Physiology: Insulin-like growth factor (IGF), IGF binding protein (IGFBP), and IGF receptor gene expression and IGFBP synthesis in human uterine leiomyomata

Oestradiol is important in the growth of uterine leiomyomataand may act primarily or secondarily through mediators suchas growth factors, including the insulin-like growth factors(IGF-I and IGF-II), mitogenic peptides. IGF binding proteins(IGFBPs) modulate IGF actions at their target cells. The objectiveof this study was to examine the possible steroid dependenceof IGF, IGFBP and IGF receptor gene expression and IGFBP synthesisin uterine leiomyomata, using tissues from women cycling normallyand made hypo-oestrogenic by a gonadotrophin-releasing hormoneagonist (GnRHa). Using a solution hybridization ribonucleaseprotection assay, anti-sense RNA probes for IGF-I, IGF-II and-actin (control) were hybridized with total RNA isolated fromleiomyomata exposed in vivo to a range of serum oestradiol (<40–240pg/ml) and progesterone (0–10 ng/ml) concentrations. IGF-Igene expression was most abundant in leiomyomata obtained duringthe late proliferative phase of the cycle and was undetectablein leiomyomata from hypo-oestrogenic patients. IGF-II gene expressionwas not dependent on endogenous steroid concentrations or cyclestage. IGFBP gene expression was investigated by Northern blotting.The order of relative abundance of IGFBP mRNAs was IGFBP-4 >> > IGFBP-3 > > IGFBP-5 > IGFBP-2 and was notdependent on the in-vivo oestrogen status. Type I and type IIIGF receptor gene expression was investigated by polymerasechain reaction using gene-specific primers. Type I and typeII IGF receptor mRNAs were detected in leiomyomata and werenot dependent on cycle stage or in-vivo oestrogen status. Explantcultures of leiomyomata and myometrium synthesized IGFBP-3 (mol.wt = 38–43 kDa), IGFBP-4, and binding proteins of mol.wt = 34 and 31 kDa. Identification of IGFBP-2 was inconclusive,and IGFBP-1 was not detected. These data support the hypothesisthat IGF-I, but not IGF-II, may be a mediator of oestradiolaction in the growth of uterine leiomyomata, and that IGFBPsmay further modulate, by an autocrine or paracrine mechanism,IGF-I action in this tissue.