It has been known for a long time that gonadotropins and steroid hormones play a pivotal role in a series of reproductive biological phenomena including the maturation of ovarian follicles and oocytes, ovulation and implantation, maintenance of
pregnancy and fetal growth & development, parturition and mammary development and lactation. Recent investigations, however, have elucidated that in addition to these classic hormones, multiple growth factors also are involved in these phenomena.
Most
growth factors in reproductive organs mediate the actions of gonadotropins and steroid hormones or synergize with them in am autocrine/paracrine manner. The insulin-like growth factor (IGF) system, which is one of the most actively investigated
areas
lately in the reproductive organs, has been found to have important roles in a wide gamut of reproductive phenomena. In the present communication, published literature pertaining to the intrauterine IGF system will be reviewed preceded by general
information of the IGF system.
The IGF family comprises of IGF-Ⅰ & IGF-Ⅱ ligands, two types of IGF receptors and six classes of IGF-binding proteins (IGFBPs) that are known to date. IGF-Ⅰ and IGF-Ⅱ peptides, which are structurally homologous to proinsulin, posses the
insulin-like
activity including the stimulatory effect of glucose and amino acid transport. Besides, IGFs as mitogens stimulate cell division, and also play a role in cellular differentiation and functions in a variety of cell lines. IGFs are expressed mainly
in the
lived and messenchymal cells, and act on almost all types of tissues in an autocrine/paracrine as well as endocrine mode. There are two types of IGF receptors. Type Ⅰ IGF receptors, which are tyrosine kinase receptors having high-affinity for
IGF-Ⅰ
and IGF-Ⅱ, mediate almost all the IGF actions that are described above. Type Ⅱ IGF receptors or IGF-Ⅱ/mannose-6-phosphate receptors have two distinct binding sites, the IGF-Ⅱblinding site exhibits a high affinity only for IGF-Ⅱ. The
principal
role
of the type Ⅱ IGF receptor is to destroy IGF-Ⅱ by targeting the ligand to the lysosome. IGFs in biological fluids are mostly bound to IGFBP. IGFBPs, in general, are IGF storage/carrier proteins or modulators of IGF actions; however, as for
distinct
roles for individual IGFBPs, only limited information is available. IGFBPs for IGFs are greater than those of IGF receptors. How IGF is released from IGFBP to reach IGF receptors is not known; however, various IGFBP protease activities that are
present
in blood and interstitial fluids are believed to play an important role in the process of IGF release from the IGFBP. According to latest reports, there is evidence that under certain in vitro circumstances, IGFBP-1, -3, -5 have their own
biological
activities independent of the IGF. This day add another dimension of complexity of the already complicated IGF system.
Messenger ribonucleic acids and proteins of the IGF family members are expressed in the uterine tissue and conceptus of the primates, rodents and farm animals to play important roles in growth and development of the uterus and fetus. Expression
of
the
uterine IGF system is regulated by gonadal hormones and local regulatory substances with temporal and spatial specificities. Locally expressed IGFs and IGFBPs act on the uterine tissue I an autocrine/paracrine manner, or are secreted into the
uterine
lumen to participate in conceptus growth ad development. Conceptus also expresses the IGF system beginning from the peri-implantation period. When an IGF family member is expressed in the conceptus, however, is determined by the presence or
absence
of
maternally inherited mRNAs, genetic programming of the conceptus itself and an interaction with the maternal tissue. The site of IGF action also follows temporal (physiological status) and spatial specificities. These facts that expression of the
IGF
system is temporally and spatially regulated support indirectly a hypothesis that IGFs play a role in conceptus growth and development. Uterine and conceptus-derived IGFs stimulated cell division and differentiation, glucose and amino acid
transport,
general protein synthesis and the biosynthesis of mammotropic hormones including placental lactogen and prolactin, and also play a role in steroidogenesis. The suggested role for IGFs in conceptus growth and development has been proven by the
result of
IGF-Ⅰ, IGF-Ⅱ or IGF receptor gene disruption (targeting) of murine embryos by the homologous recombination technique. Mice carrying a null mutation for IGF-Ⅰ and/or IGF-Ⅱor type Ⅰ IGF receptor undergo delayed prenatal and postnatal growth
and
development with 30-60% normal weights at birth. Moreover, mice lacking the type ⅠIGF receptor or IGF-Ⅰ plus IGF-Ⅱ die soon after birth. Intrauterine IGFBPs generally are believed to sequester IGF ligands within the uterus or to play a role of
negative regulators of IGF actions by inhibiting IGF binding to cognate receptors. However, when it is taken into account that IGFBP-1 is expressed and secreted in primate uteri in amounts assessedly far exceeding those of local IGFs and that
IGFBP-1 is
one of the major secretory proteins of the primate decidua, the possibility that this IGFBP may have its own biological activity independent of IGF cannot be excluded. Evidently, elucidating the exact role of each IGFBP is an essential step into
understanding the whole IGF system. As such, further research in this area is awaited with a lot of anticipation and attention.
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