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Due to their improved side-effect profiles, particularly their lack of masculinizing side effects, danazol has largely been replaced by gonadotropin-releasing hormone analogues (GnRH analogues) in the treatment of endometriosis.[4]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 is metabolized by the liver, it cannot be used by patients with liver 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 of ovarian 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 of liver tumors. These are generally benign.[26]
Danazol is described as a possessing high affinity for the androgen receptor (AR), moderate affinity for the progesterone receptor (PR) and glucocorticoid receptor (GR), and poor affinity for the estrogen receptor (ER).[4][5] As an androgen, danazol is described as weak, being about 200-fold less potent than testosterone in bioassays.[16] The drug can act as both an agonist and antagonist of the PR depending on the bioassay, indicating that it could be regarded as a selective progesterone receptor modulator (SPRM).[5] Although the affinity and efficacy 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 the in 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 a glucocorticoid.[5] In accordance, it can suppress the immune system at sufficient dosages.[5][14][16]
Relative affinities (%) of danazol and metabolites
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PRTooltip progesterone receptor, testosterone (c = DHT) for the ARTooltip androgen receptor, cortisol for the GRTooltip glucocorticoid receptor (b = dexamethasone), aldosterone for the MRTooltip mineralocorticoid receptor, DHT for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip 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 binds androgens and estrogens; and corticosteroid-binding globulin (CBG), which binds progesterone and cortisol.[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 to plasma 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 and dihydrotestosterone 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 the pituitary gland, danazol produces antigonadotropic effects.[5] Although its does not significantly affect basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in premenopausal women (and hence does not profoundly suppress gonadotropin or sex hormone levels like other, stronger antigonadotropins do),[38] the drug prevents the mid-cycle surge in the levels of these hormones during the menstrual cycle.[4][16][23][39][40] By doing this, it suppresses increases in estrogen and progesterone levels at this time and prevents ovulation.[16][23][39][40]
Because danazol reduces estrogen production and levels,[38] it has functional antiestrogenic properties.[41] The combination of its antiestrogenic, androgenic, and progestogenic or antiprogestogenic actions cause atrophy of the endometrium, 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]
The bioavailability 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 increased peak levels only by 1.3- and 2.2-fold and area-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 is lipophilic and can partition into cell membranes, which indicates that it is likely to distribute deeply into tissue compartments.[2] The volume of distribution of danazol is 3.4 L.[7] Danazol is known to be plasma protein boundtoalbumin, SHBG, and CBG.[3][4][5]
Danazol is metabolized in the liverbyenzymes such as CYP3A4.[9][6] Its elimination 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 major metabolites of danazol are 2-hydroxymethylethisterone (also known as 2-hydroxymethyldanazol; formed by CYP3A4 and described as inactive) and ethisterone (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 is eliminatedinurine and feces, 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 a syntheticandrostanesteroid and a derivativeoftestosterone and ethisterone (17α-ethynyltestosterone).[10][11][43] It is specifically the derivative of ethisterone where the C3 ketone 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 weak progestin with weak androgenic activity.[46]
Danazol is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, DCITTooltip Denominazione Comune Italiana, and JANTooltip Japanese Accepted Name.[9][10][11][12][47] It is also known by its developmental code name WIN-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 with telomere 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]
^Selak V, Farquhar C, Prentice A, Singla A (October 2007). Farquhar C (ed.). "Danazol for pelvic pain associated with endometriosis". The Cochrane Database of Systematic Reviews (4): CD000068. doi:10.1002/14651858.CD000068.pub2. hdl:2292/28213. PMID17943735.
^Letchumanan P, Thumboo J (February 2011). "Danazol in the treatment of systemic lupus erythematosus: a qualitative systematic review". Seminars in Arthritis and Rheumatism. 40 (4): 298–306. doi:10.1016/j.semarthrit.2010.03.005. PMID20541792.
^ abcdeHoffman B, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE (2012-04-12). "Chapter 10, Endometriosis". Williams Gynecology (2nd ed.). New York: McGraw-Hill Medical. ISBN9780071716727. Archived from the original on March 28, 2013.
^Cottreau CM, Ness RB, Modugno F, Allen GO, Goodman MT (November 2003). "Endometriosis and its treatment with danazol or lupron in relation to ovarian cancer". Clinical Cancer Research. 9 (14): 5142–5144. PMID14613992.
^Ojasoo T, Raynaud JP, Doé JC (January 1994). "Affiliations among steroid receptors as revealed by multivariate analysis of steroid binding data". The Journal of Steroid Biochemistry and Molecular Biology. 48 (1): 31–46. doi:10.1016/0960-0760(94)90248-8. PMID8136304. S2CID21336380.
^Pugeat MM, Dunn JF, Nisula BC (July 1981). "Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma". The Journal of Clinical Endocrinology and Metabolism. 53 (1): 69–75. doi:10.1210/jcem-53-1-69. PMID7195405.
^Cunningham GR, Tindall DJ, Lobl TJ, Campbell JA, Means AR (September 1981). "Steroid structural requirements for high affinity binding to human sex steroid binding protein (SBP)". Steroids. 38 (3): 243–262. doi:10.1016/0039-128X(81)90061-1. PMID7197818. S2CID2702353.
^Ahlem C, Kennedy M, Page T, Bell D, Delorme E, Villegas S, et al. (February 2012). "17α-alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism". Investigational New Drugs. 30 (1): 59–78. doi:10.1007/s10637-010-9517-0. PMID20814732. S2CID24785562.
^Carlström K, Döberl A, Pousette A, Rannevik G, Wilking N (1984). "Inhibition of steroid sulfatase activity by danazol". Acta Obstetricia et Gynecologica Scandinavica Supplement. 123: 107–111. doi:10.3109/00016348409156994. PMID6238495. S2CID45817485.
^Fedele L, Marchini M, Bianchi S, Baglioni A, Bocciolone L, Nava S (July 1990). "Endometrial patterns during danazol and buserelin therapy for endometriosis: comparative structural and ultrastructural study". Obstetrics and Gynecology. 76 (1): 79–84. PMID2113661.
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Dmowski WP (January 1990). "Danazol. A synthetic steroid with diverse biologic effects". The Journal of Reproductive Medicine. 35 (1 Suppl): 69–74, discussion 74–5. PMID2404115.
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Hughes E, Brown J, Tiffin G, Vandekerckhove P (January 2007). "Danazol for unexplained subfertility". The Cochrane Database of Systematic Reviews (1): CD000069. doi:10.1002/14651858.CD000069.pub2. PMID17253444.
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Craig TJ (2008). "Appraisal of danazol prophylaxis for hereditary angioedema". Allergy and Asthma Proceedings. 29 (3): 225–231. doi:10.2500/aap.2008.29.3107. PMID18387221.
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