Steroid Responses to ACTH-like Polypeptides

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Abstract
The intravenous administration in 6 hr of 75 U of purified porcine ACTH, or of commercial ACTH or of 0.75 mg of a synthetic ACTH-like polypeptide representing, from the N-terminus, amino acid residues 1-24, 1-23, or 1-20 of this hormone produced comparable increases in plasma 11-(OH) corticosteroids. Hence, full corticotropin activity as reflected by increases in plasma corticosteroids was manifested by synthetic molecules about ½ the size of the natural product. Moreover, 0.25 mg of the polypeptide composed of 24 amino acid residues proved to be equal to 75 U of purified porcine ACTH in raising plasma steroids during a prolonged 6-hr intravenous infusion, establishing that ACTH and the shorter synthetic molecule are at least equipotent on a molar basis. A synthetic MSH-type molecule, representing the first 13 amino acid residues of ACTH, did not have this property in man. The 0.75 mg dosage of the polypeptide representing amino acid residues 1–24 yielded the same increase in plasma 11-(OH) corticosteroids either with prolonged or with rapid intravenous administration (6 hr vs. 2 min). However, a smaller dosage of this synthetic polypeptide, 0.25 mg, administered intravenously during 2 min was not as effective as the same amount given during prolonged intravenous infusion in raising corticosteroids through the 6th hr. Intramuscular injection of the synthetic polypeptide duplicating amino acid residues 1–24 of ACTH, at either the 0.75 or 0.25 mg dosage level, proved less effective than similar amounts given intravenously in maintaining elevations of plasma corticosteroids beyond the 2nd and/or 3rd hr. Similarly, prolonged 6-hr intravenous administration of an ACTH-like polypeptide composed of amino acid residues 1-23 was more effective than comparable amounts of the same preparation injected intramuscularly in evoking higher levels of corticosteroids in the 6-hr intravenous stimulation test. Replacement of methionyl in position 4 of a polypeptide comprising amino acid residues 1-20 by an alpha amino-n-butyryl group decreased the efficacy of the molecule in eliciting high levels of plasma corticosteroids at the 6th hr of a prolonged 6-hr intravenous infusion. The urinary 17-ketosteroid-creatinine ratio tended to increase in all trials which resulted in rises in plasma corticosteroids, but in occasional subjects within a responding group this did not occur and the mean increment was not always statistically significant.