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Ovariectomy Accelerates the Growth of Microscopic Hepatocellular Neoplasms in the Mouse: Possible Association with Whole Body Growth and Fat Deposition¹

Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin 53706

Ovariectomy (ovex) shortens the latency for development of hepatocellular neoplasms in mice, but the mechanism by which this occurs is not known. In the present study, B6C3F₁ mice were given single i.p. injections of diethylnitrosamine (5 mg/kg) when they were 15 days old and either ovexed or sham operated 7 weeks later. Groups of 6 to 8 mice were killed after an additional 8, 14, 20, and 26 weeks. Four ovexed and four sham-operated mice were also killed after 56 weeks. By 8 weeks after surgery, the fractional volume of microscopic liver neoplasms in the ovexed mice was 4.3 times greater than in the shams and ablation had caused a 27% greater gain in body weight. During the following 18 weeks, tumor burdens were 3.9 to 10.6 times greater in the ovexed than in the sham-operated mice and the rates of weight gain were similar in the two groups. Stereological analysis indicated that ovexed animals had more tumors than sham-operated animals, 575 versus 234/liver at 8 weeks and 952 versus 724/liver at 14 weeks after surgery. The ovex-induced increase in the number of neoplasms was spread throughout most of the size classes at both times; however, the impact on tumor burden of a small number of large tumors was only apparent at 14 weeks, when 8% of them accounted for more than two thirds of the aggregate tumor volume. The effect of the early emergence of these more rapidly growing tumors was also obvious at 1 year, when the livers of ovexed mice were more than twice the size of the shams (5.1 versus 1.8 g) and they contained 4 times as many tumors larger than 1 cm in diameter than the shams (2 versus 0.5/mouse). Since these very large tumors were invariably, at least partially, composed of trabecular hepatocellular carcinoma, ovariectomy appears to have also fostered tumor progression.

The time course of ovex-stimulated weight gain and the manner in which it affected body composition were also analyzed. Eight days following ovex, the rate of weight gain abruptly increased. The acceleration persisted for only 14 days, after which it leveled off at body weights that were 24% higher than in sham-operated mice. The difference in weights resulted from 2.5 times more fat and 10% more protein in the carcasses of ovexed than sham-operated mice.

This study identifies an early 8-week period in which hormonal changes resulting from ovex maximally stimulate the growth of liver tumors. The acceleration might be confined to the even shorter 2-week interval during which ovex induced an increase in body weight.

¹ Supported by NIH Grant ES03616 (CA51549).

² To whom requests for reprints should be addressed.

Received 4/19/90. Accepted 8/ 2/90.

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