Biology of the Corpus luteum, Exercises of Biology

Download Biology of the Corpus luteum and more Exercises Biology in PDF only on Docsity! Biology of the Corpus luteum Abstract Corpus luteum (CL) is a small, transient endocrine gland formed fol- lowing ovulation from the secretory cells of the ovarian follicles. The main function of CL is the production of progesterone, a hormone which regu- lates various reproductive functions. Progesterone plays a key role in the reg- ulation of the length of estrous cycle and in the implantation of the blastocysts. Preovulatory surge of luteinizing hormone (LH) is crucial for the luteinization of follicular cells and CL maintenance, but there are also other factors which support the CL development and its functioning. In the absence of pregnancy, CL will cease to produce progesterone and induce it- self degradation known as luteolysis. This review is designed to provide a short overview of the events during the life span of corpus luteum (CL) and to make an insight in the synthesis and secretion of its main product – pro- gesterone. The major biologic mechanisms involved in CL development, function, and regression will also be discussed. INTRODUCTION Corpus luteum (CL) is a transient endocrine gland, established by residual follicular wall cells (granulosa and theca cells) following ovulation. During each ovarian cycle, up to 20 primordial follicles are activated in order to start the maturation process, but in humans usu- ally only one reaches full maturity and ovulates, while remainders re- gress (Figure 1). The main secretory product of CL is progesterone, which is required for the establishment and maintenance of pregnancy. Additionally, progesterone serves as a negative feedback mechanism to the hypothalamus to suppress further follicular development (Figure 2). The inadequate progesterone production is the major cause of infer- tility and embryonic loss, since progesterone is essential for both endo- metrial growth and embryo survival. In the absence of implantation, or at the end of the pregnancy CL will cease to produce progesterone and its tissue mass will decrease in size, accompanied by loss of cellular in- tegrity. This process allows the start of a new ovarian cycle (1). Although the term »corpus luteum« was introduced in 1681 by Marcello Malpighi in a letter to Jacobo Spon, the first description and drawings of the CL was made by Regnier de Graaf (1641–1673) who notified »globular bodies« in ovaries of pregnant rabbits (2). The cor- rect physiological function of the CL was not reported until 1901, when it was proven that mated rabbits did not maintain their pregnancies if all of their CL were destroyed (3). In mammals four types of CL can be distinguished, based on their lifespan and steroidogenic activity: CL of the pregnancy is the only one which is present in all species, CL of the cycle which is not present in induced ovulators (rabbits, ferets, cats etc.), CL of the lactation, present JELENA TOMAC \UR\ICA CEKINOVI] JURICA ARAPOVI] Department of Histology and Embryology Medical Faculty, University of Rijeka B. Branchetta 20, Rijeka, Croatia Correspondence: Jelena Tomac Department of Histology and Embryology Medical Faculty, University of Rijeka B. Branchetta 20, Rijeka, Croatia E-mail: jelenat@medri.hr Key words: Ovary, Corpus Luteum, Progesterone, Luteinization, Luteolysis Received July 21, 2010. PERIODICUM BIOLOGORUM UDC 57:61 VOL. 113, No 1, 43–49, 2011 CODEN PDBIAD ISSN 0031-5362 Review only in species which ovulate after partiturion and CL of the pseudopregnancy which does not exist in primates (4). Only in rodents all four types of CL can be detected. Extrapolating findings regarding the type of CL between species come with difficulties, for example, there are clear differences in luteal cell compartmentalization and dependence on pituitary LH for steroidogenesis (San- ders and Stouffer, 1996) that distinguish primates (ma- caques and women) from most domestic animals (e.g. cows and sheep) and rodents (5). There are also morpho- logic and temporal variations in the process of corpus luteum development and maintenance among species, such as strict time point of follicular cell differentiation into luteal cells, as well as the size and role of the theca lutal cells (5). Corpus luteum of the cycle has the shortest lifespan of any tissue structure in the mammalian body. In women, its function ceases after two weeks, while in rodents this period is even shorter. The end of CL func- tion is followed by its transformation into inactive corpus albicans (CA). The association of various types of im- mune cells with the CL during its development and re- gression indicates that the immune system is involved in CL maintenance and function. Corpus luteum is formed following ovulation, but the real stimulus for luteinization represents the preovula- tory LH surge from hypophysis. Even in case when ovu- lation does not occur, granulosa cells will differentiate and form CL, while oocyte will be trapped within the non-ovulating structure (6, 7). Also, the progesterone production can occur even if ovulation fails, so the mech- anism of luteinization does not depend on the rupture of the follicle. Conversely, oocyte release from the follicle is not a guarantee of normal development and function of CL (8, 9). Development of the corpus luteum Mature preovulatory follicle which proceeds to the CL, contains oocyte surrounded with granulosa cells (so called cumulus oophorus), immersed in the follicular fluid and surrounded with the follicular wall. In the follicular wall, which is formated from granulosa cells, until ovulation there are no other structures than cellular (capillaries, blood cells and nerve processes). The folli- cular basal lamina separates granulosa cells from the sur- rounding stromal theca layers in antral follicles (10, 11). Preovulatory decrease of gap junctions induces the cu- mulus oocyte complex (COC) detachment from the fo- llicular wall which makes COC free-floating structure within the antrum. Preovulatory surge of Luteinizing Hormone (LH) from the pituitary gland induces the activation of LH re- ceptor (LH-R) on the follicular cells and initiates ovula- tion. Simultaneously, LH induces the transformation of ovulated follicle cells into the CL, a process known as luteinization. The consequences of LH surge include preturbances in intracellular signaling, gene regulation and remodeling of tissue structures within booth cell populations of the distinctovarian compartments (12–14). Following expulsion of the ovum, the granulosa cell layer is thrown into follicular antrum, which contains folli- cular fluid and blood elements. At the same time the basement membrane that divides the avascular follicular wall (granulosa cells) from theca layer degrades. These processes facilitate the invasion of numerous cell types: theca cells, fibroblasts, and especially, endothelial cells into the incipient CL. (15, 16). Remodeling associated with luteinization also includes changes in extracellular matrix adhesion molecules such as integrin a5, which is 44 Period biol, Vol 113, No 1, 2011. Jelena Tomac et al. Corpus Luteum Figure 1. The ovarian cycle in humans is divided into 3 phases: (1) Follicular phase characterized with activation of up to 20 primordial follicles in order to begin the maturation process, but usually only one reaches full maturity, (2) Ovulatory phase in which the cumu- lus-oocite complex is released from ovulating follicle, and (3) Luteal phase when CL develops from follicular wall and produces hor- mones (prevalently progesterone). If fertilization does not occur and an ovum does not implant into the uterine wall, CL degenerates and forms the corpus albicans (4). In case that implantation does occur, the developing placenta secretes chorionic gonadotrophin which pre- vents degeneration of the corpus luteum and prolongs secretion of progesterone. In humans, placenta is sufficiently developed after 5–6 weeks and then becomes the main organ of progesterone secretion. Figure 2. Scheme of feedback mechanisms that control CL function. Together with estradiol, progesterone suppresses pituitary gonadotro- phin release during the luteal phase of the cycle. Increasing concen- trations of progesterone following ovulation gradually reduce the frequency of the GnRH/LH pulses and increase their amplitude. During this phase, FSH is synthesized and stored ready for release when the corpus luteum fails. is well established, molecular factors which regulate lu- teal regression and mechanisms of »luteal rescue« by gonadotrophins still remain partly understood (46). In contrast to prostaglandins (PG) I2 and E2, which support CL development and maintenance, the prosta- glandin F2a induces a marked decrease in secretion of progesterone from the CL in vivo and from large luteal cells in vitro, which appears to be mediated via the effects of the PKC system (47). Prostaglandin F2a has the main role in initiation of lutheolysis in most nonprimate spe- cies (48), but there are accumulating evidence that in- traluteal PGF2a may also contribute to decrease of pro- gesterone secretion and demise of the CL in primates (49, 50). The treatment with PGF2a decreases luteal concentrations of mRNA encoding receptor for LH, LDL, StAR and 3b-HSD, whereas mRNA encoding re- ceptors for HDL and P450scc are not altered signifi- cantly (51). Prostaglandin F2a treatment also reduces ovarian and luteal blood flow and induces DNA frag- mentation and apoptosis resulting in cell death, appar- ently as a result of increased intracellular free calcium (48). Endothelin 1 is also described as a factor involved in PGF2a mediated destruction of luteal tissue (52). Apoptosis plays a significant part in CL regression in animals and humans. The initiation of apoptosis is not apparent until several hours after the onset of the decline in plasma progesterone (functional luteolysis) and in- creases significantly during late luteal phase, indicating its role in CL regression (53). The expression of TNF-a and Caspase-3 correlates to some extent with the apo- ptosis rate, while other apoptosis related factors (Bcl-2, Bax and NK-kB) remain relatively constant throughout the luteal phase (54). Additional processes contributing CL regression include lipid peroxidation, which induces membrane damage, and the loss of gonadotropin recep- tors increases during luteolysis, thus resulting in the de- crease of steroidogenic capacity. On the other hand, the resultant pro-oxidative status enhances COX2 protein abundance, which amplifies ovarian PGF2a secretion (53). Increase in matrix metalloproteinase expression (MMP-2 and MMP-9) is an additional important com- ponent of CL structural regression (54–56). Depending on the microenvironment, TNF can sti- mulate cell proliferation or induce apoptosis. In ovary TNF can be implicated in follicular development and CL regression (57, 58). Experiments on tumor necrosis factor receptor type I knockout mice revealed irregular estrous cycles and an inordinate amount of time in die- strus, suggesting a defect in luteal regression (59). TNFa inhibits both luteal cell progesterone and es- tradiol secretion in vitro (60), since luteal cells and endo- thelial cells are capable of TNFa synthesis. However, macrophages remain the primary ovarian source of TNFa (48). The number of these cells increases throughout the luteal phase to a maximum in the late-luteal phase (61). HCG’s Luteal »rescue« is associated with a marked re- duction in the numbers of tissue macrophages (62), while increase in the percentage of CD8+ T cells and decrease in anti-inflammatory cytokines leads to inflam- matory and cytolytic events that take part in the final luteal regression (53). Luteal Dysfunction During the preimplantation period, the uterus under- goes important developmental changes stimulated by progesterone; hence, disorders related to its secretion are likely to affect the pregnancy outcome. Inadequate CL progesterone production causes delayed or otherwise ab- normal pattern of endometrial development which leads to disorder classically described as Luteal phase defi- ciency (LPD) (63). In humans progesterone level in se- rum lower than 10 ng/mL strongly suggest the inability of successful pregnancy. Luteal phase defect is a rela- tively uncommon but important cause of infertility and/ or habitual abortion. Approximately one-half of all LPD are due to improper function of the GnRH pulse genera- tor, namely, following ovulation the increased serum progesterone levels oversuppress the GnRH pulse gener- ator, resulting in improper luteal function. Many other endocrinological abnormalities such as thyroid disease, hypoparathyroidism or uncontrolled diabetes also can disturb this highly coordinated and delicately balanced hypothalamic-pituitary-ovarian axis and adversely affect the quality and duration of CL (64). In this context LPD may be classified as a subtle form of ovarian dysfunction. In cases where the corpus luteum is LH-responsive, such as the hypothalamic corpus luteum insufficiency and the large luteal cell defect, treatment with GnRH or hCG is advisable. In the case of LH/hCG – unresponsibility, it is defect of small luteal cell, and progesterone substitution is suggested (65). Series of case reports have recorderd microorganisms affecting the ovary, but the studies di- rectly addressing the influence of infection on ovarian function leaves its mechanisms open to speculation. Pos- sible mechanisms include an alteration in vascular sup- ply of developing CL, interference with the paracrine regulation of CL maintenance, as well as direct tissue damage (66). Concluding remarks In the field of female reproductive health the investi- gation of CL is necessary to address relevant questions not only in infertility issues, but also in the development of contraceptive methods. Our understaining of CL fun- ction has been greatly facilitated by the analysis of mu- rine CL function and maintenance. 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