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 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.(ABSTRACT TRUNCATED AT 400 WORDS)