The actions of luteinizing hormone-releasing hormone agonists, antagonists, and cytotoxic analogues on the luteinizing hormone-releasing hormone receptors on the pituitary and tumors

A. V. Schally, G. Halmos, Z. Rekasi, J. M. Arencibia-Jimenez

Research output: Contribution to journalReview articlepeer-review

31 Scopus citations


Agonists of LHRH have important clinical applications in gynecology and oncology. Potent antagonists of LHRH, such as Cetrorelix, that are suitable for clinical use are also available. In addition, cytotoxic analogues of LHRH that can be targeted to LHRH receptors on tumors have been developed. The actions of LHRH and its analogues are mediated by high-affinity receptors for LHRH found on pituitary gonadotrophs and various tumors. The mechanism of action of LHRH analogues is illustrated in Figure 8. Sustained stimulation of the pituitary with LHRH agonists produces inhibition of the hypophyseal-gonadal axis through a process of down-regulation of pituitary receptors for LHRH. This observation provides the basis for clinical applications of LHRH agonists in gynecology and oncology. The administration of agonists of LHRH into rats and sheep also causes a decrease in the levels of mRNA for pituitary receptors for LHRH. In cultures of pituitary cells, high doses of LHRH agonists can induce a down-regulation of LHRH binding sites and a decrease in mRNA for pituitary LHRH receptors. Antagonists of LHRH produce a competitive blockade of LHRH receptors and cause an immediate inhibition of the release of gonadotropins and sex steroids, reducing the time of the onset of therapeutic effects as compared with agonists. LHRH antagonists such as Cetrorelix already have major uses in gynecology and oncology and seem to have various advantages over the agonists. Our studies show that the administration of Cetrorelix to rats produces a significant down-regulation of pituitary membrane receptors for LHRH. Receptor assays carried out following in vitro desaturation of LHRH binding sites with chaotropic agents have confirmed that the LHRH antagonist Cetrorelix causes a clear down-regulation of pituitary receptors for LHRH and not merely an occupancy of binding sites. A major decrease in mRNA levels for the pituitary LHRH receptor in vivo and in vitro was also found following treatment with Cetrorelix. Some clinical results suggest that LHRH antagonists may lead to pituitary down-regulation, and this observation should be taken into consideration when planning therapy with LHRH antagonists. Direct inhibitory effects of high doses of LHRH agonists and antagonists on prostatic, mammary, ovarian, and endometrial cancer cells have been demonstrated in vitro. The presence of high-affinity binding sites for LHRH and the expression of mRNA for LHRH receptors have also been shown in human prostate, mammary, ovarian, and endometrial cancers. The LHRH antagonist Cetrorelix inhibits the growth of human prostatic, mammary, and ovarian cancers xenografted into nude mice better than the agonist [D-Trp6]LHRH. During in vivo therapy with Cetrorelix and LHRH agonists, a reduction occurs in the levels and mRNA expression of the receptors for LHRH, EGF, and IGF-I in these tumors, which could be of clinical importance. The decreases in levels and mRNA of IGF-II in some tumors produced by Cetrorelix might be also related to tumor inhibition. Treatment of nude mice bearing human ovarian OV-1063 tumors with LHRH antagonist Cetrorelix or agonist [D-Trp6]LHRH produces a fall in the number of receptors for LHRH on tumor membranes, accompanied by an increase in the concentration of LHRH receptors in the tumor cell nuclei, which might be related to internalization and translocation of receptors. The growth of prostatic, mammary, and ovarian cancers expressing LHRH receptors is powerfully suppressed in experimental animals by targeted cytotoxic analogues of LHRH, such as AN-207. The levels and mRNA expression of receptors for LHRH on tumors are usually reduced after the therapy; however, the eventual recovery in the levels of LHRH receptors should permit a repeated therapy with cytotoxic analogues.

Original languageEnglish (US)
Pages (from-to)17-44
Number of pages28
JournalInfertility and Reproductive Medicine Clinics of North America
Issue number1
StatePublished - Jan 1 2001
Externally publishedYes

ASJC Scopus subject areas

  • Obstetrics and Gynecology


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