Alterations in Hypothalamic Insulin‐Like Growth Factor‐I and its Associations with Gonadotropin Releasing Hormone Neurones During Reproductive Development and Ageing

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Abstract
Insulin-like growth factor-I (IGF-I) is thought to play a role in the onset of reproductive ability at puberty and the control of reproductive function throughout adult life. It is believed that these effects are mediated at least in part by the activation of gonadotropin releasing hormone (GnRH) neurones by IGF-I, but the interactions of IGF-I with GnRH neurones in vivo are largely unknown. We first examined the anatomical relationship between GnRH and IGF-I cells in neuroendocrine regions. Using double-label immunocytochemistry, we observed that in the preoptic area-anterior hypothalamus (POA-AH), the site of GnRH perikarya, the majority (78%) of GnRH cell bodies expressed IGF-I immunoreactivity. IGF-I immunoreactivity was also high in the median eminence, the site of GnRH release, and GnRH neuroterminals were seen to interweave among IGF-I-immunopositive cells. Due to this substantial overlap of GnRH and IGF-I immunoreactive elements, we then tested the hypothesis that changes in IGF-I may regulate the GnRH system. Animals were examined at the two important reproductive life transitions: puberty and reproductive senescence. IGF-I mRNA levels were measured in POA-AH and medial basal hypothalamus-median eminence (MBH-ME) and effects of IGF-I treatment on GnRH mRNA levels were quantified by RNase protection assay. Although IGF-I treatment did not alter GnRH gene expression, there were significant alterations in hypothalamic IGF-I gene expression at both puberty and reproductive senescence. During puberty, IGF-I mRNA levels in the MBH-ME of rats increased from the juvenile stage (P25) to the day of vaginal opening (P35), and from the day of vaginal opening to young adulthood (P45) in the POA-AH. During reproductive ageing, IGF-I mRNA levels were significantly lower in middle-aged than young rats, particularly in the MBH-ME. At all ages, IGF-I expression was greater in the MBH-ME than in the POA-AH. These experiments demonstrate that: (i) the majority of adult GnRH neurones are immunopositive for the IGF-I protein; (ii) hypothalamic IGF-I levels increase at the onset of reproductive function and decrease at reproductive senescence in a regionally specific manner; and (iii) despite the presence of IGF-I in GnRH perikarya, IGF-I does not affect GnRH gene expression, suggesting that IGF-I may act at the level of GnRH release rather than gene expression.

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