• Role and Significance of Bradykinin in Reproduction

      Shi, Beien; Institute of Molecular Medicine and Genetics (1998-04)
      The ultimate goal o f reproduction is to maintain the life and well-being o f the species In mammals, it includes the nurturance and maturation o f the individual male and femaie germ cells, their successful union, the subsequent growth and development of the newly created individual within the body o f mother, and the birth o f a new' offspring In order to achieve these goals, the female reproductive system undergoes a series of closely interrelated events involving follicle development, ovulation, fertilization, implantation, pregnancv. and parturition Ovulation, the discharge of the ovum ( female germ cell) from a mature follicle tor fertilization, is a prerequisite and central process for a new lite ot the species, and it occurs in a cyclic fashion It has been noted for a long time that the ovulatory cycle requires a highly coordinated and complex interplay ot events among the components ot the hypothalamus-pituitarv-ovarv axis (1) The central endocrinological component in the ovulatorv cycle is the preovulatory gonadotropin (luteinizing hormone, LH, and follicle stimulating hormone, FSH) surge (1-3). The LH surge induces ovulation o f a mature ovum for potential fertilization (1-3) The activity o f the pituitary gonadotrophs which secrete LH and FSH is controlled by its principal regulator, gonadotropin-releasing hormone (GnRH) (4.5) GnRH is a decapeptide secreted in a pulsatile manner by a specific group o f neurosecretory neurons in the hypothalamus (6,7). Once released into the pituitary portal capillaries in the median eminence, it is delivered to the anterior pituitary' via the hypophyseal penal veins GnRH binds to its receptor on the plasma membrane o f the gonadotrophs and stimulates the secretion o f LH and FSH ( The gonadotropins travel to the ovary via the bloodstream where they stimulate estradiol and progesterone production and initiate the process o f ovulation (1) The o \arian steroids, estradiol and progesterone, regulate GnRH and LH secretion at the hvpothalamus and pituitary level There is a large release o f GnRH shortly before ovulation on proestnjs day in the rat in response to the elevated levels o f estradiol and progesterone 0-M !> This GnRH surge results in the gonadotropin surge and subsequent ovulation Therefore, it is now d ear that estradiol and progesterone are actually the ke\ regulators o f the preovu!atorv gonadotropin surge (12-16) There is a voluminous literature that indicates that ovarian estradiol is a positive stimulus for the gonadotropin surge ( whereas progesterone is thought to synchronize, potentiate, and limit the uonadotropin surge to a single day (20-24) Although the roles o f ovarian steroids are clear, the site and mechanisms underlving their actions remain poorly understood. Since GnRH neurons do not possess steroid hormone receptors (25-27). steroid regulation o f GnRH secretion appears to be through an indirect neuronal circuitry involving several neurotransmitters and/or neuropeptides, which in turn regulate GnRH secretion. Within the last decade, rapid progress has been made concerning the mechanisms by which GnRH neurons are regulated Information available so far has already shown a clearer picture o f the control o f G nR H secretion However, the real challenge still lies in our ability to understand how G nRH secretion is regulated and how information is integrated into coherent patterns o f regulation Recently, bradykinin has been demonstrated to be present in the central nervous system (CNS) (2S-30). and work presented in this dissertation demonstrates that bradykinin is present in key hypothalamic sites responsible for the control of GnRH secretion This finding raises the possibility that bradykinin may be an important transmitter in the control o f GnRH secretion. This possibility was the foundation for manv o f the aims proposed and work conducted in this study A second focus o f this dissertational work was to examine the role o f bradykinin in the reproductive processes o f implantation and parturition. Implantation is the process wherebv the embryo becomes fixed in the uterus in physical contact with the maternai oruanism Implantation includes adhesion o f the blastocyst to the uterine epithelium, increased permeabilitv at implantation sites, the decidual cell reaction (deciduaiization). and loss o f epithelial cells surrounding the implanting blastocyst (31-33) file process 01 implantation, especiallv decidual transformation is very similar to an inflammatory response (34). in that there is hyperemia and tissue remodeling. Steroid hormones are major regulators o f implantation, and various inflamm atory mediators, such as cytokines and growth factors, are also involved in this process (35,36). During pregnancy, the fetus continues to grow until term, at which point the uterus acts to expel the mature fetus. This event is called parturition. Uterine smooth muscle contractility is reduced during pregnancy and dramatically increases during parturition (37) Since bradykinin is a well know n inflammatory mediator during inflammation and tissue injury, and a potent stimulator o f uterine smooth muscle contraction, the physiological roles o f endogenous bradykinin in the processes o f implantation and parturition were examined in addition to its potential role in the control o f GnRH secretion.