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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

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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.

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      References

        • Miller GJ
        • Miller NE
        Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease.
        Lancet. 1975; 1: 16-19
        • Miller NE
        • Thelle DS
        • Forde OH
        • Mjos OD
        The Tromsθ Heart-Study. High-density lipoprotein and coronary heart-disease: A prospective case-control study.
        Lancet. 1977; 1: 965-968
        • Miller NE
        • La Ville A
        • Crook D
        Direct evidence that reverse cholesterol transport is mediated by high-density lipoprotein in rabbit.
        Nature. 1985; 314: 109-111
        • Sampietro T
        • Bigazzi F
        • Dal Pino B
        • et al.
        Increased plasma C-reactive protein in familial hypoalphalipoproteinemia: A proinflammatory condition?.
        Circulation. 2002; 105: 11-14
        • Eichinger S
        • Pecheniuk NM
        • Hron G
        • et al.
        High-density lipoprotein and the risk of recurrent venous thromboembolism.
        Circulation. 2007; 115: 1609-1614
        • Bisoendial RJ
        • Hovingh GK
        • Levels JH
        • et al.
        Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein.
        Circulation. 2003; 107: 2944-2948
        • Hovingh GK
        • Brownlie A
        • Bisoendial RJ
        • et al.
        A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease.
        J Am Coll Cardiol. 2004; 44: 1429-1435
        • Birjmohun RS
        • Hutten BA
        • Kastelein JJ
        • Stroes ES
        Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: A meta-analysis of randomized controlled trials.
        J Am Coll Cardiol. 2005; 45: 185-197
        • Gooren LJ
        • Giltay EJ
        Review of studies of androgen treatment of female-to-male transsexuals: Effects and risks of administration of androgens to females.
        J Sex Med. 2008; 5: 765-776
        • Weidmann P
        • de Courten M
        • Ferrari P
        • Böhlen L
        Serum lipoproteins during treatment with antihypertensive drugs.
        J Cardiovasc Pharmacol. 1993; 22: S98-S105
        • Hoogerbrugge N
        • Jansen H
        • Birkenhäger JC
        Danazol in the treatment of endometriosis and hereditary angiooedema.
        J Intern Med. 1995; 237: 603-604
        • Gelfand JA
        • Sherins RJ
        • Alling DW
        • Frank MM
        Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities.
        N Engl J Med. 1976; 295: 1444-1448
        • Pappalardo E
        • Zingale LC
        • Cicardi M
        Increased expression of C1-inhibitor mRNA in patients with hereditary angioedema treated with danazol.
        Immunol Lett. 2003; 86: 271-276
        • Drouet C
        • Désormeaux A
        • Robillard J
        • et al.
        Metallopeptidase activities in hereditary angioedema: Effect of androgen prophylaxis on plasma aminopeptidase P.
        J Allergy Clin Immunol. 2008; 121: 429-433
        • Széplaki G
        • Varga L
        • Valentin S
        • et al.
        Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema.
        J Allergy Clin Immunol. 2005; 115: 864-869
        • Packard CJ
        • Shepherd J
        Action of danazol on plasma lipids and lipoprotein metabolism.
        Acta Obstet Gynecol Scand Suppl. 1994; 159: 35-40
        • Shepherd J
        Danazol and plasma lipoprotein metabolism.
        Int J Gynaecol Obstet. 1995; 50: S23-S26
        • Szegedi R
        • Széplaki G
        • Varga L
        • et al.
        Long-term danazol prophylaxis does not lead to increased carotid intimamedia thickness in hereditary angioedema patients.
        Atherosclerosis. 2008; 198: 184-191
        • Friedewald WT
        • Levy RI
        • Fredrickson DS
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Mackness B
        • Durrington P
        • McElduff P
        • et al.
        Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study.
        Circulation. 2003; 107: 2775-2779
        • Mezdour H
        • Kora I
        • Parra HJ
        • et al.
        Two-site enzyme immunoassay of cholesteryl ester transfer protein with monoclonal and oligoclonal antibodies.
        Clin Chem. 1994; 40: 593-597
        • Hovingh GK
        • Hutten BA
        • Holleboom AG
        • et al.
        Compromised LCAT function is associated with increased atherosclerosis.
        Circulation. 2005; 112: 879-884
        • Dullaart RP
        • Sluiter WJ
        • Dikkeschei LD
        • et al.
        Effect of adiposity on plasma lipid transfer protein activities: A possible link between insulin resistance and high density lipoprotein metabolism.
        Eur J Clin Invest. 1994; 24: 188-194
        • Speijer H
        • Groener JE
        • van Ramshorst E
        • van Tol A
        Different locations of cholesteryl ester transfer protein and phospholipid transfer protein activities in plasma.
        Atherosclerosis. 1991; 90: 159-168
        • van Doorn MB
        • Burggraaf J
        • van Dam T
        • et al.
        A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema.
        J Allergy Clin Immunol. 2005; 116: 876-883
        • Allen JK
        • Fraser IS
        Cholesterol, high density lipoprotein and danazol.
        J Clin Endocrinol Metab. 1981; 53: 149-152
        • Burry KA
        • Patton PE
        • Illingworth DR
        Metabolic changes during medical treatment of endometriosis: Nafarelin acetate versus danazol.
        Am J Obstet Gynecol. 1989; 160 ([published correction appears in Am J Obstet Gynecol. 1989;161:1755]) (discussion 1459-1461): 1454-1459
        • Crook D
        • Gardner R
        • Worthington M
        • et al.
        Zoladex versus danazol in the treatment of pelvic endometriosis: Effects on plasma lipid risk factors.
        Horm Res. 1989; 32: 157-160
        • Fåhraeus L
        • Larsson-Cohn U
        • Ljungberg S
        • Wallentin L
        Plasma lipoproteins during and after danazol treatment.
        Acta Obstet Gynecol Scand Suppl. 1984; 123: 133-135
        • Fåhraeus L
        • Larsson-Cohn U
        • Ljungberg S
        • Wallentin L
        Profound alterations of the lipoprotein metabolism during danazol treatment in premenopausal women.
        Fertil Steril. 1984; 42: 52-57
        • Fraser IS
        • Shearman RP
        • Jansen RP
        • Sutherland PD
        A comparative treatment trial of endometriosis using the gonadotrophin-releasing hormone agonist, nafarelin, and the synthetic steroid, danazol.
        Aust N Z J Obstet Gynaecol. 1991; 31: 158-163
        • Henzl MR
        • Corson SL
        • Moghissi K
        • et al.
        Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter doubleblind comparative clinical trial.
        N Engl J Med. 1988; 318: 485-489
        • The Nafarelin European Endometriosis Trial Group (NEET)
        Nafarelin for endometriosis: A large-scale, danazol-controlled trial of efficacy and safety, with 1-year follow-up.
        Fertil Steril. 1992; 57: 514-522
        • Schweppe KW
        • Assmann G
        Changes of plasma lipids and lipoprotein levels during danazol treatment for endometriosis.
        Horm Metab Res. 1984; 16: 593-597
        • Telimaa S
        • Penttilä I
        • Puolakka J
        • et al.
        Circulating lipid and lipoprotein concentrations during danazol and high-dose medroxyprogesterone acetate therapy of endometriosis.
        Fertil Steril. 1989; 52: 31-35
        • Välimäki M
        • Nilsson CG
        • Roine R
        • Ylikorkala O
        Comparison between the effects of nafarelin and danazol on serum lipids and lipoproteins in patients with endometriosis.
        J Clin Endocrinol Metab. 1989; 69: 1097-1103
        • Crook D
        • Seed M
        Endocrine control of plasma lipoprotein metabolism: Effects of gonadal steroids.
        Baillieres Clin Endocrinol Metab. 1990; 4: 851-875
        • Birjmohun RS
        • van Leuven SI
        • Levels JH
        • et al.
        High-density lipoprotein attenuates inflammation and coagulation response on endotoxin challenge in humans.
        Arterioscler Thromb Vasc Biol. 2007; 27: 1153-1158
        • Nicholls SJ
        • Dusting GJ
        • Cutri B
        • et al.
        Reconstituted high-density lipoproteins inhibit the acute prooxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits.
        Circulation. 2005; 111: 1543-1550
        • Saidi P
        • Lega BZ
        • Kim HC
        • Raska Jr, K
        Effect of danazol on clotting factor levels, bleeding incidence, factor infusion requirements, and immune parameters in hemophilia.
        Blood. 1986; 68: 673-679
        • Cugno M
        • Cicardi M
        • Bottasso B
        • et al.
        Activation of the coagulation cascade in C1-inhibitor deficiencies.
        Blood. 1997; 89: 3213-3218
        • Cugno M
        • Cicardi M
        • Agostoni A
        Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: A rationale for prophylactic use of tranexamic acid.
        J Allergy Clin Immunol. 1994; 93: 870-876