Danazol

Danazol is a synthetic steroid derived from ethisterone. Chemically, danazol is 17a-Pregna-2,4-dien-20-yno[2,3-d]-isoxazol-17-ol, which has the molecular formula: C22H27NO2 with a molecular weight of 337.46. Danazol is antiestrogenic and weakly androgenic. It is a synthetic steroid hormone structurally resembling a group of natural hormones (androgens) found in the body. It acts on the pituitary gland in the brain, a gland that controls the amounts of hormones that are produced by the body. Danazol inhibits the production of hormones called gonadotrophins by the pituitary gland. Gonadotrophins normally stimulate the production of sex hormones such as oestrogen and progestogen, which are responsible for body processes such as menstruation and ovulation.

Danazol is used in the treatment of endometriosis, unless the process has advanced to the stage of surgical correction. Danazol also is used in the palliative treatment of fibrocystic breast disease. Hereditary angioedema in both males and females also has been successfully treated with danazol. Frequency of attacks can be limited by careful dose reduction after the initial response has been achieved. Danazol was approved by the FDA in 1976.

Mechanism of Action: Through its action on the pituitary, danazol indirectly reduces estrogen production by lowering the output of follicle-stimulating hormone and luteinizing hormone. There is also evidence that danazol binds to sex hormone receptors in target tissues, thereby exibiting anabolic, antiestrognic and weakly androgenic activity. With higher doses, amenorrhea generally occurs after about 6 weeks of therapy; ovulation and cyclic bleeding returns to normal 60-90 days after therapy is discontinued. Danazol is used to treat endometriosis because it causes atrophy of ectopic endometrial tissue, which relieves symptoms completely. It also decreases the growth rate of abnormal breast tissue, making it useful in fibrocystic breast disease. Heriditary angioedema is an inherited disorder characterized by a deficiency in C1 esterase inhibitor (C1 INH), a serum inhibitor of the activated first component of complement. Danazol increases circulating levels of C1 INH and therby increases C4 of the complement system, which also is deficient in hereditary angioedema. Consequently, danazol prevents attacks of hereditary angioedema in both males and females. The exact mechanism by which danazol increases C1 INH is not known. Danazol does not possess any progestogenic activity, and does not suppress normal pituitary release of corticotropin, or release of cortisol by the adrenal glands.

Pharmacokinetics: Danazol is administered orally. The bioavailability of danazol is not directly dose-related; dosage increases are not proportional to increases in plasma concentrations. For example, doubling the dose may yield only a 30-40% increase in plasma concentration. Peak concentrations occur within 2 hours, but the onset of a therapeutic effect (anovulation or amenorrhea) does not occur for approximately 6-8 weeks after taking daily doses. Pain reduction in fibrocystic breast disease will begin to be realized at 1 month, with a peak effect at 2-3 months. Distribution data are limited, but extensive hepatic metabolism produces the primary metabolite, 2-hydroxymethylethisterone. Danazol is excreted in the urine and has an elimination half-life of 4-5 hours.