Chronic periadolescent leuprolide exposure affects the expression of multiple genes in the hypothalamus and pituitary gland with a different pattern of expression in female and male Long-Evans rats

Protracted exposure to drugs like Lupron Depot® suppresses pubertal development. How the brain responds and develops in the face of pharmacological suppression is not well understood. The present study tested the effects of daily leuprolide acetate (LEU) treatment (50 μg/kg, postnatal day (PD) 25–50) on gene expression (Kiss1, Esr1, Esr2, Ar, Gnrh1, Gnrhr) in the hypothalamus and pituitary of female and male Long-Evans rats using real-time PCR. Brains and trunk blood were harvested on PD 50. In the pituitary gland of both sexes, expression of Esr2 and Gnrhr expression was higher in LEU-treated rats than in saline controls. Esr1 expression in females was lower and Ar expression in males was higher in LEU-treated rats than saline controls. In the preoptic area of the hypothalamus in male rats, Kiss1 expression was significantly lower in LEU than in saline controls. In the mediobasal hypothalamus, Gnrh1 and Kiss1 expression was higher in LEU-treated male rats than in saline controls; for females, only Kiss1 was increased by LEU. Serum gonadal hormone levels were not significantly different in LEU-treated rats than saline controls at the end of treatment, although hormones trended lower in the LEU-treated rats. LEU affected expression of genes involved in reproduction, potentially explaining sex-specific effects of LEU on behavior reported earlier. The changes in hypothalamic and pituitary gene expression may represent compensation that permits early stages of pubertal development (e.g., VO and PPS), but not complete maturation (e.g., estrous cyclicity, sexual behavior) during LEU treatment.