The hypothalamus-pituitary-thyroid axis was studied in rats with the "low T(3) syndrome" caused by the implantation of the Walker-256 mammary carcinoma. Male adult rats were injected s.c. with 1 x 106 viable tumoral cells and killed 10 days later. The tumor development was associated with decreased thyroid activity characterized by a approximately 15% reduction in the nuclear area of the thyrocytes and 131I-thyroid uptake (down by approximately 50%), as well as about 70% lower serum levels of T4 and rTg. The functional thyroidal response to exogenous TSH was decreased in the tumor-bearing rats, as well as the rTSH secretion in response to TRH (50 microg/kg). To investigate the role of other hypothalamic neuromediators in this process, tumor-bearing rats received an i.v. injection of metoclopramide (5 mg/kg) and/or physostigmine (12.5 microg/kg), with or without concomitant stimulus with TRH. Each drug improved the rTSH response to TRH, which in the case of physostigmine, almost normalized. When both drugs were injected simultaneously the rTSH response to TRH returned to normal. Thus, in addition to the well known alterations in the extrathyroidal metabolism of thyroid hormones, TSH secretion is decreased in rats with the Walker-256 tumor, indicating a generalized reduction in the thyroid function.