Elevated Free IGF-I Levels in Prepubertal Hispanic Girls with Premature Adrenarche: Relationship with Hyperandrogenism and Insulin Sensitivity

Abstract

Girls with premature adrenarche (PA) (the onset of pubic hair before the age of 8 yr associated with elevated levels of adrenal androgens and no evidence of true puberty or adrenal dysfunction) may be at increased risk for development of polycystic ovarian syndrome (PCOS). Alterations in the IGF system, including elevated free IGF-I, have been demonstrated in PCOS and may be involved in its pathogenesis. Hyperinsulinemia, elevated total IGF-I, and decreased IGF-binding protein-1 (IGFBP-1) have also been reported in PA. Dysregulation of the IGF system may be involved in the pathogenesis of PA and its progression to PCOS. We compared the insulin/IGF system in 17 prepubertal girls with PA and nine prepubertal controls. Both groups were predominantly obese. Total and free IGF-I were elevated in the premature adrenarche group. No differences in basal insulin, insulin area under the curve in response to an oral glucose tolerance test, or IGFBP-1 were noted. These effects persisted when adjusted for adiposity using body mass index-Z score. Total and free IGF-I were positively correlated, and IGFBP-1 was negatively correlated with Delta4-androstenedione, but not with dehydroepiandrosterone sulfate. Free IGF-I trended toward higher levels in the insulin-resistant subgroup, compared with the insulin-sensitive subgroup. These results suggest altered regulation of the insulin/IGF system in prepubertal girls with PA and a possible role for free IGF-I in the pathogenesis of the hyperandrogenism of PA as well as its progression to PCOS.

Adrenals

“…The early growth acceleration supports Ken Ong's findings in a population-based investigation of postnatal growth and DHEA-S [32]. The elevated IGF-1 findings supports data from Silfen et al [33]. The causes of adrenarche are poorly understood but this study suggests that early events such as growth acceleration and IGF-1 production may be linked with it and could be causative.…”

Opposing Influences of Prenatal and Postnatal Weight Gain on Adrenarche in Normal Boys and Girls

“…It has been suggested that increased IGF-I or insulin activity stimulates serine phosphorylation of P450c17, which by increasing 17,20-lyase activity promotes adrenal androgen production and could stimulate adrenarche (21). Case control studies have reported that IGF-I and insulin levels are higher in girls (22,23) and boys (24) with premature adrenarche than in control children. In these ALSPAC children, the combination of low birth weight and rapid weight gain in early postnatal life predicts increased total and central adiposity at age 5 yr (7), higher IGF-I levels at age 5 yr (25), and lower insulin sensitivity at age 8 yr (26).…”

Premature adrenarche: novel lessons from early onset androgen excess

“…From a mechanistic point of view, this hypothesis seems to be plausible as insulin and insulin-like growth factors (IGF1 and IGF2) are able to stimulate steroidogenesis in human foetal and adult adrenal cells in vitro (101,102). Low levels of IGF binding protein 1 (IGFBP1) would increase the amount of active unbound IGF1, and several studies in children with PP have described disturbances in the IGF system (77,83,103,104). However, a recent meta-analysis examining the available evidence for a decrease in IGFBP1 in PCOS patients concluded that IGFBP1 levels inversely correlate with BMI and thus are primarily associated with obesity rather than androgen excess (105).…”