The effect of the new opioid antagonist naltrexone-estrone azine (EH-NX) on pituitary luteinizing hormone (LH) secretion in the ovariectomized rat was studied. EH-NX is a hybrid between the steroid component estrone and the opioid antagonist naltrexone (NX). It is a potent and long-acting opioid antagonist in vitro and in vivo, but its effect upon in vivo LH secretion has not been tested before. The aims of the study were to investigate whether, unlike naltrexone, EH-NX can stimulate LH secretion without the need of additional estrogen pretreatment and whether EH-NX has peripheral estrogenic effects upon the uterine weight, when administered chronically to long-term ovariectomized rats. Female rats were injected subcutaneously with EH-NX 21 days after ovariectomy. The effects of EH-NX injections on LH secretion were compared to the effects of NX and estrone hydrazone (EH) alone, or in combination, with or without estradiol-benzoate (EB) pretreatment. Inhibition of LH secretion and uterine proliferation were observed in rats treated chronically with EH-NX in dosages of 0.250 mg/kg bw and higher. These effects were similar to those caused by EH and EB. In short-term OVX rats EH-NX appeared to act faster than EH. In contrast to NX, no stimulatory effect on LH secretion was seen with EH-NX in EB primed OVX rats. These results surprisingly demonstrate that EH-NX behaves like an estrogen and not like an opioid antagonist. The unexpected pharmacological profile of this new drug may open up doors for several medical applications.