Role of the Hypothalamo-Pituitary-Liver Axis in Sex Differences in Susceptibility of the Liver to Toxic Agents

Abstract

At birth testicular androgens irreversibly program brain centers involved in hypothalamopituitary control of hepatic sex-dependent steroid and drug metabolism. This imprinting process results in activation of a hypothalamic "feminostatin"-a secreting center that is turned on just before puberty. Feminostatin inhibits pituitary secretion of "feminizing factor," a pituitary hormone that feminizes the basal type of metabolism characterizing the liver of hypophysectomized and gonadectomized rats. Consequently, female rats that are devoid of feminostatin will secrete feminizing factor from the pituitary, leading to a feminine type of hepatic metabolism. Male rats have an active feminostatin-secreting center, and inhibition of pituitary feminizing factor release results in an autonomous type of liver metabolism. Female rats show a relative androgen unresponsiveness and seem incapable of releasing feminostatin after treatment with natural androgens, possibly because of more efficient metabolism (breakdown) of androgen in the female than in the male rat brain.Frontal deafferentation at the retrochiasmatic and suprachiasmatic level resulted in a complete "feminization" of hepatic steroid metabolism in male rats. Such an effect was also seen when lesions involving mainly the anterior periventricular hypothalamic area and the suprachiasmatic nucleus were performed in male rats. No effects were seen in analogous lesions in female rats in any of the cases studied. These findings suggest that a region including the anterior hypothalamic periventricular area, the suprachiasmatic nucleus and adjacent areas is involved in the control of hepatic steroid metabolism. It is postulated that the neuronal cell bodies that produce feminostatin have their origins in this area of the hypothalamus or may send axons through this area to the basal hypothalamus and thus directly or indirectly influence the anterior pituitary gland.Regulation by the central nervous system of a "lactogenic" (prolactin, Prl) receptor, present in the female rat liver, was also studied. This receptor is present in very low concentration or absent in the male rat. Anterior hypothalamic deafferentation at the retrochiasmatic level in male rats increased the hepatic Prl receptor concentration to the female level 3-4 days following the operation. A transection rostral to the suprachiasmatic nucleus had no effect on the concentration of Prl receptors in male animals. Our results demonstrate that the number of Prl receptors is regulated by the hypothalamo-pituitary system. The receptor-inducing pituitary factor might be related to the feminizing factor. Experiments were carried out to elucidate the nature of the Prl receptor-inducing pituitary factor. April 1981 129Human growth hormone (hGH) continuously administered was shown to induce Prl receptors in livers from male and female hypophysectomized-gonadectomized rats. The prolactin receptors were increased to a level found in control female rat livers. This inductive effect of hGH was also seen in adrenalectomized and...