CHRONIC ADMINISTRATION OF THE LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) ANTAGONIST CETRORELIX DECREASES GONADOTROPE RESPONSIVENESS AND PITUITARY LHRH RECEPTOR MESSENGER-RIBONUCLEIC-ACID LEVELS IN RATS

Continuous exposure to LHRH or its agonistic analogs results in a redu ction of LHRH receptor sites and messenger RNA (mRNA) transcripts as w ell as in desensitization of the pituitary gonadotropes. To determine, whether LHRH antagonists might be similar in this respect to the agon ists, we treated male rats for 4 weeks with daily sc injections of LHR H antagonist [Ac-D-Nal(2),Phe(4Cl)(2),D-Pal(3)(3), D-Cit(6),D-Ala(10)] LHRH (Cetrorelix acetate) or LHRH agonist, [D-Trp(6)]LHRH, in doses of 100 mu g/animal . day. Another group of rats received a single im inj ection of 4.5 mg Cetrorelix pamoate depot, a sustained delivery formul ation of the LHRH antagonist. An iv stimulation test with LHRH (200 ng /rat) was performed after 4 weeks of treatment. The rats were killed, and pituitary LHRH receptor characteristics mere measured by RRA. To e xamine the effect of LHRH antagonist treatment on the expression of th e pituitary LHRH receptor gene, some of the rats injected with Cetrore lix pamoate depot were killed after 2 weeks, and levels of LHRH recept or mRNA were determined by Northern blot and dot blot hybridization to a P-32-labeled rat complementary DNA probe. Our data show that LHRH-s timulated LH secretion at 30 min was suppressed by approximately 33% ( P < 0.01) in rats pretreated with [D-Trp(6)]LHRH compared to that in a nimals injected with LHRH alone. Pretreatment of the rats with the LHR H antagonist suppressed the LH response to LHRH more markedly; the LH levels at 30 min were decreased by 89.8% and 96% in groups treated wit h Cetrorelix acetate and Cetrorelix pamoate depot, respectively. The t estosterone response was virtually abolished in groups receiving Cetro relix. The concentration of pituitary receptors for LHRH fell by 69% i n the [D-Trp(6)]LHRH group, whereas the reductions in the Cetrorelix a cetate group and in the group that received Cetrorelix pamoate depot w ere 77% and 82%, respectively. Treatment with Cetrorelix pamoate depot led to a 75-80% decrease in the levels of 5.0- and 4.5-kilobase forms of LHRH receptor mRNA compared to those in the control group. Dot blo t analysis also showed 83% reduction in the mRNA for LHRH receptor. In conclusion, these data demonstrate that prolonged administration of L HRH antagonists such as Cetrorelix causes an impairment of gonadotropi n secretion and a marked decrease in the levels of LHRH receptors as w ell as in the expression of the LHRH receptor gene. Thus, the downregu lation of pituitary LHRH receptors produced by LHRH antagonists appear s to be similar to that resulting from the agonists.