Lipidated analogues of luteinizing hormone-releasing hormone (LHRH) reduce serum levels of follicle-stimulating hormone (FSH) after oral administration

A diverse range of diseases involving the reproductive system are treated with luteinizing hormone-releasing hormone (LHRH) agonists which must be administered daily. Currently, an efficient oral delivery system is not available. Here, we show the facile inclusion of lipoamino acids into the peptide sequence of LHRH, rendering it more stable towards enzymatic degradation, as well as enhancing permeability across Caco-2 cell monolayers. Selected LHRH derivatives were tested in vivo by daily oral administration to rats. The size and weight of the sex organs remained unchanged and the levels of LH were stable over the course of the experiment. However, some of the lipidic peptides (3, 8 and 9) were able to reduce serum levels of follicle-stimulating hormone (FSH), an important finding towards the development of orally available LHRH agonists.