After the heart and estrogen/progestin replacement study and the women's health initiative study, the prospect of hormone replacement therapy (HRT) on cardiovascular diseases (CVD) has changed dramatically. These findings led to various attempts to search for alternatives for classical HRT, e.g. phytoestrogens. The flavanone 8-prenylnaringenin (8-PN) was identified as a phytoestrogen with strong estrogen receptor-alpha activity. As the pituitary and the liver are targets for estrogen action, we assessed the effect of ovariectomy (OVX) and long-term treatment (3 months) with 17-beta estradiol benzoate (E(2)B) and 8-PN on pituitary and liver functions in adult OVX rats. Tested doses were 6.8 and 68.4 mg/kg body weight (BW) of 8-PN and 0.17 and 0.7 mg/kg BW of E(2)B. Our results demonstrate that 8-PN and E(2)B decreased BW and increased uterus weight. The high doses of E(2)B and 8-PN increased serum GH and decreased serum IGF-1 levels. E(2)B dose dependently decreased cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) concentrations in OVX rats. The high dose of 8-PN showed an estrogenic activity regarding cholesterol and LDL regulation but had no effect on HDL concentrations. By contrast, the low dose of 8-PN augmented HDL levels compared with intact rats. Triglyceride levels were raised in response to the high E(2)B dose but unaffected by 8-PN treatment. Taken together, 8-PN displays an anti-atherosclerotic profile that appears to be even more beneficial than the one displayed by E(2)B, and thus might demonstrate a remarkable potential for the prevention of CVD associated with estrogen deficiency.