2,3,7,8-tetrachlorodibenzo-p-dioxin increases the potency of androgens and estrogens as feedback inhibitors of luteinizing hormone secretion in male rats

Abstract

Tetrachlorodibenzo-p-dioxin (TCDD) decreases plasma androgen concentrations in male rats, without increasing plasma luteinizing hormone (LH) concentrations. If plasma LH concentrations had increased appropriately, plasma androgen concentrations in these animals would have returned to normal. The mechanism by which TCDD prevents the compensatory increase in plasma LH concentrations was therefore investigated. TCDD was found to have no effect on the plasma disappearance of iv administered LH. Therefore, the failure of plasma LH concentrations to rise was not due to increased clearance of LH from the circulation, but rather to an effect of TCDD on LH synthesis and/or secretion by the pituitary. In the absence of gonadal steroids (i.e., in castrated rats) TCDD did not prevent the compensatory increase in plasma LH concentrations from occurring. This was shown by 20-fold increases in plasma LH concentrations in both control and TCDD-treated rats 1 week after castration. Thus, (1) the presence of gonadal steroids is required for TCDD to prevent the compensatory increase in plasma LH concentrations, and (2) TCDD does not impair LH secretion by acting, itself, as an androgen or estrogen. TCDD treatment also did not affect pituitary LH content in castrated, testosterone-implanted rats. The above findings demonstrate that TCDD does not decrease the maximum rate at which the pituitary can synthesize and secrete LH. Rather, TCDD alters the feedback regulation of LH secretion when gonadal steroids are present. To determine if TCDD affects the potency of testosterone and its metabolites 5 alpha-dihydrotestosterone and 17 beta-estradiol as feedback inhibitors of LH secretion, rats were dosed with TCDD, castrated, and implanted with sustained-release capsules containing graded amounts of each steroid. Seven days later, the potencies of all three hormones as feedback inhibitors of LH secretion were increased by TCDD, with little effect on their plasma concentrations. The TCDD dose dependence for the increased effectiveness of testosterone as a feedback inhibitor of LH secretion (ED50 10 micrograms/kg) was similar to that reported for the imbalance between plasma LH and androgen concentrations (ED50 15 micrograms/kg). Also, time courses for both responses were similar; each was detected within 1 day of TCDD dosing and each was fully developed after 7 days. We conclude that the mechanism by which TCDD prevents the compensatory increase in plasma LH concentrations in male rats is by increasing the potencies of androgens (and estrogens) as feedback inhibitors of LH secretion.