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Abstract
Background: Danazol is a synthetic androgen derivative frequently used as prophylaxis in patients
with hereditary angioedema (HAE) due to complement-1 esterase inhibitor deficiency.
However, danazol has been reported to decrease high-density lipoprotein cholesterol
(HDL-C) levels and to adversely affect coagulation parameters, which are considered
to be proatherothrombotic.
Objective: The short- and long-term effects of danazol were evaluated on proatherogenic intermediate
end points in healthy volunteers and patients with HAE.
Methods: Short-term effects were evaluated in healthy men randomly assigned to 200 mg/d of
danazol or placebo for 4 weeks in a crossover trial with no washout period. Long-term
effects of danazol on lipoproteins, coagulation, and carotid intima-media thickness
(CIMT) were evaluated in a cross-sectional study in which patients with HAE treated
with danazol, a mean dose of 170 mg/d for ≥2 years, were compared with healthy controls
matched for age, sex, and body mass index (BMI). Drug tolerability was assessed by
questionnaires and adherence was measured by pill count whendrug bottles were returned
after every study visit.
Results: Patients in the short-term study were 15 men with a mean (SD) age of 32.6 (6.9) years
and BMI of 24.3 (4.1) kg/m2. In the long-term study, patients with HAE were 10 women and 7 men with a mean (SD)
age of 41.1 (12.9) years and BMI of 25.4 (2.6) kg/m2; the 17 matched controls had a mean (SD) age of 39.8 (11.8) years and BMI of 25.4
(2.6) kg/m2. Short-term danazol treatment was associated with a decrease from baseline in apolipoprotein
A-I of 21% and in HDL-C of 23%. Flow-mediated dilation and coagulation parameters
were unaffected after 4 weeks. Longterm danazol treatment did not adversely affect
HDL-C concentration (1.1 [0.5] vs baseline, 1.2 [0.5] pmol/L), HDL-related transfer
proteins such as paraoxonase-1 activity (92 [62] vs 80 [40] U/mM), cholesteryl-ester
transfer protein mass (1.5 [0.4] vs 2.2 [0.6] µg/mL), lecithin cholesterol acyltransferase
activity (21.2 [4.5] vs 32.1 [7.2] nmol CE · mL-1 · h-1), plasma phospholipid transfer protein activity (15.4 [1.5] vs 14.9 [1.2] AU), and
apolipoproteins between patients with HAE and controls. The mean (SD) CIMT was similar
between patients with HAE and controls (0.62 [0.09] vs 0.59 [0.08] mm; P = NS). However, HAE patients using danazol had increased coagulation activation when
compared with controls (prothrombin fragments, 286 [119] vs 164 [57] pmol/L, P = 0.002; thrombinantithrombin complex, 3.9 [1.4] vs 2.6 [1.1] µg/L, P = 0.01).
Conclusions: Short-term danazol treatment in healthy volunteers was associated with a reduction
in HDL-C levels without a significant effect on endothelial function or coagulation
parameters. In contrast, patients with HAE treated for >2 years with danazol had increased
activation of coagulation, but there were no significant differences in HDL-C or CIMT
compared with matched healthy controls.
Key words
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Article info
Publication history
Accepted:
September 24,
2008
Identification
Copyright
© 2008 Excerpta Medica Inc. All rights reserved. Published by Elsevier Inc.
