Blockade of the LH response induced by the agonist D‐Trp‐6‐LHRH in rats by a highly potent LH‐RH antagonist SB‐75

J. Pinski, T. Yano, G. Miller, A. V. Schally

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


During treatment of prostate cancer patients with luteinizing hormone- releasing hormone agonist, a transient LH and sex steroid release, which precedes the secretion blockade, may result in a flare-up of the disease, whereas the antagonists induce an immediate suppression. The administration of the modern, superactive LHRH antagonist SB-75 before or together with the agonist D-Trp-6-LHRH should prevent the 'flare-up' phenomena. In order to demonstrate that the LHRH antagonist can prevent the initial stimulation of gonadotropins in response to LHRH agonists, groups of 5-7 male rats were injected s.c. with the antagonist SB-75 in doses in 100, 500, and 1,000 μg/rat 1 hour prior to or 1, 2, and 3 days before administration of D-Trp-6- LHRH agonist (50 μg/rat). Supraphysiological doses of the agonist were used in order to obtain prolonged stimulation of LH release, which was necessary to study the duration and the extent of LH release inhibition. Blood samples were taken before and 2, 6, 24, 48, and 72 hours after D-Trp-6-LHRH stimulation for measurement of LH levels. The administration of SB-75 in doses of 500 and 1,000 μg/rat 3 days prior to administration of the agonist significantly lowered LH response (P < 0.01), as compared to animals injected with D-Trp-6-LHRH alone. The D-Trp-6-LHRH-stimulated LH secretion was markedly more suppressed by all 3 doses of the antagonist in rats pretreated with SB-75 2 days prior to the stimulation with the agonist. An even greater reduction in LH response could be observed in rats injected with SB-75 1 day prior to the agonist, the magnitude of LH response being decreased by 75% with 500 μg/rat SB-75 and by 90% with 1 mg/rat SB-75. The LH response was virtually abolished when the antagonist, SB-75 was given in doses of 500 or 1,000 μg/rat 1 hour prior to the D-Trp-6-LHRH injection. Under these conditions, the agonist-induced LH and testosterone secretion was completely suppressed during the whole period of the experiment. The antagonist to agonist dose ratio of 2 to 1 produced a 90% decrease in the LH response to D- Trp-6-LHRH at 2 hours and 75% at 5 hours after agonist administration. The effects of LHRH decapeptide itself (500 μg/rat) on LH secretion could be totally suppressed by an injection of 50 μg/rat of SB-75 1 hour beforehand. Likewise, the response to leuprolide (100 μg/rat) was suppressed more than 90% by an injection of 500 μg/rat of SB-75. These findings indicate that pretreatment with the LHRH antagonist SB-75 1 hour before the agonists can completely prevent the elevation of LH. Since a 10-fold lower dose of SB-75 than of LHRH suppressed the LH response, this reflects the higher affinity of SB-75 to pituitary LHRH receptors. Exclusive or combined use of a modern LHRH antagonist such as SB-75 with LHRH agonist, at an appropriate schedule, may lessen the risk of tumor flare in patients.

Original languageEnglish (US)
Pages (from-to)213-224
Number of pages12
JournalThe Prostate
Issue number3
StatePublished - 1992
Externally publishedYes


  • LH suppression
  • LH‐RH agonist
  • LH‐RH antagonist
  • flare‐up in disease

ASJC Scopus subject areas

  • Oncology
  • Urology


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