Danazol was discovered in 1963 and was introduced for medical use in 1971.[14][17][18][19] Due to their improved side-effect profiles, particularly their lack of masculinizing side effects, danazol has largely been replaced bygonadotropin-releasing hormone analogues (GnRH analogues) in the treatment of endometriosis.[4]
Danazol comes in the form of 50, 100, and 200 mgoralcapsules.[2] It is taken at a dose of 50 to 400 mg two or three times per day, for a total of 100 to 800 mg per day depending on the indication.[2]
Since danazol ismetabolized by theliver, it cannot be used by patients withliver disease, and in patients receiving long-term therapy, liver function must be monitored on a periodic basis.[24]
The use of danazol for endometriosis has been linked to an increased risk ofovarian cancer.[25] Patients with endometriosis have specific risk factors for ovarian cancer, so this may not apply for other uses. Danazol, like most other anabolic steroids, has been linked with an increased risk ofliver tumors. These are generallybenign.[26]
Danazol is described as a possessing high affinity for theandrogen receptor (AR), moderate affinity for theprogesterone receptor (PR) andglucocorticoid receptor (GR), and poor affinity for theestrogen receptor (ER).[4][5] As an androgen, danazol is described as weak, being about 200-fold less potent than testosterone inbioassays.[16] The drug can act as both an agonist andantagonist of the PR depending on the bioassay, indicating that it could be regarded as aselective progesterone receptor modulator (SPRM).[5] Although theaffinity andefficacy of danazol itself at the PR are relatively low, ethisterone, one of the major metabolites of danazol, is described as a weak progestogen (and has been employed clinically as a progestogen), and this presumably serves to increase thein vivo progestogenic activity of danazol.[8] The activity of danazol at the ER is considered to be minimal, although at very high concentrations the drug can act significantly as an ER agonist.[5] Danazol is considered to act significantly as an agonist of the GR, and, thus, as aglucocorticoid.[5] In accordance, it cansuppress the immune system at sufficient dosages.[5][14][16]
Relative affinities (%) of danazol and metabolites
Notes: Values are percentages (%). Reference ligands (100%) wereprogesterone for thePRTooltip progesterone receptor,testosterone (c =DHT) for theARTooltip androgen receptor,cortisol for theGRTooltip glucocorticoid receptor (b =dexamethasone),aldosterone for theMRTooltip mineralocorticoid receptor,DHT forSHBGTooltip sex hormone-binding globulin, and cortisol forCBGTooltip corticosteroid-binding globulin.a = 1-hour incubation time (4 hours is standard for this assay; may affect affinity value).Sources:[27][28][29][30][31][32]
Danazol is known to bind to two steroid hormone carrier proteins:sex hormone-binding globulin (SHBG), which bindsandrogens andestrogens; andcorticosteroid-binding globulin (CBG), which binds progesterone andcortisol.[4][5] Binding of danazol to SHBG is considered to be more important clinically.[5] By occupying SHBG and CBG, danazol increases the ratio of free toplasma protein-bound testosterone, estradiol, progesterone, and cortisol.[4][5] The table to the right shows the difference in testosterone levels in premenopausal women treated with danazol.[5]
As can be seen, the percentage of free testosterone is tripled in women being treated with danazol.[5][35] The ability of danazol to increase free testosterone levels suggests that a portion of its weak androgenic effects are mediated indirectly by facilitating the activity of testosterone anddihydrotestosterone through the displacement of them from SHBG.[5][35] In addition to binding to and occupying SHBG however, danazol also decreases the hepatic production of SHBG and therefore SHBG levels, and so downregulation of SHBG may be involved as well.[4][5] Danazol likely decreases hepatic production of SHBG by reducing estrogenic and increasing androgenic activity in the liver (as androgens and estrogens decrease and increase, respectively, hepatic SHBG synthesis).[36] In accordance with the notion that suppression of SHBG is involved in the androgenic effects of danazol, the drug has synergistic rather than additive androgenic effects in combination with testosterone in bioassays (which is most likely secondary to the increased free testosterone levels).[16]
It is noteworthy that 2-hydroxymethylethisterone, a major metabolite of danazol, circulates at concentrations 5–10 times greater than those of danazol and is twice as potent as danazol in displacing testosterone from SHBG.[37] As such, most of the occupation of SHBG by danazol may actually be due to this metabolite.[37]
Via its weak progestogenic and androgenic activity, through activation of the PR and AR in thepituitary gland, danazol producesantigonadotropic effects.[5] Although its does not significantly affect basalluteinizing hormone (LH) andfollicle-stimulating hormone (FSH) levels in premenopausal women (and hence does not profoundly suppressgonadotropin or sex hormone levels like other, stronger antigonadotropins do),[38] the drug prevents the mid-cycle surge in the levels of these hormones during themenstrual cycle.[4][16][23][39][40] By doing this, it suppresses increases in estrogen and progesterone levels at this time and preventsovulation.[16][23][39][40]
Because danazol reduces estrogen production and levels,[38] it has functionalantiestrogenic properties.[41] The combination of its antiestrogenic, androgenic, and progestogenic orantiprogestogenic actions causeatrophy of theendometrium, which alleviates the symptoms of endometriosis.[4][5][16][38][42]
In men, danazol has been found to inhibit gonadotropin secretion and markedly decrease testosterone levels, likely due to its actions as a steroidogenesis inhibitor and antigonadotropin.[43] However, even at the highest dosage assessed (800 mg/day),spermatogenesis remained unaffected.[43]
Thebioavailability of danazol is low.[7] In addition, circulating levels of danazol do not increase proportionally with increasing doses, indicating that there is a saturation of bioavailability.[2] With single-dose administration, it has been found that a 4-fold increase in dosage of danazol increasedpeak levels only by 1.3- and 2.2-fold andarea-under-the-curve levels by 1.6- and 2.5-fold in the fasted and fed states, respectively.[2] Similar findings were observed for chronic administration.[2] Intake of danazol with food (>30 grams of fat) has been found to increase the bioavailability and peak levels of danazol by 3- to 4-fold with a single dose and by 2- to 2.5-fold with chronic administration.[2] Following administration of danazol, peak concentrations occur after 2 to 8 hours, with a median of 4 hours.[2]Steady-state levels of danazol are achieved after 6 days of twice-daily administration.[2] Danazol islipophilic and can partition intocell membranes, which indicates that it is likely todistribute deeply intotissue compartments.[2] Thevolume of distribution of danazol is 3.4 L.[7] Danazol is known to beplasma protein bound toalbumin, SHBG, and CBG.[3][4][5]
Danazol ismetabolized in theliver byenzymes such asCYP3A4.[9][6] Itselimination half-life has varied across studies, but has been found to be 3 to 10 hours after a single dose and 24 to 26 hours with repeated administration.[9][2] The majormetabolites of danazol are 2-hydroxymethylethisterone (also known as 2-hydroxymethyldanazol; formed by CYP3A4 and described as inactive) andethisterone (a progestogen and androgen),[6][2][7][44] and other, minor metabolites include δ2-hydroxymethylethisterone, 6β-hydroxy-2-hydroxymethylethisterone, and δ1-6β-hydroxy-2-hydroxymethylethisterone.[45] At least 10 different metabolites have been identified.[2] Danazol iseliminated inurine andfeces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone.[2]
Danazol, also known as 2,3-isoxazol-17α-ethynyltestosterone or as 17α-ethynyl-17β-hydroxyandrost-4-en-[2,3-d]isoxazole, is asyntheticandrostanesteroid and aderivative oftestosterone andethisterone (17α-ethynyltestosterone).[10][11][43] It is specifically the derivative of ethisterone where the C3ketone is replaced with a 2,3-isoxazolemoiety (i.e., an isoxazole ring is fused to the A ring at the C2 and C3 positions).[6][14] Ethisterone is a weakprogestin with weak androgenic activity.[46]
Danazol is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,USPTooltip United States Pharmacopeia,BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française,DCITTooltip Denominazione Comune Italiana, andJANTooltip Japanese Accepted Name.[9][10][11][12][47] It is also known by its developmental code nameWIN-17757.[9][10][11][12][47]
Danazol is or has been marketed under many brand names throughout the world including Anargil, Azol, Benzol, Bonzol, Cyclolady, Cyclomen, Danal, Danalol, Danamet, Danamin, Danasin, Danatrol, Danazant, Danazol, Danocrine, Danodiol, Danogen, Danokrin, Danol, Danonice, Danoval, Danzol, Dogalact (veterinary), Dorink, Dzol, Ectopal, Elle, Gonablok, Gong Fu Yi Kang, Gynadom, Kodazol, Kupdina, Ladogal, Lozana, Mastodanatrol, Nazol, Norciden, Vabon, and Winobanin.[9][10][11][12][47]
A 2016 phase I/II prospective study orally administered 800 mg per day to 27 patients withtelomere diseases. The primary efficacy endpoint was a 20% reduction in the annual rate of telomere attrition measured. Toxic effects formed the primary safety endpoint. The study was halted early, after telomere attrition was reduced in all 12 patients who could be evaluated. 12 of 27 patients achieved the primary efficacy end point, 11 of whom increased telomere length at 24 months.Hematologic responses (secondary efficacy endpoint) occurred in 10 of 12 patients who could be evaluated at 24 months. Elevated liver-enzyme levels and muscle cramps (known adverse effects) of grade 2 or less occurred in 41% and 33% of the patients, respectively.[52]
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