Estrogen-independent mechanisms for which there are both experimental and epidemiological supports involve insulin resistance, hyperinsulinemia, greater bioavailability of insulin-like growth factor-I (IGF-I), which represents the more relevant obesity-related growth factor, and dysregulation of insulin-like growth factor-I receptor (IGF-IR) downstream signaling pathways (22). Here, IGF1R is linked to obesity due to melanocortin 4 receptor deficiency.