This work (62) originated with the observation that there was a very high incidence of abortion in rats subjected earlier to section of the portal vein and which subsequently had become pregnant. The experiments demonstrated that elimination of blood flow through the liver via the portal vein always led to disturbed sexual function in female rats and that the changes were often drastic in magnitude.

After portal vein section no female rat of either Sprague-Dawley or Long-Evans strain had normal sexual function. Disturbances were always seen in the rhythm of the sexual cycle and, in most rats, in the ability to support normal pregnancy. After portal vein section, many rats were flooded with amounts of steroid hormones, which were excessive for the normal physiological economy. In some rats the predominating hormones had androgenic properties; in other animals excessive amounts of estrogens prevailed; in a third group large amounts of several classes of steroids seemed to be present.

The administration of testosterone or related compounds to female rats induces characteristic changes. Among these are (a) increased growth rate; (b) pigmentation of skin; (c) growth of nipples; (d) hyperplasia of mammary glands; (e) growth of the vestigial prostate; (f) enlargement of preputial glands; (g) persistent diestrus; (h) mucification of the vaginal epithelium. Many rats subjected to portal vein section manifested all these effects.

Other rats had persistent estrus which was sustained continuously for many days. They refused to accept the male. The vaginal epithelium was keratinized, and the uterus was large and ballooned with fluid. These are manifestations which follow the administration of effective amounts of phenolic estrogens to rats.

Disturbed ovarian function is not due to deleterious venous congestion with back pressure in the ovary caused by ligation of the portal vein, for the ovarian veins drain into the inferior vena cava rather than the portal system. Second, ligation of the ovarian veins caused no significant changes in ovarian function.

Following portal vein section, infarcts in the liver were not observed, and there were no remarkable histologic differences from normal liver. Indeed, no great changes were detected in the liver except that the content of ether-extracted lipids was diminished about one-half. After portal vein section there was no significant difference from normal hepatic values of the soluble enzymes which were studied. These included dehydrogenases in the Krebs cycle (isocitric and malic dehydrogenases), in the Warburg pentose pathway (G-6-PD; 6-PGD), or in the Embden-Meyer-hof-Parnas pathway (LAD). Also, there were no significant changes in the concentrations of hepatic hydrolytic enzymes (β-glucuronidase; acid and alkaline phosphatases). Certainly the liver was not profoundly damaged following section of the portal vein.

The threshold dosage of estrogens required to exert a physiological effect was lowered in the portal vein sectioned series. Significandy smaller doses of stilbestrol, administered by mouth, were required in the portal vein sectioned series of ovariectomized rats than were needed to produce estrus in mates with an intact portal vein.

The evidence points to the conclusion that rapid passage of blood through the liver is necessary to conjugate excessive amounts of ovarian steroids and that the normal portal vein is an essential unit in this mechanism. It is a newly recognized principle of endocrinology that a gland (ovary) is forced to secrete excessive amounts of hormones to compensate for their partial inactivation by a filter (liver) before reaching the targets in which they promote growth.

The results of the experiments demonstrating disturbances in reproductive function after interruption of the portal vein are the converse of those in which the ovary is implanted in the spleen. In the experiments of the Biskinds (Proc. Soc. Exper. Biol. & Med., 55:176,1944), function of the ovary is abolished after its intrasplenic implantation because the transport of ovarian steroids through the portal vein causes their rapid inactivation in the liver. In the present work (62), lack of integrity of the portal vein prevents the transport of growth-promoting steroids to the liver with sufficient rapidity to inactivate excessive amounts so that disturbed function results in the reproductive tract.

Section of the portal vein of the rat provides a novel, simple, and useful method for the experimental study of abortion. The animals are healthy, are not unusually prone to infection or other intercurrent illnesses, and the difficulties in conception or in maintenance of pregnancy are due to changes of several sorts in the hormonal status of the female rats.

In summary, integrity of the portal vein is a condition for normal function of the reproductive tract in female rats. Section of the portal vein always abolished periodic sexual function. In a series of 23 animals, 6 developed continuous estrus and other signs of the presence of excessive amounts of estrogenic hormones; yet the ovaries of these rats were small. In 6 other rats there was growth of the prostate and additional evidence of increased activity of androgenic hormones. Many rats failed to become pregnant, and nearly all pregnant rats aborted. Except for a decrease in lipid content, the composition of the liver of portal vein sectioned rats resembled that of intact mates in the criteria which were applied.

The rapid passage of blood through the liver is necessary to conjugate the excessive amounts of steroids which the rat ovary normally produces, and an intact portal vein is an essential unit in the mechanism necessary for their partial inactivation.