Altered regulation of pituitary gonadotropin-releasing hormone (GnRH) receptor number and pituitary responsiveness to GnRH in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated male rats.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases the potency of androgens as feedback inhibitors of luteinizing hormone (LH) secretion. Our objectives were to determine if this increase is due to pituitary or hypothalamic dysfunction (or both), and to investigate the mechanism by which TCDD produces this effect. Seven days after dosing, TCDD inhibited the compensatory increases in (i) pituitary gonadotropin-releasing hormone (GnRH) receptor number, (ii) LH secretory responsiveness of the pituitary to GnRH, and (iii) plasma LH concentrations which should have occurred in response to TCDD-induced decreases in plasma testosterone concentrations. TCDD did not inhibit these compensatory responses in the absence of testicular hormones, while treatment of castrated rats with testosterone restored the ability of TCDD to prevent these increases. These findings demonstrate that TCDD alters the androgenic regulation of pituitary GnRH receptor number and pituitary responsiveness to GnRH stimulation. The pituitary is therefore a target organ for TCDD; whether a hypothalamic defect is also involved in the altered regulation of LH secretion was not resolved. The compensatory increases in pituitary GnRH receptor number and plasma LH concentration elicited by low plasma testosterone concentrations were inhibited by similar doses of TCDD (ED50 20 micrograms TCDD/kg for both responses). We concluded that TCDD increases the potency of androgens as feedback inhibitors of LH secretion by increasing their potency as regulators of both pituitary GnRH receptor number and GnRH responsiveness. This is the first demonstration that TCDD treatment (i) affects pituitary responsiveness to a hormone secreted by a peripheral organ (testosterone), and (ii) alters the regulation of pituitary responsiveness to a hypothalamic hormone (GnRH).
Bookstaff
R C
RC
School of Pharmacy, University of Wisconsin, Madison 53706.
Kamel
F
F
Moore
R W
RW
Bjerke
D L
DL
Peterson
R E
RE
D000728:Androgens / Q000502:physiology*; D000818:Animals; D004147:Dioxins / Q000494:pharmacology*; D005246:Feedback / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D009919:Orchiectomy; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011966:Receptors, LHRH / Q000187:drug effects*; D013739:Testosterone / Q000097:blood / Q000494:pharmacology
D000728:Androgens; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone