Danazol-induced augmentation of serum alpha 1-antitrypsin levels in individuals with marked deficiency of this antiprotease.
Individuals with serum alpha1-antitrypsin levels below 80 mg/dl are clearly at risk for the development of accelerated panacinar emphysema. One possible approach to the therapy of this disorder would be to raise serum levels of this major antiprotease to establish protease-antiprotease homeostasis within the lung parenchyma. Because danazol, an impeded androgen, elevates levels of C1 inhibitor in patients deficient of that serum antiprotease, we hypothesized that this agent might also increase alpha1-antitrypsin levels in patients with alpha1-antitrypsin deficiency. To evaluate this concept, seven patients with severe emphysema associated with alpha1-antitrypsin deficiency (six PiZ and 1 M(Duarte)Z) and one asymptomatic individual (PiSZ) received 600 mg of danazol daily for 30 d. Five of the six PiZ patients responded to danazol therapy with significant increases in serum alpha1-antitrypsin levels (mean increase of 37%; P < 0.03). The two individuals who were heterozygous for the Z protein increased their serum levels by 85% (PiM(Duarte)Z) and 87% (PiSZ), respectively. These increases in serum alpha1-antitrypsin antigen were accompanied by commensurate increases in serum trypsin inhibition. Crossed immunoelectrophoresis showed no alterations of the microheterogeneity of the alpha1-antitrypsin or the presence of protease-antiprotease complexes in serum during danazol therapy. These data demonstrate that serum alpha1-antitrypsin levels can be augmented by danazol therapy in PiZ individuals as well as those heterozygotes with severe deficiency of alpha1-antitrypsin. The clinical relevance of these increases in serum alpha1-antitrypsin remains speculative, but these findings suggest that danazol may provide a means of improving the protease-antiprotease balance in these individuals and thus impede the progression of their lung disease.
D000328:Adult; D000368:Aged; D003613:Danazol / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011245:Pregnadienes / Q000627:therapeutic use*; D011656:Pulmonary Emphysema / Q000150:complications; D000515:alpha 1-Antitrypsin / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency
D011245:Pregnadienes; D000515:alpha 1-Antitrypsin; D003613:Danazol