The antigonadal activity of potent gonadotropin-releasing hormone (GnRH) analogs may be associated with undesirable secondary effects on other aspects of the endocrine system. In preliminary studies, rats treated with GnRH agonists were noted to have altered adrenal weights. To determine whether this was associated with alterations in the pituitary-adrenal axis we have studied male and female rats treated with the GnRH agonist [(imBzl)-D-His6, Pro9-NEt]-GnRH (GnRH-A). Animals receiving daily doses of this peptide showed normal adrenal corticosteroid responsivity to both ether and immobilization stress. Brain, pituitary, and plasma concentrations of immunoreactive (IR) beta-endorphin and ACTH were unaffected in treated animals after four weeks of daily injections, although after one week plasma levels of the two hormones were transiently elevated in female rats. Adrenal, thyroid, and pituitary lobe weights were unchanged with treatment, except for an increase in anterior pituitary weight in males receiving the lowest dose of GnRH-A. In conclusion, long-term treatment with GnRH-A, while significantly affecting gonadal and secondary sexual tissue, had little impact on the hypothalamo-pituitary-adrenal system or on stress responsivity in rats.