GnRH peptide analogs are widely used to treat diverse clinical conditions. However, they have poor oral activity and exhibit rapid metabolic clearance thus requiring injection and depot formulation. As steroid hormones are bound to plasma proteins we explored the possibility of conjugating hydroxylated progesterones to GnRH analogs to reduce metabolic clearance of the peptides. Conjugation of [D-Lys⁶]GnRH agonist to the 11-hydroxyl of 11-hydroxyl progesterone via a hemi-succinate bridge increased the plasma half-life after iv injection in rabbits by 3.6 fold while retaining high binding affinity, thus providing proof of concept. Five GnRH antagonists were then synthesized with 21-hydroxyprogesterone conjugated via C21-hydroxyl to positions six (conjugates A and B) and position seven (conjugates C and D) of GnRH antagonists. In the fifth compound the NH₂ terminus of a GnRH antagonist lacking the first two amino acids was conjugated via the C21-hydroxyl to 21-hydroxyprogesterone (conjugate E). All five analogs bound to guinea pig progesterone binding globulin with relatively high affinities (264-1020 nM). Moreover, all five conjugates retained high progestogenic activity in stimulating a progesterone-response-element-driven chloramphenicol acetyltransferase reporter gene in the T47D breast cancer cell line. Conjugation via the -amino function of D-Lys⁶ (conjugates A and B) produced compounds with high binding affinity for the human GnRH receptor (15 and 7 nM) comparable to that of the unconjugated GnRH antagonists (4 and 26 nM). Conjugation via the amino function of Lys⁷ (conjugates C and D) or the NH₂ terminus of an N terminally truncated antagonist (conjugate E) produced compounds of low binding affinity. Conjugates A and B also exhibited high functional antagonism of GnRH stimulation of inositol phosphate production in COS-7 cells expressing the human GnRH receptor (2.6 and 16 nM) compared with the unconjugated antagonists (1.3 and 122 nM). In accordance with their poor receptor binding affinity conjugates C, D and E had poor functional antagonism. Preliminary dose finding studies in female marmosets showed transitory progesterone inhibition by 0.25 mg and prolonged suppression of 12 and 17 days by 0.5 mg and 1.0 mg doses. Injection of conjugate A in adult male marmosets (0.5 mg sc) rapidly suppressed plasma testosterone levels which remained suppressed for at least 3 days. In contrast, the unconjugated parent antagonist alone or with progesterone suppressed testosterone for only 8 h to 1 day. The findings demonstrate that conjugation of progesterone to GnRH antagonists conveys plasma binding and progestogenic properties and increases their efficacy and duration of action in vivo. These new GnRH antagonists show promise as therapeutic agents for hormone-dependent diseases and as contraceptives.