Hyperferritinemia: An Unexpected Effect of Treatment with Danazol

Hyperferritinemia is most often found in patients as a result of iron overload, infection, inflammation, or malignancy. Danazol, a synthetic derivative of ethinyl testosterone, has not been reported to cause hyperferritinemia. We present three patients observed to have extreme increases in serum ferritin during treatment with danazol.

CASES: The first case is a 67 year old male with autoimmune hemolytic anemia, whose ferritin level rose from 983 to 3472 μg/L six months after starting danazol 200mg three times daily. The second is a 79 year old woman with immune thrombocytopenic purpura, whose ferritin was found to be 1109 μg/L after one month on danazol 200mg twice daily (BID) then decreased to188 μg/L one month after discontinuation. The third case had the most dramatic findings. This is a 56 year old female with autoimmune hemolytic anemia characterized by both warm and cold agglutinins with a refractory course. After less than one month on danazol 200 mg BID her ferritin increased from 521 to 2877μg/L. Severe hyperferritinemia persisted until danazol was discontinued. At this time, there was an abrupt fall from 2628 to 191μg/L. In each of these cases, there was no alternative explanation for the changes in ferritin level. In particular, there was no evidence of activation of the acute phase response, nor any indication of hepatotoxicity as reflected in liver enzymes or bilirubin levels. Since observing these cases, we have monitored ferritin levels in 3 other patients being treated in our clinic with danazol, and have seen no change in ferritin level in these 3 patients.

DISCUSSION: The effect of danazol in these cases may represent a direct androgenic effect or a non-specific effect. The synthesis of a number of plasma proteins by hepatocytes is known to be influenced by androgen receptor interactions, but this has not been reported to be the case for ferritin; instead it is thought that higher ferritin levels in men are a result of higher iron stores. Nonetheless it is possible that there is a previously unreported influence of androgens on ferritin synthesis, which might be more apparent in patients with moderate iron overload (two of our patients had mildly elevated baseline ferritin levels). An idiosyncratic effect unrelated to androgenic activity seems more likely. (Similarly, there is an inconsistent therapeutic effect of danazol in immune thrombocytopenia and hemolytic anemia and the exact mechanism of action, possibly related to immunosuppression rather than androgen effect, is unknown.) The rapid return of the ferritin level to baseline after discontinuation of danazol shows that the effect is not a result of a change in iron stores. The possibility that danazol (or a metabolite thereof) interferes with the assay of ferritin in serum is made unlikely by our observations in several other danazol-treated patients, in whom no change in ferritin levels were seen. The findings in our cases should be considered when measuring ferritin in patients receiving danazol. Hyperferritinemia in these patients is an unreliable predictor of iron overload. Whether this observation has any implication with respect to the toxicity of danazol is not known.