Niswender et al. 1976).When animals do not become pregnant, regression ofthe CL, termed luteolysis, is essential for normalcyclicity as it allows development of a new ovulatoryfollicle. In the cow, luteolysis is initiated by prostaglandin(PG)F 2a released from the uterus at the late lutealstage. Luteolysis consists of two phases, functionalluteolysis and structural luteolysis in mammals (McCrackenet al. 1999). A rapid functional regression of CLis characterized by a decrease of P4 production,followed by a phase of structural regression (McCrackenet al. 1999). During structural luteolysis, CL cellsundergo apoptosis, a process that has been describedby morphological and biochemical parameters in ruminants(Juengel et al. 1993; Rueda et al. 1995, 1997). It isgenerally accepted that the immune response playscentral roles in apoptosis of several tissues and celltypes (Nagata 1997). Recently, intraluteal mediatorsincluding cytokines and nitric oxide (NO) are thought toplay some roles as pro-apoptotic and anti-apoptoticfactors in the bovine CL, respectively (Petroff et al.2001; Skarzynski et al. 2005).This review focuses on mediators for regulatingbovine CL function throughout the oestrous cycle.Furthermore, some of our and others’ data on mediators(EDN1, cytokines, NO) of uterine PGF 2a action onbovine CL as well cell-to-cell contact and interactionsduring luteolysis have also been reviewed. Moreover,intra-luteal mechanisms controlling sensitivity of the CLto extragonadal PGF 2a are discussed.Development and Maintenance of the CorpusLuteumThe mechanism controlling development, maintenanceand secretory function of the CL may involve factorsthat are produced both within the CL and outside theovary (Fig. 1). Some of these regulators, that act asÓ 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag