Identification of a new target tissue for growth hormone: the placenta.
Doctoral thesis, UCL (University College London).
Growth hormone variant (GH-V) is expressed in the human placenta. Placental GH-V is not produced in rodents, but pituitary GH production is increased in pregnancy. In both cases, pulsatile GH secretion is replaced by a more continuous GH pattern. The placenta also expresses GH receptors, so it itself could represent a target tissue for direct GH action. GH effects are mediated in part via the JAK/Stat5b pathway, and detection of phosphorylation and nuclear translocation of Stat5b can be used to identify cells responding directly to GH in vivo. I have now tested whether the rodent placenta shows Stat5b responses to GH in vivo. This has been studied under basal conditions, following continuous GH replacement, and during fasting, with or without insulin injection. Following a single iv injection of recombinant bovine GH (bGH) in female dwarf rats or GHRH-M2 GH-deficient mice, tissues were processed for phospho-Stat5 (pYStat5) immunocytochemistry. As expected, both non-pregnant and pregnant animals showed marked hepatic pYStat5 responses. Notably, pYStat5 responses were also seen in placental syncytiotrophoblast cells in response to injections of GH but not saline. GH exposure during pregnancy is continuous, and it has previously been shown in male dwarf rats that continuous GH exposure is much less effective in inducing hepatic Stat5 phosphorylation, and blunts the pYStat5 response to a GH pulse. Pregnant rats receiving continuous bGH, showed an increased cellular pYStat5 staining compared to saline controls. However, like in the male rats, the response to GH was blunted following continuous exposure. Fasting is known to impair GH effects, with lower pYStat5 responses in target tissues. GH-induced pYStat5 responses were reduced in fasted animals, a single injection of insulin was able to restore the response to GH during the continuing state of fasting, however, this was variable depending on the extent of endogenous GH. GH deficiency was also associated with reduced litter size, average pup and placental weights. A preliminary microarray analysis was carried to identify potential GH target genes in the placenta. A few well known GH target genes or placental genes containing potential Stat5b response elements showed no change in response to GH or a change in secretory pattern. However, some novel genes were identified as GH-responsive and might be important in growth during pregnancy. In conclusion, my results show that the placenta is a direct target for GH, but what role this plays in placental function or fetal growth remains to be determined.
|Title:||Identification of a new target tissue for growth hormone: the placenta|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Funded by the MRC and undertaken at the MRC National Institute for Medical Research|
Archive Staff Only