Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary angioedema.
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 >or=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 when drug 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/m(2). 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/m(2); the 17 matched controls had a mean (SD) age of 39.8 (11.8) years and BMI of 25.4 (2.6) kg/m(2). 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] microg/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] microg/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.
Birjmohun
Rakesh S
RS
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. r.s.birjmohun@amc.uva.nl
Kees Hovingh
G
G
Stroes
Erik S G
ES
Hofstra
Jorit J
JJ
Dallinga-Thie
Geesje M
GM
Meijers
Joost C M
JC
Kastelein
John J P
JJ
Levi
Marcel
M
D000328:Adult; D054179:Angioedemas, Hereditary / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D016632:Apolipoprotein A-I / Q000097:blood; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D001777:Blood Coagulation / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D018592:Cross-Over Studies; D003430:Cross-Sectional Studies; D003613:Danazol / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011795:Surveys and Questionnaires; D045165:Testosterone Congeners / Q000009:adverse effects / Q000627:therapeutic use; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D016632:Apolipoprotein A-I; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008074:Lipoproteins; D045165:Testosterone Congeners; D014280:Triglycerides; D003613:Danazol