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British Medical Bulletin 56:761-772 (2000)
© 2000 The British Council

research-article

Progress towards the development of non-peptide orally-active gonadotropin-releasing hormone (GnRH) antagonists: therapeutic implications

R P Millar*, Y-F Zhu{dagger} and R S Struthers{dagger}

*MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology Edinburgh, UK
{dagger}Neurocrine Biosciences, Inc. San Diego, California, USA

Correspondence to Prof R P Millar, MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, 37 Chalmers Streeet, Edinburgh EH3 9ET, UK

Abstract

Gonadotropin-releasing hormaone (GnRH) is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly.NH2) which is produced form a precursor polypeptide in hypothalamic neurons and secreted in a pulsatile fashion to stimulate the secretion of LH and FSH via its interaction with a cognate receptor on gonadotropes1,2. Low doses of the native peptide delivered in a pulsatile manner to mimic that found in the hypothalamic portal vessels restore fertility in hypogonadal patients, and are also effective in treating cryptorchidism and delayed puberty2–4. Administration of high doses of GnRH, or agonist analogues, causes desenitization of the gonadotrope with consequent decline in gonadal gametogenesis and steroid and peptide hormone synthesis2–4. This phenomenon finds extensive therapeutic application in clinical medicine in a wide specturm of disease (Table 1)2–5. In addition, GnRH analogues have promise as new generation male and female contraceptives in conjunction with steroid hormone replacement6,7. GnRH antagonists inhibit the reproductive system through competition with endogenous GnRH for the receptor and, in view of their rapid effects, are being increasingly used for the above mentioned applications. The peptide agonists and antagonists currently availabel require parenteral administration, typically in the form of long-acting depots. A new generation of non-peptide GnRH antagonists are beginning to emerge which should allow oral administration and, therefore, may provide greater flexibility of dosing, lower costs and increased patient acceptance.


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