CHRONIC ADMINISTRATION OF THE LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) ANTAGONIST CETRORELIX DECREASES GONADOTROPE RESPONSIVENESS AND PITUITARY LHRH RECEPTOR MESSENGER-RIBONUCLEIC-ACID LEVELS IN RATS
J. Pinski et al., CHRONIC ADMINISTRATION OF THE LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) ANTAGONIST CETRORELIX DECREASES GONADOTROPE RESPONSIVENESS AND PITUITARY LHRH RECEPTOR MESSENGER-RIBONUCLEIC-ACID LEVELS IN RATS, Endocrinology, 137(8), 1996, pp. 3430-3436
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.