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 cat.
Legal status
Routes Oral
Pharmacokinetic data
Metabolism Hepatic (extensive to 2-hydroxymethyl ethisterone, ethisterone and 17-hydroxymethylethisterone)[1]
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
PubChem CID 28417
DrugBank DB01406
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 
Mol. mass 337.5 g/mol
 YesY (what is this?)  (verify)

Danazol is a derivative of the synthetic steroid ethisterone that suppresses the production of gonadotrophins 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[edit]

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[edit]

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[edit]

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]

Side effects[edit]

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.[10] 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.[11]

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

Contraindications[edit]

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[edit]

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.[12]

References[edit]

  1. ^ a b c d Brayfield, A, ed. (30 October 2013). "Danazol". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 1 April 2014. 
  2. ^ a b 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. 
  3. ^ Selak V, Farquhar C, Prentice A, Singla A (2007). Farquhar, Cindy, ed. "Danazol for pelvic pain associated with endometriosis". Cochrane database of systematic reviews (Online) (4): CD000068. doi:10.1002/14651858.CD000068.pub2. PMID 17943735. 
  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. 
  5. ^ a b c d e f Hoffman, Barbara L; Schorge JO; Schaffer JI; Halvorson LM; Bradshaw KD; Cunningham FG; Calver LE. Williams Gynecology: Chapter 10, Endometriosis (2nd ed. ed.). New York: McGraw-Hill Medical. ISBN 9780071716727. 
  6. ^ Floyd, WS (1980). "Danazol: endocrine and endometrial effects.". Int J Fertil. 25 (1): 75–80. PMID 6104649. 
  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. 
  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. 
  9. ^ "Efficacy of vaginal danazol treatment in women with menorrhagia during fertile age" 92 (4). October 2009. pp. 1351–4. doi:10.1016/j.fertnstert.2008.08.017. PMID 18930222. 
  10. ^ 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. 
  11. ^ Velazquez I, Alter BP (2004). "Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions". Am. J. Hematol. 77 (3): 257–67. doi:10.1002/ajh.20183. PMID 15495253. 
  12. ^ 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