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Pituitary Responses to Thyrotropin-Releasing Hormone after Treatment with the Breast Carcinogen Nitrosomethylurea: Inhibition of Prolactin but Not Thyrotropin Release^*

Thyroid Unit and Departments of Medicine and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address requests for reprints to: Dr. J. David Kieffer, Thyroid Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.

Abstract

N-Nitrosomethylurea (NMU) is a widely used experimental breast carcinogen. The present report describes the effects of NMU on the plasma PRL and TSH increases in response to exogenous TRH. Female Buffalo rats, 75–80 days old, were given a single ip injection of NMU (10 mg/100 g) or vehicle. At various times after injection, NMU-treated rats and vehicle-injected controls were tested with exogenous TRH (625 ng/100 g, ip). Groups of four to six rats were bled at 10, 20, 30, 45, and 60 min after TRH and at 10 min after saline (baseline group). The response to TRH (A) was determined by subtracting the mean plasma PRL or TSH level of the baseline group from the mean peak level observed after TRH. For four separate control experiments, PRL averaged 104± 19 ng/ml (mean± SE). At 20 h, 42 h, 6 days, and 2, 3,4, 8, and 12 weeks after NMU, PRL was 87, 0, 0, 16, 10, 3, 49, and 65 ng/ml, respectively. PRL was statistically significant in all four control experiment, and remained significant at 20 h after NMU. However, from 42 h through 4 weeks, no significant PRL occurred. A significant PRL reappeared at 8 and 12 weeks, the approximate time of appearance of the first palpable breast cancers. Pituitary PRL concentrations (micrograms PRL per mg protein) were significantly lower in NMU-treated groups than in vehicle-treated controls at 42 h, 3 weeks, and 12 weeks. In contrast to its marked inhibitory effect on APRL, NMU had no effect on TSH. This is consistent with the hypothesis that treatment with NMU resulted in a selective impairment of pituitary PRL-secreting cells. Moreover, our data show that the plasma PRL response to TRH was inhibited at times after NMU when pituitary PRL was not significantly depleted. This observation is in accord with the concept of impairment of either TRH receptor binding or events which couple receptor binding and hormone release.

Footnotes

^* A preliminary account of this research was presented as Abstract 655 at the 63rd Annual Meeting of The Endocrine Society, Cincinnati, Ohio, 1981. This work was supported by American Cancer Society Grant BC-293 and USPHS Grant AM-16791.

Received October 30, 1981.