Danazol

Source: Wikipedia, the free encyclopedia.
Not to be confused with
Danabol
.
Danazol
Clinical data
Trade namesDanatrol, Danocrine, Danol, Danoval, others
Other namesWIN-17757; 2,3-Isoxazolethisterone; 2,3-Isoxazol-17α-ethynyltestosterone; 17α-Ethynyl-17β-hydroxyandrost-4-en-[2,3-d]isoxazole
AHFS/Drugs.comMonograph
MedlinePlusa682599
Pregnancy
category
  • AU: D
Progestin; Antigonadotropin; Steroidogenesis inhibitor; Antiestrogen
ATC code
Legal status
Legal status
CBGTooltip corticosteroid-binding globulin[3][4][5]
MetabolismLiver (CYP3A4)[9][6]
Metabolites• 2-OHM-Ethisterone[6]
• Ethisterone[7][8]
Elimination half-lifeAcute: 3–10 hours[9][2]
Chronic: 24–26 hours[9]
ExcretionUrine, feces[9][2]
Identifiers
  • (1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-oxa-6-azapentacyclo[11.7.0.02,10.04,8.014,18]icosa-4(8),5,9-trien-17-ol
JSmol)
  • C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=Cc5oncc5C[C@]4(C)[C@H]3CC[C@@]21C
  • InChI=1S/C22H27NO2/c1-4-22(24)10-8-18-16-6-5-15-11-19-14(13-23-25-19)12-20(15,2)17(16)7-9-21(18,22)3/h1,11,13,16-18,24H,5-10,12H2,2-3H3/t16-,17+,18+,20+,21+,22+/m1/s1 checkY
  • Key:POZRVZJJTULAOH-LHZXLZLDSA-N checkY
  (verify)

Danazol, sold as Danocrine and other brand names, is a medication used in the treatment of

fibrocystic breast disease, hereditary angioedema and other conditions.[9][2][10][11][12] It is taken by mouth.[2]

The use of danazol is limited by

voice deepening.[2][13] Danazol has a complex mechanism of action, and is characterized as a weak androgen and anabolic steroid, a weak progestogen, a weak antigonadotropin, a weak steroidogenesis inhibitor, and a functional antiestrogen.[5][14][15][16]

Danazol was discovered in 1963 and was introduced for medical use in 1971.

gonadotropin-releasing hormone analogues (GnRH analogues) in the treatment of endometriosis.[4]

Medical uses

Danazol is used primarily in the treatment of

systemic lupus erythematosus.[22]

Available forms

Danazol comes in the form of 50, 100, and 200 mg oral capsules.[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]

Contraindications

Danazol is

contraception to prevent pregnancy if sexually active.[23]

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]

Side effects

See also: Anabolic steroid § Adverse effects

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (

acne, irreversible deepening of the voice,[4] or adverse blood lipid profiles.[23] In addition, breast atrophy and decreased breast size may occur.[4] The drug may also cause hot flashes, elevation of liver enzymes, and mood changes.[23]

The use of danazol for endometriosis has been linked to an increased risk of

liver tumors. These are generally benign.[26]

Pharmacology

Pharmacodynamics

Danazol possesses a complex

carrier proteins and consequent displacement of steroid hormones from these proteins.[4][5][14][15] The drug is characterized as a weak androgen and anabolic, a weak progestogen, a weak antigonadotropin, a weak steroidogenesis inhibitor, and a functional antiestrogen.[14][16]

Modulation of steroid hormone receptors

Danazol is described as a possessing high affinity for 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
Steroid PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Danazol 9 8 ? <0.2a ? 40 10
Ethisterone 35 <1 <1 <1b <1 92–121 0.33
5α-Dihydroethisterone 12 38–100c 4 120b ? 100 ?
Notes: Values are percentages (%). Reference ligands (100%) were
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]
Absolute affinities (nM) of danazol
Receptor
Affinity
 Action
Androgen receptor 90 Agonist
Progesterone receptor 6,000
Agonist–antagonist
Glucocorticoid receptor 5,000 Agonist
Estrogen receptor 80,000 Agonist
Sources: [4][5]

Inhibition of steroidogenesis enzymes

Danazol has been found to act as an

11β-hydroxylase.[5] It has also been found to be a weak inhibitor of steroid sulfatase (Ki = 2.3–8.2 μM), the enzyme that converts DHEA-STooltip dehydroepiandrosterone sulfate into DHEATooltip dehydroepiandrosterone and estrone sulfate into estrone (which can then respectively be transformed into estrone (with androstenedione as an intermediate) and estradiol),[33] though another study reported its inhibition to be potent and potentially clinically relevant.[34] Although in contradiction with the above data, another study found that danazol weakly inhibited aromatase as well, with 44% inhibition at a concentration of 10 μM.[33]

In accordance with its steroidogenesis inhibition, clinical studies have demonstrated that danazol directly and markedly inhibits adrenal, ovarian, and testicular steroidogenesis in vivo.[5] The enzymatic production of estradiol, progesterone, and testosterone have all specifically been found to be inhibited.[5]

Danazol at steroiodgenic enzymes
Enzyme Affinity (Ki) Inhibition type Estimated inhibition at 2 μM
Cholesterol side-chain cleavage enzyme 20 μM Competitive ?
3β-Hydroxysteroid dehydrogenase/Δ5-4 isomerase 5.8 μM Competitive 4.3%
17α-Hydroxylase
 2.4 μM Competitive 2.9%
17,20-Lyase
 1.9 μM Competitive 3.9%
17β-Hydroxysteroid dehydrogenase 4.4 μM Competitive 15%
21-Hydroxylase 0.8 μM Competitive 37%
11β-Hydroxylase
 1 μM Competitive 21%
Aromatase >100 μM – 0%
Sources: [5]

For reference, circulating concentrations of danazol are in the range of 2 μM at a dosage of 600 mg/day in women.[5]

Occupation and downregulation of carrier proteins

Protein binding of testosterone in women
Group Free Albumin SHBG
Normal (no danazol) 1% 39% 60%
Danazol treatment 3% 79% 18%
Sources: [5]

Danazol is known to bind to two steroid hormone carrier proteins:

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]

Antigonadotropic activity

Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the

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]

Mechanism of action in endometriosis

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]

Effects in men

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]

Pharmacokinetics

The

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 bound to albumin, SHBG, and CBG.[3][4][5]

Danazol is

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 eliminated in urine and feces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone.[2]

Chemistry

See also:
List of androgens/anabolic steroids and List of progestogens

Danazol, also known as 2,3-isoxazol-17α-ethynyltestosterone or as 17α-ethynyl-17β-hydroxyandrost-4-en-[2,3-d]isoxazole, is a

progestin with weak androgenic activity.[46]

History

Danazol was synthesized in 1963 by a team of scientists at Sterling Winthrop in Rensselaer, New York by a team that included Helmutt Neumann, Gordon Potts, W.T. Ryan, and Frederik W. Stonner.[17][18] It was approved by the U.S.Tooltip United States Food and Drug Administration in 1971 as the first drug in the country to specifically treat endometriosis.[14][19]

Society and culture

Generic names

Danazol is the

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]

Brand names

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]

Availability

Danazol is available in the United States, Europe, and widely elsewhere throughout the world.[9][11][47]

Research

Danazol has been studied in the treatment of

response rates of about 15 to 20%.[48][49]

Low-dose danazol has been investigated in the treatment of

diabetic macular edema in a phase III clinical trial.[50][51]

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]

References

  1. FDA
    . Retrieved 22 Oct 2023.
  2. ^ a b c d e f g h i j k l m n o p q r s "Danocrine Brand of Danazol Capsules, USP" (PDF). Sanofi-Aventis U.S. LLC. U.S. Food and Drug Administration.
  3. ^
    ISBN 978-0-08-052583-9
    .
  4. ^
    ISBN 978-3-540-78355-8
    .
  5. ^
    ISBN 978-94-011-3864-2
    .
  6. ^
    ISBN 978-1-60913-345-0
    .
  7. ^
    ISBN 978-3-527-64565-7
    .
  8. ^
    ISBN 978-1-4757-3889-6
    .
  9. ^ a b c d e f g h i j k Brayfield A, ed. (30 October 2013). "Danazol". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 1 April 2014.
  10. ^
    ISBN 978-1-4757-2085-3
    .
  11. ^
    ISBN 978-3-88763-075-1
    .
  12. ^
    ISBN 978-94-011-4439-1
    .
  13. PMID 17943735
    .
  14. ^
    ISBN 978-1-4963-1521-2
    .
  15. ^
    ISBN 978-0-8493-5973-6
    .
  16. ^
    ISBN 978-0-08-049451-7
    .
  17. ^
    PMID 4318768
    .
  18. ^
    ISBN 9780030603211
    .
  19. ^
    PMID 5538758
    .
  20. ISBN 978-0-443-06911-6
    .
  21. PMID 18930222
    .
  22. PMID 20541792
    .
  23. ^
    ISBN 9780071716727. Archived from the original
    on March 28, 2013.
  24. ^ "Danazol: MedlinePlus Drug Information". medlineplus.gov. Retrieved 2018-11-07.
  25. PMID 14613992
    .
  26. S2CID 42150333
    .
  27. S2CID 21336380
    .
  28. PMID 359134
    .
  29. PMID 7382482
    .
  30. PMID 7195405
    .
  31. S2CID 2702353
    .
  32. S2CID 24785562
    .
  33. ^
    S2CID 25273633
    .
  34. S2CID 45817485
    .
  35. ^
    ISBN 978-0-7817-5734-8
    .
  36. ISBN 978-1-4822-2286-9
    .
  37. ^
    ISBN 978-3-642-82486-9
    .
  38. ^
    ISBN 978-0-7817-3160-7
    .
  39. ^
    PMID 6104649
    .
  40. ^
    ISBN 978-0-07-176401-8
    .
  41. ISBN 978-0-387-98569-5
    .
  42. PMID 2113661
    .
  43. ^
    PMID 4422449. Archived from the original
    on 2018-09-04. Retrieved 2018-03-04. Danazol (2-3-isoxazol-17alpha-ethinyl-testosterone)
  44. ISBN 978-1-61779-222-9
    .
  45. ^ "PRODUCT INFORMATION" (PDF). Therapeutic Goods Administration. June 21, 2005.
  46. ISBN 978-81-85790-03-9
    .
  47. ^ a b c d "Danazol : Uses, Dosage, Side Effects".
  48. ISBN 978-0-8493-5973-6
    .
  49. ISBN 978-3-662-22346-8
    .
  50. ^ "A Safety and Efficacy Study of Oral Danazol (a Previously Approved Drug)in the Treatment of Diabetic Macular Edema". Clinicaltrials.gov. Ampio Pharmaceuticals. Inc. Retrieved 27 June 2015.
  51. ^ "Ampio Pharmaceuticals Announces Additional Statistically Significant Study Results for Optina™ in the Treatment of Diabetic Macular Edema (DME)". Ampio Pharmaceuticals. Inc. Archived from the original on 29 June 2015. Retrieved 27 June 2015.
  52. PMID 27192671
    .

Further reading