Danazol

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Danazol
Danazol.svg
Systematic (IUPAC) name
(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
Clinical data
Trade names Azol, Bonzol, Cyclomen, Danol, Nazol
AHFS/Drugs.com monograph
MedlinePlus a682599
Pregnancy
category
  • AU: D
  • US: X (Contraindicated)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Metabolism Hepatic (extensive to 2-hydroxymethyl ethisterone, ethisterone and 17-hydroxymethylethisterone)[1]
Biological half-life 3-6 hours (single dose), 26 hours (repeated dosing)[1]
Excretion Urine, faeces[1]
Identifiers
CAS Number 17230-88-5 YesY
ATC code G03XA01 (WHO)
PubChem CID: 28417
IUPHAR/BPS 6942
DrugBank DB01406 YesY
ChemSpider 26436 YesY
UNII N29QWW3BUO YesY
KEGG D00289 YesY
ChEBI CHEBI:4315 YesY
ChEMBL CHEMBL1479 YesY
Synonyms 17β-hydroxy-2,4,17α-pregnadien-20-yno[2,3-D]isoxazole
Chemical data
Formula C22H27NO2
Molecular mass 337.5 g/mol
  (verify)

Danazol is a derivative of the synthetic steroid ethisterone that suppresses the production of gonadotropins and has some weak androgenic effects.[1] Before becoming available as a generic drug, danazol was marketed as Danocrine in the United States. It was approved by the US Food and Drug Administration (FDA) as the first drug to specifically treat endometriosis in the early 1970s.[2] Although effective for endometriosis, its use is limited by its masculinizing side-effects.[3] Its role as a treatment for endometriosis has been largely replaced by the GnRH agonists.

Chemistry

The agent is fat-soluble. It is an isoxazole of testosterone with isolated weak androgenic activity and no estrogenic or progestagenic effects.[2]

Mechanism of action

Danazol exhibits hypoestrogenic, hyperandrogenic effects that cause atrophy of the endometrium, which can alleviate the symptoms of endometriosis.[4]

Danazol prevents ovulation by suppressing the increase of luteinizing hormone during the middle of the menstrual cycle.[5][6] Danazol inhibits ovarian steroidogenesis resulting in decreased secretion of estradiol and may increase androgens. Danazol displaces testosterone from sex hormone-binding globulin (SHBG), displacing it and increasing serum testosterone levels.[5] Danazol also directly stimulates androgen and progesterone receptors.[5]

Pituitary hormones are largely unaffected, although luteinizing hormone may be slightly elevated.[7]

Indications

Danazol has been used—mostly off-label—for other indications, namely in the management of menorrhagia, fibrocystic breast disease, immune thrombocytopenic purpura ,premenstrual syndrome, breast pain (mastodynia) and hereditary angioedema.[8] Although not currently a standard treatment for menorrhagia, danazol has resulted in significant relief in young women with menorrhagia in a study, and, because of a lack of significant adverse effects, it was proposed as an alternative treatment.[9] Low-dose danazol has also been investigated in the treatment of diabetic macular edema in a phase 3 trial.[10][11]

Side effects

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, deepening of the voice (sometimes irreversible), or adverse blood lipid profiles.[5] Danazol may also cause hot flashes, elevation of liver enzyme levels, and mood changes.[5] Some patients who use danazol experience weight gain and fluid retention. Due to these limitations, danazol is seldom prescribed continuously beyond six months.

The use of danazol for endometriosis has been linked to an increased risk of ovarian cancer.[12] Patients with endometriosis have specific risk factors for ovarian cancer, so this may not apply for other uses.

Danazol, like most other androgenic agents, has been linked with an increased risk of liver tumors. These are generally benign.[13]

Unlike GnRH agonists, danazol does not induce osteoporosis. Also, symptoms of hot flushes tend to be less common or severe.

Contraindications

Danazol is contraindicated during pregnancy because it could masculinize a female fetus. Females taking danazol should also take effective contraceptive therapy to prevent pregnancy.[5]

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.

History

Danazol was synthesized 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.[14]

References

  1. 1.0 1.1 1.2 1.3 Brayfield, A, ed. (30 October 2013). "Danazol". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 1 April 2014.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. 2.0 2.1 Dmowski WP, Scholer HF, Mahesh VB, Greenblatt RB (1971). "Danazol--a synthetic steroid derivative with interesting physiologic properties". Fertil. Steril. 22 (1): 9–18. PMID 5538758. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  3. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  4. 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. PMID 2113661.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  5. 5.0 5.1 5.2 5.3 5.4 5.5 Hoffman, Barbara L; Schorge JO; Schaffer JI; Halvorson LM; Bradshaw KD; Cunningham FG; Calver LE. Williams Gynecology: Chapter 10, Endometriosis (2nd ed.). New York: McGraw-Hill Medical. ISBN 9780071716727.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  6. Floyd, WS (1980). "Danazol: endocrine and endometrial effects". Int J Fertil. 25 (1): 75–80. PMID 6104649.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  7. Steingold KA, Lu JK, Judd HL, Meldrum DR (1986). "Danazol inhibits steroidogenesis by the human ovary in vivo". Fertil Steril. 45 (5): 649–54. PMID 3084301. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  8. Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  10. "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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  11. "Ampio Pharmaceuticals Announces Additional Statistically Significant Study Results for Optina™ in the Treatment of Diabetic Macular Edema (DME)". Ampio Pharmaceuticals. Inc. Retrieved 27 June 2015.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  12. Cottreau CM, Ness RB, Modugno F, Allen GO, Goodman MT (2003). "Endometriosis and Its Treatment with Danazol or Lupron in Relation to Ovarian Cancer". Clinical Cancer Research. 9 (14): 5142–4. PMID 14613992. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  13. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  14. G.P. Ellis and G.B. Ellis, doi:10.1016/S0079-6468(08)70187-5 (1979), pp. 126, note 158, 130, notes 1513, 2369, citing doi:10.1021/jm00299a034