Physiological insulin resistance and hyperinsulinemia occurs at the onset of puberty, and is thought to contribute to peri-pubertal growth and development. However, in contrast to IGF-1, little is known about how insulin affects the hypothalamic-pituitary-ovarian (HPO) axis in peri-pubertal girls. Insulin has mitogenic and metabolic activity through splice-variant isoform receptors IR-A and IR-B, respectively. We hypothesize that insulin signaling in HPO tissues contributes to the initiation of puberty, and sought to determine whether IR isoform expression is differentially regulated during puberty.

We evaluated female, FVB/NJ mice: pre-pubertal, 3-4 week old mice (n=4) and peri-pubertal mice (n=7) identified within 24 hours of vaginal opening, an external marker of puberty. IR-A, IR-B, IGF-1R were quantified using a qRT-PCR assay previously validated for receptor comparison. Receptor expression was analyzed by Student’s t-test after log transformation.

IR-A was the predominant IR isoform in the prepubertal hypothalamus, pituitary, and ovary, in a 20:1, 10:1, and 2:1 ratio with IR-B, respectively (p<0.05, all). At puberty, IR-A did not change in the hypothalamus, whereas IR-A increased by 3.6-fold (p=0.059) in the pituitary. IR-B remained largely unchanged during puberty in both the hypothalamus and pituitary (p=NS, respectively). Interestingly, in the peripubertal ovary which has active folliculogenesis and steroid hormone synthesis, both IR-A and IR-B decreased by 33% and 68%, respectively (p<0.03). As expected, IGF-1R levels were higher than IR isoforms in HPO tissues, at both developmental stages. Similar to mitogenic IR-A, IGF-1R increased in the pituitary (p<0.059) during puberty.

An increase in pituitary IR-A expression at the onset of puberty suggests a role for insulin signaling in regulating pituitary hormone production related to puberty. Obesity, a known risk factor for early puberty development in girls, may alter normal insulin signaling in the HPO axis.


F. Saleh: None. H.S. Taylor: None. C. Flannery: None.

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